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 risk of birth defects with conception by ART.

STUDY QUESTION: What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and 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 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but 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 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). 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). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was 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. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. 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. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER: N/A.

Sixth grade academic achievement among children conceived with IVF: a population-based study in Texas, USA.

PURPOSE: To compare academic achievement in reading and mathematics at the end of sixth grade and progress from third to sixth grade by children conceived with in vitro fertilization (IVF) to those conceived naturally. METHODS: This was a retrospective population-based cohort study of IVF-conceived singleton and twin children who took the 3rd grade and 6th grade public school standardized reading and mathematics testing in Texas. RESULTS: There were 6623 children with reading scores in both the third and sixth grades and 6374 children with mathematics scores in both the third and sixth grades. Mean (± SE) scaled test scores for IVF and control singleton children for reading were 1544.6 ± 3.4 and 1527.7 ± 1.9, respectively, in third grade and 1701.2 ± 3.6 and 1681.0 ± 2.0, respectively, in sixth grade; for mathematics, the scores were 1564.4 ± 3.7 and 1548.9 ± 2.1, respectively, in third grade and 1774.0 ± 4.2 and 1752.0 ± 2.3, respectively, in sixth grade. In multivariate models, singleton IVF children scored significantly higher than control children in reading and mathematics, averaging 17.7 ± 4.0 points and 20.1 ± 4.1 points higher, respectively, in reading in third and sixth grades and 17.8 ± 4.4 points and 25.0 ± 4.8 points higher, respectively, in mathematics in third and sixth grades. CONCLUSIONS: Children conceived with IVF and aged 8-9 years and aged 10-12 years performed as well on third and sixth grade reading and mathematics assessments as their counterparts conceived naturally.

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 multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count.

RESEARCH QUESTION: What concentration of anti-Müllerian hormone (AMH) corresponds to an antral follicle count (AFC) >15 for determination of ovarian reserve? DESIGN: A prospective study conducted at 13 US fertility clinics in women aged 21-44 years who presented for AFC evaluation by transvaginal ultrasound. Serum samples were collected at the time of AFC evaluation (menstrual cycle day 2-4). AMH concentrations were measured by the Elecsys® AMH immunoassay; oestradiol and follicle-stimulating hormone (FSH) concentrations were also measured. The serum AMH cut-off able to detect AFC >15 with high sensitivity was determined (derivation cohort). Clinical performance of the AMH assay at the derived cut-off was evaluated (validation cohort). Receiver operating characteristic (ROC) analyses were also performed. RESULTS: In the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC >15 with 89.63% sensitivity and 69.01% specificity, using the Elecsys AMH assay. In the validation cohort (n = 856), this 1.77 ng/ml cut-off could identify women with an AFC >15 with a sensitivity of 88.34% and a specificity of 68.29%; corresponding positive predictive and negative predictive values were 75.19% and 84.34%, respectively. ROC analyses demonstrated that AMH performed better than oestradiol or FSH in predicting AFC, with area under the curves of 85.7%, 57.1% and 69.7%, respectively, in the validation cohort. CONCLUSION: The Elecsys AMH immunoassay provides a robust and fully automated method to measure serum AMH levels. Women with AMH values below the cut-off of 1.77 ng/ml are unlikely to have AFC >15.

Risk of severe maternal morbidity by maternal fertility status: a US study in 8 states.

