Geographic Access to Fertility Counseling among Adolescent and Young Adult Women with Cancer in North Carolina.

BACKGROUND: Fertility counseling is recommended for adolescent and young adult women facing gonadotoxic cancer therapy. However, fertility care is subspecialized medical care offered at a limited number of institutions, making geographic access a potential barrier to guideline-concordant care. We assessed the relationship between geographic access and receipt of fertility counseling among adolescent and young adult women with cancer. METHODS: Using data from the North Carolina Central Cancer Registry, we identified women diagnosed with lymphoma, gynecologic cancer, or breast cancer at ages 15 to 39 years during 2004 to 2015. Eligible women were invited to complete an online survey on various topics, including fertility counseling. Geographic access was measured, using geocoded addresses, as vehicular travel time from residence to the nearest fertility clinic available at diagnosis. Multivariable regression models were used to examine the association between travel time and receipt of fertility counseling by provider type: health care provider versus fertility specialist. RESULTS: Analyses included 380 women. The median travel time to a fertility clinic was 31 (IQR: 17-71) minutes. Overall, 75% received fertility counseling from a health care provider and 16% by a fertility specialist. Women who lived ≥30 minutes from a clinic were 13% less likely to receive fertility counseling by a health care provider (prevalence ratio: 0.87; 95% confidence interval, 0.75-1.00) and 49% less likely to receive counseling by a fertility specialist (prevalence ratio: 0.51; 95% confidence interval, 0.28-0.93). CONCLUSIONS: Women who lived further away from fertility clinics were less likely to receive fertility counseling. IMPACT: Interventions to improve access to fertility counseling should include strategies to alleviate the burden of geographic access.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer: potential etiologies and strategies for prevention.

PURPOSE: In the first of two companion papers, we comprehensively reviewed the recent evidence in the primary literature, which addressed the increased prevalence of hypertensive disorders of pregnancy, late-onset or term preeclampsia, fetal overgrowth, postterm birth, and placenta accreta in women conceiving by in vitro fertilization. The preponderance of evidence implicated frozen embryo transfer cycles and, specifically, those employing programmed endometrial preparations, in the higher risk for these adverse maternal and neonatal pregnancy outcomes. Based upon this critical appraisal of the primary literature, we formulate potential etiologies and suggest strategies for prevention in the second article. METHODS: Comprehensive review of primary literature. RESULTS: Presupposing significant overlap of these apparently diverse pathological pregnancy outcomes within subjects who conceive by programmed autologous FET cycles, shared etiologies may be at play. One plausible but clearly provocative explanation is that aberrant decidualization arising from suboptimal endometrial preparation causes greater than normal trophoblast invasion and myometrial spiral artery remodeling. Thus, overly robust placentation produces larger placentas and fetuses that, in turn, lead to overcrowding of villi within the confines of the uterine cavity which encroach upon intervillous spaces precipitating placental ischemia, oxidative and syncytiotrophoblast stress, and, ultimately, late-onset or term preeclampsia. The absence of circulating corpus luteal factors like relaxin in most programmed cycles might further compromise decidualization and exacerbate the maternal endothelial response to deleterious circulating placental products like soluble fms-like tyrosine kinase-1 that mediate disease manifestations. An alternative, but not mutually exclusive, determinant might be a thinner endometrium frequently associated with programmed endometrial preparations, which could conspire with dysregulated decidualization to elicit greater than normal trophoblast invasion and myometrial spiral artery remodeling. In extreme cases, placenta accreta could conceivably arise. Though lower uterine artery resistance and pulsatility indices observed during early pregnancy in programmed embryo transfer cycles are consistent with this initiating event, quantitative analyses of trophoblast invasion and myometrial spiral artery remodeling required to validate the hypothesis have not yet been conducted. CONCLUSIONS: Endometrial preparation that is not optimal, absent circulating corpus luteal factors, or a combination thereof are attractive etiologies; however, the requisite investigations to prove them have yet to be undertaken. Presuming that in ongoing RCTs, some or all adverse pregnancy outcomes associated with programmed autologous FET are circumvented or mitigated by employing natural or stimulated cycles instead, then for women who can conceive using these regimens, they would be preferable. For the 15% or so of women who require programmed FET, additional research as suggested in this review is needed to elucidate the responsible mechanisms and develop preventative strategies.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer.

