Time to cancer treatment and reproductive outcomes after fertility preservation among adolescent and young adult women with cancer.

BACKGROUND: Fertility preservation (FP) may be underused after cancer diagnosis because of uncertainty around delays to cancer treatment and subsequent reproductive success. METHODS: Women aged 15 to 39 years diagnosed with cancer between 2004 and 2015 were identified from the North Carolina Central Cancer Registry. Use of assisted reproductive technology (ART) after cancer diagnosis between 2004 and 2018 (including FP) was assessed through linkage to the Society for Assisted Reproductive Technology. Linear regression was used to examine time to cancer treatment among women who did (n = 95) or did not (n = 469) use FP. Modified Poisson regression was used to estimate risk ratios (RRs) and 95% CIs for pregnancy and birth based on timing of ART initiation relative to cancer treatment (n = 18 initiated before treatment for FP vs n = 26 initiated after treatment without FP). RESULTS: The median time to cancer treatment was 9 to 33 days longer among women who used FP compared with women who did not, matched on clinical factors. Women who initiated ART before cancer treatment may be more likely to have a live birth given pregnancy compared with women who initiated ART after cancer treatment (age-adjusted RR, 1.47; 95% CI, 0.98-2.23), though this may be affected by the more frequent use of gestational carriers in the former group (47% vs 20% of transfer cycles, respectively). CONCLUSIONS: FP delayed gonadotoxic cancer treatment by up to 4.5 weeks, a delay that would not be expected to alter prognosis for many women. Further study of the use of gestational carriers in cancer populations is warranted to better understand its effect on reproductive outcomes.

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.

Vanquishing multiple pregnancy in in vitro fertilization in the United States-a 25-year endeavor.

The practice of in vitro fertilization has changed tremendously since the birth of the first in vitro fertilization infant in 1978. With the success of early in vitro fertilization programs in the United States, there was a substantial rise in twin births nationwide. In the mid-1990s, more than 30% of in vitro fertilization cycles resulted in twin or higher-order multifetal pregnancies. Since that time, we not only have witnessed improvements in laboratory and treatment efficacy but also have seen a dramatic impact on pregnancy outcomes, specifically regarding twin pregnancies. Because the field evolved and the risks of multifetal pregnancies became more salient, in 2019, the rate of twin pregnancies had dropped to <7% of cycles. This improvement was largely because of technical advancements and revised professional guidance: culturing embryos longer before transfer, improved freezing technology, embryo preimplantation genetic testing, and revised professional guidance regarding the number of embryos to transfer. These developments have led to single-embryo transfer becoming the standard of care in most scenarios. We used national in vitro fertilization surveillance data of all autologous in vitro fertilization cycles from 1996 to 2019 to illustrate trends in the following improved outcomes: autologous embryo transfer cycles involving blastocyst-stage embryos, vitrified embryos, preimplantation genetic testing cycles, total number of embryos being transferred per cycle, and single-embryo transfer usage over time. Among deliveries from autologous embryo transfers, we highlighted trends in singleton births over time and proportion of deliveries involving twins, triplets, quadruplets, or greater. The notable progress in reducing the rate of multifetal pregnancies with in vitro fertilization was largely attributed to a series of technical and clinical actions, culminating in an 80% reduction in the incidence of multiple births without a loss in overall treatment effectiveness.

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.

Status of racial disparities between black and white women undergoing assisted reproductive technology in the US.

BACKGROUND: Numerous studies have demonstrated substantial differences in assisted reproductive technology outcomes between black non-Hispanic and white non-Hispanic women. We sought to determine if disparities in assisted reproductive technology outcomes between cycles from black non-Hispanic and white non-Hispanic women have changed and to identify factors that may have influenced change and determine racial differences in cumulative live birth rates. METHODS: This is a retrospective cohort study of the SARTCORS database outcomes for 2014-2016 compared with those previously reported in 2004-2006 and 1999/2000. Patient demographics, etiology of infertility, and cycle outcomes were compared between black non-hispanic and white non-hispanic patients. Categorical values were compared using Chi-squared testing. Continuous variables were compared using t-test. Multiple logistic regression was used to assess confounders. RESULTS: We analyzed 122,721 autologous, fresh, non-donor embryo cycles from 2014 to 2016 of which 13,717 cycles from black and 109,004 cycles from white women. The proportion of cycles from black women increased from 6.5 to 8.4%. Cycles from black women were almost 3 times more likely to have tubal and/or uterine factor and body mass index ≥30 kg/m2. Multivariate logistic regression demonstrated that black women had a lower live birth rate (OR 0.71;P < 0.001) and a lower cumulative live birth rate for their initial cycle (OR 0.64; P < 0.001) independent of age, parity, body mass index, etiology of infertility, ovarian reserve, cycle cancellation, past spontaneous abortions, use of intra-cytoplasmic sperm injection or number of embryos transferred. A lower proportion of cycles in black women were represented among non-mandated states (P < 0.001) and cycles in black women were associated with higher clinical live birth rates in mandated states (P = 0.006). CONCLUSIONS: Disparities in assisted reproductive technology outcomes in the US have persisted for black women over the last 15 years. Limited access to state mandated insurance may be contributory. Race has continued to be an independent prognostic factor for live birth and cumulative live birth rate from assisted reproductive technology in the US.

