Donna R. Session

Trends and Outcomes for Donor Oocyte Cycles in the United States, 2000-2010

IMPORTANCE The prevalence of oocyte donation for in vitro fertilization (IVF) has increased in the United States, but little information is available regarding maternal or infant outcomes to improve counseling and clinical decision making. OBJECTIVES To quantify trends in donor oocyte cycles in the United States and to determine predictors of a good perinatal outcome among IVF cycles using fresh (noncryopreserved) embryos derived from donor oocytes. DESIGN, SETTING, AND PARTICIPANTS Analysis of data from the Centers for Disease Control and Preventions National ART Surveillance System, to which fertility centers are mandated to report and which includes data on more than 95% of all IVF cycles performed in the United States. Data from 2000 to 2010 described trends. Data from 2010 determined predictors. MAIN OUTCOMES AND MEASURES Good perinatal outcome, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more. RESULTS From 2000 to 2010, data from 443 clinics (93% of all US fertility centers) were included. The annual number of donor oocyte cycles significantly increased, from 10,801 to 18,306. Among all donor oocyte cycles, an increasing trend was observed from 2000 to 2010 in the proportion of cycles using frozen (vs fresh) embryos (26.7% [95% CI, 25.8%-27.5%] to 40.3% [95% CI, 39.6%-41.1%]) and elective single-embryo transfers (vs transfer of multiple embryos) (0.8% [95% CI, 0.7%-1.0%] to 14.5% [95% CI, 14.0%-15.1%]). Good perinatal outcomes increased from 18.5% (95% CI, 17.7%-19.3%) to 24.4% (95% CI, 23.8%-25.1%) (P < .001 for all listed trends). Mean donor and recipient ages remained stable at 28 (SD, 2.8) years and 41 (SD, 5.3) years, respectively. In 2010, 396 clinics contributed data. For donor oocyte cycles using fresh embryos (n = 9865), 27.5% (95% CI, 26.6%-28.4%) resulted in good perinatal outcome. Transfer of an embryo at day 5 (adjusted odds ratio [OR], 1.17 [95% CI, 1.04-1.32]) and elective single-embryo transfers (adjusted OR, 2.32 [95% CI, 1.92-2.80]) were positively associated with good perinatal outcome; tubal (adjusted OR, 0.72 [95% CI, 0.60-0.86]) or uterine (adjusted OR, 0.74 [95% CI, 0.58-0.94]) factor infertility and non-Hispanic black recipient race/ethnicity (adjusted OR, 0.48 [95% CI, 0.35-0.67]) were associated with decreased odds of good outcome. Recipient age was not associated with likelihood of good perinatal outcome. CONCLUSIONS AND RELEVANCE In the United States from 2000 to 2010, there was an increase in number of donor oocyte cycles, accompanied by an increase in good outcomes. Further studies are needed to understand the mechanisms underlying the factors associated with less successful outcomes.

Tubal Factor Infertility and Perinatal Risk After Assisted Reproductive Technology

OBJECTIVE: To assess trends of tubal factor infertility and to evaluate risk of miscarriage and delivery of preterm or low birth weight (LBW) neonates among women with tubal factor infertility using assisted reproductive technology (ART). METHODS: We assessed trends of tubal factor infertility among all fresh and frozen, donor, and nondonor ART cycles performed annually in the United States between 2000 and 2010 (N=1,418,774) using the National ART Surveillance System. The data set was then limited to fresh, nondonor in vitro fertilization cycles resulting in pregnancy to compare perinatal outcomes for cycles associated with tubal compared with male factor infertility. We performed bivariate and multivariable analyses controlling for maternal characteristics and calculated adjusted risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: The percentage of ART cycles associated with tubal factor infertility diagnoses decreased from 2000 to 2010 (26.02–14.81%). Compared with male factor infertility, tubal factor portended an increased risk of miscarriage (14.0% compared with 12.7%, adjusted RR 1.08, 95% CI 1.04–1.12); risk was increased for both early and late miscarriage. Singleton neonates born to women with tubal factor infertility had an increased risk of preterm birth (15.8% compared with 11.6%, adjusted RR 1.27, 95% CI 1.20–1.34) and LBW (10.9% compared with 8.5%, adjusted RR 1.28, 95% CI 1.20–1.36). Significant increases in risk persisted for early and late preterm delivery and very low and moderately LBW delivery. A significantly elevated risk was also detected for twin, but not triplet, pregnancies. CONCLUSION: Tubal factor infertility, which is decreasing in prevalence in the United States, is associated with an increased risk of miscarriage, preterm birth, and LBW delivery as compared with couples with male factor infertility using ART. LEVEL OF EVIDENCE: II

Trends and correlates of good perinatal outcomes in assisted reproductive technology.

