International attitudes towards medical and planned oocyte cryopreservation.

PURPOSE: This study aims to better understand the knowledge and attitudes of men and women internationally towards oocyte cryopreservation (OC). METHODS: An online 25-question survey was distributed internationally via email and social media. Knowledge and attitudes towards OC among different regions and genders were assessed. The study population consisted of adults from North America (NA, 15.7%), Southeastern and Eastern Europe (SE, 34.7%), Central and Western Europe (CWE, 12.7%), Asia (12.7%), and Middle East (ME, 8.9%). RESULTS: A total of 496 respondents initiated the survey and the completion rate was 80.2%. The mean (SD) age was 35.2 (12.1) years. Over 70% were aware of OC, but only 4.8% had previously undergone the procedure. Most considered ages 26-31 as optimal for OC and correctly identified conditions that could impact the chance of spontaneous conception. Significant differences were observed regarding etiologies that would render OC acceptable. Only in NA and ME did solid majorities strongly agree that it is acceptable to proceed with OC to allow more time to find the right partner or for professional opportunities. More similar opinions were observed between genders. When medical conditions existed, large majorities across all nationalities and genders strongly agreed that OC is acceptable. In NA, SE, and ME most respondents would consider or recommend OC for any reason, whereas most respondents in CWE and Asia would do that only for certain social reasons or medical necessity. CONCLUSION: A good understanding of OC was observed. Nationality appeared to impact opinions on appropriate indications for this procedure, though overall positive attitudes were documented.

The impact of cryopreserved sperm on intrauterine insemination outcomes: is frozen as good as fresh?

Introduction: Frozen sperm utilization might negatively impact cycle outcomes in animals, implicating cryopreservation-induced sperm damage. However, in vitro fertilization and intrauterine insemination (IUI) in human studies are inconclusive. Methods: This study is a retrospective review of 5,335 IUI [± ovarian stimulation (OS)] cycles from a large academic fertility center. Cycles were stratified based on the utilization of frozen (FROZEN, n = 1,871) instead of fresh ejaculated sperm (FRESH, n = 3,464). Main outcomes included human chorionic gonadotropin (HCG) positivity, clinical pregnancy (CP), and spontaneous abortion (SAB) rates. Secondary outcome was live birth (LB) rate. Odds ratios (OR) for all outcomes were calculated utilizing logistic regression and adjusted (adjOR) for maternal age, day-3 FSH, and OS regimen. Stratified analysis was performed based on OS subtype [gonadotropins; oral medications (OM): clomiphene citrate and letrozole; and unstimulated/natural]. Time to pregnancy and cumulative pregnancy rates were also calculated. Further subanalyses were performed limited to either the first cycle only or to the partner's sperm only, after excluding female factor infertility, and after stratification by female age (<30, 30-35, and >35 years old). Results: Overall, HCG positivity and CP were lower in the FROZEN compared to the FRESH group (12.2% vs. 15.6%, p < 0.001; 9.4% vs. 13.0%, p < 0.001, respectively), which persisted only among OM cycles after stratification (9.9% vs. 14.2% HCG positivity, p = 0.030; 8.1% vs. 11.8% CP, p = 0.041). Among all cycles, adjOR (95% CI) for HCG positivity and CP were 0.75 (0.56-1.02) and 0.77 (0.57-1.03), respectively, ref: FRESH. In OM cycles, adjOR (95% CI) for HCG positivity [0.55 (0.30-0.99)] and CP [0.49 (0.25-0.95), ref.: FRESH] favored the FRESH group but showed no differences among gonadotropin and natural cycles. SAB odds did not differ between groups among OM and natural cycles but were lower in the FROZEN group among gonadotropin cycles [adjOR (95% CI): 0.13 (0.02-0.98), ref.: FRESH]. There were no differences in CP and SAB in the performed subanalyses (limited to first cycles or partner's sperm only, after excluding female factors, or after stratification according to female age). Nevertheless, time to conception was slightly longer in the FROZEN compared to the FRESH group (3.84 vs. 2.58 cycles, p < 0.001). No significant differences were present in LB and cumulative pregnancy results, other than in the subgroup of natural cycles, where higher LB odds [adjOR (95% CI): 1.08 (1.05-1.12)] and higher cumulative pregnancy rate (34% vs. 15%, p = 0.002) were noted in the FROZEN compared to the FRESH group. Conclusion: Overall, clinical outcomes did not differ significantly between frozen and fresh sperm IUI cycles, although specific subgroups might benefit from fresh sperm utilization.

