A Randomized Trial to Evaluate the Effects of Folic Acid and Zinc Supplementation on Male Fertility and Livebirth: Design and Baseline Characteristics.

The Folic Acid and Zinc Supplementation Trial (FAZST) was a multicenter, double-blind, block-randomized, placebo-controlled trial to determine whether folic acid and zinc supplementation in men improves semen quality and increases livebirth rate among couples seeking infertility treatment (2013-2017). Eligible men were aged 18 years or older with female partners aged 18-45 years, seeking infertility treatment. Men were randomized (1:1) to 5 mg folic acid and 30 mg elemental zinc daily or matching placebo for 6 months. Randomization was stratified by site and intended infertility treatment (in vitro fertilization (IVF), non-IVF/study site, and non-IVF/outside clinic). Follow-up of men continued for 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. Overall, 2,370 men were randomized during 2013-2017 (1,185 folic acid and zinc, 1,185 placebo); they had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Here we describe the study design, recruitment, data collection, lessons learned, and baseline participant characteristics.

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.

Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality.

PURPOSE: To evaluate the risk of prematurity and infant mortality by maternal fertility status, and for in vitro fertilization (IVF) pregnancies, by oocyte source and embryo state combinations. METHODS: Women in 14 States who had IVF-conceived live births during 2004-13 were linked to their infant's birth and death certificates; a 10:1 sample of non-IVF births was selected for comparison; those with an indication of infertility treatment on the birth certificate were categorized as subfertile, all others were categorized as fertile. Risks were modeled separately for the fertile/subfertile/IVF (autologous-fresh only) group and for the IVF group by oocyte source-embryo state combinations, using logistic regression, and reported as adjusted odds ratios (AORs) and 95% confidence intervals (CI). RESULTS: The study population included 2,474,195 pregnancies. Placental complications (placenta previa, abruptio placenta, and other excessive bleeding) and prematurity were both increased with pregestational and gestational diabetes and hypertension, among subfertile and IVF groups, and in IVF pregnancies using donor oocytes. Both subfertile and IVF pregnancies were at risk for prematurity and NICU admission; IVF infants were also at risk for small-for-gestation birthweight, and subfertile infants had greater risks for neonatal and infant death. Within the IVF group, pregnancies with donor oocytes and/or thawed embryos were at greater risk of large-for-gestation birthweight, and pregnancies with thawed embryos were at greater risk of neonatal and infant death. CONCLUSIONS: Prematurity was associated with placental complications, diabetes and hypertension, subfertility and IVF groups, and in IVF pregnancies, donor oocytes and/or thawed embryos.

High FSH dosing is associated with reduced live birth rate in fresh but not subsequent frozen embryo transfers.

