Racial Disparities in Fertility Care: A Narrative Review of Challenges in the Utilization of Fertility Preservation and ART in Minority Populations.

Significant ethnic and racial disparities exist in the utilization and outcomes of assisted reproductive technology (ART) in the United States. The popularity of fertility preservation (FP) procedures, a specific application of ART for those desiring to delay childbearing, has increased; however, many minority populations have seen a less rapid uptake of these services. Minority patients pursuing ART are more likely to have poorer in vitro fertilization (IVF) and pregnancy outcomes. These outcomes are used to predict success after FP and may lessen the appeal of such procedures in these populations. Suboptimal outcomes are further compounded by challenges with receiving referrals to, accessing, and paying for FP services. Resolving these disparities in minority populations will require culturally appropriate education surrounding the benefits of ART and FP, the demonstration of favorable outcomes in ART and FP through continued research engaging minority participants, and continued advocacy for expanded access to care for patients.

The Status of Fertility Preservation (FP) Insurance Mandates and Their Impact on Utilization and Access to Care.

Fertility preservation (FP) is the use of a specific medical intervention to protect the fertility of individuals whose disease or disease treatment may lead to infertility. These medical interventions include the cryopreservation of oocytes, embryos, ovarian tissue, sperm, and testicular tissue; oocyte and embryo cryopreservation are the most widely used interventions in the United States. Although guidelines recommend FP prior to undergoing gonadotoxic treatments, cost barriers are high. For example, the average cost of an oocyte cryopreservation cycle in the United States exceeds $10,000. High cost and lack of insurance coverage are two of the most cited reasons explaining the low Reproductive Endocrinology and Infertility (REI) referral rates and limited FP utilization. Broadening insurance mandates for FP prior to gonadotoxic treatments could improve utilization and provide cancer survivors with improved quality of life post treatment.

Survey of young women with breast cancer to identify rates of fertility preservation (FP) discussion and barriers to FP care.

PURPOSE: To identify the proportion of reproductive age women with breast cancer that engaged in a fertility preservation discussion and reproductive endocrinology and infertility (REI) consultation. METHODS: This cross-sectional survey recruited women 18-42 years who were diagnosed with breast cancer from 2006 to 2016 by phone or email and asked them to complete an online survey. Demographic characteristics, barriers to FP, utilization of FP consultation, and FP procedures (oocyte and embryo cryopreservation) were analyzed. RESULTS: A majority of women (64%) did not have FP discussed by any provider. Older women and those who were parents at the time of diagnosis were less likely to engage in a FP discussion. However, there were no significant differences in partner status or cancer stage between women with or without FP discussions. Of the women who desired future children prior to the cancer diagnosis, 93% received chemotherapy; however, only 34% of these women had a consultation with an REI. The most common reasons for declining FP consultation were already having their desired number of children (41%), financial barriers (14%), and concern about delaying cancer treatment and cancer recurrence (12%). Forty percent of women who desired future children and met with an REI pursued FP procedures. CONCLUSION: Younger women were more likely to receive FP counseling. FP consultations and procedures were low even in women who desired future fertility, with the predominant barriers being cost, fears concerning a delay in cancer treatment, and future cancer recurrence.

Fluoroscopically-Guided Hysteroscopic Tubal Cannulation: A Procedure for Proximal Tubal Obstruction.