The impact of anti-Müllerian hormone on endometrial thickness in gonadotropin stimulation/intrauterine insemination cycles: is there an effect on pregnancy outcomes?

PURPOSE: To study the association, if any, between anti-Müllerian hormone (AMH) and pre-ovulatory endometrial thickness (ET) in gonadotropin/intrauterine insemination (IUI) cycles. METHODS: This retrospective cohort study included a total of 964 patients undergoing 1926 gonadotropin/IUI cycles at an academic fertility center. Primary outcome measure was the association between serum AMH and measured ET on the day of and the day before human chorionic gonadotropin hormone (hCG) ovulation trigger. The effect of a model combining AMH and ET on early pregnancy outcomes was a secondary measure. RESULTS: In 52.8% of cycles, ET was last assessed and recorded on the day of hCG administration, while in the remaining 47.2% on the day prior to trigger. In unadjusted regression models, AMH was weakly correlated with ET on hCG trigger day [bAMH (95%CI) = 0.032 (- 0.008, 0.070), p = 0.015]. When adjusting for potential confounders, the positive correlation became significant [0.051 (0.006, 0.102), p = 0.047]. Similar findings were observed when assessing the correlation between AMH and ET on the day prior to hCG trigger. ET was non-significantly associated with the odds of clinical pregnancy, when adjusting for potential confounders, except for when restricting the analysis to couples with idiopathic infertility [OR (95%CI), p-value: 0.787 (0.623, 0.993), 0.044]. CONCLUSION: Our findings support an effect of serum AMH on endometrial development in gonadotropin induced cycles, even when adjusting for the diagnosis of PCOS. ET was not associated with the odds of achieving a clinical pregnancy, except for couples with idiopathic infertility.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The impact of single-step and sequential embryo culture systems on obstetric and perinatal outcomes in singleton pregnancies: the Massachusetts Outcomes Study of Assisted Reproductive Technology.

OBJECTIVE: To compare the obstetric and perinatal outcomes of deliveries conceived with embryos from single-step vs. sequential culture media systems. DESIGN: Historical cohort of Massachusetts vital records linked to assisted reproductive technology clinic data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and laboratory embryology data from two large academic hospital fertility centers. SETTING: Not applicable. PATIENTS: Patients with singleton live birth deliveries between 2004 and 2017 conceived with autologous assisted reproductive technology cycles with fresh blastocyst transfer using either single-step (n = 1,058) or sequential (n = 474) culture media systems. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Associations of single-step vs. sequential culture with obstetric outcomes (mode of delivery, placental abnormalities, pregnancy-induced hypertension, and gestational diabetes) and perinatal outcomes (preterm birth, low birthweight, small-for-gestational-age, and large-for-gestational-age [LGA]) were assessed with multivariate logistic modeling, adjusted for maternal age, race/ethnicity, education, parity, insurance type, protein supplementation, oxygen concentration, fertilization method, and number of transferred embryos. RESULTS: Compared with sequential culture, single-step culture was associated with increased odds of LGA (adjusted odds ratio 2.1, 95% confidence interval 1.04-4.22). There were no statistically significant differences between single-step and sequential culture media systems in the odds of placental abnormalities, pregnancy-induced hypertension, gestational diabetes, prematurity, small-for-gestational-age, or low birthweight. CONCLUSIONS: Single-step culture is associated with increased odds of LGA, indicating that embryo culture media systems may affect perinatal outcomes.

The effect of semen collection at home on intrauterine insemination outcomes.