STUDY QUESTION: Do live birth rates (LBRs) differ between fresh embryo transfer (fresh ET) cycles and their subsequent paired frozen ET (FET) cycles, when comparing cycles based on the total FSH dose used during the fresh cycle? SUMMARY ANSWER: When compared to the paired frozen embryo transfer cycles, the LBR in the fresh cycle of the highest total FSH dose group (>2500 IU) was reduced by 38%. WHAT IS KNOWN ALREADY: There may be a negative association with high gonadotropin doses and LBR after fresh ET. It is unknown whether a similar effect is seen in FET cycles, which are done with increasing frequency. STUDY DESIGN, SIZE, DURATION: In this retrospective observational paired study, we studied IVF cycles between 10 January 2005 and 19 September 2015, for all patients who underwent a fresh, autologous IVF cycle that resulted in at least one fresh ET and at least one FET. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 862 women, treated in our academic medical centre, who underwent 935 fresh ET and 1274 FET cycles. Cycles were allocated into three groups based on the total gonadotropin dose they received during their fresh IVF cycle: Group 1 (≤1800 IU FSH), Group 2 (1801-2500 IU), Group 3 (>2500 IU). The primary outcome was LBR after fresh ET and its subsequent paired FET(s), as well as LBR among fresh ETs and FETs as independent samples, based on the total FSH dose used. Implantation rates obtained from fresh and FET cycles were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: The unadjusted fresh LBR was similar between Groups 1 and 2 (46.0% [95% CI: 40.4-51.6] versus 43.8% [38.3-49.4], respectively) but significantly lower in Group 3 (34.4% [29.5-39.8]). The unadjusted frozen transfer LBR was similar among all groups (51.4% [46.7-56.1] versus 46.3% [41.3-51.4] versus 47.5% [42.5-52.4], respectively). When logistic regression analysis with generalized estimating equations was used to control for confounders, the adjusted LBR was found to be similar between the groups both for fresh (odds ratio [OR] = 0.97 [95% CI: 0.61-1.56] Group 2 versus Group 1, OR = 0.69 [0.39-1.21] Group 3 versus Group 1) and FET cycles (OR = 0.87 [0.58-1.31] Group 2 versus Group 1, OR = 0.95 [0.58-1.55] Group 3 versus Group 1). However, for Group 3, the adjusted fresh LBR was 38% lower than its subsequent frozen transfer LBR (OR = 0.62 [0.41-0.93]); this was a statistically significant difference, which was not observed in Group 1 (OR = 0.85 [0.56-1.27]) or Group 2 (OR = 0.95 [0.64-1.41]). LIMITATIONS, REASONS FOR CAUTION: This study is a retrospective cohort, with all of the associated inherent biases. WIDER IMPLICATIONS OF THE FINDINGS: Fresh LBR is negatively impacted by a high dose of total FSH used, as compared to the LBR in subsequent paired FET cycles. Frozen transfer LBR seems unaffected by the total FSH dose used in the fresh cycle, suggesting that the endometrium may be adversely affected, probably indirectly, by high dose gonadotropin use in the fresh IVF cycle only. STUDY FUNDING/COMPETING INTEREST(S): No funding source was used for the completion of this project. There are no conflicts of interest.

Cytidine deaminase Apobec3a induction in fallopian epithelium after exposure to follicular fluid.

OBJECTIVE: Ovarian carcinomas that originate from fallopian epithelial cells are suggested to arise due to repeated exposure to ovulatory follicular fluid (FF). Mechanistic explanation(s) for how this occurs are unknown. Here, we sought to understand if FF exposure to fallopian epithelial cells could induce DNA damage and expression of a known family of DNA mutators, apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) cytidine deaminases. METHODS: Follicular fluid and matched patient plasma samples were obtained from donors. Fallopian epithelial cells (FT33-TAg, FT189, FT190, and FT194) were cultured with FF or plasma for 24h, and cell proliferation and DNA damage were assessed. Effects of FF on Apobec gene expression were determined by qRT-PCR and western blot analyses. Fallopian epithelial cells were transfected with an APOBEC3A expression vector and DNA damage was assessed. RESULTS: Follicular fluid exposure increased epithelial cell proliferation as measured by three independent methods, and DNA damage accumulation as assessed using three independent measures. This effect was specific to FF, as matched patient plasma did not have the same effects. Increased expression of Apobec3a was observed in fallopian epithelial cells following exposure to 5 of 8 patient FF samples, and transient overexpression of APOBEC3A was sufficient to induce double strand DNA breaks. CONCLUSIONS: Follicular fluid can induce cell proliferation and DNA damage accumulation in cultured fallopian epithelial cells. Increased expression of APOBEC3A, a known DNA mutator, may explain the high incidence of DNA damage after FF exposure. The role of Apobec3a in ovulation-induced inflammation warrants further investigation.

Ultrasound in Infertility Treatments.

Ultrasound (US) is very useful in diagnosing causes of infertility. Pelvic masses, mullerian anomalies, ovarian reserve, and tubal patency can all be assessed using ultrasonographic techniques. US has also proven to be a very useful aid in managing infertility treatments. In this chapter, we review the uses of US in monitoring follicular development, assessing the endometrium during treatment, and as an aid to embryo transfer during in vitro fertilization.

Association Between Body Mass Index, Uterine Size, and Operative Morbidity in Women Undergoing Minimally Invasive Hysterectomy.

