Reproductive and obstetric outcomes in women of racial minorities aged 40 years and older undergoing IVF.

RESEARCH QUESTION: Do women of racial minorities aged 40 years or older have similar reproductive and obstetric outcomes as white women undergoing IVF? DESIGN: A retrospective cohort study conducted at a single academic university-affiliated centre. The study population included women aged 40 years or older undergoing their first IVF cycle with fresh cleavage-stage embryo transfer stratified by racial minority status: minority (black or Asian) versus white. Clinical intrauterine pregnancy and live birth rate were the primary outcomes. Preterm delivery (<37 weeks) and small for gestational age were the secondary outcomes. Odds ratios with 95% confidence intervals were estimated. P < 0.05 was considered to be statistically significant. RESULTS: A total of 2050 cycles in women over the age of 40 years were analysed, 561 (27.4%) of which were undertaken by minority women and 1489 (72.6%) by white women. Minority women were 30% less likely to achieve a pregnancy compared with their white (non-Hispanic) counterparts (adjusted OR 0.68, CI 0.54 to 0.87). Once pregnant, however, the odds of live birth were similar (adjusted OR 1.23, CI 0.91 to 1.67). Minority women were significantly more likely to have lower gestational ages at time of delivery (38.5 versus 39.2 weeks, P = 0.009) and were more likely to have extreme preterm birth delivery 24-28 weeks (5.5 versus 1.0%, P = 0.021). CONCLUSION: Minority women of advanced reproductive age are less likely to achieve a pregnancy compared with white (non-Hispanic) women. Once pregnancy is achieved, however, live birth rates are similar albeit with minority women experiencing higher rates of preterm delivery.

Outcomes in, and characteristics of, patients who undergo intrauterine insemination immediately after failed oocyte retrieval.

OBJECTIVE: To describe the patient and cycle characteristics of women who undergo intrauterine insemination (IUI) immediately after an unsuccessful oocyte retrieval. DESIGN: Retrospective case series. SETTING: University-affiliated center. PATIENTS: Women who underwent an oocyte retrieval procedure in which no oocytes were retrieved followed by an IUI on the same morning. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Live birth rate, subsequent live birth rate. RESULTS: From 2011 to 2019, 63 cycles in 57 patients were identified. The mean (SD) age was 39.6 (4.6) years, and diminished ovarian reserve (94.7%) was the most common diagnosis. The median (IQR) number of previous IVF cycles in this cohort was 3 (1-7), with 56.1% having had at least one previous canceled IVF cycle. The majority of patients had undergone either controlled ovarian hyperstimulation (COH) (64.9%) or modified natural cycles (21.1%). The mean (SD) number of follicles >14 mm at the time of trigger was 1.9 (1.4), with 38.9% of patients manifesting a drop in their estradiol levels after the trigger. One pregnancy resulting in a live birth was identified (1.8%). For patients who underwent subsequent IVF cycles, 60.7% had at least one subsequent cancelled cycle. Three patients went on to achieve a live birth using autologous oocytes (6.5%). CONCLUSIONS: Same-day IUI for patients who have no oocytes retrieved is associated with a <2% chance of achieving a live birth. Of patients who attempt subsequent IVF cycles, nearly two thirds will go on to have at least one subsequent cancelled cycle. In this poor-prognosis cohort, fewer than 10% will ultimately achieve a live birth by the use of autologous oocytes.

Keeping the Zika Virus Out of the Assisted Reproductive Technology Laboratory.

The Zika virus (ZIKV) epidemic spreading through South and Central America, as well as several U.S. territories has created worldwide concern as the linkage between ZIKV infection and microcephaly has been established. Both travel associated and sexually transmitted cases have put couples who live in nonendemic areas at risk of falling victim to effects of Zika. The presence of ZIKV within reproductive tissues may pose a significant threat to patients seeking fertility services and to safety of the tissues currently housed in assisted reproductive technology (ART) laboratories. There are still many unanswered questions regarding the mechanism of ZIKV sexual transmission. Just as strict guidelines have been set regarding the screening and handling of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus-positive patient tissues, similar recommendations are needed to prevent contamination and inadvertent transmission within the ART laboratory.

