The use of follicle flushing during oocyte retrieval in assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does follicular flushing during assisted reproductive technologies (ART) improve the number of oocytes retrieved? SUMMARY ANSWER: Follicular flushing during ART does not result in a greater number of oocytes in normal responders. WHAT IS KNOWN ALREADY: Despite limited evidence supporting the use of follicular flushing, it continues to be a common procedure in many ART clinics. Prior studies have provided conflicting results regarding the routine use of flushing during oocyte retrieval. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis of 518 patients who participated in 6 randomized trials over 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Literature searches were conducted to retrieve randomized controlled trials on follicle or ovarian flushing in ART. Databases searched included PubMed, EMBASE, Web of Science and the Cochrane Database of Clinical Trials (CENTRAL). Six trials that included 518 subjects matched the inclusion criteria. Studies included were limited to trials that were published, randomized trials comparing oocyte retrieval with a single-lumen pick-up needle versus follicle flushing after direct aspiration with a multi-channel oocyte pick-up needle in ART patients. MAIN RESULTS AND THE ROLE OF CHANCE: In each of the trials, measures of the oocyte yield (oocytes retrieved divided by follicles aspirated), total oocytes retrieved, fertilization or pregnancy were not different when comparing direct aspiration with follicle flushing. Four trials reported a higher operative time with follicle flushing. Results of the meta-analysis indicated no significant differences in the oocytes retrieved [weighted mean difference: 0.07, 95% confidence interval (CI): -0.13 to 0.29] or the oocyte yield (odds ratio: 1.06, 95% CI: 0.95-1.18) between the non-flushing and flushing groups. LIMITATIONS, REASONS FOR CAUTION: All trials featured an open label design and the majority of patients in this meta-analysis were normal responders. The applications of these results to poor responders, patients undergoing natural cycle ART or minimal stimulation ART should be made with caution. WIDER IMPLICATIONS OF THE FINDINGS: Follicle flushing does not improve ART outcomes in normal-responding patients and should not be performed. This meta-analysis should solidify this recommendation as it includes the largest trial published on the subject and is consistent with a recently published Cochrane review. STUDY FUNDING/COMPETING INTEREST(S): This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature.

A review of the scientific literature on the use of exogenous LH in assisted reproductive technology was performed by searching the MEDLINE, PubMed and Cochrane online databases. Scientific evidence was reviewed comparing recombinant FSH-only protocols to protocols supplemented with exogenous LH activity: human menopausal gonadotrophin (HMG), recombinant LH and mid-follicular human chorionic gonadotrophin (HCG). Studies were further compared based on pituitary suppression with gonadotrophin- releasing hormone (GnRH) antagonist and agonist protocols. Primary focus was given to randomized controlled trials and meta-analyses. Data from hypogonadotrophic hypogonadal patients demonstrated the importance of LH activity for success of assisted reproduction treatment. However, the majority of normogonadotrophic patients had adequate endogenous LH to successfully drive ovarian steroidogenesis and oocyte maturation. Exogenous LH supplementation was consistently associated with higher peak oestradiol concentrations. The use of HMG in long GnRH agonist cycles was associated with a 3­4% increase in live birth rate. There was insufficient evidence to make definitive conclusions on the need for exogenous LH activity in GnRH antagonist cycles or the benefit of recombinant LH and HCG protocols. Poor responders and patients 35 years of age and older may benefit from exogenous LH.

Is there a benefit in follicular flushing in assisted reproductive technology?