Objectives: To evaluate the cannulation success rate, cumulative pregnancy, and time to intrauterine pregnancy rate following fluoroscopically-guided hysteroscopic tubal cannulation (FHTC) for infertile subjects with proximal tubal obstruction. Methods: This retrospective study evaluated subjects with unilateral or bilateral proximal tubal obstruction on hysterosalpingography, who failed concomitant selective salpingography and subsequently underwent FHTC at the time of a hysteroscopy performed for findings seen on sonohysterography. FHTC employed a Novy Catheter (CooperSurgical, Inc, Trumbull, CT.) with or without the 3 French inner catheter and guidewire, to cannulate the occluded fallopian tube(s), followed by the injection of HypaqueTM (Amersham Health, Inc, Princeton, NJ.) contrast under C-arm imaging. Technical success rates, complications, post-procedure pregnancies, and average time from surgery to pregnancy were evaluated. Results: Thirty-two women between January 1, 2017 and December 31, 2019 met the entry criteria and underwent FHTC. Of those women with bilateral obstruction, 6/6 (100%) of subjects achieved at least unilateral patency, while patency was achieved in 23/26 (88.5%) subjects with unilateral obstruction. Twenty-nine of 32 (90.6%) subjects had at least one tube successfully cannulated with 34/38 (89.5%) of proximally obstructed tubes opened. Asymptomatic tubal perforation occurred in 1/38 tubes (2.6%). Ten subjects (34.5%) achieved intrauterine pregnancies without in vitro fertilization in an average of 64.9 days from the procedure. There were no multiple pregnancies and one ectopic pregnancy. Conclusions: FHTC is a safe, effective, incision free procedure that results in 90% of tubes successfully cannulated, and an observed short time to intrauterine pregnancy.

Fertility Treatments and Breast Cancer: A Significant Risk for Our Patients?

Fertility medications have been postulated to increase the risk of breast cancer because of the transient but substantial elevation in hormones occurring with their use. Multiple studies exploring the relationship between fertility medications and risk of breast cancer are limited by the wide variety of fertility treatment regimens and confounded by infertility as an independent risk factor for breast cancer. The Practice Committee Guidelines of the American Society of Reproductive Medicine acknowledge that although this relationship is complex, no additional risk of breast cancer has been consistently linked to infertility medications. This article reviews the major studies both supporting and refuting this statement and makes recommendations regarding risk counseling and breast cancer screening in patients with a history of fertility treatments and infertility.

Society for Assisted Reproductive Technology advertising guidelines: How likely are member clinics to maintain compliance after resolving their violations?

OBJECTIVE: To evaluate the Society for Assisted Reproductive Technology (SART) member in vitro fertilization centers' compliance with SART's advertising guidelines after delayed correction of previous violations. DESIGN: Retrospective cohort study. SETTING: Internet. PATIENTS: None. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinics that were cited for noncompliance with SART advertising guidelines in 2019 and exceeded the two-week grace period in correcting their violations were studied. These clinics were rereviewed in 2020, at least 6 months after their initial citation, for violations of SART advertising guidelines in all six categories: supplemental data noncompliance, link to SART Clinical Summary Report and disclaimer statement missing, unsubstantiated claims, statements denigrating other clinics, and claims of superiority. RESULTS: In 2019, 44 (27%) of 161 of clinics reviewed by the SART advertising committee had at least one violation that was eventually resolved but not within the two-week grace period. On rereview in 2020, one clinic had not renewed its SART membership and 10 (23%) of the remaining 43 clinics were noted to have violations at the subsequent review. Improper presentation of supplemental data was the most common violation category in both the initial review, 32 (73%) of 44 clinics, and on rereview, 7 (70%) of 10 clinics cited a second time for violations. CONCLUSIONS: Of the in vitro fertilization clinics with previous violations with delayed correction in 2019, 77% were subsequently compliant when reevaluated in 2020, indicating that advertising committee disciplinary and educational measures were largely effective. The most common citation for both years was maintaining consistent and transparent supplemental data on their websites.

Do endometrial natural killer and regulatory T cells differ in infertile and clinical pregnancy patients? An analysis in patients undergoing frozen embryo transfer cycles.