STUDY OBJECTIVE: Although the selection of an approach to minimally invasive hysterectomy is relatively straightforward in an ideal patient scenario, it is more difficult in patients who pose operative challenges such as high body mass index (BMI) and enlarged uteri. The objective of this study was to explore the association between surgical approach and operative morbidity after minimally invasive hysterectomy and examine whether the association varies based on patient BMI and uterine size. DESIGN: Retrospective cohort (Canadian Task Force classification II-2). SETTING: Data abstracted from the American College of Surgeons National Safety and Quality Improvement Project registry. PATIENTS: Thirty-six thousand seven hundred fifty-seven women undergoing vaginal, laparoscopic-assisted vaginal, or total laparoscopic hysterectomy for benign indications between January 2005 and December 2012. INTERVENTIONS: Associations between surgical approach, BMI, and operative morbidity were examined, stratifying by uterine size (< or >250 g) and adjusting for covariates. Adjusted means, rate ratios, or odds ratios with 95% confidence intervals (CI) were calculated using linear, Poisson, or logistic regression. MEASUREMENTS AND MAIN RESULTS: Operative times were shortest in women undergoing vaginal hysterectomy regardless of BMI or uterine size (all p < .02). Although operative time increased with BMI, the association varied with uterine size in women undergoing vaginal hysterectomy; increasing BMI had a minimal impact on operative time with small uteri <250 g but lengthened operative time in uteri >250 g. Compared with vaginal hysterectomy, total laparoscopic hysterectomy had lower odds of blood transfusion (all p < .02) and shorter hospitalizations (all p < .03) regardless of uterine size or BMI. Stratifying by uterine size, the association was strongest in morbidly obese women with small uteri; women with uteri <250 g and BMI >40 kg/m2 had 76% lower odds of blood transfusion (95% CI, 0.10-0.54) and 18% shorter hospitalization (95% CI, 0.75-0.90) after laparoscopic hysterectomy compared with vaginal hysterectomy. CONCLUSION: Major operative morbidity after minimally invasive hysterectomy is rare regardless of the surgical approach. A vaginal approach to hysterectomy is associated with the shortest operative times, but increasing BMI results in a rapid escalation of operative time in women with large uteri. Total laparoscopic hysterectomy is associated with shorter hospitalizations and lower odds of blood transfusion across the BMI spectrum, particularly in women with small uteri. Laparoscopic-assisted vaginal hysterectomy appears to confer no specific advantage over the vaginal or laparoscopic approaches.

Differentially expressed genes in preimplantation human embryos: potential candidate genes for blastocyst formation and implantation.

PURPOSE: The aim of this study was to determine which genes and gene pathways are differentially expressed when comparing human blastocysts with cleavage-stage embryos. METHODS: We individually assessed gene expression in preimplantation human embryos at cleavage (n = 3) and blastocyst (n = 3) stages. Gene expression patterns were then validated in publically available datasets and then independently validated in vitro with additional human embryos using TaqMan gene expression assays. Immunolocalization studies were conducted to identify protein expression in intact blastocyst-stage embryos. RESULTS: Compared to cleavage-stage embryos, blastocyst-stage embryos differentially expressed 51 genes (p < 0.001), with overrepresentation in amoebiasis pathways and pathways in cancer. Of these 51 genes, 21 were found to be independently validated in a separate, publically available dataset, with a substantial agreement with our initial findings (κ = 0.8). In an independent set of cleavage- and blastocyst-stage embryos, we validated that six of eight tested genes were differentially expressed (p < 0.05) by RT-qPCR. Immunofluorescence studies documented the presence of two studied proteins in the trophectoderm of blastocyst-stage embryos. CONCLUSIONS: Differentially expressed genes may be implicated in the invasion and proliferation of the early embryo. Our research highlights specific genes that may be further studied for their role in the implantation process and additionally raises questions about localized gene and/or protein expression in the trophectoderm, which could affect protocols for, and interpretation of, trophectoderm biopsies performed in in vitro fertilization cycles.