PURPOSE OF REVIEW: Follicular flushing utilizing double-lumen retrieval needles attempts to increase oocyte yield during transvaginal retrieval. The original work on this topic, now more than 2 decades old, examined its utility in normal-responding assisted reproductive technologies (ART) patients. Newer studies examining its utility have focused on special populations expected to demonstrate benefit: poor responders, natural cycle and minimal stimulation ART, and in-vitro maturation cycles. This review assesses the current evidence regarding the effectiveness of ovarian follicular flushing in improving oocyte yield. RECENT FINDINGS: Follicular flushing offers no substantive benefit in oocyte yield, fertilization rates, or pregnancy outcomes for normal and poor-responding ART patients. Patients undergoing natural cycle or minimal stimulation ART may benefit from follicular flushing resulting in more mature embryos but unclear effects on cycle outcome. SUMMARY: Randomized controlled trials consistently demonstrate no benefit and increased procedural time with follicular flushing in both normal and poor-responding ART patients. Nonrandomized data suggest a possible role for follicular flushing in natural cycle or minimal stimulation ART and in those undergoing in-vitro maturation IVF cycles; however, randomized controlled trials are needed to verify this finding. Presently, there is insufficient evidence to recommend the routine use of follicular flushing.

Is transferring a lower-quality embryo with a good-quality blastocyst detrimental to the likelihood of live birth?

OBJECTIVE: To determine if transferring a lower-quality embryo with a good-quality blastocyst is detrimental, given that evidence suggests that embryos can signal the endometrium and that embryo quality may affect negatively endometrial receptivity. DESIGN: Retrospective cohort study. SETTING: In vitro fertilization center. INTERVENTION(S): Single- versus double-embryo transfer. PATIENT(S): Patients with a double-embryo transfer of a good-quality blastocyst plus a lower-quality blastocyst, early blastocyst, or morula were compared with patients receiving a single good-quality blastocyst. MAIN OUTCOME MEASURE(S): Live birth, multiple gestation. RESULT(S): In this study, 4,640 in vitro fertilization cycles were analyzed. In none of the analyses did transferring a second lower-quality embryo negatively affect birth rate. In the primary analysis, transferring a second lower-quality embryo increased live birth by 10% and the multiple birth rate by 15%. The addition of a fair- or poor-quality blastocyst or early blastocyst markedly increased the twin birth rate by 22%-27% with an 8%-12% increase in live birth. The addition of a morula did not increase live birth but resulted in 12% more multiples. In women younger than 38 years, adding a lower-quality embryo increased the birth rate by 7% but resulted in 18% increase in multiples. In women 38 years or older, adding a lower-quality embryo increased the live birth rate by 9% with a 15% increase in multiples. CONCLUSION(S): Addition of a lower-quality embryo does not have a detrimental effect on a good-quality blastocyst and results in a small increase in live births. However, this is at the expense of a marked increase in the likelihood of multiple gestations.

Selective venous sampling for androgen-producing ovarian pathology.

OBJECTIVE: Multiple diagnostic modalities may be needed to establish the source of excessive androgen production in women. The role of selective venous catheterization in this process has not been established fully. DESIGN: A study of hyperandrogenaemic subjects and literature review. PATIENTS: Four hyperandrogenaemic women and an additional 132 previously reported cases with available testing data and a pathological diagnosis were evaluated. MEASUREMENTS: Serum androgens, diagnostic imaging and ovarian venous effluent sampling. Criteria to distinguish ovarian tumours from other ovarian conditions and to localize the lesion(s) were evaluated. RESULTS: Basal peripheral testosterone levels >or= 4.51 nmol/l (>or= 130 ng/dl) discriminated ovarian tumours from benign causes of hyperandrogenism (sensitivity: 93.8%, 95% CI 85.0-98.2; specificity: 77.8%, 95% CI 66.4-86.7). Single lesions produced higher ipsilateral testosterone concentrations (612.6 +/- 162.0 nmol/l; 17 653 +/- 4670 ng/dl) compared to contralateral values (26.4 +/- 5.2 nmol/l; 761 +/- 150 ng/dl). In women with peripheral testosterone >or= 4.51 nmol/l, a right-to-left (R:L) ovarian testosterone ratio >or= 1.44 correctly identified all 18 women with right-sided tumours and misclassified two with bilateral lesions; 12 out of 14 women with left-sided or bilateral lesions had a lower R:L value. When this criterion was combined with a left-to-right (L:R) ovarian testosterone effluent ratio of > 15 to identify left-sided tumours, overall 66% of women were correctly categorized. CONCLUSIONS: Peripheral testosterone concentrations identified ovarian androgen-producing tumours, and venous sampling could correctly localize 66% of these, suggesting a role for sampling when imaging studies are not revealing.

Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: implications for research and clinical care.

OBJECTIVES: To compare magnetic resonance and ultrasound imaging for uterine fibroid measurement. STUDY DESIGN: Eighteen women undergoing hysterectomy for symptomatic fibroids underwent preoperative pelvic ultrasound and magnetic resonance imaging. Resected fibroids were correlated with the images. Weighted kappa agreement statistics and Spearman correlations for patient characteristics were calculated. RESULTS: Magnetic resonance imaging identified 121 of 151 pathologically confirmed fibroids, yielding 91% positive predictive value (95% confidence interval [CI], 85-95) and 80% sensitivity (95% CI, 73-86). Positive predictive value and sensitivity for ultrasound were 97% (95% CI, 89-100) and 40% (95% CI, 32-48), respectively. Mean diameter-equivalent discrepancies between imaging and pathologic measurements were 0.51 +/- 0.68 cm for magnetic resonance imaging and 0.76 +/- 0.88 cm for ultrasound. kappa statistics comparing imaging to pathology showed better agreement for magnetic resonance than ultrasound (kappa = 0.60 vs 0.36). The number of fibroids detected by magnetic resonance imaging predicted measurement errors (r = 0.76; P = .0002). CONCLUSION: Superior sensitivity and minimal measurement discrepancies suggest magnetic resonance imaging may be preferentially used for fibroid assessment in clinical research.

CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.

OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T2) daily or to placebo (PLC) for 3 cycles or 90-102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914 -29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90-102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251 LEVEL OF EVIDENCE: I.

Revisiting the progesterone to oocyte ratio.

OBJECTIVE: To critically evaluate the P to oocyte (O) ratio (P/O) in the prediction of live birth in assisted reproductive technology (ART) cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 7,608 fresh autologous ART ET cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Generalized estimating equation (GEE) models and receiver operating characteristic curves assessed the ability of P, O, and the P/O ratio to predict live birth. In univariate GEE models, P, O, and P/O were each associated with live birth. However, in multivariate GEE models, the P/O ratio was not associated with live birth, but P alone was. This suggested that converting P and O into a ratio of P/O was not more helpful than the two independent variables themselves. Measures of overall model fit further suggested that P/O did not increase the predictive ability of the model over P and O alone. Receiver operating characteristic curves using incremental predictors further demonstrated that the P/O provided no incremental improvement in predicting live birth over P and O separately. CONCLUSION(S): These data suggest that P and O have utility in prediction modeling but demonstrate that additional oocytes were not protective from the negative association of P with live birth. There was no incremental improvement related to the P/O ratio specifically for predicting live birth over each variable independently.

Is FMR1 CGG repeat length a predictor of in vitro fertilization stimulation response or outcome?

OBJECTIVE: To study a broad range of FMR1 CGG repeat lengths and assisted reproduction technology (ART) outcomes. DESIGN: Retrospective cohort study. SETTING: Private ART practice. PATIENT(S): Fresh autologous ART stimulation cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Oocyte yield, live birth. RESULT(S): We screened 14,088 fresh autologous ART cycles from 2012 to 2015, of which 4,690 cycles in 3,290 patients met the inclusion criteria. The FMR1 repeat length was statistically significantly but weakly associated with oocyte yield and other markers of ovarian response. The receiver operating characteristic curve analysis suggested extremely limited predictive ability. Moreover, the FMR1 repeat length was not statistically significantly associated with outcomes in multivariable models, including other markers of ovarian reserve. The FMR1 repeat length was not associated with embryo quality or live birth. Only patient age had a strong ability to predict live birth. CONCLUSION(S): The FMR1 repeat length is associated with ART response, but only weakly. It provides no incremental predictive ability beyond the conventionally used predictors, including patient age, antimüllerian hormone concentration, antral follicle count, and follicle-stimulating hormone level. These data suggest a possible role of the FMR1 repeat length within the normal range in ovarian response but demonstrate no clinically relevant indication for testing FMR1 as a predictor of ART outcomes.

Optimal oocyte retrieval and embryo transfer techniques: where we are and how we got here.

