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.

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.

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.

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.

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.

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.

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.

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US.

Importance: Children with birth defects have a greater risk of developing cancer, but this association has not yet been evaluated in children conceived with in vitro fertilization (IVF). Objective: To assess whether the association between birth defects and cancer is greater in children conceived via IVF compared with children conceived naturally. Design, Setting, and Participants: This cohort study of live births, birth defects, and cancer from Massachusetts, New York, North Carolina, and Texas included 1 000 639 children born to fertile women and 52 776 children conceived via IVF (using autologous oocytes and fresh embryos) during 2004-2016 in Massachusetts and North Carolina, 2004-2015 in New York, and 2004-2013 in Texas. Children were followed up for an average of 5.7 years (6 008 985 total person-years of exposure). Data analysis was conducted from April 1 to August 31, 2020. Exposures: Conception by IVF for state residents who gave birth to liveborn singletons during the study period. Birth defect diagnoses recorded by statewide registries. Main Outcomes and Measures: Cancer diagnosis as recorded by state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for birth defect-cancer associations separately in fertile and IVF groups. Results: A total of 1 000 639 children (51.3% boys; 69.7% White; and 38.3% born between 2009-2012) were in the fertile group and 52 776 were in the IVF group (51.3% boys; 81.3% White; and 39.6% born between 2009-2012). Compared with children without birth defects, cancer risks were higher among children with a major birth defect in the fertile group (hazard ratio [HR], 3.15; 95% CI, 2.40-4.14) and IVF group (HR, 6.90; 95% CI, 3.73-12.74). The HR of cancer among children with a major nonchromosomal defect was 2.07 (95% CI, 1.47-2.91) among children in the fertile group and 4.04 (95% CI, 1.86-8.77) among children in the IVF group. The HR of cancer among children with a chromosomal defect was 15.45 (95% CI, 10.00-23.86) in the fertile group and 38.91 (95% CI, 15.56-97.33) in the IVF group. Conclusions and Relevance: This study found that among children with birth defects, those conceived via IVF were at greater risk of developing cancer compared with children conceived naturally.

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).

Third grade academic achievement among children conceived with the use of in vitro fertilization: a population-based study in Texas.

OBJECTIVE: To evaluate if there are differences in standardized testing results at the end of third grade between children conceived with the use of in vitro fertilization (IVF) and those conceived spontaneously. DESIGN: Retrospective population-based cohort. SETTING: Texas public school system. PATIENT(S): Singleton and twin children 8-9 years of age who took the third-grade public school standardized testing in Texas from 2012 to 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Standardized testing in reading and mathematics. RESULT(S): After exclusions, there were 6,970 IVF and 12,690 non-IVF children with reading scores and 6,973 IVF and 12,729 non-IVF children with mathematics scores. IVF children scored significantly higher in reading (singletons: 1,543 ± 2 vs. 1,525 ± 1; twins: 1,534 ± 2 vs. 1,504 ± 5 [mean ± SE]), and mathematics (singletons: 1,566 ± 2 vs. 1,550 ± 1; twins: 1,557 ± 2 vs. 1,529 ± 5). Children of mothers ≥30 years of age scored consistently higher than children of mothers 18-29 years of age. The differences were of similar magnitude between IVF and control children for older ages, but not significant for IVF. Within the IVF group, there were no significant differences between children born from fresh versus froze-thawed embryos. CONCLUSION(S): Children of ages 8-9 years who were conceived with the use of IVF performed as well on third-grade reading and math assessments as their counterparts who were conceived spontaneously. We also found consistent racial and ethnic differences, gender differences, and beneficial effects of older maternal age. Because we were not able to adjust adequately for socioeconomic status and other confounding factors, which may explain some of the observed differences, we conclude that there is no negative effect of IVF conception on academic achievement in third grade.

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.

National survey of the Society for Assisted Reproductive Technology membership regarding insurance coverage for assisted reproductive technologies.

OBJECTIVE: To assess the attitudes of Society for Assisted Reproductive Technology (SART) members regarding expanding insurance coverage for patients seeking assisted reproductive technologies (ART) and identify some of the factors that may influence such attitudes. DESIGN: An anonymous online 14-question survey of SART membership; 1,556 surveys were sent through the SART Research Portal from June to December 2017. Questions were incremental in scope, beginning with expanding insurance coverage for ART for vulnerable populations (e.g., fertility preservation for cancer, couples with same recessive gene, fertility preservation for transgender individuals) to extending coverage to include patients who were uninsured for ART. Additional questions assessed attitudes about assuming some fiscal responsibility if mandated insurance were contingent on elective single-embryo transfer (eSET) and lower charges in anticipation of increased number of cases. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Specific response to 14 survey questions. RESULT(S): The overall response rate was 43.4% (675/1,556). A large majority (>95%) favored insurance for fertility preservation for cancer patients and for avoidance of genetic disorders; 62.3% were supportive of infertility insurance coverage for transgender patients; 78% supported expanding insurance for the broadest segment of the general uninsured population; 76.7% supported expanding insurance contingent on eSET; and 51.3% would consider expanding insurance contingent on lowering charge per cycle in general, but only 23% responded as to what lower charge would be acceptable. Three of four factors were shown by multivariable logistic regression to be predictive of attitudes willing to expand insurance: practice setting (academic > hybrid > private), practicing in a mandated state, and higher annual volume of cases (>500 cycles); these had significant increased adjusted odds ratios ranging from 1.7 to 2.9. A fourth factor, the professional role one had in the practice, was not found to be of significant predictive value. CONCLUSION(S): The great majority of respondents were supportive of expanding insurance for specific segments of vulnerable populations with special needs and for the population who are presently uninsured. Furthermore, the majority of respondents would consider expanding insurance coverage contingent on age-appropriate eSET but have concerns about reduced reimbursement. Those most likely to be willing to expand insurance are those who practice in an academic setting or a mandated state and/or have a high annual volume of cases.