PROBLEM: Clinical significance of endometrial and peripheral blood natural killer (NK) and regulatory T cells (Tregs) during frozen embryo transfer (FET) cycles has not been well characterized. DESIGN: Retrospective cohort study. METHOD OF STUDY: Endometrial tissue was collected from infertility patients prior to a frozen embryo transfer cycle as part of an endometrial receptivity analysis (ERA® ) biopsy or endometrial scratch test. Uterine NK (uNK) and Treg cell density was compared based on pregnancy status in the subsequent frozen embryo transfer cycle. Peripheral blood was also collected from a separate cohort of patients undergoing frozen embryo transfer. Treg cell density was compared by the presence or the absence of a clinical pregnancy in each phase of the cycle. RESULTS: In the 33 luteal phase biopsies there were more endometrial Tregs, similar uNK and a trend toward lower CD16+ uNK cells in women with a future ongoing clinical pregnancy compared to non-pregnant women. There were no differences in uNK and Treg density in natural scratch cycles vs programmed cycles or in non-receptive vs receptive endometrium (ERA® cycles). In the peripheral blood analysis, the pregnant group had higher peripheral blood Tregs on the day of serum ß-hCG time point when compared to the non-pregnant group. CONCLUSION: Higher levels of endometrial Tregs and lower levels of CD16+ uNK cells are positive prognostic factors for infertile women prior to frozen embryo transfer. Our work on phenotypic and proportional analyses of endometrial immune cells may complement the ERA® in predicting improved pregnancy rates in patients with implantation failure.

Society for Assisted Reproductive Technology advertising guidelines: How are member clinics doing?

OBJECTIVE: To examine whether Society for Assisted Reproductive Technology (SART) member in vitro fertilization (IVF) centers adhere to the Society's new advertising policy, updated in January 2018, and evaluate other services advertised by region, insurance mandate and university affiliation status. Historically, a large percentage of IVF clinics have not adhered to SART guidelines for IVF clinic website advertising and have had variability in how financial incentives and other noncore fertility services are advertised. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adherence of SART participating websites to objective criteria from the 2018 SART advertising guidelines. RESULT(S): All 361 SART participating clinic websites were evaluated. Approximately one third of clinics reported success rate statistics directly on their websites, but only 52.6% of those clinics reported current statistics. Similarly, only 67.5% of SART member clinics included the required disclaimer statement regarding their outcome statistics. Only 10.5% of websites were wholly compliant with SART guidelines regarding presentation of supplemental data. There were no significant differences between academic and nonacademic centers, programs in mandated versus nonmandated states, or East versus West Coast clinics in any of these areas. CONCLUSION(S): Many of the SART member websites failed to adhere to core guidelines surrounding reporting IVF clinic success rates. Consideration for additional education and streamlining as well as simplifying success rate advertising guidelines is recommended.

Novel predictive and therapeutic options for better pregnancy outcome in frozen embryo transfer cycles.

Since 1978, in the first decades of in vitro fertilization (IVF), the use of ovarian hyperstimulation allowed for the development and transfer of multiple embryos. As IVF technology improved, the number of multiple pregnancies increased, which led to gradual reduction in the number of embryos that were transferred. Embryo freezing (vitrification) was recommended to allow subsequent transfer if the fresh cycle was unsuccessful. However, experimentation has continued to improve pregnancy outcomes. We discuss here the significance of frozen embryo transfer cycle and the impact of uterine and peripheral immunity dominated by NK cells and regulatory T cells and human chorionic gonadotropin on pregnancy outcome in this innovative mode of IVF therapy.

Human chorionic gonadotropin-mediated modulation of pregnancy-compatible peripheral blood natural killer cells in frozen embryo transfer cycles.