Application of a validated prediction model for in vitro fertilization: comparison of live birth rates and multiple birth rates with 1 embryo transferred over 2 cycles vs 2 embryos in 1 cycle.

OBJECTIVE: The purpose of this study was to use a validated prediction model to examine whether single embryo transfer (SET) over 2 cycles results in live birth rates (LBR) comparable with 2 embryos transferred (DET) in 1 cycle and reduces the probability of a multiple birth (ie, multiple birth rate [MBR]). STUDY DESIGN: Prediction models of LBR and MBR for a woman considering assisted reproductive technology developed from linked cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System for 2006-2012 were used to compare SET over 2 cycles with DET in 1 cycle. The prediction model was based on a woman's age, body mass index (BMI), gravidity, previous full-term births, infertility diagnoses, embryo state, number of embryos transferred, and number of cycles. RESULTS: To demonstrate the effect of the number of embryos transferred (1 or 2), the LBRs and MBRs were estimated for women with a single infertility diagnosis (male factor, ovulation disorders, diminished ovarian reserve, and unexplained); nulligravid; BMI of 20, 25, 30, and 35 kg/m2; and ages 25, 35, and 40 years old by cycle (first or second). The cumulative LBR over 2 cycles with SET was similar to or better than the LBR with DET in a single cycle (for example, for women with the diagnosis of ovulation disorders: 35 years old; BMI, 30 kg/m2; 54.4% vs 46.5%; and for women who are 40 years old: BMI, 30 kg/m(2); 31.3% vs 28.9%). The MBR with DET in 1 cycle was 32.8% for women 35 years old and 20.9% for women 40 years old; with SET, the cumulative MBR was 2.7% and 1.6%, respectively. CONCLUSION: The application of this validated predictive model demonstrated that the cumulative LBR is as good as or better with SET over 2 cycles than with DET in 1 cycle, while greatly reducing the probability of a multiple birth.

Do alterations in follicular fluid proteases contribute to human infertility?

PURPOSE: Cathepsin L and ADAMTS-1 are known to play critical roles in follicular rupture, ovulation, and fertility in mice. Similar studies in humans are limited; however, both are known to increase during the periovulatory period. No studies have examined either protease in the follicular fluid of women with unexplained infertility or infertility related to advanced maternal age (AMA). We sought to determine if alterations in cathepsin L and/or ADAMTS-1 existed in these infertile populations. METHODS: Patients undergoing in vitro fertilization (IVF) for unexplained infertility or AMA-related infertility were prospectively recruited for the study; patients with tubal or male factor infertility were recruited as controls. Follicular fluid was collected to determine gene expression (via quantitative polymerase chain reaction), enzyme concentrations (via enzyme-linked immunosorbent assays), and enzymatic activities (via fluorogenic enzyme cleavage assay or Western blot analysis) of cathepsin L and ADAMTS-1. RESULTS: The analysis included a total of 42 patients (14 per group). We found no statistically significant difference in gene expression, enzyme concentration, or enzymatic activity of cathepsin L or ADAMTS-1 in unexplained infertility or AMA-related infertility as compared to controls. We also found no statistically significant difference in expression or concentration with advancing age. CONCLUSIONS: Cathepsin L and ADAMTS-1 are not altered in women with unexplained infertility or AMA-related infertility undergoing IVF, and they do not decline with advancing age. It is possible that differences exist in natural cycles, contributing to infertility; however, our findings do not support a role for protease alterations as a common cause of infertility.

Lack of carbon air filtration impacts early embryo development.