PURPOSE: In this first of two companion papers, we critically review the evidence recently published in the primary literature, which addresses adverse maternal and neonatal pregnancy outcomes associated with programmed embryo transfer cycles. We next consider whether these pathological pregnancy outcomes might be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation. Finally, in the second companion article, we explore potential etiologies and suggest strategies for prevention. METHODS: Comprehensive review of primary literature. RESULTS: The preponderance of retrospective and prospective observational studies suggests that increased risk for hypertensive disorders of pregnancy (HDP) and preeclampsia in assisted reproduction involving autologous embryo transfer is associated with programmed cycles. For autologous frozen embryo transfer (FET) and singleton live births, the risk of developing HDP and preeclampsia, respectively, was less for true or modified natural and stimulated cycles relative to programmed cycles: OR 0.63 [95% CI (0.57-0.070)] and 0.44 [95% CI (0.40-0.50)]. Though data are limited, the classification of preeclampsia associated with programmed autologous FET was predominantly late-onset or term disease. Other adverse pregnancy outcomes associated with autologous FET, especially programmed cycles, included increased prevalence of large for gestational age infants and macrosomia, as well as higher birth weights. In one large registry study, FET was associated with fetal overgrowth of a symmetrical nature. Postterm birth and placenta accreta not associated with prior cesarean section, uterine surgery, or concurrent placenta previa were also associated with autologous FET, particularly programmed cycles. The heightened risk of these pathologic pregnancy outcomes in programmed autologous FET does not appear to be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation, although the latter may contribute a modest degree of increased risk for fetal overgrowth and perhaps HDP and preeclampsia in FET irrespective of the endometrial preparation. CONCLUSIONS: Programmed autologous FET is associated with an increased risk of several, seemingly diverse, pathologic pregnancy outcomes including HDP, preeclampsia, fetal overgrowth, postterm birth, and placenta accreta. Though the greater risk for preeclampsia specifically associated with programmed autologous FET appears to be well established, further research is needed to substantiate the limited data currently available suggesting that the classification of preeclampsia involved is predominately late-onset or term. If substantiated, then this knowledge could provide insight into placental pathogenesis, which has been proposed to differ between early- and late-onset or term preeclampsia (see companion paper for a discussion of potential mechanisms). If a higher prevalence of preeclampsia with severe features as suggested by some studies is corroborated in future investigations, then the danger to maternal and fetal/neonatal health is considerably greater with severe disease, thus increasing the urgency to find preventative measures. Presupposing significant overlap of these diverse pathologic pregnancy outcomes within subjects who conceive by programmed embryo transfer, there may be common etiologies.

Disparities in Fertility-Sparing Treatment and Use of Assisted Reproductive Technology After a Diagnosis of Cervical, Ovarian, or Endometrial Cancer.

OBJECTIVE: To assess the presence of sociodemographic and clinical disparities in fertility-sparing treatment and assisted reproductive technology (ART) use among patients with a history of cervical, endometrial, or ovarian cancer. METHODS: We conducted a population-based cohort study of patients aged 18-45 years who were diagnosed with cervical cancer (stage IA, IB), endometrial cancer (grade 1, stage IA, IB), or ovarian cancer (stage IA, IC) between January 1, 2000, and December 31, 2015, using linked data from the CCR (California Cancer Registry), the California Office of Statewide Health Planning and Development, and the Society for Assisted Reproductive Technology. The primary outcome was receipt of fertility-sparing treatment , defined as surgical or medical treatment to preserve the uterus and at least one ovary. The secondary outcome was fertility preservation , defined as ART use after cancer diagnosis. Multivariable logistic regression analysis was used to estimate odds ratios and 95% CIs for the association between fertility-sparing treatment and exposures of interest: age at diagnosis, race and ethnicity, health insurance, socioeconomic status, rurality, and parity. RESULTS: We identified 7,736 patients who were diagnosed with cervical, endometrial, or ovarian cancer with eligible histology. There were 850 (18.8%) fertility-sparing procedures among 4,521 cases of cervical cancer, 108 (7.2%) among 1,504 cases of endometrial cancer, and 741 (43.3%) among 1,711 cases of ovarian cancer. Analyses demonstrated nonuniform patterns of sociodemographic disparities by cancer type for fertility-sparing treatment, and ART. Fertility-sparing treatment was more likely among young patients, overall, and of those in racial and ethnic minority groups among survivors of cervical and ovarian cancer. Use of ART was low (n=52) and was associated with a non-Hispanic White race and ethnicity designation, being of younger age (18-35 years), and having private insurance. CONCLUSION: This study demonstrates that clinical and sociodemographic disparities exist in the receipt of fertility-sparing treatment and ART use among patients with a history of cervical, endometrial, or ovarian cancer.