Introduction: Access to fertility care.

Given that only an estimated 24% of infertile couples in the United States can fully engage in the medical care required to successfully conceive, the American Society for Reproductive Medicine (ASRM) has incorporated improved access to the full gamut of fertility therapies as an integral component of the Society's strategic plan that was launched in 2014. Toward this end, the ASRM hosted a two-day summit held in Washington D.C. in September 2015 that attracted thought leaders, both speakers and attendees, from around the world. This issue's Views and Reviews focuses on several key areas integral to this effort: an appreciation of the economic challenges to access, as well as the impact and interplay of racial, ethnic, emotional and gender-specific issues in the treatment of infertility. The potential to broaden access to care through modification of existing assisted reproductive techniques is also explored.

Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women ≥43 years old?

OBJECTIVE: To determine the number of cleavage-stage embryos that can be safely transferred in women ≥43 years old. DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENT(S): All patients ≥43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): A total of 567 cycles in 464 patients aged 43-45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred. RESULT(S): Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos. CONCLUSION(S): Transferring five or more day 3 embryos may be a safe option for patients ≥43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional embryo(s) for transfer or the inherently better prognosis of such patients remains to be determined.

Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles.

OBJECTIVE: To identify risk factors for breakthrough LH surge despite GnRH antagonist (GnRH-ant) suppression in IVF cycles. DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): All patients undergoing IVF from August 2004 through July 2012 in whom GnRH-ant pituitary suppression (0.25 mg/d) was used in a flexible protocol. INTERVENTION(S): GnRH-ant-based IVF. MAIN OUTCOME MEASURE(S): Breakthrough LH surges as evidenced by an increase in LH (minimum 2.5-fold increase from baseline above a threshold of 17 mIU/mL) associated with a decrease in E2, and free fluid on ultrasound. RESULT(S): Breakthrough LH surges despite GnRH-ant administration occurred in 37 (0.34%) of the 10,809 antagonist cycles during the study period. Compared with all patients remaining suppressed, patients with breakthrough surges were significantly older and had significantly increased FSH and decreased antral follicle counts. Compared with age-matched controls (allocation ratio, 1:50), significant differences in ovarian reserve remained evident. CONCLUSION(S): The occurrence of a breakthrough LH surge despite GnRH-ant treatment is a reassuringly rare event. However, patients with diminished ovarian reserve are at risk for this outcome despite GnRH-ant down-regulation. Further studies are needed to determine whether these patients can be prospectively identified and whether they may benefit from higher doses of GnRH-ant.

IVF stimulation: protocols for poor responders.

One of the most vexing challenges in the practice of reproductive medicine is the management of the "poor responder," specifically the patient manifesting an inadequate follicular response to ovarian stimulation. Poor response predicts a reduction in the number of mature oocytes retrieved, with the consequences of fewer embryos available for selection and transfer, reduced pregnancy rates, and a markedly decreased likelihood of residual embryos for cryopreservation. This chapter reviews the definition and prediction of poor response and discusses strategies that have been developed and incorporated into the reproductive endocrinologist's clinical armamentarium in an effort to optimize outcomes for these women. It should be stated at the outset that no single approach is successful for all patients, and that there is currently no firm clinical consensus regarding the relative efficacy of the different stimulation protocols. This arises in part due to inconsistency regarding the definition of what constitutes a poor response and a paucity of well-designed, randomized controlled trials.

In vitro fertilization versus conversion to intrauterine insemination in the setting of three or fewer follicles: how should patients proceed when follicular response falls short of expectation?