OBJECTIVE: To estimate trends in good perinatal outcomes (singleton live births at term with birthweight more than 2,500 g) among live births after assisted reproductive technology in the United States from 2000 to 2008, and associated factors among singletons in 2008. METHODS: Using retrospective cohort data from the National Assisted Reproductive Technology Surveillance System from 2000 to 2008, we calculated relative change and &khgr;2 tests for trend in the proportion of good perinatal outcomes among assisted reproductive technology live births (n=444,909) and liveborn singletons (n=222,500). We conducted univariable analyses followed by multiple logistic regression to estimate the effects of various characteristics on the outcome among singletons born in 2008 after fresh, nondonor assisted reproductive technology cycles (n=20,780). RESULTS: The proportion of good perinatal outcomes among all liveborn neonates increased from 38.6% in 2000 to 42.5% in 2008, whereas it declined marginally among singletons from 83.6% to 83.4%. One previous birth, transfer of fewer than three embryos, and the presence of fewer than three fetal hearts on 6-week ultrasound examination were associated with good perinatal outcome among singletons. Non-Hispanic black race, tubal factor infertility, uterine factor infertility, ovulatory disorder, and 5-day embryo culture were associated with reduced odds for a good outcome. The strongest association was the presence of one fetal heart compared with more than two (adjusted odds ratio 2.43, 95% confidence interval 1.73–3.42). CONCLUSION: From 2000 to 2008, good perinatal outcomes increased among assisted reproductive technology live births. Among singleton live births, odds for good outcome were greatest with the presence of a single fetal heart and lowest in women of non-Hispanic black race. LEVEL OF EVIDENCE: II

Safety of assisted reproductive technology in the United States, 2000-2011.

Use of assisted reproductive technology (ART) continues to increase in the United States and globally. In an effort to improve patient safety, stimulation protocols have become less aggressive, oocyte retrieval has transitioned from laparoscopic to transvaginal, and pregnancy rates have improved.1 However, limited data exist regarding the incidence of maternal complications.2 We explored incidence and trends in reported patient and donor complications in fresh ART cycles using the US Centers for Disease Control and Prevention National ART Surveillance System (NASS).

Current status of the approach to assisted reproduction.

Assisted reproductive technologies are important tools in the clinical armamentarium used to treat both female and male infertility disorders. Pre-implantation genetic diagnosis offers couples at risk of having children with inheritable disorders the ability to analyze the genetic make-up of embryos before transfer. For patients undergoing treatment of cancer with chemotherapy or radiation therapy, these technologies offer the potential for the preservation of future fertility. As technology evolves, it is likely the clinical applications of assisted reproduction will continue to develop and expand in the future to enhance fertility.

Analysis of follicular fluid retinoids in women undergoing in vitro fertilization: retinoic acid influences embryo quality and is reduced in women with endometriosis.

Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, including ATRA in women undergoing in vitro fertilization (IVF) and to investigate the relationship between retinoid levels and embryo quality. Retinoid levels were evaluated in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality assessed on a daily basis after retrieval for 3 days until uterine transfer. Analysis compared the retinoid levels with day 3 embryo grades and between endometriosis versus control patients. Results demonstrated distinctive levels of retinoid metabolites and isomers in FF versus PP. There was a significantly larger percentage of high-quality grade I embryos derived from the largest versus smallest follicles. An increase in follicle size also correlated with a >50% increase in FF ROL and ATRA concentrations. Independent of follicle size, FF yielding grade I versus nongrade I embryos showed higher mean levels of ATRA but not ROL. In a nested case–control analysis, control participants had 50% higher mean levels of ATRA in their FF and PP than women with endometriosis. These findings strongly support the proposition that ATRA plays a fundamental role in oocyte development and quality, and that reduced ATRA synthesis may contribute to decreased fecundity of participants with endometriosis.

Spontaneous intrauterine pregnancy after unilateral placement of tubal occlusive microinsert

OBJECTIVE To present a case in which the use of a titanium/nickel microinsert in the management of unilateral hydrosalpinx contributed to a spontaneous intrauterine pregnancy. DESIGN Case report. SETTING University hospital. PATIENT(S) A 37-year-old nulligravid female with dense pelvic adhesive disease and unilateral hydrosalpinx. INTERVENTION(S) Unilateral proximal occlusion of left fallopian tube with titanium/nickel microinsert. MAIN OUTCOME MEASURE(S) Pregnancy. RESULT(S) Spontaneous intrauterine pregnancy after confirmation via hysterosalpingogram of left tubal occlusion and right tubal patency. CONCLUSION(S) Transcervical proximal tubal occlusion using titanium/nickel microinserts provides an alternative in the management of hydrosalpinx in the setting of tubal factor infertility. Additionally, in the setting of a unilateral hydrosalpinx, unilateral occlusion can contribute to spontaneous intrauterine pregnancy.