Disparities in the use of assisted reproductive technologies after breast cancer: a population-based study.

PURPOSE: Equitable access to oncofertility services is a key component of cancer survivorship care, but factors affecting access and use remain understudied. METHODS: To describe disparities in assisted reproductive technology (ART) use among women with breast cancer in California, we conducted a population-based cohort study using linked oncology, ART, and demographic data. We identified women age 18-45 years diagnosed with invasive breast cancer between 2000 and 2015. The primary outcome was ART use-including oocyte/embryo cryopreservation or embryo transfer-after cancer diagnosis. We used log-binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) to identify factors associated with ART use. RESULTS: Among 36,468 women with invasive breast cancer, 206 (0.56%) used ART. Women significantly less likely to use ART were age 36-45 years at diagnosis (vs. 18-35 years: PR = 0.17, 95% CI 0.13-0.22); non-Hispanic Black or Hispanic (vs. non-Hispanic White: PR = 0.31, 95% CI 0.21-0.46); had at least one child (vs. no children: adjusted PR [aPR] = 0.39, 95% CI 0.25-0.60); or lived in non-urban areas (vs. urban: aPR = 0.28, 95% CI 0.10-0.75), whereas women more likely to use ART lived in high-SES areas (vs. low-/middle-SES areas: aPR = 2.93, 95% CI 2.04-4.20) or had private insurance (vs. public/other insurance: aPR = 2.95, 95% CI 1.59-5.49). CONCLUSION: Women with breast cancer who are socially or economically disadvantaged, or who already had a child, are substantially less likely to use ART after diagnosis. The implementation of policies or programs targeting more equitable access to fertility services for women with cancer is warranted.

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.

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.

Association between programmed frozen embryo transfer and hypertensive disorders of pregnancy.

Dissociation of embryo transfer from the ovarian stimulation cycle has afforded patients increased flexibility for genetic testing and fertility preservation. Although frozen embryo transfer (FET) has largely been demonstrated to be safe and effective compared with fresh transfer, programmed FET cycles, where a corpus luteum is absent, have come under increasing scrutiny. In observational trials, programmed FET protocols appear to be associated with an increased risk of ineffective decidualization and impaired placental function. Together with the appropriate preexisting risk factors, this additive risk may potentiate hypertensive disorders of pregnancy later in gestation. Efforts to understand the reasons for this apparent risk may afford us opportunities to better individualize the FET cycle type offered to patients with cryopreserved embryos. Randomized controlled trials will help us to understand whether the apparent risk is due to patient factors, which influence protocol choice, or a characteristic of the protocol itself, such as the absence of the corpus luteum or suboptimal replacement of estradiol and progesterone.

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.

Survival outcomes following pregnancy or assisted reproductive technologies after breast cancer: A population-based study.