BACKGROUND: The WHO 2010 guidelines recognize at-home semen collection as an acceptable alternative to standard collection at the clinic in "exceptional circumstances." There is lack of sufficient data to determine the need for revisiting these recommendations for treatment purposes. OBJECTIVES: To determine whether at-home semen collection has any effect on intrauterine insemination (IUI) cycle outcomes. MATERIALS AND METHODS: This is a retrospective cohort study of 729 IUI treatment cycles (382 patients) performed at an academic fertility center from September 19, 2019 to December 31, 2020. Semen collected at the "clinic" was used for 343 cycles before the Coronavirus Disease 2019 (COVID-19) pandemic (September 19, 2019 to March 21, 2020), and "at-home" collected specimens were used for 386 cycles following revised protocols with COVID-19-driven changes (May 30, 2020 to December 31, 2020). Logistic regression models were performed to evaluate the effect of "at-home" semen collection on achieving a positive pregnancy test (PPT) and a clinical pregnancy (CP). RESULTS: Male and female partners' age, ovarian reserve biomarkers, and stimulation regimens used were similar in the "clinic" and "at-home" groups. In unadjusted models, "at-home" collection had no significant effect on the odds for a PPT [OR (95%CI): 0.733 (0.503-1.069)] or CP [0.816 (0.543-1.226)]. These results persisted even when adjusting for maternal age and anti-Müllerian hormone: PPT [0.739 (0.505-1.081)] and CP [0.826 (0.547-1.248)]. Of the semen analysis parameters under evaluation, only motility appeared to significantly impact the odds of achieving a PPT [1.014 (1.004-1.025)] and a CP [1.017 (1.006-1.029)]. This effect was slightly attenuated for samples collected "at-home" [1.012 (0.997-1.027) and 1.015 (0.999-1.031), respectively, for PPT and CP]. DISCUSSION: This study adds important information to the limited literature regarding the effect of at-home semen collection on IUI outcomes. Under adequate protocols, at-home semen collection should be considered a safe alternative. Additional research is needed to optimize such protocols. CONCLUSION: Our data suggest that at-home semen collection does not negatively impact IUI pregnancy outcomes.

Placental pathology of term singleton live births conceived with fresh embryo transfer compared with those conceived without assisted reproductive technology.

OBJECTIVE: To compare placental pathology from term singleton live births conceived with fresh embryo transfer vs. those conceived without assisted reproductive technology (ART). DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): Women with a term singleton live birth who conceived after fresh autologous in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles (ART group) and those who conceived without ART. INTERVENTION(S): An experienced placental pathologist categorized placental pathology as anatomic, inflammatory, or vascular. Patient characteristics were compared by chi-squared tests, Student's t-test, or nonparametric tests. Multivariate logistic regression models were used to compare placental pathology between pregnancies conceived with and without ART. MAIN OUTCOME MEASURE(S): Incidence of anatomic, inflammatory, and vascular placental pathology. RESULT(S): There was a higher incidence of placental pathology in the ART group (n = 511) than in the non-ART group (n = 121), specifically anatomic (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.42-4.40) and vascular (aOR 2.00, 95% CI 1.13-3.53) pathology. These findings were driven primarily by the significantly higher odds of anatomic (aOR 2.97, 95% CI 1.55-5.66) and vascular (aOR 1.98, 95% CI 1.04-3.75) pathology observed in ICSI pregnancies. Single blastocyst transfers remained associated with increased anatomic pathology (ART: aOR 4.89, 95% CI 2.28-10.49; ICSI: aOR 3.38, 95% CI 1.49-7.71). CONCLUSION(S): Fresh embryo transfer is associated with increased anatomic and vascular placental pathology in term singleton live births compared with conception without ART. This finding should be investigated prospectively in a larger cohort of patients.