BACKGROUND: Over the past 2 decades the characteristics of women giving birth in the United States and the nature of the births themselves have changed dramatically, with increases in older maternal age, plural births, cesarean deliveries, and conception from infertility treatment. OBJECTIVE: We sought to evaluate the risk of severe maternal morbidity by maternal fertility status, and for in vitro fertilization pregnancies, by oocyte source and embryo state combinations. STUDY DESIGN: Women in 8 states who underwent in vitro fertilization cycles resulting in a live birth during 2004 through 2013 were linked to their infant's birth certificates; a 10:1 sample of births from non-in vitro fertilization deliveries were selected for comparison; those with an indication of infertility treatment on the birth certificate were categorized as subfertile, all others were categorized as fertile. In vitro fertilization pregnancies were additionally categorized by oocyte source (autologous vs donor) and embryo state (fresh vs thawed). Maternal morbidity was identified from the birth certificate, modeled using logistic regression, and reported as adjusted odds ratios [95% confidence intervals]. The reference group was fertile women. RESULTS: The study population included 1,477,522 pregnancies (1,346,118 fertile, 11,298 subfertile, 80,254 in vitro fertilization autologous-fresh, 21,964 in vitro fertilization autologous-thawed, 13,218 in vitro fertilization donor-fresh, and 4670 in vitro fertilization donor-thawed pregnancies): 1,420,529 singleton, 54,573 twin, and 2420 triplet+ pregnancies. Compared to fertile women, subfertile and the 4 groups of in vitro fertilization-treated women had increased risks for blood transfusion and third- or fourth-degree perineal laceration (subfertile, 1.58 [1.23-2.02] and 2.08 [1.79-2.43]; autologous-fresh, 1.33 [1.14-1.54] and 1.37 [1.26-1.49]; autologous-thawed, 1.94 [1.60-2.36] and 2.10 [1.84-2.40]; donor-fresh, 2.16 [1.69-2.75] and 2.11 [1.66-2.69]; and donor-thawed, 2.01 [1.38-2.92] and 1.28 [0.79-2.08]). Also compared to fertile women, the risk of unplanned hysterectomy was increased for in vitro fertilization-treated women in the autologous-thawed group (2.80 [1.96-4.00]), donor-fresh group (2.14 [1.33-3.44]), and the donor-thawed group (2.46 [1.33-4.54]). The risk of ruptured uterus was increased for in vitro fertilization-treated women in the autologous-fresh group (1.62 [1.14-2.29]). Among women with a prior birth, the risk of blood transfusion after a vaginal birth was increased for subfertile women (2.91 [1.38-6.15]), and women in all 4 in vitro fertilization groups (autologous-fresh, 1.93 [1.23-3.01]; autologous-thawed, 2.99 [1.78-5.02]; donor-fresh, 5.13 [2.39-11.02]; and donor-thawed, 5.20 [1.83-14.82]); the risk after a cesarean delivery was increased in the autologous-thawed group (1.74 [1.29-2.33]) and the donor-fresh group (1.62 [1.07-2.45]). Unplanned hysterectomy was increased in the autologous-thawed (2.31 [1.43-3.71]) and donor-thawed (2.45 [1.06-5.67]) groups. CONCLUSION: The risks of severe maternal morbidity are increased for subfertile and in vitro fertilization births, particularly in pregnancies that are not from autologous, fresh cycles.

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.

Comparing blastocyst quality and live birth rates of intravaginal culture using INVOcell™ to traditional in vitro incubation in a randomized open-label prospective controlled trial.

PURPOSE: The purpose of this study is to to compare the efficacy of intravaginal culture (IVC) of embryos in INVOcell™ (INVO Bioscience, MA, USA) to traditional in vitro fertilization (IVF) incubators in a laboratory setting using a mild pre-determined stimulation regimen based solely on anti-mullerian hormone (AMH) and body weight with minimal ultrasound monitoring. The primary endpoint examined was total quality blastocysts expressed as a percentage of total oocytes placed in incubation. Secondary endpoints included percentage of quality blastocysts transferred, pregnancy, and live birth rates. METHODS: In this prospective randomized open-label controlled single-center study, 40 women aged <38 years of age with a body mass index (BMI) of <36 and an AMH of 1-3 ng/mL were randomized prior to trigger to receive either IVC or IVF. Controlled ovarian stimulation was administered with human menopausal gonadotropin (hMG) in a fixed gonadotropin-releasing hormone (GnRH) agonist cycle based solely on AMH and body weight. A single ultrasound-monitoring visit was performed on the 10th day of stimulation. One or two embryos were transferred following 5 days of culture. RESULTS: IVF produced a greater percentage of total quality embryos as compared to IVC (50.6 vs. 30.7 %, p = 0.0007, respectively). There was no significant difference between in IVF and IVC in the percentage of quality blastocysts transferred (97.5 vs. 84.9 %, p = 0.09) or live birth rate (60 % IVF, 55 % IVC). CONCLUSIONS: IVF was shown to be superior to IVC in creating quality blastocysts. However, both IVF and IVC produced identical blastocysts for transfer resulting in similar live birth rates. IVC using INVOcell™ is effective and may broaden access to fertility care in selected patient populations by ameliorating the need for a traditional IVF laboratory setting. Further studies will help elucidate the potential physiological, psychological, geographic, and financial impact of IVC on the delivery of fertility care.

Public reporting of assisted reproductive technology outcomes: past, present, and future.