BACKGROUND: This study sought to determine the impact of pregnancy or assisted reproductive technologies (ART) on breast-cancer-specific survival among breast cancer survivors. METHODS: The authors performed a cohort study using a novel data linkage from the California Cancer Registry, the California birth cohort, and the Society for Assisted Reproductive Technology Clinic Outcome Reporting System data sets. They performed risk-set matching in women with stages I-III breast cancer diagnosed between 2000 and 2012. For each pregnant woman, comparable women who were not pregnant at that point but were otherwise similar based on observed characteristics were matched at the time of pregnancy. After matching, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of pregnancy with breast-cancer-specific survival. We repeated these analyses for women who received ART. RESULTS: Among 30,021 women with breast cancer, 553 had a pregnancy and 189 attempted at least one cycle of ART. In Cox proportional hazards modeling, the pregnancy group had a higher 5-year disease-specific survival rate; 95.6% in the pregnancy group and 90.6% in the nonpregnant group (HR, 0.43; 95% CI, 0.24-0.77). In women with hormone receptor-positive cancer, we found similar results (HR, 0.43; 95% CI, 0.2-0.91). In the ART analysis, there was no difference in survival between groups; the 5-year disease-specific survival rate was 96.9% in the ART group and 94.1% in the non-ART group (HR, 0.44; 95% CI, 0.17-1.13). CONCLUSION: Pregnancy and ART are not associated with worse survival in women with breast cancer. LAY SUMMARY: We sought to determine the impact of pregnancy or assisted reproductive technologies (ART) among breast cancer survivors. We performed a study of 30,021 women by linking available data from California and the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. For each pregnant woman, we matched at the time of pregnancy comparable women who were not pregnant at that point but were otherwise similar based on observed characteristics. We repeated these analyses for women who received ART. We found that pregnancy and ART were not associated with worse survival.

Polycystic ovary syndrome: a "risk-enhancing" factor for cardiovascular disease.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is hallmarked by hyperandrogenism, oligo-ovulation, and polycystic ovarian morphology. Polycystic ovary syndrome, particularly the hyperandrogenism phenotype, is associated with several cardiometabolic abnormalities, including obesity, dyslipidemia, elevated blood pressure, and prediabetes or type 2 diabetes. Many, but not all, studies have suggested that PCOS is associated with increased risk of cardiovascular disease (CVD), including coronary heart disease and stroke, independent of body mass index and traditional risk factors. Interpretation of the data from these observational studies is limited by the varying definitions and ascertainment of PCOS and CVD across studies. Recent Mendelian randomization studies have challenged the causality of PCOS with coronary heart disease and stroke. Future longitudinal studies with clearly defined PCOS criteria and newer genetic methodologies may help to determine association and causality. Nevertheless, CVD risk screening remains critical in this patient population, as improvements in metabolic profile and reduction in CVD risk are achievable with a combination of lifestyle management and pharmacotherapy. Statin therapy should be implemented in women with PCOS who have elevated atherosclerotic CVD risk. If CVD risk is uncertain, measurement of subclinical atherosclerosis (carotid plaque or coronary artery calcium) may be a useful tool to guide shared decision-making about initiation of statin therapy. Other medications, such as metformin and glucagon-like peptide-1 receptor agonists, also may be useful in reducing CVD risk in insulin-resistant populations. Additional research is needed to determine the best pathways to mitigate PCOS-associated CVD risk.

Embryo biopsy and perinatal outcomes of singleton pregnancies: an analysis of 16,246 frozen embryo transfer cycles reported in the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System.