PROBLEM: To evaluate pregnancy-compatible phenotypic and functional changes in peripheral blood natural killer (pNK) cells during frozen embryo transfer (FET) cycles. METHOD OF STUDY: Peripheral blood was collected from patients undergoing frozen embryo transfer cycles at three separate time points in the cycle. pNK cell phenotype was analyzed by flow cytometry. Impact of pregnancy status on pNK cell cytotoxicity was characterized by two methods: (1) a three-dimensional endovascular tube formation approach and (2) a NK cell-specific K562 cell kill assay. RESULTS: A total of 35 patients were enrolled, 15 with clinical pregnancies and 20 with negative serum ß-hCG levels. Overall percentage of CD45+ CD3- CD56+ pNK cell did not change during the FET cycle. Pregnancy resulted in an increase in CD45+ CD3- CD56+ pNK cell population on the day of serum ß-hCG. pNK cells from non-pregnant patients caused significant tube disruption when compared to pregnant patients. Addition of serum from pregnant women reduced the tube disruption by pNK cells from non-pregnant patients. pNK cells from pregnant patients showed significantly lower cytotoxicity toward K562 cells in serum-free conditions. The addition of pregnancy serum decreased non-pregnant pNK cell cytotoxicity. Pregnancy status had no impact on VEGF-A and VEGF-C serum levels. Recombinant hCG added to non-pregnant serum resulted in a significant reduction in non-pregnant pNK cell-mediated K562 cell kill. CONCLUSION: There was no difference in pNK cell populations based on timing of the FET cycle. However, pregnancy increased the percentage of CD45+ CD3- CD56+ pNK cells. Additionally, pNK cells from pregnant women have reduced cytotoxicity and this is possibly mediated by hCG.

Is intracytoplasmic sperm (ICSI) better than traditional in vitro fertilization (IVF): confirmation of higher blastocyst rates per oocyte using a split insemination design.

PURPOSE: To explore the effects of traditional vs. intracytoplasmic sperm injection (ICSI) insemination method on the outcome of high-quality blastocyst development in a split sibling oocyte cohort. METHODS: In this retrospective cohort study, we analyzed 62 ICSI/IVF split cycles. Sibling oocytes were randomly assigned to ICSI or IVF insemination. Two hundred thirty-four ICSI-only cycles and 152 IVF-only cycles were also analyzed for comparison. Blastocysts were graded by Gardner's embryo grading and were considered a high-quality blastocyst if 3BB or better (Gardner 1999). RESULTS: In the ICSI/IVF split group, (1) ICSI oocytes had a higher fertilization rate per oocyte allocated (73% vs 62%, p < 0.001), (2) more high-quality day 2 embryos (69% vs 55%, p < 0.005), (3) ICSI oocytes had a lower blastulation rate per 2PN (46% vs 54%, p < 0.05), but a higher blastulation rate when calculated per oocyte allocated (40% vs 32%, p < 0.05). The ICSI-only group had a lower fertilization rate (65% vs 70%, p < 0.001) but more high-quality day 2 embryos in comparison to the IVF-only group (68% vs 64%, p < .05). The total high-quality blastulation rate was higher for the IVF-only group per 2PN (49% vs 43%, p < 0.05) and per oocyte retrieved (34% vs 28%, p < 0.05). CONCLUSIONS: This distinctive IVF/ICSI sibling oocyte split design demonstrated a higher-quality blastulation rate in the IVF group compared to the ICSI group when calculated per 2PN, but not per oocyte allocated to each insemination procedure.

Short- and long-term impact of gonadotropin-releasing hormone analogue treatment on bone loss and fracture.

Gonadotropin-releasing hormone analogues (GnRH-a) are commonly utilized in moderate to severe endometriosis to induce atrophy of endometriotic lesions. Unfortunately, cessation of therapy can lead to recurrence of symptoms. Therefore, long term therapy is sometimes necessary. GnRH analogues cause an immediate decrease in bone mineral density which usually recovers after cessation of its use. However, this recovery in bone mineral density may not always occur after long term use. In order to prevent the deleterious effects on bone, add-back therapy is used frequently. This review will explore the impact of GnRH analogues on both bone loss and fracture risk as well as describe different add-back regimens.

Oocyte zona pellucida dysmorphology is associated with diminished in-vitro fertilization success.