Endometriosis and Assisted Reproductive Technology: United States Trends and Outcomes 2000–2011

OBJECTIVE To assess endometriosis-associated infertility trends among assisted reproductive technology (ART) cycles, and to compare cancellation and hyperstimulation risks and pregnancy and live birth rates among women using ART for endometriosis-associated vs. male factor infertility. DESIGN Descriptive and multivariable analyses of Centers for Disease Control and Prevention (CDC) National ART Surveillance System data. SETTING Fertility centers. PATIENT(S) All reported fresh autologous ART cycles in the United States between 2000 and 2011 (n = 1,589,079). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Oocyte yield, hyperstimulation, cancellation, implantation, pregnancy, live birth. RESULT(S) The absolute number of ART cycles with an endometriosis diagnosis fell in recent years, from 16,751 (2000) to 15,311 (2011); the percentage fell over time, from 17.0% (2000) to 9.6% (2011) of all cycles. Compared with male factor (n = 375,557), endometriosis-associated cycles (n = 112,475) yielded fewer oocytes (50.5% vs. 42.5% of cycles with only 0-10 oocytes retrieved), lower risk of hyperstimulation (1.1% vs. 1.3%, adjusted risk ratio [aRR] 0.82, 95% confidence interval [CI] 0.74-0.91), and an increased risk of cancellation (12.9% vs. 10.1%, aRR 1.30, 95% CI 1.25-1.35). Endometriosis was associated with a statistically decreased but likely clinically insignificant difference in the following outcomes: chance of pregnancy per transfer (43.7% vs. 44.8%, aRR 0.96, 95% CI 0.95-0.98) among couples who did not also have tubal factor infertility and live birth per transfer (37.2% vs. 37.6%, aRR 0.96, 95% CI 0.94-0.98). CONCLUSION(S) The percentage of endometriosis-associated ART cycles has decreased over time. As compared with male factor infertility, endometriosis is associated with increased cancellation and decreased hyperstimulation risks. Despite decreased oocyte yield and higher medication dose, the difference in pregnancy and live birth rates may be of limited clinical significance, suggesting comparable pregnancy outcomes per transfer.

A role for retinoids in human oocyte fertilization: regulation of connexin 43 by retinoic acid in cumulus granulosa cells

Retinoids are essential for ovarian steroid production and oocyte maturation in mammals. Oocyte competency is known to positively correlate with efficient gap junction intercellular communication (GJIC) among granulosa cells in the cumulus-oocyte complex. Connexin 43 (C x 43) is the main subunit of gap junction channels in human cumulus granulosa cells (CGC) and is regulated by all-trans retinoic acid (ATRA) in other hormone responsive cell types. The objectives of this study were to quantify retinoid levels in human CGC obtained during IVF oocyte retrievals, to investigate the potential relationship between CGC ATRA levels and successful oocyte fertilization, and to determine the effects of ATRA on C x 43 protein expression in CGC. Results showed that CGC cultures actively metabolize retinol to produce ATRA. Grouped according to fertilization rate tertiles, mean ATRA levels were 2-fold higher in pooled CGC from women in the highest versus the lowest tertile (P < 0.05). ATRA induced a rapid dephosphorylation of C x 43 in CGC and granulosa cell line (KGN) cultures resulting in a >2-fold increase in the expression of the functional non-phosphorylated (P0) species (P < 0.02). Similar enhancement of P0 by ATRA was shown in CGC and KGN cultures co-treated with LH or hCG which, by themselves, enhanced the protein levels of C x 43 without altering its phosphorylation profile. Correspondingly, the combination of ATRA+hCG treatment of KGN caused a significant increase in GJIC compared with single agent treatments (P < 0.025) and a doubling of GJIC from that seen in untreated cells (P < 0.01). These findings indicate that CGC are a primary site of retinoid uptake and ATRA biosynthesis. Regulation of C x 43 by ATRA may serve an important role in folliculogenesis, development of oocyte competency, and successful fertilization by increasing GJIC in CGC.

Horizontal uterine torsion in the setting of complete cervical and partial vaginal agenesis: a case report

OBJECTIVE To report a case in which uterine torsion in a nulligravid female adolescent was noted upon surgical management of complete cervical and partial vaginal agenesis. DESIGN Case report. SETTING University hospital. PATIENT(S) A 13-year-old nulligravid adolescent female. INTERVENTION(S) Ultrasound-guided vaginal exploration, diagnostic laparoscopy, and hysterectomy. MAIN OUTCOME MEASURE(S) Uterine torsion as complication of cervical agenesis and its management. RESULT(S) Complete cervical agenesis, hematometra, and resultant 180-degree horizontal uterine torsion and sacral entrapment. CONCLUSION(S) Cervical agenesis can be a risk factor for uterine torsion. Hysterectomy is a common treatment due to resultant hematometra, pelvic pain, and severe endometriosis, although rare case reports show success with uterovaginal recanalization in cases with cervical dysgenesis.