BACKGROUND: Preimplantation genetic testing is commonly performed by removing cells from the trophectoderm, the outer layer of the blastocyst, which subsequently forms the placenta. Because preimplantation genetic testing removes the cells that are destined to form the placenta, it is possible that preimplantation genetic testing could be associated with an increased risk for adverse outcomes associated with abnormal placentation. Despite the increasing utilization of preimplantation genetic testing, few studies have investigated the perinatal outcomes, with published studies yielding contradictory findings and using small sample sizes. OBJECTIVE: This study aimed to compare the perinatal outcomes of singleton pregnancies conceived following frozen embryo transfer of a single, autologous blastocyst either with or without preimplantation genetic testing. STUDY DESIGN: This was a retrospective analysis of autologous frozen embryo transfer cycles that led to singleton live births per the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System, including cycles initiated between 2014 and 2015. The perinatal outcomes, including birthweight, Z-score, small for gestational age, large for gestational age, macrosomia, and preterm birth, were compared between pregnancies with or without preimplantation genetic testing. We conducted multivariable linear regression analyses for the birthweight and Z-score and logistic regression for the binary outcomes. A false discovery rate was adjusted to decrease the type I error from multiple hypothesis testing. RESULTS: Of the 16,246 frozen embryo transfers resulting in singleton births included in this analysis, 6244 involved the transfer of a single blastocyst that had undergone preimplantation genetic testing, and the remainder (n=10,002) involved the transfer of a single blastocyst that had not undergone a biopsy. When compared with the women from the nonpreimplantation genetic testing group, the average maternal age (35.8±4.1 vs 33.7±3.9; P<.001) and prevalence of prior spontaneous abortion (37.3% vs 27.7%; P<.001) were higher among women from the preimplantation genetic testing group. Bivariate analysis revealed a higher prevalence of small-for-gestational-age newborns (4.8% vs 4.0%; P=.008) and premature delivery (14.1% vs 12.5%; P=.005) and a lower prevalence of large-for-gestational-age newborns (16.3% vs 18.2%; P=.003) and macrosomia (11.1% vs 12.4%; P=.013) among the preimplantation genetic testing pregnancies. Multivariate regression analyses, adjusting for the year of transfer, maternal age, maternal body mass index, smoking status (3 months before the treatment cycle), obstetrical histories (full-term birth, preterm birth, and spontaneous abortion), infertility diagnosis, and infant sex suggested a significantly increased odds of preterm birth (adjusted odds ratio, 1.20; 95% confidence interval, 1.09-1.33; P<.001) from preimplantation genetic testing blastocysts. Birthweight (-14.63; 95% confidence interval, -29.65 to 0.38; P=.056), birthweight Z-score (-0.03; 95% confidence interval, -0.06 to 0.00; P=.081), and odds of small-for-gestational-age newborns (adjusted odds ratio, 1.17; 95% confidence interval, 0.99-1.38; P=.066), large-for-gestational-age newborns (adjusted odds ratio, 0.96; 95% confidence interval, 0.88-1.06; P=.418), and macrosomia (adjusted odds ratio, 0.96; 95% confidence interval, 0.85-1.07; P=.427) did not differ between the frozen transfer cycles with or without preimplantation genetic testing in the analysis adjusted for the confounders. Subgroup analysis of the cycles with a stated infertility diagnosis (n=14,285) yielded consistent results. CONCLUSION: Compared with frozen embryo transfer cycles without preimplantation genetic testing, the frozen embryo transfer cycles with preimplantation genetic testing was associated with a small increase in the likelihood of preterm birth. Although the increase in the risk for prematurity was modest in magnitude, further investigation is warranted.

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.

Determinants of Maternal Renin-Angiotensin-Aldosterone-System Activation in Early Pregnancy: Insights From 2 Cohorts.

CONTEXT: The corpus luteum (CL) secretes prorenin, renin's inactive precursor. It may thus contribute to the renin-angiotensin-aldosterone-system (RAAS) activation that is required for maternal adaptation in pregnancy. Whether this activation is disturbed in pregnancies lacking a CL is unknown. OBJECTIVE: The objective of this work is to investigate maternal RAAS determinants in early pregnancy. DESIGN AND SETTING: Two observational prospective cohort studies. TOOK PLACE AT: 2 tertiary referral hospitals. PATIENTS AND INTERVENTION(S): Pregnancies (n = 277) were stratified by CL number and in vitro fertilization (IVF) protocol: 0 CL (programmed cycle frozen embryo transfer [FET], n = 28), 1 CL (natural cycle FET, n = 41 and spontaneous conceptions, n = 139), and more than 1 CL (ovarian stimulation and fresh embryo transfer, n = 69). METHODS: Quantification was performed for maternal prorenin, renin, and aldosterone blood levels at 5, 9, and 11 weeks of gestation. RESULTS: Prorenin and renin were lower in the absence of a CL at all time points when compared to 1 CL, whereas prorenin, renin, and aldosterone were higher in the presence of more than 1 CL vs 1 CL (P < .05). Ovarian stimulation with menopausal gonadotropin resulted in higher prorenin, renin, and aldosterone concentrations during the late first trimester than recombinant follicle-stimulating hormone (P < .05). Prorenin, and to a lesser degree renin, correlated positively with serum progesterone and relaxin, but not serum estradiol. Total follicle diameter, body mass index (BMI), polycystic ovary syndrome (PCOS), and antimüllerian hormone (AMH) were additional determinants of circulating prorenin. Finally, pregnancies conceived in the absence of a CL were more disposed to develop preeclampsia. CONCLUSIONS: CL number, IVF protocol, BMI, PCOS, and AMH affect maternal RAAS activation in early pregnancy, and may thus contribute to pregnancy complications.