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.

Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles.

BACKGROUND: Children born from fresh in vitro fertilization (IVF) cycles are at greater risk of being born smaller and earlier, even when limited to singletons; those born from frozen cycles have an increased risk of large-for-gestational age (LGA) birthweight (z-score ≥1.28). This analysis sought to overcome limitations in other studies by using pairs of siblings, and accounting for prior cycle outcomes, maternal characteristics, and embryo state and stage. METHODS: Pairs of singleton births conceived with IVF and born between 2004 and 2013 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database, matched for embryo stage (blastocyst versus non-blastocyst) and infant gender, categorized by embryo state (fresh versus frozen) in 1st and 2nd births (four groups). RESULTS: The data included 7795 singleton pairs. Birthweight z-scores were 0.00-0.04 and 0.24-0.26 in 1st and 2nd births in fresh cycles, and 0.25-0.34 and 0.50-0.55 in frozen cycles, respectively. LGA was 9.2-9.8 and 14.2-15.4% in 1st and 2nd births in fresh cycles, and 13.1-15.8 and 20.8-21.0% in 1st and 2nd births in frozen cycles. The risk of LGA was increased in frozen cycles (1st births, adjusted odds ratios (AOR) 1.74, 95% CI 1.45, 2.08; and in 2nd births when the 1st birth was not LGA, AOR 1.70, 95% CI 1.46, 1.98 for fresh/frozen and 1.40, 1.11, 1.78 for frozen/frozen). CONCLUSIONS: Our results with siblings indicate that frozen embryo state is associated with an increased risk for LGA. The implications of these findings for childhood health and risk of obesity are unclear, and warrant further investigation.

Cumulative birth rates with linked assisted reproductive technology cycles.

BACKGROUND: Live-birth rates after treatment with assisted reproductive technology have traditionally been reported on a per-cycle basis. For women receiving continued treatment, cumulative success rates are a more important measure. METHODS: We linked data from cycles of assisted reproductive technology in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for the period from 2004 through 2009 to individual women in order to estimate cumulative live-birth rates. Conservative estimates assumed that women who did not return for treatment would not have a live birth; optimal estimates assumed that these women would have live-birth rates similar to those for women continuing treatment. RESULTS: The data were from 246,740 women, with 471,208 cycles and 140,859 live births. Live-birth rates declined with increasing maternal age and increasing cycle number with autologous, but not donor, oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates with autologous oocytes had declined from 63.3% and 74.6%, respectively, for women younger than 31 years of age to 18.6% and 27.8% for those 41 or 42 years of age and to 6.6% and 11.3% for those 43 years of age or older. When donor oocytes were used, the rates were higher than 60% and 80%, respectively, for all ages. Rates were higher with blastocyst embryos (day of transfer, 5 or 6) than with cleavage embryos (day of transfer, 2 or 3). At the third cycle, the conservative and optimal estimates of cumulative live-birth rates were, respectively, 42.7% and 65.3% for transfer of cleavage embryos and 52.4% and 80.7% for transfer of blastocyst embryos when fresh autologous oocytes were used. CONCLUSIONS: Our results indicate that live-birth rates approaching natural fecundity can be achieved by means of assisted reproductive technology when there are favorable patient and embryo characteristics. Live-birth rates among older women are lower than those among younger women when autologous oocytes are used but are similar to the rates among young women when donor oocytes are used. (Funded by the National Institutes of Health and the Society for Assisted Reproductive Technology.).

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

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

Live birth rates and birth outcomes by diagnosis using linked cycles from the SART CORS database.