OBJECTIVE: To determine whether in vitro fertilization (IVF) cycles with suboptimal response should be converted to intrauterine insemination (IUI) or proceed to oocyte retrieval (OR). DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENT(S): All patients initiating IVF from January 2004 through December 2011. INTERVENTION(S): OR versus conversion to IUI. MAIN OUTCOME MEASURE(S): A total of 1,098 patients were identified whose IVF cycles were characterized by recruitment of three or fewer follicles, excluding patients with bilateral tubal disease or severe male factor. Cycles with three follicles were defined as those with three follicles ≥ 14 mm with no fourth follicle ≥ 10 mm. Cycles with two or fewer follicles were similarly defined. Outcomes were compared for patients proceeding with OR (n = 624) versus converting to IUI (n = 474). Age-adjusted relative risks for pregnancy were calculated, stratifying for number of follicles. RESULT(S): The likelihood of retrieving at least one mature oocyte (82.9% vs. 94.8% vs. 96.2%), having at least one zygote (61.9% vs. 76.8% vs. 84.2%), and undergoing transfer (57.1% vs. 73.0% vs. 83.3%) increased significantly with increasing follicle number. Patients with three or fewer follicles were 2.6 times more likely to achieve a live birth with IVF versus IUI (9.3% vs. 3.4%). This benefit was only apparent when at least two follicles were present. No benefit was gained by performing OR in the setting of one follicle. CONCLUSION(S): IVF compared with IUI presents superior pregnancy rates in the setting of two or more follicles. Assisted reproduction programs may benefit their patients by pursuing IVF in this scenario.

Fertility preservation using controlled ovarian hyperstimulation and oocyte cryopreservation in a premenarcheal female with myelodysplastic syndrome.

OBJECTIVE: To report the first case of fertility preservation in a premenarcheal female by use of controlled ovarian hyperstimulation and oocyte cryopreservation. DESIGN: Case report. SETTING: Reproductive endocrinology and infertility unit of a tertiary care university-based medical center. PATIENT(S): A 13-year-old premenarcheal female with Tanner stage 3 breast development and Tanner stage 1 pubic hair diagnosed with myelodysplastic syndrome, referred by her medical oncologist for fertility preservation before undergoing a potentially sterilizing antineoplastic therapy. INTERVENTION(S): Evaluation of ovarian reserve, ovarian stimulation, transvaginal oocyte aspiration, in vitro maturation of immature oocytes, and oocyte cryopreservation. MAIN OUTCOME MEASURE(S): Cryopreservation of mature oocytes. RESULT(S): Successful controlled ovarian hyperstimulation allowed for the cryopreservation of 18 mature oocytes before the patient's gonadotoxic treatment. The oocyte retrieval and cryopreservation did not delay the patient's planned chemotherapy. CONCLUSION(S): Ovarian stimulation and oocyte cryopreservation can be successfully performed in premenarcheal/peripubertal patients, thus providing a viable alternative to ovarian tissue freezing for fertility preservation in the pediatric population.

Stimulation of the young poor responder: comparison of the luteal estradiol/gonadotropin-releasing hormone antagonist priming protocol versus oral contraceptive microdose leuprolide.

OBJECTIVE: To evaluate in vitro fertilization (IVF) cycle outcomes in young poor responders treated with a luteal estradiol/gonadotropin-releasing hormone antagonist (E(2)/ANT) protocol versus an oral contraceptive pill microdose leuprolide protocol (OCP-MDL). DESIGN: Retrospective cohort. SETTING: Academic practice. PATIENT(S): Poor responders: 186 women, aged <35 years undergoing IVF with either E(2)/ANT or OCP-MDL protocols. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancies, oocytes retrieved, cancellation rate. RESULT(S): Patients in the E(2)/ANT group had a greater gonadotropin requirement (71.9 ± 22.2 vs. 57.6 ± 25.7) and lower E(2) level (1,178.6 ± 668 vs. 1,627 ± 889), yet achieved similar numbers of oocytes retrieved and fertilized, and a greater number of embryos transferred (2.3 ± 0.9 vs. 2.0 ± 1.1) with a better mean grade (2.14 ± .06 vs. 2.7 ± 1.8) compared with the OCP/MDL group. The E2/ANT group exhibited a trend toward improved implantation rates (30.5% vs. 21.1%) and ongoing pregnancy rates per started cycle: 44 out of 117 (37%) versus 17 out of 69 (25%). CONCLUSION(S): Poor responders aged <35 years may be treated with the aggressive E(2)/ANT protocol to improve cycle outcomes. Both protocols remain viable options for this group. Adequately powered, randomized clinical comparison appears justified.