BACKGROUND: Although irregularities in human zona pellucida (ZP) morphology are well described, there is scant literature on the clinical significance of ZP dysmorphology. We, therefore, designed a retrospective cohort trial of ZP dysmorphology to assess the clinical significance of ZP dysmorphology and its affect on IVF outcome. Over the same time period a random sample of 77 cycles of 77 subjects with all normal oocyte morphology were selected as controls. METHODS: Between July 2006 and December 2010, all fresh non-donor cases performed at a university hospital IVF center were assessed for ZP dysmorphology. ZP dysmorphology included extracytoplasmic abnormalities (dark ZP and large perivitelline space) and oocyte shape (oval or irregularly shaped ZP). 136 IVF cycles from 119 subjects were identified where a majority of oocytes displayed ZP dysmorphology. Over the same time period a random sample of 77 cycles of 77 subjects with all normal oocyte morphology were selected as controls. IVF prognostic and outcome parameters were compared between the patients with dysmorphic and normal oocytes. RESULTS: 136/1710 (8.0%) cycles of fresh non-donor IVF displayed predominant ZP dysmorphology. Dysmorphic and normal oocytes showed no difference in the oocyte quality predictors such as FSH (6.03+/-2.5 vs. 6.8+/-2.3 IU/L), or AMH (2.5+/-2.0 vs. 2.30+/-1.5 ng/ml levels). ZP dysmorphology was associated with markedly diminished clinical pregnancy rates (44% vs. 70%; RR:0.62 [0.48, 0.80]; p = 0.0002), implantation rates (.17 vs. .36; IRR: 0.48 [0.34, 0.68]; p < 0.0001) and live birth rates as compared to non dysmorphic oocytes (29% vs. 52%; RR:0.55 [0.39, 0.79]; p = 0.001). CONCLUSIONS: ZP dysmorphology is associated with markedly diminished pregnancy and implantation rates in IVF. The poorer outcome appears to be independent of the usual markers of ovarian reserve.

Antibiotics for asymptomatic bacteriuria.

BACKGROUND: Asymptomatic bacteriuria is commonly detected in women aged up to 60 years, patients with diabetes, and the elderly. The benefit of antibiotic treatment for this condition is controversial. OBJECTIVES: To assess the effectiveness and safety of antibiotics treatment for asymptomatic bacteriuria in adults. Specific objectives were to assess 1) the effectiveness of antibiotics for preventing development of symptomatic UTI, UTI-related complications, overall mortality, UTI-related mortality, and resolution of bacteriuria; 2) the development of resistance to antibiotic treatment by comparing resistance of grown bacteria in urine before and after therapy; and 3) the frequency of adverse events. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register up to 24 February 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing antibiotics to placebo or no treatment for asymptomatic bacteriuria in adults were included. The outcomes of interest were the development of symptomatic urinary tract infection (UTI), complications, death, any adverse event, development of antibiotic resistance, bacteriological cure, and decline in kidney function. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed study quality. Statistical analyses were performed using the random effects model and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included nine studies (1614 participants) in this review. Symptomatic UTI (RR 1.11, 95% CI 0.51 to 2.43), complications (RR 0.78, 95% CI 0. 35 to 1.74), and death (RR 0.99, 95% CI 0.70 to 1.41) were similar between the antibiotic and placebo or no treatment arms. Antibiotics were more effective for bacteriological cure (RR 2.32, 95% CI 1.11 to 4.83) but also more adverse events developed in this group (RR 3.77, 95% CI 1.40 to 10.15). No decline in the kidney function was observed across the studies; minimal data were available on the emergence of resistant strains after antimicrobial treatment.The included studies were of medium and high quality, used different treatments for different durations of treatment and follow-up, different populations, but this did not appear to influence the results of review. AUTHORS' CONCLUSIONS: No differences were observed between antibiotics versus no treatment of asymptomatic bacteriuria for the development of symptomatic UTI, complications or death. Antibiotics were superior to no treatment for the bacteriological cure but with significantly more adverse events. There was no clinical benefit from treating asymptomatic bacteriuria in the studies included in this review.

In vitro maturation and its role in clinical assisted reproductive technology.