PURPOSE: To assess human fertilization and preimplantation embryo development in the presence and in the absence of carbon filtration METHODS: This is a retrospective cohort analysis of fresh, controlled ovarian hyperstimulation cycles as well as previously cryopreserved pronuclear stage embryo transfer cycles in a single IVF center. Embryo development and cycle-based outcomes were compared among three groups: 1) when carbon filtration was present, 2) when carbon filtration was absent, and 3) when carbon filtration had been restored. RESULTS: A total of 524 fresh cycles and 156 cryopreserved embryo cycles were analyzed. Fertilization, cleavage, and blastocyst conversion rates for fresh cycles all declined during the period of absent carbon filtration and recovered after the restoration of carbon filtration. Cryopreserved embryos that were thawed and cultured during the period of absent filtration did not have changes in cleavage or blastocyst conversion rates compared to periods where carbon filtration was present. Clinical pregnancy and live birth rates were unchanged among the three time periods. CONCLUSIONS: The absence of carbon filtration in an IVF laboratory air handler is associated with poor fertilization and early embryo development for fresh cycles. Because development of previously frozen pronuclear stage embryos was unaffected, the lack of carbon filtration may preferentially affect embryos in the peri-fertilization period. Carbon filtration is an integral part to a successful human in-vitro fertilization laboratory.

MicroRNA-31 is significantly elevated in both human endometrium and serum during the window of implantation: a potential biomarker for optimum receptivity.

The window of implantation of human embryos into the endometrium spans Cycle Days 20-24 of the 28-day menstrual cycle. However, uterine receptivity may not be reliably replicated in infertile patients throughout this span. Thus, it is of importance to be able to determine optimal receptivity through a minimally invasive measure. We screened expression of a number of candidate micro-RNAs (miRNAs) in endometrial tissues and serum collected from a panel of fertile women during both the proliferative phase and the secretory phase of a normal menstrual cycle. We found that several miRNAs were significantly elevated in endometrial tissues in the secretory phase versus the proliferative phase. One of these, miR-31, was found to be not only detectable in serum samples but also significantly elevated in the secretory phase versus the proliferative phase. MiR-31 is known to target several immunomodulatory factors, such as FOXP3 and CXCL12. We find that both of these factors are significantly downregulated in endometrial tissues during the secretory phase. Our data suggest that miR-31 is a potential biomarker for optimal endometrial receptivity, possibly operating through an immunosuppressive mechanism.

The Association of Female and Male Preconception Dyslipidemia with Live Birth in Couples Seeking Fertility Treatment.

CONTEXT: Dyslipidemia is common, and resultant endothelial dysfunction may impact reproductive outcomes. No prospective study has examined the effect of preconception lipid parameters in both female and male partners or their interaction on live birth. OBJECTIVE: To determine whether live birth is associated with preconception lipids in both partners by planned fertility treatment. DESIGN: Secondary analysis of the Folic Acid and Zinc Supplementation Trial, conducted between June 2013-December 2017. Couples were followed for nine months after randomization and until delivery. SETTING: Multicenter study. PARTICIPANTS: Couples seeking fertility treatment (n = 2370; females 18-45 years, males ≥18 years). EXPOSURES: Female, male, and couple abnormal versus normal preconception lipid concentrations (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides [TG]). MAIN OUTCOME MEASURES: Live birth. RESULTS: Among 2370 couples, most males (84%) and females (76%) had at least one abnormal lipid parameter. Males planning in vitro fertilization (IVF, n = 373) with elevated LDL had lower probability of live birth than those with normal levels (47.4% vs. 59.7%, aRR 0.79, 95% CI 0.65-0.98). In couples planning IVF where both partners had elevated TC or LDL, live birth was lower than those with normal levels (TC: 32.4% vs. 58.0%, aRR 0.53, 95% CI 0.36-0.79; and LDL: 41.9% vs. 63.8%, aRR 0.69, 95% CI 0.55-0.85). Lipid parameters were not associated with live birth for couples planning non-IVF treatments. CONCLUSIONS: Couples planning IVF where both partners had elevated TC or LDL and males planning IVF with elevated LDL had decreased probability of live birth. These findings may support lipid screening in patients seeking fertility treatment for prognostic information for reproductive outcomes.

Healthcare expenses associated with multiple vs singleton pregnancies in the United States.