Intracytoplasmic sperm injection (ICSI) using cryopreserved sperm from men with malignant neoplasm yields high pregnancy rates.

OBJECTIVE: To investigate the efficacy of IVF-intracytoplasmic sperm injection (ICSI) in patients who cryobanked semen before cancer treatment. DESIGN: Retrospective consecutive study. SETTING: University-based IVF unit. PATIENT(S): One hundred eighteen couples undergoing IVF-ICSI using pretreatment frozen sperm. INTERVENTION(S): Treatment follow-up. MAIN OUTCOME MEASURE(S): Semen parameters and clinical pregnancy rates. RESULT(S): One hundred eighteen couples underwent 169 IVF cycles using pretreatment cryopreserved sperm; the average sperm count was 66.5 x 10(6)/mL, and the average motility was 45.6%. Post-thaw sperm average density was 40.9 x 10(6)/mL with 14.2% motility. The clinical pregnancy rate was 56.8% per retrieval; 96 pregnancies were achieved, resulting in 126 children born and 11 spontaneous abortions. Patients with prostate cancer had the worst semen parameters before sperm banking and the lowest clinical pregnancy rates. CONCLUSION(S): IVF-ICSI is the recommended treatment for most couples with cryopreserved sperm for male cancer. High pregnancy and delivery rates after IVF-ICSI using cryopreserved sperm from patients with cancer should encourage all reproductive-age males to cryobank semen immediately after diagnosis; physicians should discuss this and advise freezing multiple samples before treatment.

Outcome of in vitro fertilization in women 45 years and older who use autologous oocytes.

OBJECTIVE: To determine the IVF outcome in women over the age of 44 years. DESIGN: Retrospective analysis. SETTING: University-based IVF center. PATIENT(S): Two hundred eighty-eight consecutive IVF cycles in women over the age of 44 years. INTERVENTION(S): IVF. MAIN OUTCOME MEASURE(S): Ovarian response and cycle outcome. RESULTS: The mean age of the patients was 45.4 (+/-0.73) years, with a range of 45-49 years. Fifty-seven of 288 (19.8%) did not start because of an elevated FSH or ovarian cyst. Just over 30% (70/231) had their cycle cancelled before retrieval. The mean number of oocytes was 6.8 (+/-3.8), and the mean number of fertilized zygotes was 5.4 (+/-3.4). On average, the mean numbers of embryos replaced were 3.2 (+/-1.5). An overall pregnancy rate of 21.1% (34/161) per retrieval was found. Of these, 85.3% (29/34) experienced a pregnancy loss. The overall delivery rate was 3.1% (5/161) per retrieval. Only patients at 45 years of age with a good response (>5 oocytes) achieved a delivery. CONCLUSION(S): We have shown that IVF is a reasonable option for women of very advanced maternal age (>44 years) but is limited to those at the age of 45 years with a response of >5 oocytes.

Simultaneous bilateral ovarian torsion in the follicular phase after gonadotropin stimulation.

OBJECTIVE: To present and discuss the first report of follicular phase bilateral ovarian torsion following a cancelled IVF cycle. DESIGN: Case report. SETTING: University-based assisted reproductive technology program. PATIENT(S): A 41-year-old nulligravid patient on day 3 of her menses following a cancelled IVF cycle. INTERVENTION(S): Gonadotropin ovulation induction; laparoscopy with detorsion of left and right ovaries; aspiration of cysts. RESULT(S): Ovarian torsion resolved; follicular development in the following natural cycle. CONCLUSION(S): This is a unique case of simultaneous bilateral ovarian torsion following a cancelled IVF cycle and presenting in the ensuing follicular phase. Physicians should be aware of this unusual risk related to persistently enlarged ovaries in the cycle following gonadotropin stimulation. Furthermore, management of the infertility patient should be conservative and focused on ovarian preservation whenever feasible. Early surgical intervention can permit reperfusion and salvage of the affected adnexa.