The clinic-specific public reporting of assisted reproductive technology (ART) outcomes has been mandated by Federal law since 1992. As of late, a series of scientific and medical advances have all but deconstructed ART practice patterns thereby demanding that current reporting platforms be reevaluated for their continued ability to afford the public with credible and understandable estimates of conception per initiated cycle. In this Clinical Opinion, we trace the history of the public reporting of ART, describe the recently modified (present day) reporting platform, and explore potential future improvements thereof.

Patients' administration preferences: progesterone vaginal insert (Endometrin®) compared to intramuscular progesterone for Luteal phase support.

BACKGROUND: Administration of exogenous progesterone for luteal phase support has become a standard of practice. Intramuscular (IM) injections of progesterone in oil (PIO) and vaginal administration of progesterone are the primary routes of administration. This report describes the administration preferences expressed by women with infertility that were given progesterone vaginal insert (PVI) or progesterone in oil injections (PIO) for luteal phase support during fresh IVF cycles. METHODS: A questionnaire to assess the tolerability, convenience, and ease of administration of PVI and PIO given for luteal phase support was completed by infertile women diagnosed with PCOS and planning to undergo IVF. The women participated in an open-label study of highly purified human menopausal gonadotropins (HP-hMG) compared with recombinant FSH (rFSH) given for stimulation of ovulation. RESULTS: Most women commented on the convenience and ease of administration of PVI, while a majority of women who administered IM PIO described experiencing pain. In addition, their partners often indicated that they had experienced at least some anxiety regarding the administration of PIO. The most distinguishing difference between PVI and PIO in this study was the overall patient preference for PVI. Despite the need to administer PVI either twice a day or three times a day, 82.6% of the patients in the PVI group found it "very" or "somewhat convenient" compared with 44.9% of women in the PIO group. CONCLUSIONS: The results of this comprehensive, prospective patient survey, along with findings from other similar reports, suggest that PVI provides an easy-to-use and convenient method for providing the necessary luteal phase support for IVF cycles without the pain and inconvenience of daily IM PIO. Moreover, ongoing pregnancy rates with the well-tolerated PVI were as good as the pregnancy rates with PIO. TRIAL REGISTRATION: ClinicalTrial.gov, NCT00805935.

Predictive value of postwashed total progressively motile sperm count using CASA estimates in 6871 non-donor intrauterine insemination cycles.

PURPOSE: To determine whether postwashed total progressively motile sperm count (TPMSC) obtained by CASA estimates could predict positive pregnancy test result in non-donor IUI cycles. METHODS: Six thousand eight hundred and seventy one (6,871) IUI cycles with non-donor semen were retrospectively analyzed. Patient, cycle characteristics and prewashed and postwashed semen parameters were included in analysis. The main outcome measure was the positive pregnancy test result. RESULTS: The pregnancy rate per cycle (PR/cycle) when postwashed TPMSC is between 0-0.5 million, 0.51-1 million, 1.01-5 million, 5.01-10 million and greater than 10 million were 8.1% (42/520), 14.4 % (41/285), 16.1% (237/1,469), 18.4% (193/1,046) and 18.8% (668/3,551) respectively. The predicted odd of positive pregnancy result is statistically significantly higher when TPMSC is >0.51 million compared to the TPMSC of <0.51 million (OR = 1.68, 95% CI: 1.04-2.71). The predicted odd of positive pregnancy result is greatest when TPMSC is at least 5 million (OR = 2, 95% CI: 1.38 to 2.9). CONCLUSION: TPMSC is an independent predictor of pregnancy test result and TPMSC of half million or greater is adequate to achieve statistically similar pregnancy test results after non-donor IUI cycles.

Clinical comparison of ovarian stimulation and luteal support agents in patients undergoing GnRH antagonist IVF cycles.

OBJECTIVE: To explore the comparative efficacy, safety, and tolerability of agents used for ovarian stimulation and luteal support when applied in a population of women undergoing in vitro fertilization (IVF) using a gonadotropin-releasing hormone (GnRH) antagonist protocol. STUDY DESIGN: A phase 4, multicenter, randomized, open-label, exploratory clinical trial was performed at 7 assisted reproductive technology centers in the United States. Subjects included 173 women aged 18-42 years with a documented history of infertility who were undergoing IVF. Subjects were randomized to treatment with highly purified human menopausal gonadotropin (HP-hMG) or recombinant human follicle-stimulating hormone (rhFSH) for ovarian stimulation and progesterone vaginal inserts (PVIs) or intramuscular injection of progesterone in oil (PIO) for luteal support. Protocols for IVF followed the standard practices of participating centers within the parameters of the study. RESULTS: Biochemical, clinical, and ongoing pregnancy rates were the main outcome measures. Ongoing pregnancy rates for individual treatment groups ranged from 44.0-46.9%. No statistically significant differences were observed in pregnancy outcomes for the comparisons of HP-hMG vs. rhFSH or PVI vs. PIO. All study medications were generally safe and well tolerated. CONCLUSION: In this study HP-hMG and rhFSH were equally effective for ovarian stimulation during GnRH antagonist IVF cycles. Both PVI and PIO are viable options for luteal support.