Assessing efficacy of intravenous acetaminophen for perioperative pain control for oocyte retrieval: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effect of preoperative intravenous (IV) acetaminophen versus oral (PO) acetaminophen or placebo on postoperative pain scores and the time to discharge in women undergoing oocyte retrieval. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single academic fertility center. PATIENT(S): Women aged 18-43 years undergoing oocyte retrieval. INTERVENTION(S): Randomization to preoperative 1,000 mg IV acetaminophen and PO placebo (group A), IV placebo and 1,000 mg PO acetaminophen (group B), or IV and PO placebo (group C) MAIN OUTCOME MEASURE(S): Difference in patient-reported postoperative visual analog scale pain scores from baseline and the time to discharge. RESULT(S): Of the 159 women who completed the study, there were no differences in the mean postoperative pain score differences or the time to discharge. Although not statistically significant, the mean postoperative opioid dose requirement in group A was lower than that in groups B and C (0.24 vs. 0.59 vs. 0.58 mg IV morphine equivalents, respectively) due to fewer women in group A requiring rescue pain medication (8% vs. 19% vs. 15%, respectively). Group A also reported less constipation when compared with groups B and C (19% vs. 33% vs. 40%, respectively). The rates of postoperative nausea were similar, and there were no differences in embryology or early pregnancy outcomes between the study groups. CONCLUSION(S): Preoperative IV acetaminophen for women undergoing oocyte retrieval did not reduce postoperative pain scores or shorten the time to discharge when compared with PO acetaminophen or placebo and, thus, cannot currently be recommended routinely in this patient population. CLINICAL TRIAL REGISTRATION NUMBER: NCT03073980.

Urinary phthalate metabolite concentrations are negatively associated with follicular fluid anti-müllerian hormone concentrations in women undergoing fertility treatment.

Exposure to phthalates, endocrine-disrupting chemicals commonly used as plasticizers and in consumer products, has been associated with infertility and premature ovarian failure. Our objective was to investigate whether urinary phthalate metabolite concentrations were associated with pre-ovulatory follicular fluid (FF) anti-müllerian hormone (AMH) concentrations in women undergoing fertility treatment. This cross-sectional analysis included 138 women with urinary phthalate data available in the Environment and Reproductive Health (EARTH) Study (2010-2016) in whom FF AMH concentrations were quantified using a sandwich enzyme-linked immunosorbent assay (ELISA). We also quantified 8 phthalate metabolite concentrations using tandem mass spectrometry in 1-2 urine samples per cycle (total 331 urines) and calculated the cycle-specific geometric mean for each metabolite. We applied cluster-weighted generalized estimating equation models (CWGEE) to evaluate the associations of tertiles of urinary phthalate metabolite concentrations with log-transformed FF AMH concentrations adjusting for potential confounders. Study participants had median age of 34.0 years (IQR 32.0, 37.0), 83% were white, and median BMI of 23.1 kg/m2 (IQR 21.2, 26.1). The following stimulation protocols were used: luteal phase agonist (70%), antagonist (14%), or flare (16%). Urinary concentrations of select phthalate metabolites were negatively associated with FF AMH. For example, women whose urinary mEOHP was in the lowest tertile (range 0.30-4.04 ng/ml) had an adjusted mean FF AMH of 0.72 ng/mL (95% CI = 0.36, 1.44), compared to women in the highest tertile (range 9.90-235), who had an adjusted mean of 0.24 ng/mL (95% CI = 0.12-0.48, p < 0.05). The negative association between urinary concentrations of certain phthalate metabolites with FF AMH concentrations may have implications for antral follicle recruitment and fertility treatment outcomes.

Response to ovulation induction treatments in women with polycystic ovary syndrome as a function of serum anti-Müllerian hormone levels.