Increased risk of severe maternal morbidity among infertile women: analysis of US claims data.

BACKGROUND: Severe maternal morbidity continues to be an issue of national and global concern and is increasing in incidence. The incidence of infertility is also on the rise, and infertile women experience a higher risk of incident chronic medical disease and cancer, suggesting that fertility may serve as a window to a woman's overall health. OBJECTIVE: To investigate the risk of severe maternal morbidity by maternal fertility status. MATERIALS AND METHODS: This was a retrospective cohort analysis using Optum's de-identifed Clinformatics Data Mart Database between 2003 and 2015. Infertile women stratified by infertility diagnosis, testing, or treatment were compared to fertile women seeking routine gynecologic care. In both groups, only women who underwent pregnancy and delivery of a singleton during the follow-up period were included. Main outcomes were severe maternal morbidity indicators, defined by the Centers for Disease Control and Prevention and identified by International Classification of Diseases 10th Revision and Common Procedural Technology codes within 6 weeks of each delivery. Results were adjusted for maternal age, race, education, nulliparity, smoking, obesity, delivery mode, preterm birth, number of prenatal visits, and year of delivery. RESULTS: A total of 19,658 women comprised the infertile group and 525,695 women comprised the fertile group. The overall incidence of any severe maternal morbidity indicator was 7.0% among women receiving fertility treatment, 6.4% among women receiving a fertility diagnosis, 5.5% among women receiving fertility testing, and 4.3% among fertile women. Overall, infertile women had a significantly higher risk of developing any severe maternal morbidity indicator (adjusted odds ratio, 1.22; confidence interval, 1.14-1.31, P < .01) as well as a significantly higher risk of disseminated intravascular coagulation (adjusted odds ratio, 1.48; confidence interval, 1.26-1.73, P < .01), eclampsia (adjusted odds ratio, 1.37; confidence interval, 1.05-1.79, P < .01), heart failure during procedure or surgery (adjusted odds ratio, 1.54; confidence interval, 1.21-1.97, P < .01), internal injuries of the thorax, abdomen, or pelvis (adjusted odds ratio, 1.59; confidence interval, 1.12-2.26, P < .01), intracranial injuries (adjusted odds ratio, 1.77; confidence interval, 1.20-2.61, P < .01), pulmonary edema (adjusted odds ratio, 2.18; confidence interval, 1.54-3.10, P < .01), thrombotic embolism (adjusted odds ratio, 1.58; confidence interval, 1.14-2.17, P < .01), and blood transfusion (adjusted odds ratio, 1.50; confidence interval, 1.30-1.72, P < .01) compared to fertile women. Fertile women did not face a significantly higher risk of any maternal morbidity indicator compared to infertile women. In subgroup analysis by maternal race/ethnicity, the likelihood of severe morbidity was significantly higher among fertile black women compared to fertile white women. There was no difference between infertile black women and infertile white women after multivariable adjustment. CONCLUSION: Using an insurance claims database, we report that women diagnosed with infertility and women receiving fertility treatment experience a significantly higher risk of multiple indicators of severe maternal morbidity compared to fertile women. The increased risk of severe maternal morbidity noted among fertile black women compared to fertile white women is attenuated among infertile black women, who face risks similar to those of infertile white women.

Maternal and neonatal outcomes associated with trophectoderm biopsy.