OBJECTIVE: The purpose of this study was to document cost that is associated with multiple births vs singleton births in the United States. STUDY DESIGN: This was a retrospective cohort study that used a claims database. Women 19-45 years old with live-born infants from 2005-2010 were identified. Infant deliveries were identified by International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes. The cost entailed all payment made by insurers and patients. For mothers, the cost included expenses from 27 weeks before delivery to 1 month after delivery. For infants, the cost contained all expenses until their first birthday. Adjusted cost was estimated by generalized linear models after adjustment for the potential confounding variables with a gamma distribution and a log link. RESULTS: The analysis included 437,924 eligible deliveries. Of them, 97.02% were singletons; 2.85% were twins, and 0.13% was triplets or more. Women with multiple pregnancies had higher systemic and localized comorbidities compared with women with singleton pregnancies (P < .0001). Twins and triplets or more were more likely to have stayed in a neonatal intensive care unit than were singletons (P < .0001). On average, adjusted total all-cause health care cost was $21,458 (95% confidence interval [CI], $21,302-21,614) per delivery with singletons, $104,831 (95% CI, $103,402-106,280) with twins, and $407,199 (95% CI, $384,984-430,695) with triplets or more. CONCLUSION: Pregnancies with the delivery of twins cost approximately 5 times as much when compared with singleton pregnancies; pregnancies with delivery of triplets or more cost nearly 20 times as much.

Low oocyte maturity ratio is associated with a reduced in vitro fertilization and intracytoplasmic sperm injection live birth rate.

OBJECTIVE: To determine whether a low oocyte maturity ratio in a cohort of oocytes from an in vitro fertilization cycle predicts outcomes and to examine clinical factors associated with oocyte maturity. DESIGN: A retrospective cohort study. SETTING: An academic medical center. INTERVENTION(S): Determination of oocyte maturity immediately after the retrieval and 6 hours later if intracytoplasmic sperm injection was performed. MAIN OUTCOME MEASURE(S): The primary outcome was live birth rate after the first embryo transfer. Secondary outcomes included clinical pregnancy, miscarriage, and fertilization rates. RESULT(S): After adjusting for age, preimplantation genetic testing, and number of embryos transferred, we found that a low oocyte maturity ratio was associated with a decreased live birth rate (adjusted odds ratio [AOR], 0.41; 95% confidence interval [CI], 0.22-0.77) and clinical pregnancy rate (AOR, 0.32; 95% CI, 0.17-0.61). We did not find a relationship between oocyte maturity and miscarriage rate (AOR, 0.25; 95% CI, 0.03-1.91) or fertilization rate (Welch test). The number of 2 pronuclei embryos per retrieved oocyte was found to be associated with the maturity ratio at retrieval. Patients with anovulation had slightly reduced oocyte maturity compared with other diagnostic groups. CONCLUSION(S): Low oocyte maturity ratio is an important factor related to poor in vitro fertilization outcomes, including decreased pregnancy and live birth rates.

Intracytoplasmic sperm injection vs. conventional in vitro fertilization in patients with non-male factor infertility.

OBJECTIVE: To compare the cumulative live birth rates (CLBRs) and cost effectiveness of intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (cIVF) for non-male factor infertility. DESIGN: A retrospective cohort study. SETTING: Society for Assisted Reproductive Technology clinics. PATIENT(S): A total of 46,967 patients with non-male factor infertility with the first autologous oocyte retrieval cycle between January 2014 and December 2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcomes were CLBR, defined as up to 1 live birth from an autologous retrieval cycle between 2014 and 2015, and linked fresh and frozen embryo transfers through 2016. The secondary outcomes included miscarriage rate, 2 pronuclei per oocyte retrieved, and the total number of transferred and frozen embryos. Analyses were performed on subsamples with and without preimplantation genetic testing for aneuploidy (PGT-A). A cost analysis was performed to determine the costs accrued by ICSI. RESULT(S): Among cycles without PGT-A in patients with non-male factor infertility, the CLBR was 60.9% for ICSI cycles vs. 64.3% for cIVF cycles, a difference that was not significantly different after adjustment for covariates (adjusted risk ratio, 0.99; 95% confidence interval, 0.99-1.00). With PGT-A, no difference in CLBR was found between ICSI and cIVF cases after adjustment (64.7% vs. 69.0%, respectively; adjusted risk ratio, 0.97; 95% confidence interval, 0.93-1.01). The patients were charged an estimated additional amount of $37,476,000 for ICSI without genetic testing and an additional amount of $7,213,500 for ICSI with PGT-A over 2 years by Society for Assisted Reproductive Technology clinics. CONCLUSION(S): In patients with non-male factor infertility, ICSI did not improve CLBR. Given the additional cost and the lack of CLBR benefit, our data show that the routine use of ICSI in patients with non-male factor infertility is not warranted.