PURPOSE: To assess whether anti-Müllerian hormone (AMH) can predict response to ovulation induction (OI) with clomiphene citrate (CC), letrozole (LET), or follicle-stimulating hormone (FSH) in women with polycystic ovary syndrome (PCOS) undergoing OI/intrauterine inseminations (IUI). METHODS: A total of 738 OI/IUI cycles from 242 patients at an academic center were stratified in three groups by medication: CC (n = 295), LET (n = 180), and FSH (n = 263), in a retrospective fashion. Ovarian response to treatment (RT, development of at least one dominant follicle) was assessed using mixed effects logistic regression models. RESULTS: Overall, RT cycles had lower AMH levels compared to no-RT cycles (p < 0.001). This finding persisted when analysis was limited to oral agents but attenuated in FSH cycles. For CC and LET cycles, the predicted probability (PProb) for RT decreased as AMH levels increased (PProb (95%CI): 97% (93-100), 79% (70-88), and 75% (61-89); 85% (78-93), 75% (67-83), and 73% (63-86) for AMH pct.: ≤ 25th, ≥ 50th, and ≥ 75th, for CC and LET, respectively)). However, RT was noted in 98.5% of FSH/IUI cycles regardless of AMH. For CC cycles, those with AMH ≥ 75th pct. had lower odds for RT over cycles with AMH < 75th pct. (OR 0.2, 95%CI 0.04-0.8, p = 0.02). Similarly, lower odds for RT were observed in LET cycles with AMH ≥ 75th pct. (0.6, 0.3-1.4, p = 0.25). CONCLUSION: In PCOS, increasing serum AMH levels are associated with lower probability of RT to oral agents. Our findings constitute a valuable tool for the clinician when counseling PCOS patients and designing a personalized ovulation induction treatment strategy.

Pretreatment antimüllerian hormone levels and outcomes of ovarian stimulation with gonadotropins/intrauterine insemination cycles.

OBJECTIVE: To evaluate the association, if any, between serum antimüllerian hormone (AMH) levels and probability of clinical pregnancy and spontaneous abortion (SAB) in the infertility setting. DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): A total of 1,861 gonadotropin stimulation/intrauterine insemination cycles stratified by AMH levels into 3 groups: Low, <25th percentile (<0.7 ng/mL); Middle, ≥25th and <75th percentile (0.7-4.4 ng/mL); and High, ≥75th percentile (≥4.5 ng/mL). INTERVENTION(S): Intrauterine insemination after stimulation with gonadotropins. MAIN OUTCOME MEASURE(S): Cumulative probability of clinical pregnancy over a maximum of 3 and/or 6 cycles and SAB incidence risk rate (IRR). The Kaplan-Meier failure function (log rank test), Cox proportional hazards models, and multilevel mixed-effects Poisson regression models were performed to compare outcomes among the AMH groups. RESULT(S): Overall, in both unadjusted and adjusted models, the probability of achieving a clinical pregnancy was higher in the Middle and High AMH groups compared with that in the Low AMH group, both over 3 (hazard ratios [95% confidence interval], 1.55 [1.05-2.29] and 1.85 [1.22-2.81], respectively) and 6 (1.71 [1.17-2.48] and 2.12 [1.42-3.16], respectively) cycles. In the unadjusted models, the SAB IRR was higher among the Low AMH group (IRR [95% confidence interval], 2.17 (1.11-4.24]), with the relationship persisting after adjusting for age (1.83 [0.93-3.60]). When the SAB IRR were calculated separately for the subpopulations with and without polycystic ovary syndrome, a similar relationship was noted among the latter in the unadjusted (1.94 [0.97-3.88]) and adjusted (1.74 [0.86-3.49]) analyses. CONCLUSION(S): In women undergoing gonadotropin stimulation/intrauterine insemination, AMH appears to affect the probability of achieving a clinical pregnancy. A possible negative impact, independent of age, on the risk of SAB was also suggested.

The effect of semen collection location and time to processing on sperm parameters and early IVF/ICSI outcomes.