IMPORTANCE: In vitro maturation (IVM) refers to maturation in culture of immature oocytes that may or may not have been exposed to short courses of gonadotropins. Approximately 5000 live births have occurred as a result of IVM since the 1970s. Currently, IVM is reserved for carefully selected patients at risk for ovarian hyperstimulation syndrome and for those with contraindications to hormone administration. The technology is still considered experimental. OBJECTIVE: The objective of this study was to identify a role for IVM and discuss clinical practices based on the current literature. EVIDENCE ACQUISITION: We conducted a literature review of all available and published data. Relevant studies were identified using PubMed and MEDLINE. Search parameters included "in vitro maturation or IVM" and "oocyte maturation." Multiple case-control studies were identified comparing reproductive outcomes between conventional in vitro fertilization (IVF) and IVM, but no randomized controlled trials have been reported to date comparing IVF and IVM. RESULTS: Results from retrospective and prospective observational studies have shown decreased live birth and implantation rates in comparison to conventional IVF/intracytoplasmic sperm injection for patients with various indications for IVM. However, rates of ovarian hyperstimulation syndrome were significantly reduced in studies with patients with polycystic ovary syndrome. CONCLUSIONS: Although the pregnancy rate is lower than conventional IVF, IVM is a safer and simpler alternative to conventional IVF. Future research needs to focus on improving implantation and live birth rates before universal implementation.

Positive Chlamydia trachomatis serology result in women seeking care for infertility is a negative prognosticator for intrauterine pregnancy.

BACKGROUND: There are no prior studies that assess the non-in vitro fertilization (IVF) pregnancy rates in chlamydia serology-positive versus serology-negative women. Therefore, we wanted to determine whether a positive Chlamydia trachomatis immunoglobulin G serology result predicts reduced clinical pregnancy rates without IVF. METHODS: A prospective observational study was performed at a university-affiliated reproductive center. A total of 1279 new infertility patients seen at the Continuum Reproductive Center between January 2007 and June 2009 underwent C. trachomatis immunoglobulin G screening. Charts were later reviewed for hysterosalpingography, laparoscopy, treatment cycles, and ultrasound evidence of an intrauterine pregnancy. The main outcome measure was non-IVF cumulative pregnancy rates. RESULTS: Seventy (5.5%) of 1279 of the participants were found to have a positive chlamydia serology result. Serology-positive participants had significantly more tubal block on hysterosalpingography (37.5% vs. 10.1%, P = 0.001) and laparoscopically confirmed tubal damage (85.7% vs. 48.9%, P = 0.002). The percent of all participants who achieved an ultrasound documented clinical pregnancy, at our center, without IVF was significantly lower among Chlamydia-positive participants (10.0% versus 21.7%) in seronegative participants (P < 0.02). The hazard rate of non-IVF clinical pregnancy among chlamydia antibody testing-positive patients was 57% less than the rate of pregnancy among chlamydia antibody testing-negative patients (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92). Both the per-cycle and the cumulative IVF pregnancy rates were equivalent in seropositive and in seronegative participants. CONCLUSIONS: This is the first large study to report that a positive serology screening result is both predictive of tubal damage and a reduced cumulative pregnancy rate when excluding treatment with IVF.

Do in utero events contribute to current health disparities in reproductive medicine?

Health disparities exist in reproductive medicine as discussed in detail in the subsequent articles of this issue; however, in most cases, the exact cause of these differences is unknown. Some of these disparities can be linked to environmental exposures such as alcohol and other hazardous toxic exposures (polycarbonate, pesticides, nicotine) in adults. In addition, low socioeconomic status, behavioral risk factors, and lack of education have been linked to poor obstetric and reproductive outcomes in minority groups. Aside from these various environmental exposures later in life, there is evidence that adverse events in utero could contribute to poor reproductive outcome in specific minority groups. We will focus on the developmental origins of health and disease as a possible causal mechanism for health disparities in reproductive diseases, as this perspective may suggest tractable solutions of how to address and eliminate these health disparities.