Fresh embryo transfer after in vitro insemination of fresh vs. cryopreserved anonymous donor oocytes: which has a better live birth rate? A Society for Assisted Reproductive Technology Clinic Outcome Reporting System analysis.

OBJECTIVE: To determine if transfer of fresh embryos derived from fresh or cryopreserved donor oocytes yields a higher live birth rate. DESIGN: Historical cohort study. SETTING: Society for Assisted Reproductive Technology Clinic Outcome Reporting System database. PATIENT(S): A total of 24,663 fresh embryo transfer cycles of donor oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live births per number of embryos transferred on day 5. The secondary outcomes included number of infants per embryo transfer, surplus embryos cryopreserved, and characterization of US oocyte recipients. RESULT(S): A total of 16,073 embryo transfers were from fresh oocytes and 8,590 were from cryopreserved oocytes. Recipient age, body mass index (BMI), gravidity, and parity were similar between the groups. Most recipients were of White non-Hispanic race (66.9%), followed by Asian (13.7%), Black non-Hispanic (9.3%), and Hispanic (7.2%). Fresh oocyte cycles were more likely to use elective single embryo transfer (42.5% vs. 37.8%) or double embryo transfer (53.2% vs. 50.4%) and resulted in more surplus embryos for cryopreservation (4.6 vs. 1.2). The live birth rate from fresh oocytes was 57.5% vs. 49.7% from cryopreserved oocytes. Negative predictors of live birth included the use of cryopreserved oocytes (odds ratio [OR] 0.731, 95% confidence interval [CI] 0.665-0.804), Black non-Hispanic race (OR 0.603, 95% CI 0.517-0.703), Asian race (OR 0.756, 95% CI 0.660-0.867), and increasing recipient BMI (OR 0.982, 95% CI 0.977-0.994) after controlling for recipient age, number of embryos transferred on day 5, and unexplained infertility diagnosis. The proportion of multifetal deliveries was greater in cycles utilizing fresh (26.4%) vs. cryopreserved (20.6%) oocytes. CONCLUSION(S): The live birth rate is higher with use of fresh oocytes vs. cryopreserved oocytes in fresh embryo transfer cycles. Negative live birth predictors include recipient Black non-Hispanic or Asian race and increasing BMI.

Cumulative live birth rate in women aged ≤37 years after in vitro fertilization with or without preimplantation genetic testing for aneuploidy: a Society for Assisted Reproductive Technology Clinic Outcome Reporting System retrospective analysis.

Objective: To investigate cumulative live birth rates (CLBRs) in cycles with and without preimplantation genetic testing for aneuploidy (PGT-A) among patients aged <35 and 35-37 years. Design: Retrospective cohort study. Setting: Society for Assisted Reproductive Technology reporting clinics. Patients: A total of 31,900 patients aged ≤ 37 years with initial oocyte retrievals between January 2014 and December 2015 followed through December 2016. Interventions: None. Main outcome measures: The primary outcome was CLBR among patients aged <35 and 35-37 years. The secondary outcomes included multifetal births, miscarriage, preterm birth, perinatal mortality, and the time to pregnancy resulting in a live birth. Adjusted odds ratios (aORs) adjusting for age, body mass index, total 2 pronuclei embryos, embryos transferred, and follow-up timeframe. Results: Among patients aged <35 years, PGT-A was associated with reduced CLBRs (70.6% vs. 71.1%; aOR, 0.82; 95% CI [confidence interval], 0.72-0.93). No association was found between PGT-A and CLBRs among patients aged 35-37 years (66.6% vs. 62.5%; aOR, 0.92; 95% CI, 0.83-1.01). Overall, there was no significant difference in the miscarriage rate (aOR, 0.97; 95% CI, 0.82-1.14). Multifetal birth rates were lower with PGT-A (9.5% vs. 23.1%); however, PGT-A was not an independent predictor of multifetal birth (aOR, 1.11; 95% CI, 0.91-1.36). The average time to pregnancy resulting in a live birth was 2.37 months (SD 3.20) for untested transfers vs. 4.58 months (SD 3.53) for PGT-A transfers. Conclusions: In women aged <35, the CLBR was lower with PGT-A than with the transfer of untested embryos. In women aged 35-37 years, PGT-A did not improve CLBRs.