The sensitivity and specificity of hyperglycosylated hCG (hhCG) levels to reliably diagnose clinical IVF pregnancies at 6 days following embryo transfer.

OBJECTIVE: To determine the sensitivity and specificity of hyperglycosylated hCG (hhCG) measurements for the diagnosis of clinical pregnancies in the IVF setting and how soon post embryo transfer (ET) a pregnancy can be detected using an ultrasensitive (hhCG) assay. To determine if a single, early hhCG measurement can discriminate between biochemical and clinical pregnancies. DESIGN: A 4 center prospective blinded clinical trial was performed with patients undergoing IVF-ET. Patients had blood drawn and submitted for hhCG analysis on the day of ET and at days 4, 6, 8, and 12 thereafter. First morning urines were collected and submitted for hhCG analysis on days 0, 4, 6, 8, 10 and 12. SETTING: Fertility Centers OUTCOME MEASURES: Clinical pregnancies were defined as an ultrasound study demonstrating a gestational sac and/or heart beat at appropriate gestational ages. RESULTS: Fifty-six of 58 enrolled patients completed the study. There were 25 clinical and 6 biochemical pregnancies. For blastocyst transfers, a single serum or urine hhCG measurement identified pregnancies (both biochemical and clinical) at 6 days post ET with 100% sensitivity and specificity. There were 6 biochemical pregnancies, all following blastocyst transfers. All of these pregnancies were identified by lower values.

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.

No association between endogenous LH and pregnancy in a GnRH antagonist protocol: part I, corifollitropin alfa.

The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 µg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25mg ganirelix from stimulation day 5. Patients were retrospectively stratified by serum LH percentiles (< 25th, 25th-75th and >75th) on stimulation day 8 and day of human chorionic gonadotrophin administration. Odds ratios (OR) with and without adjustment for predictive factors for ongoing pregnancy were estimated. LH concentration was not associated with pregnancy rates in either treatment arm, in contrast to ovarian response and serum progesterone. With adjustment for these predictors and age, OR (95% confidence interval) for ongoing pregnancy on stimulation day 8 for LH categories < P25 versus ≥ P25, >P75 versus ≤ P75 and < P25 versus >P75 were 0.75 (0.53-1.06), 1.26 (0.87-1.83) and 0.70 (0.46-1.09) in the corifollitropin alfa arm and 0.80 (0.54-1.17), 1.28 (0.87-1.87) and 0.73 (0.46-1.16) in the rFSH arm respectively. There was also no significant difference in pregnancy rates between LH categories on day of human chorionic gonadotrophin administration with either treatment.

Infertility Treatment Now and in the Future.

Treatment of infertility has evolved as understanding of reproduction has improved. Fertility promoting surgery still is performed and recent advances have broken new ground. Hormonal treatments to correct gonadal dysfunction have been developed, but multiple gestation continues to be a significant complication. Assisted reproductive technologies have improved such that in vitro fertilization and its variants increasingly are used to treat nearly all causes of infertility. Advances in assisted reproduction are of 2 types: (1) incremental optimization of existing techniques and (2) development of new, disruptive technologies. Artificial intelligence and stem cell technologies are poised to have impact in the near future.

Real-world experience with intravaginal culture using INVOCELL: an alternative model for infertility treatment.