Oocyte retrieval is most safely accomplished with conscious sedation via a transvaginal approach under ultrasound guidance with low-pressure aspiration. Follicle flushing has not been shown to improve outcomes. The type of vaginal surgical preparation and the use of antibiotics have not been demonstrated to affect outcomes. As the final step in a rigorous assisted reproductive technology (ART) cycle, precise technique in embryo transfer is essential. Based on current findings, the recommended embryo transfer technique includes the use of an ultrasound-guided transcervical approach with a full bladder using a soft catheter. The transfer depth of the embryo should be in the mid-portion of the uterus with a quick steady insertion followed by pressure on the syringe during withdrawal of the catheter. It is acceptable to encourage immediate ambulation after embryo transfer.

Single vitrified blastocyst transfer maximizes liveborn children per embryo while minimizing preterm birth.

OBJECTIVE: To compare live-birth rates, blastocyst to live-birth efficiency, gestational age, and birth weights in a large cohort of patients undergoing single versus double thawed blastocyst transfer. DESIGN: Retrospective cohort study. SETTING: Assisted reproduction technology (ART) practice. PATIENT(S): All autologous frozen blastocyst transfers (FBT) of one or two vitrified-warmed blastocysts from January 2009 through April 2012. INTERVENTION(S): Single or double FBT. MAIN OUTCOME MEASURE(S): Live birth, blastocyst to live-birth efficiency, preterm birth, low birth weight. RESULT(S): Only supernumerary blastocysts with good morphology (grade BB or better) were vitrified, and 1,696 FBTs were analyzed. No differences were observed in patient age, rate of embryo progression, or postthaw blastomere survival. Double FBT yielded a higher live birth per transfer, but 33% of births from double FBT were twins versus only 0.6% of single FBT. Double FBT was associated with statistically significant increases in preterm birth and low birth weight, the latter of which was statistically significant even when the analysis was limited to singletons. Of the blastocysts transferred via single FBT, 38% resulted in a liveborn child versus only 34% with double FBT. This suggests that two single FBTs would result in more liveborn children with significantly fewer preterm births when compared with double FBT. CONCLUSION(S): Single FBT greatly decreased multiple and preterm birth risk while providing excellent live-birth rates. Patients should be counseled that a greater overall number of live born children per couple can be expected when thawed blastocysts are transferred one at a time.

Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation?

OBJECTIVE: To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. DESIGN: Retrospective cohort study. SETTING: Large, private, assisted reproductive technology (ART) practice. PATIENT(S): One thousand six hundred twenty fresh autologous ART cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. CONCLUSION(S): An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis.

Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location.

OBJECTIVE: To assess ovarian reserve after methotrexate treatment for ectopic pregnancy or pregnancy of unknown location after assisted reproductive technology (ART). DESIGN: Retrospective cohort study. SETTING: Large ART practice. PATIENT(S): Women receiving methotrexate or surgery after ART. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Follicle-stimulating hormone (FSH), antral follicle count (AFC), and oocyte yield compared between women treated with methotrexate or surgery, with secondary outcomes of clinical pregnancy and live birth. RESULT(S): There were 153 patients in the methotrexate group and 36 patients in the surgery group. Neither group demonstrated differences in ovarian reserve or oocyte yield in a comparison of the before and after treatment values. The change in ovarian reserve and oocyte yield after treatment were similar between the two groups. The number of doses of methotrexate was not correlated with changes in ovarian reserve, indicating no dose-dependent effect. Time between treatment and repeat ART was not correlated with outcomes. Live birth in subsequent cycles was similar in the two groups. CONCLUSION(S): Ovarian reserve and subsequent ART cycle outcomes were reassuring after methotrexate or surgical management of ectopic pregnancy. No adverse impact of methotrexate was detected in this large fertility cohort as has been previously described elsewhere.

Single-donor and double-donor sperm intrauterine insemination cycles: does double intrauterine insemination increase clinical pregnancy rates?