PURPOSE: We aimed to assess whether home collection and increased time to semen processing are associated with altered sperm parameters, fertilization rates (FR), day 5 usable quality blastocyst development rates (D5-UQBR), or pregnancy rates (PR) in patients undergoing IVF/ICSI. METHODS: This was a retrospective cohort study of patients undergoing IVF/ICSI before the coronavirus disease 2019 (COVID-19) pandemic ("clinic" collection, n = 119) and after COVID-19 ("home" collection, n = 125) at an academic fertility practice. Home collection occurred within 2 h of semen processing. Patient sperm parameters, FR (#2PN/MII), D5-UQBR (# transferable and freezable quality blastocysts/# 2PN), and PR in fresh transfer cycles were compared between clinic and home groups with t-tests. The association between time to processing on outcomes was assessed with regression modeling, controlling for potential confounders. RESULTS: Mean male age was 37.9 years in the clinic group and 37.2 years in the home group (p = 0.380). On average, men were abstinent for 3.0 days (SD 1.7) in the clinic group and 4.1 days (SD 5.4) in the home group (p = 0.028). Mean time to semen processing was 35.7 min (SD 9.4) in the clinic group and 82.6 min (SD 33.8) in the home group (p < 0.001). There was no association between collection location and increased time to processing on sperm motility, total motile count, FR, D5-UQBR, or PR. CONCLUSIONS: Our data suggest that increased time to processing up to 2 h with home semen collection does not negatively impact sperm parameters or early IVF/ICSI outcomes.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

A patient-specific model combining antimüllerian hormone and body mass index as a predictor of polycystic ovary syndrome and other oligo-anovulation disorders.

OBJECTIVE: To determine whether a patient-specific predictive model combining antimüllerian hormone (AMH) levels and body mass index (BMI) can aid in the diagnosis of polycystic ovary syndrome (PCOS) and other ovulatory dysfunction disorders (OVDYS) among infertile women. DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): One thousand and ten infertile women undergoing 3,160 intrauterine insemination (IUI) cycles, stratified by diagnosis in three groups: PCOS, OVDYS, and other etiologies. INTERVENTION(S): Ovulation induction followed by IUI or ultrasound-monitored natural cycles. MAIN OUTCOME MEASURE(S): The probability of either PCOS or OVDYS diagnosis based on AMH levels alone and a patient-specific predictive model that combines serum AMH and patient's BMI. RESULT(S): Median and interquartile range (IQR) for the serum AMH levels (ng/mL) were the highest in women with PCOS, and lowest in those with other infertility causes. Overall, for every 1 ng/mL increase in AMH, the odds of PCOS and OVDYS versus other causes increased by 55% and 24%, respectively. Postestimation from multivariate logistic regression models showed that PCOS diagnosis can be predicted with lower AMH values in women with a higher BMI compared with the AMH values predicting PCOS in normal-weight or underweight patients. The receiver operating characteristic curves reinforced these findings, and the best cutoffs for PCOS diagnosis were 7.5, 4.4, and 4.1 ng/mL for women belonging to the BMI groups 18.5-24.9, 25.0-29.9, and ≥30.0 kg/m2, respectively. CONCLUSION(S): Taking into account AMH and BMI, we developed a model that predicts the probability of an oligo-anovulation diagnosis, thus facilitating patient-specific counseling in the infertility setting.

Follicular fluid anti-Müllerian hormone (AMH) concentrations and outcomes of in vitro fertilization cycles with fresh embryo transfer among women at a fertility center.

PURPOSE: To enhance the understanding of the clinical significance of anti-Müllerian hormone (AMH) in follicular fluid, we aimed to determine the variability of AMH concentrations in follicular fluid within and across IVF cycles and whether high follicular fluid AMH concentrations are associated with improved clinical IVF outcomes. METHODS: This was a retrospective cohort study of companion follicular fluid and serum samples from 162 women enrolled in the Environment and Reproductive Health (EARTH) Study between 2010 and 2016. AMH concentrations were quantified using a sandwich enzyme-linked immunosorbent assay. Spearman correlation and intra-class correlation (ICC) were calculated to assess variability of follicular fluid AMH, and generalized linear mixed models were used to evaluate the associations of FF AMH with IVF outcomes. RESULTS: The median (interquartile range, IQR) age of the 162 women was 34.0 years (32.0, 37.0). Follicular fluid AMH concentrations were highly correlated between follicles within each IVF cycle (Spearman r = 0.78 to 0.86) and across cycles for each woman (ICC 0.87 (95% CI 0.81 to 0.92)). Compared with women in the highest tertile of FF AMH (mean AMH = 2.3 ng/ml), women in the lowest tertile (mean AMH = 0.2 ng/ml) had lower serum AMH (T1 = 0.1 ng/ml vs. T3 = 0.6 ng/ml, p < 0.0001). In adjusted models, higher tertiles of follicular fluid AMH concentrations were associated with lower mean endometrial thickness and higher probability of clinical pregnancy. CONCLUSIONS: Follicular fluid AMH concentrations show little variability between pre-ovulatory follicles, and higher pre-ovulatory follicular fluid AMH may predict a higher probability of clinical pregnancy.