OBJECTIVE: To describe the current practice indications, methodology, and outcomes from a real-world experience of intravaginal culture (IVC) using INVOCELL. DESIGN: A descriptive study outlining real-world experience with INVOCELL that addresses patient selection, ovarian stimulation, embryology laboratory practices, and outcomes. SETTING: Five fertility centers in Missouri, Texas, North Carolina, South Carolina, and Virginia. PATIENTS: Four hundred sixty-three patients undergoing 526 cycles. INTERVENTION: IVC using INVOCELL. MAIN OUTCOME MEASURES: Cumulative pregnancy rate and live births. Secondary outcomes of interest included percent good quality embryos. RESULTS: IVC with INVOCELL was primarily used in women <38 years with anti-Mullerian hormone level >0.8 ng/mL. The mean numbers of retrieved oocytes ranged from 9.2 to 16. Mean numbers of oocytes and sperm-injected oocytes loaded per INVOCELL ranged from a mean of 6.4-9.5 with a reported maximum of 34 oocytes loaded into the device. Most (95%) of the embryos were transferred on day 5. The mean blastocyst recovery per oocyte loaded into the device ranged from 19% to 34%; mean cumulative live birth plus ongoing pregnancy rates ranged from 29% to 53% per cycle start and 40% to 61% per transfer. CONCLUSIONS: This study of IVC using INVOCELL as an alternative model for infertility treatment confirms its utility as a viable alternative to standard incubator-based in vitro fertilization. The technology is compatible within the current framework of practice patterns and, when appropriately used, results in acceptable blastocyst recovery and live birth rates. Further use of INVOCELL in other clinical situations is warranted.

Natural vs. programmed cycles for frozen embryo transfer: study protocol for an investigator-initiated, randomized, controlled, multicenter clinical trial.

BACKGROUND: Randomized trials of assisted reproductive technology (ART) have been designed for outcomes of clinical pregnancy or live birth and have not been powered for obstetric outcomes such as preeclampsia, critical for maternal and fetal health. ART increasingly involves frozen embryo transfer (FET). Although there are advantages of FET, multiple studies have shown that risk of preeclampsia is increased with FET compared with fresh embryo transfer, and the reason for this difference is not clear. NatPro will compare the proportion of preeclampsia between two commonly used protocols for FET,modified natural and programmed cycle. METHODS: In this two-arm, parallel-group, multi-center randomized trial, NatPro will randomize 788 women to either modified natural or programmed FET and follow them for up to three FET cycles. Primary outcome will be the proportion of preeclampsia in women with a viable pregnancy assigned to a modified natural cycle FET (corpus luteum present) protocol compared to the proportion of preeclampsia in pregnant women assigned to a programmed FET (corpus luteum absent) protocol. Secondary outcomes will compare the proportion of live births and the proportion of preeclampsia with severe features between the protocols. CONCLUSION: This study has a potential significant impact on millions of women who pursue ART to build their families. NatPro is designed to provide clinically relevant guidance to inform patients and clinicians regarding maternal risk with programmed and modified natural cycle FET protocols. This study will also provide accurate point estimates regarding the likelihood of live birth with programmed and modified natural cycle FET. TRIAL REGISTRATION: ClinicalTrials.gov NCT04551807 . Registered on September 16, 2020.

Randomized, assessor-blinded trial comparing highly purified human menotropin and recombinant follicle-stimulating hormone in high responders undergoing intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the efficacy and safety of highly purified human menotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH) for controlled ovarian stimulation in a population of patients predicted to be high responders. DESIGN: Randomized, open-label, assessor-blinded, parallel-group, noninferiority trial. SETTING: Fertility centers. PATIENT(S): A total of 620 women with serum antimüllerian hormone (AMH) ≥5 ng/mL. INTERVENTION(S): Controlled ovarian stimulation with HP-hMG or rFSH in a GnRH antagonist assisted reproductive technology (ART) cycle. Fresh transfer of a single blastocyst was performed unless ovarian response was excessive, in which all embryos were cryopreserved. Subjects could undergo subsequent frozen blastocyst transfer within 6 months of randomization. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) after fresh transfer (primary endpoint), as well as cumulative live birth, ovarian hyperstimulation syndrome (OHSS), and pregnancy loss rates. RESULTS: OPR/cycle start after fresh transfer was 35.5% with HP-hMG and 30.7% with rFSH (difference: 4.7%, 95% CI -2.7%, 12.1%); noninferiority was established. Compared to rFSH, HP-hMG was associated with significantly lower OHSS (21.4% vs. 9.7% respectively; difference: -11.7%, 95% CI -17.3%, -6.1%) and cumulative early pregnancy loss rates (25.5% vs. 14.5% respectively; difference: -11.0%, 95% CI -18.8%, -3.14%). Despite 43 more transfers in the rFSH group, cumulative live birth rates were similar with HP-hMG and rFSH at 50.6% and 51.5% respectively (difference: -0.8%, 95% CI -8.7%, 7.1%). CONCLUSION(S): In high responders, HP-hMG provided comparable efficacy to rFSH with fewer adverse events, including pregnancy loss, suggesting its optimized risk/benefit profile in this population. CLINICAL TRIAL REGISTRATION NUMBER: NCT02554279 (clinicaltrials.gov).