Use of a luteal estradiol patch and a gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation for in vitro fertilization in poor responders.

The administration of a luteal E2 patch/GnRH antagonist protocol before gonadotropins in poor responders may improve ovarian stimulation and result in greater uniformity in follicular development and improved pregnancy rates.

Autologous endometrial coculture in patients with IVF failure: outcome of the first 1,030 cases.

OBJECTIVE: To analyze the effectiveness of autologous endometrial coculture (AECC) in improving embryo quality and pregnancy rates in 1,030 consecutive cycles of in vitro fertilization-embryo transfer (IVF-ET) utilizing AECC from January 1996 to December 2001. STUDY DESIGN: Embryos from each of 1,030 patients allocated to growth on AECC were analyzed for outcome. All patients had previously undergone failed IVF cycles. During a luteal phase biopsy (5-12 days after the luteinizing hormone surge) performed prior to the treatment cycle, glandular (G) and stromal (S) endometrial cells were isolated by enzymatic digestion and separated based on differential sedimentation rates. These cells were cryopreserved, then plated as a 50%/50% combination of G and S cells prior to embryo exposure. The conditioned medium was changed every 2 days. Embryos were randomly grown on endometrial coculture (ECC) or conventional media if > 6 oocytes were normally fertilized. Otherwise, all embryos were grown on AECC. RESULTS: The patients' mean age was 36.9 (+/-3.1) years. The patients had on average a history of 3.1 (+/- 1.7) failed prior attempts. When comparing a previous cycle (same institution only), the cleaved embryos on day 3 were of an improved quality (6.8+/-1.2 vs. 5.5+/-1.0 blastomeres and 14.6% +/- 9.3 vs. 27.2% +/- 9.8 fragmentation, P <.05). Twenty-two (2.13%) patients did not undergo ET secondary to poor embryonic development. Overall positive and clinical pregnancy rates of 49.8% and 41.5% were noted, respectively. Age remained the most important predictor of outcome. CONCLUSION: We demonstrated a significant improvement in embryo quality with ECC. We also demonstrated that patients with a poor prognosis secondary to prior IVF failures can have a good outcome when utilizing AECC.

Relationship between maternal age and aneuploidy in in vitro fertilization pregnancy loss.

OBJECTIVE: To determine the fetal loss rate after documented fetal cardiac activity (7-week sonogram) and to evaluate the chromosomal makeup of these losses in IVF pregnancies. DESIGN: Retrospective analysis. SETTING: University-based IVF center. PATIENT(S): Two thousand fourteen consecutive IVF pregnancies with documented fetal cardiac activity. MAIN OUTCOME MEASURE(S): Miscarriage rates and karyotypes of pregnancy losses were analyzed. RESULT(S): The overall pregnancy loss rate after demonstrated fetal cardiac activity was 11.6% (233/2014). A highly significant increase in fetal loss with advancing maternal age was observed (<30 years = 5.3% vs. 31-34 years = 7.6% vs. 35-39 years = 12.8% vs. > or =40 years = 22.2%). Patients with a multiple gestation were more likely to deliver a live infant, compared with those with a singleton detected at a 7-week sonogram. Of the 233 losses in the study period, cytogenetic analyses were obtained for 74 (31.8%). Three specimens were nondiagnostic. Fifty-two patients had abnormal karyotypes (71.2% [52/71]). Eighty-two percent of the pregnancy losses in women aged > or =40 years were associated with chromosomally abnormal fetuses, compared with 65% of the losses in women aged <40 years (odds ratio, 3.35; 95% confidence interval, 0.96-11.97). CONCLUSION(S): Pregnancy loss after documentation of fetal cardiac activity is >10%. This loss is significantly increased with advancing maternal age. The major underlying cause of these losses seems to be chromosomal aneuploidy.

Are variations in individual physician success rates within an in vitro fertilization program due to patient demographics or methodology?

Apparent variations in individual physician success rates in a large in vitro fertilization program may indeed be due to patient demographics, but this contention cannot be substantiated by the data presented.