Common practices among consistently high-performing in vitro fertilization programs in the United States: 10-year update.

OBJECTIVE: To evaluate similarities and differences in clinical and laboratory practices among high-performing fertility clinics. DESIGN: Cross-sectional questionnaire study of selected programs. SETTING: Academic and private fertility practices performing in vitro fertilization (IVF). PATIENT(S): Not applicable. INTERVENTION(S): A comprehensive survey was conducted of 13 IVF programs performing at least 100 cycles a year and having high cumulative singleton delivery rates for 2 years. MAIN OUTCOME MEASURE(S): Clinical and laboratory IVF practices. RESULT(S): Although many areas of clinical practice varied among top programs, some commonalities were observed. All programs used a combination of follicle-stimulating hormone and luteinizing hormone for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, ultrasound-guided embryo transfers, and a required semen analysis before starting the IVF cycle. Common laboratory practices included vitrification of embryos at the blastocyst stage, air quality control with positive air pressure and high-efficiency particulate air filtration, use of incubator gas filters, working on heated microscope stages, and incubating embryos in a low-oxygen environment, most often in benchtop incubators. CONCLUSION(S): Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success. High-performing programs focused on singleton deliveries. As the field of IVF is rapidly evolving, it is imperative that we share best practices in an effort to improve outcomes from all clinics for the good of our patients.

Predicting personalized cumulative live birth following in vitro fertilization.

OBJECTIVE: To develop in vitro fertilization (IVF) prediction models to estimate the individualized chance of cumulative live birth at two time points: pretreatment (i.e., before starting the first complete cycle of IVF) and posttreatment (i.e., before starting the second complete cycle of IVF in those couples whose first complete cycle was unsuccessful). DESIGN: Population-based cohort study. SETTING: National data from the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System. PATIENT(S): Based on 88,614 women who commenced IVF treatment using their own eggs and partner's sperm in SART member clinics. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The pretreatment model estimated the cumulative chance of a live birth over a maximum of three complete cycles of IVF, whereas the posttreatment model did so over the second and third complete cycles. One complete cycle included all fresh and frozen embryo transfers resulting from one episode of ovarian stimulation. We considered the first live birth episode, including singletons and multiple births. RESULT(S): Pretreatment predictors included woman's age (35 years vs. 25 years, adjusted odds ratio 0.69, 95% confidence interval 0.66-0.73) and body mass index (35 kg/m2 vs. 25 kg/m2, adjusted odds ratio 0.75, 95% confidence interval 0.72-0.78). The posttreatment model additionally included the number of eggs from the first complete cycle (15 vs. 9 eggs, adjusted odds ratio 1.10, 95% confidence interval 1.03-1.18). According to the pretreatment model, a nulliparous woman aged 34 years with a body mass index of 23.3 kg/m2, male partner infertility, and an antimüllerian hormone level of 3 ng/mL has a 61.7% chance of having a live birth over her first complete cycle of IVF (and a cumulative chance over three complete cycles of 88.8%). If a live birth is not achieved, according to the posttreatment model, her chance of having a live birth over the second complete cycle 1 year later (age 35 years, number of eggs 7) is 42.9%. The C-statistic for all models was between 0.71 and 0.73. CONCLUSION(S): The focus of previous IVF prediction models based on US data has been cumulative live birth excluding cycles involving frozen embryos. These novel prediction models provide clinically relevant estimates that could help clinicians and couples plan IVF treatment at different points in time.