Vanishing Twins Conceived Through Fresh In Vitro Fertilization: Obstetric Outcomes and Placental Pathology.

OBJECTIVE: To characterize the obstetric outcomes and placental pathology in live births arising from vanishing twin pregnancies compared with nonreduced in vitro fertilization (IVF) pregnancies. METHODS: This is a retrospective cohort study of live births resulting from fresh embryo transfers after IVF cycles with autologous oocytes from 2004 through 2017 at a large academic fertility center. Clinical information and pathology reports were reviewed. Placental diagnoses were coded using established nosology by expert placental pathologists. Analysis of variance, Kruskal-Wallis, Pearson's χ, and Fisher exact tests were used, as appropriate, to compare pathology categories between pregnancy outcomes. Mixed effects logistic regression models were generated to reveal the association between pregnancy outcome and placenta pathology, controlling for pregnancies arising in the same woman and various suspected confounders. RESULTS: Of 905 fresh autologous IVF cycles with placental pathology available for review, we identified 73 vanishing twin pregnancies (8.1%), 556 singleton pregnancies (61.4%), and 276 twin pregnancies (30.5%). Vanishing twin syndrome was not associated with preterm delivery, route of delivery, growth restriction or other obstetric outcomes as compared with IVF singleton pregnancies. However, vanishing twin syndrome pregnancies showed distinctive placental pathologies including an increased rate of small placentas (less than the 10th percentile by weight), with more anatomical abnormalities than IVF singleton pregnancies (odds ratio 1.73, 95% CI 0.94-3.19; adjusted odds ratio 2.15, 95% CI 1.08-4.28). The frequency of placental vascular and inflammatory pathologies associated with IVF vanishing twin syndrome pregnancies were similar to that of IVF singleton pregnancies. Loss of a twin after 8 weeks of gestation was not associated with greater risks of placental pathologies. CONCLUSION: In vitro fertilization pregnancies affected by vanishing twin syndrome did not have significant differences in obstetric or perinatal outcomes as compared with twin or singleton gestations. However, early twin loss was potentially associated with differences in placental development associated with a higher rate of small placentas and other anatomic pathologies.

Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer.