OBJECTIVE: To assess whether pregnancies achieved with trophectoderm biopsy for preimplantation genetic testing (PGT) have different risks of adverse obstetric and neonatal outcomes compared with pregnancies achieved with IVF without biopsy. DESIGN: Observational cohort. SETTING: University-affiliated fertility center. PATIENT(S): Pregnancies achieved via IVF with PGT (n = 177) and IVF without PGT (n = 180) that resulted in a live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Maternal outcomes including preeclampsia and placenta previa and neonatal outcomes including birth weight and birth defects. RESULT(S): There was a statistically significant increase in the risk of preeclampsia among IVF+PGT pregnancies compared with IVF without PGT pregnancies, with an incidence of 10.5% versus 4.1% (adjusted odds ratio [aOR] = 3.02; 95% confidence interval [95% CI], 1.10, 8.29). The incidence of placenta previa was 5.8% in IVF+PGT pregnancies versus 1.4% in IVF without PGT pregnancies (aOR = 4.56; 95% CI, 0.93, 22.44). Similar incidences of gestational diabetes, preterm premature rupture of membranes, and postpartum hemorrhage were observed. IVF+PGT and IVF without PGT neonates did not have a significantly different gestational age at delivery or rate of preterm birth, low birth weight, neonatal intensive care unit admission, neonatal morbidities, or birth defects. All trends, including the significantly increased risk of preeclampsia in IVF+PGT pregnancies, persisted upon stratification of analysis to only singleton live births. CONCLUSION(S): To date, this is the largest and most extensively controlled study examining maternal and neonatal outcomes after trophectoderm biopsy. There was a statistically significant three-fold increase in the odds of preeclampsia associated with trophectoderm biopsy. Given the rise in PGT use, further investigation is warranted.

Risk of cancer in infertile women: analysis of US claims data.

STUDY QUESTION: Is female infertility associated with higher risk of cancer? SUMMARY ANSWER: Although absolute risks are low, infertility is associated with higher risk of cancer compared to a group of non-infertile women. WHAT IS KNOWN ALREADY: Infertile women are at higher risk of hormone-sensitive cancers. Information on risk of non-gynecologic cancers is rare and conflicting, and the effect of pregnancy on these risk associations is known for only a minority of cancer types. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis between 2003 and 2016 using an insurance claims database. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 64 345 infertile women identified by infertility diagnosis, testing or treatment were compared to 3 128 345 non-infertile patients seeking routine gynecologic care. Women with prior diagnosis of cancer or within 6 months of index event were excluded. Main outcomes were development of any malignancy and individual cancers as identified by ICD-9/ICD-10 codes. Results were adjusted for age at index date, index year, nulliparity, race, smoking, obesity, number of visits per year and highest level of education. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile women had an overall higher risk of developing cancer compared to non-infertile women (2.0 versus 1.7%, adjusted hazard ratio (aHR) = 1.18; CI: 1.12-1.24). In addition, the risk of uterine cancer (0.10 versus 0.06%, aHR = 1.78; CI: 1.39-2.28), ovarian cancer (0.14 versus 0.09%, aHR 1.64; CI: 1.33-2.01), lung cancer (0.21 versus 0.21%, aHR = 1.38; CI: 1.01-1.88), thyroid cancer (0.21 versus 0.16%, aHR = 1.29; CI: 1.09-1.53), leukemia (0.10 versus 0.06%, aHR = 1.55; CI: 1.21-1.98) and liver and gallbladder cancer (0.05 versus 0.03%, aHR = 1.59; CI: 1.11-2.30) were higher in infertile women compared to non-infertile women. In a subgroup analysis of women in each cohort who became pregnant and had a delivery during enrollment, the risk of uterine and ovarian cancer were similar between infertile and non-infertile women. In a subgroup analysis excluding women with PCOS and endometriosis from both cohorts, the risk of uterine cancer was similar between infertile and non-infertile women. LIMITATIONS, REASONS FOR CAUTION: Absolute risk of cancer was low, average follow up for each individual was limited, and average age at index date was limited. Insurance databases have known limitations. WIDER IMPLICATIONS OF THE FINDINGS: Using claims-based data, we report that infertile women may have a higher risk of certain cancers in the years after infertility evaluation; continued follow up should be considered after reproductive goals are achieved. STUDY FUNDING/COMPETING INTEREST(S): None.

Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data.

BACKGROUND: The risk of common chronic medical conditions among infertile women is not known. OBJECTIVE: The objective of the study was to study the association between female infertility and the risk of incident chronic disease. STUDY DESIGN: This was a retrospective cohort analysis using the Optum deidentified Clinformatics Datamart from 2003 through 2016. A total of 64,345 infertile women were identified by infertility diagnosis, testing, or treatment and compared with 3,128,345 noninfertile patients seeking routine gynecologic care. Women with a prior diagnosis of the relevant chronic disease or cancer or with either diagnosis within 6 months of the index event were excluded. The main outcome was a diagnosis of incident chronic disease as identified by International Classification of Diseases, ninth revision/International Classification of Diseases, 10th revision codes. Results were adjusted for age, index year, nulliparity, race, smoking, obesity, number of visits per year, and highest level of education. RESULTS: Infertile patients were more likely to develop diabetes (adjusted hazard risk, 1.44, confidence interval, 1.38-1.49), renal disease (adjusted hazard risk, 1.22, confidence interval, 1.12-1.32), liver disease (adjusted hazard risk, 1.25, confidence interval, 1.20-1.30), cerebrovascular disease (adjusted hazard risk, 1.26, confidence interval, 1.15-1.38), ischemic heart disease (adjusted hazard risk, 1.16, confidence interval, 1.09-1.24), other heart disease (adjusted hazard risk, 1.16, confidence interval, 1.12-1.20), and drug abuse (adjusted hazard risk, 1.24, confidence interval, 1.15-1.33) compared with noninfertile patients. Infertile patients were significantly less likely to develop alcohol abuse (adjusted hazard risk, 0.86, confidence interval, 0.79-0.95) compared with noninfertile patients. Risk associations were similar after excluding women with polycystic ovarian syndrome and premature ovarian insufficiency. In subgroup analyses of women who underwent pregnancy and childbirth during enrollment, several previously noted risk associations were attenuated compared with the overall cohort. CONCLUSION: While the absolute risk of chronic disease is low, infertility is associated with an increased risk of incident chronic disease compared with a group of noninfertile women.

Practice patterns, satisfaction, and demographics of reproductive endocrinologists: results of the 2014 Society for Reproductive Endocrinology and Infertility Workforce Survey.

OBJECTIVE: To identify the current and future state of the practice of reproductive medicine. DESIGN: Cross-sectional survey. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The survey included 57 questions designed to assess practice patterns/metrics and professional satisfaction and morale. RESULT(S): A total of 336/1,100 (31%) responded, and they were 38% women, 61% men, and 76% Caucasian, with a mean age of 54. Respondents averaged 2.3 jobs and averaged 53 hours of work per week: 44% work in academia and 50% in private groups. Average practice size was 5.5, with an average of 470 fresh IVF cycles performed per year. Percent effort included 63% infertility, 10% endocrinology, 10% surgery, and 9% research. Respondents performed an average of 13 major surgeries, 69 minor surgeries, and 128 oocyte retrievals per year. A total of 60% were salaried, and 40% were equity partners. Compensation was highly skewed. Greater than 84% had a positive morale and had a positive view of the future, and 92% would again choose REI as a career. The most satisfying areas of employment were patient interactions, intellectual stimulation, interactions with colleagues, and work schedule. The least satisfying areas were work schedule and financial compensation. Training was felt to be too focused on female factor infertility and basic research with insufficient training on embryology, genetics, male factor infertility, and clinical research. In the next 5 years, 57% suggested that the need for specialists would stay the same, while 20% predicted a decrease. A total of 58% felt we are training the correct number of fellows (37% felt we are training a surplus). Compared with academia, those in private practice reported higher compensation, less major surgery, more IVF, less endocrinology, and less research. Men worked more hours, conducted more surgery and IVF cycles, and had higher compensation than women. Morale was similar across age, gender, practice type, and geography. CONCLUSION(S): Our subspecialty has an extremely high morale. We are a middle-aged subspecialty with disparate compensation and a focused practice. Some respondents sense a need for a change in our training, and most anticipate only mild growth in our field.