OBJECTIVE: To compare the pregnancy outcomes in the setting of a single- vs. double-donor sperm intrauterine insemination (IUI) treatment cycle. DESIGN: Retrospective cohort study. SETTING: Large, private assisted reproductive technology practice. PATIENT(S): Donor sperm IUI recipients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): There were 2,486 double and 673 single-donor sperm IUI cycles. The two groups were similar for age, body mass index, and the number of prior cycles. The clinical pregnancy rates were similar between the two groups (single: 16.4% vs. double: 13.6%). In univariate regression analysis, age, total motile sperm, and diminished ovarian reserve (DOR) were associated with pregnancy. Generalized estimating equation models accounting for repeated measures, age, DOR and total motile sperm and the interactions of these factors demonstrated that single and double IUI had similar odds of pregnancy (odds ratio 1.12; 95% confidence interval, 0.96-1.44). Pregnancy rates remained similar between the two groups in matched comparison and other subgroup analyses. CONCLUSION(S): Single and double-donor IUI cycles had similar clinical pregnancy rates. This large data set did not demonstrate a benefit to routine double IUI in donor sperm cycles.

Money-back guarantees.

As fertility rates among women of advanced reproductive age have steadily increased, so has the utilization of fertility services. National health policies provide infertility treatment coverage in several developed countries; however, in the United States infertility treatment is largely privately funded, resulting in limited access to care. In response to the lack of insurance coverage, many practices offer fertility treatment on a risk-sharing or contingency fee basis. The ethical delivery of care under the auspices of these programs requires adherence to core principles including transparency, patient autonomy, and the delivery of appropriate medical care. Moreover, concerns regarding patient understanding and decision making have also been of foremost concern. Patients must be able to fully appreciate the financial and clinical implications of contingency fee programs. To further explore patient comprehension and satisfaction, we surveyed participants in our shared risk assisted reproductive technology program. The overwhelming majority of respondents felt adequately informed of and fairly charged for their treatment. Our results demonstrate that shared risk programs can receive strong endorsement from participants, which may lead to improved utilization of and perseverance with fertility treatment.

Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of luteal phase P support after ovulation induction IUI. DESIGN: A systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Undergoing ovulation induction IUI. INTERVENTION(S): Any form of exogenous P in ovulation induction IUI cycles. MAIN OUTCOME MEASURE(S): Clinical pregnancy and live birth. RESULT(S): Five trials were identified that met inclusion criteria and comprised 1,298 patients undergoing 1,938 cycles. Clinical pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.15-1.98) and live birth (OR 2.11, 95% CI 1.21-3.67) were more likely in P-supplemented patients. These findings persisted in analyses evaluating per IUI cycle, per patient, and first cycle only data. In subgroup analysis, patients receiving gonadotropins for ovulation induction had the most increase in clinical pregnancy with P support (OR 1.77, 95% CI 1.20-2.6). Conversely, patients receiving clomiphene citrate (CC) for ovulation induction showed no difference in clinical pregnancy with P support (OR 0.89, 95% CI 0.47-1.67). CONCLUSION(S): Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUI cycles. Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction.

Trophectoderm grade predicts outcomes of single-blastocyst transfers.

OBJECTIVE: To estimate the effect of the embryo stage, trophectoderm (TE) morphology grade, and inner cell mass (ICM) morphology grade on live birth in single-blastocyst transfers. DESIGN: Retrospective cohort study. SETTING: Large private assisted reproductive technologies (ART) practice. PATIENT(S): Fresh autologous ART cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): A total of 694 single-blastocyst transfers met the inclusion criteria. Univariate regression analysis showed embryo stage and TE score to be correlated with implantation and live birth. Live birth rates were 57%, 40%, and 25% for TE grades A, B, and C, respectively. There was no significant association between ICM grade and implantation or live birth. Live birth rates were 53%, 52%, and 0% for ICM grades A, B, and C respectively. Multiple logistic regression analysis showed that only patient age and TE grade were significantly associated with implantation and live birth, whereas ICM grade was not significantly associated with outcome. The TE score had the strongest correlation with live birth. CONCLUSION(S): TE grading, but not ICM grading, significantly correlated with implantation and live birth for single-blastocyst transfers.