BACKGROUND: The availability and use of frozen embryos after ovarian hyperstimulation for assisted reproduction has increased with improvement in vitrification techniques and the rise of preimplantation genetic testing. However, there are conflicting data regarding whether obstetric outcomes differ between fresh and frozen embryo transfer cycles. OBJECTIVE: To compare placental pathology from live births arising from fresh and frozen embryo transfer cycles. MATERIALS AND METHODS: A cohort of 1140 live births with placental pathology arising from autologous in vitro fertilization cycles with fresh or frozen programmed transfer performed at MGH Fertility Center between 2004 and 2017 was retrospectively reviewed. An experienced placental pathologist categorized the reported placental pathology as anatomic, infectious, inflammatory, or vascular/thrombotic. Our primary outcomes were differences in these placental pathologies between the 2 groups. Patient demographic, cycle, and birth outcomes were compared with the use of χ2 tests, Student t test, or nonparametric tests, as appropriate. Multivariate logistic regression models were used to compare placental pathology between the fresh and frozen transfer groups. RESULTS: Of the 1140 cycles included in our analysis, 929 arose from fresh embryo transfers (81.3%) and 211 arose from programmed frozen embryo transfers (18.5%). For both transfer types, the average age of the women at time of treatment was 35 years; mean body mass indices were within the normal range (23.6 kg/m2 for fresh transfers and 23.2 kg/m2 for frozen transfers, P = .26), and mean day 3 follicle-stimulating hormone values were 7.1 and 7.0 IU/L (P = .44), respectively. Deliveries occurred on average at 37.5 and 38.0 weeks' gestational age (P = .04) in the fresh versus frozen transfer group, with similar rates of obstetric complications. However, frozen transfers were more likely to be associated with marginal cord insertion (adjusted odds ratio, 1.87; confidence interval, 1.21, 2.91; P = .01), accessory lobe formation (adjusted odds ratio, 2.96; confidence interval, 1.12, 7.79; P = 0.03), subchorionic thrombi (adjusted odds ratio, 3.72; confidence interval, 1.80, 7.71; P < .001), and fetal vascular malperfusion characteristics with cord anomalies (adjusted odds ratio, 2.34; confidence interval, 1.22, 4.46; P = .01). These trends persisted when we analyzed day 5 transfers alone, and single frozen embryo transfers remained associated with increased rates of subchorionic thrombi compared to single fresh embryo transfers. CONCLUSION: Pregnancies arising from frozen embryo transfers demonstrated more anatomic and vascular placental pathology than those from fresh transfers in our cohort of patients, despite similar maternal outcomes. More research is needed to explore how these differences in pathology may influence obstetric and perinatal outcomes.

The "secret" in secretions: methodological considerations in deciphering primate olfactory communication.

Olfactory communication in primates is gaining recognition; however, studies on the production and perception of primate scent signals are still scant. In general, there are five tasks to be accomplished when deciphering the chemical signals contained in excretions and secretions: (1) obtaining the appropriate samples; (2) extracting the target organic compounds from the biological matrix; (3) separating the extracted compounds from one another (by gas chromatography, GC or liquid chromatography, LC); (4) identifying the compounds (by mass spectrometry, MS and associated procedures); and (5) revealing biologically meaningful patterns in the data. Ultimately, because some of the compounds identified in odorants may not be relevant, associated steps in understanding signal function involve verifying the perception or biological activity of putative semiochemicals via (6) behavioral bioassays or (7) receptor response studies. This review will focus on the chemical analyses and behavioral bioassays of volatile, primate scent signals. Throughout, we highlight the potential pitfalls of working with highly complex, chemical matrices and suggest ways for minimizing problems. A recurring theme in this review is that multiple approaches and instrumentation are required to characterize the full range of information contained in the complex mixtures that typify primate or, indeed, many vertebrate olfactory cues. Only by integrating studies of signal production with those verifying signal perception will we better understand the function of olfactory communication.

Eulemur, me lemur: the evolution of scent-signal complexity in a primate clade.

Signal complexity has been linked to social complexity in vocal, but not chemical, communication. To address this gap, we examined the chemical complexity of male and female glandular secretions in eight species of Eulemur. In this diverse clade of macrosmatic primates, species differ by social or mating system and dominance structure. We applied principal component and linear discriminate analyses to data obtained by gas chromatography/mass spectrometry. Beyond the significant effects on chemical signals of gland type, sex, season and species, we found effects of social variables and phylogeny. Notably, female odours were more chemically complex in multimale-multifemale species than pair-bonded species, whereas male odours were more chemically complex in codominant species than female-dominant species. Also, the traditional sexual dimorphism, whereby male signal complexity exceeds that of females, was present in codominant species, but reversed in female-dominant species. Lastly, a positive relationship between the species' pairwise chemical distances and their pairwise phylogenetic distances supported a gradual, but relatively fast mode of signal evolution. We suggest that the comparative method can be a powerful tool in olfactory research, revealing species differences relevant to the understanding of current signal utility and evolutionary processes. In particular, social complexity in lemurs may have selected for olfactory complexity.