PURPOSE: This study uses linked cycles of assisted reproductive technology (ART) to examine cumulative live birth rates, birthweight, and length of gestation by diagnostic category. METHODS: We studied 145,660 women with 235,985 ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System during 2004-2010. ART cycles were linked to individual women by name, date of birth, social security number, partner's name, and sequence of ART treatments. The study population included the first four autologous oocyte cycles for women with a single diagnosis of male factor, endometriosis, ovulation disorders, diminished ovarian reserve, or unexplained infertility. Live birth rates were calculated per cycle, per cycle number (1-4), and cumulatively. Birthweight and length of gestation were calculated for singleton births. RESULTS: Within each diagnosis, live birth rates were highest in the first cycle and declined with successive cycles. Women with diminished ovarian reserve had the lowest live birth rate (cumulative rate of 28.3 %); the live birth rate for the other diagnoses were very similar (cumulative rates from 62.1 % to 65.7 %). Singleton birthweights and lengths of gestation did not differ substantially across diagnoses, ranging from 3,112 to 3,286 g and 265 to 270 days, respectively. These outcomes were comparable with national averages for singleton births in the United States (3,296 g and 271 days). CONCLUSION: Women with the diagnosis of diminished ovarian reserve had substantially lower live birth rates. However, singleton birthweights and lengths of gestation outcomes were similar across all other diagnoses.

Disparities in fertility preservation use among adolescent and young adult women with cancer.

PURPOSE: Women face multiple barriers to fertility preservation after cancer diagnosis, but few studies have examined disparities in use of these services. METHODS: Women aged 15-39 years diagnosed with cancer during 2004-2015 were identified from the North Carolina Central Cancer Registry and linked to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Women who cryopreserved oocytes or embryos for fertility preservation (n = 96) were compared to women who received gonadotoxic treatment but did not use fertility preservation (n = 7964). Conditional logistic and log-binomial regression were used to estimate odds ratios (ORs) or prevalence ratios (PRs) and 95% confidence intervals (CIs). RESULTS: Few adolescent and young adult women with cancer in our study (1.2%) used fertility preservation. In multivariable regression, women less likely to use fertility preservation were older at diagnosis (ages 25-29 vs. 35-39: OR = 6.27, 95% CI: 3.35, 11.73); non-Hispanic Black (vs. non-Hispanic White: PR = 0.44, 95% CI: 0.24, 0.79); and parous at diagnosis (vs. nulliparous: PR = 0.24, 95% CI: 0.13, 0.45); or lived in census tracts that were non-urban (vs. urban: PR = 0.12, 95% CI: 0.04, 0.37) or of lower socioeconomic status (quintiles 1-3 vs. quintiles 4 and 5: PR = 0.39, 95% CI: 0.25, 0.61). CONCLUSIONS: Women with cancer who were older, non-Hispanic Black, parous, or living in areas that were non-urban or of lower socioeconomic position were less likely to use fertility preservation. IMPLICATIONS FOR CANCER SURVIVORS: Clinical and policy interventions are needed to ensure equitable access to fertility services among women facing cancer treatment-related infertility.

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.

AMH Highly Correlates With Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve Independent of Age.

CONTEXT: Antimüllerian hormone (AMH) level is strongly associated with ovarian response in assisted reproductive technology (ART) cycles but is a poor predictor of live birth. It is unknown whether AMH is associated with cumulative live birth rates (CLBRs) in women with diminished ovarian reserve (DOR). OBJECTIVE: To examine the association between serum AMH and CLBR among women with DOR undergoing ART. METHODS: Retrospective analysis of Society for Assisted Reproductive Technology Clinic Outcome Reporting System database 2014-16. A total of 34 540 index retrieval cycles of women with AMH <1 ng/mL. The main outcome measure was cumulative live birth. RESULTS: A total of 34 540 (25.9%) cycles with AMH <1 ng/mL out of 133 442 autologous index retrieval cycles were analyzed. Cycles with preimplantation genetic testing or egg/embryo banking were excluded. Data were stratified according to AMH and, age and regression analysis of AMH and CLBR was performed for each age stratum. Multiple logistic regression demonstrated that AMH is an independent predictor of CLBR (odds ratio [OR] 1.39, 95% CI 1.18-1.64). Serum AMH was strongly associated with number of oocytes retrieved, embryos cryopreserved, mean number of cumulative embryos transferred, and percentage of cycles that had an embryo transfer. Linear regression analysis demonstrated that AMH highly correlated with CLBR in each age stratum. CONCLUSION: Serum AMH is highly correlated with CLBR in women with DOR independent of age. The addition of AMH to current age-based prognostication counseling particularly in women with DOR would provide more informative and personalized CLBR prediction prior to ART.

The Adolescent and Young Adult (AYA) Horizon Study: An AYA Cancer Survivorship Cohort.

BACKGROUND: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States. METHODS: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data. RESULTS: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall (N = 1,679), and notably lower among minority groups compared with non-Hispanic white women. CONCLUSIONS: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements. IMPACT: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.

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.