Barbara J. Stegmann

Five-years of a mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate without lowering pregnancy rates

OBJECTIVE To report the outcomes of a program policy instituted in 2004 mandating single-embryo transfer (mSET) for all women aged <38 years, with at least seven zygotes, no prior failed fresh cycle at our center, and at least one good-quality blastocyst. DESIGN Retrospective cohort study. SETTING Academic medical center. PATIENT(S) All women <38 years old undergoing a fresh cycle with autologous oocytes and all women undergoing a fresh cycle with donor oocytes from June 1, 1999, to May 31, 2004 (before mSET) and from June 1, 2004, to May 31, 2009 (after mSET). INTERVENTION(S) mSET policy implementation. MAIN OUTCOME MEASURE(S) Live-birth rate, multiple pregnancy rate, clinical volume, and outcomes of all mSET fresh IVF transfers were analyzed. RESULT(S) Clinical volume was unchanged between the two time groups. After implementation of mSET, live-birth rates improved from 51.1% to 55.9% and multiple-birth rates dropped from 34.8% to 17.5%. A total of 364 mSET fresh transfers were performed with a live-birth rate of 64.6% and a multiple-birth rate of 3.4%. CONCLUSION(S) A mandatory SET policy based on prognostic factors can be instituted with no drop in clinical volume and no negative effect on delivery rates. Multiple gestation rates can be dramatically lowered.

Effect of vitrification and thawing on human oocyte ATP concentration

Vitrification/thawing has a significant negative impact on oocyte ATP concentration. However, incubating oocytes up to 180 minutes after thawing allowed oocytes to regain some ATP level.

Cervical surgery for cervical intraepithelial neoplasia and prolonged time to conception of a live birth: a case-control study

To determine whether women with a history of surgery for cervical intraepithelial neoplasia (CIN) are at an increased risk of subfertility, measured as a time to pregnancy of more than 12 months.

Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.

STUDY QUESTION What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. REPORTS grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speakers bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER Not applicable.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization

OBJECTIVE To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN Phase 3 randomized, double-blind, noninferiority trial. SETTING Multicenter trial. PATIENT(S) A total of 1,390 women aged 35-42 years. INTERVENTION(S) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S) Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER NCT01144416.

Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles

BACKGROUND Various experiments suggest that ovarian follicular recruitment and growth may be increased by testosterone priming. Our aim was to determine the effects of exogenous testosterone supplementation in older women on ovarian folliculogenesis and steroidogenesis. METHODS A prospective randomized double-blind placebo-controlled crossover study was carried out. Twelve regularly menstruating non-obese women aged 38-45 years received a 12-day course of transdermal testosterone (2.5 mg per patch) or placebo patch, followed by 7 days of gonadotrophin stimulation. After at least a 1 month washout period, subjects underwent the same protocol using the opposite treatment. The main outcomes were follicular development (ultrasound measures) and hormone levels. RESULTS Following gonadotrophin stimulation, there were no differences in average number of follicles over 10 mm diameter in cycles pre-treated with testosterone versus placebo [2.10 (95% confidence interval (CI) 1.11, 3.22) versus 2.08 (95% CI 1.03, 3.14), P = 0.55]. No crossover, period (first or second test) or sequence (order of treatment) effects were noted. As expected, total and free testosterone levels were increased following testosterone treatment (312.7 +/- 122.4 versus 12.3 +/- 4.5 ng/dl and 45.5+/- 16.7 versus 1.4 +/- 0.5 ng/dl, respectively, P < 0.001) but no differences in free or total testosterone were noted by period. LH, FSH, estradiol and antral follicle counts before gonadotrophin stimulation were not altered by testosterone pretreatment or by period. CONCLUSIONS Despite increased testosterone levels, a short course of androgens had no significant effect on the number of follicles over 10 mm during stimulation with FSH in women of late reproductive age.

Unique ethical and legal implications of fertility preservation research in the pediatric population

Research in fertility preservation for children and adolescents receiving gonadotoxic chemotherapy has brought forth ethical and legal concerns that require special consideration. This article will discuss many of these issues and possible methods to safeguard the rights of these children.

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

Study Question What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels? Summary Answer The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm. What Is Known Already In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1–2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. Study Design, Size, Duration From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. Participants/Materials, Setting, Methods The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. Main Results and the Role of Chance The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. Limitations, Reasons for Caution This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. Wider Implications of the Findings For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. Trial Registration ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878

Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.

A meta-analysis was conducted of individual patient data (n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18-36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35-42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5-1.5); vital pregnancy rate: -2.2% (95% CI: -5.3%-0.9%); ongoing pregnancy rate: -1.7% (95% CI: -4.7%-1.4%); and live birth rate: -2.0% (95% CI: -5.0%-1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82-1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81-2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH.

A logistic model for the prediction of endometriosis.

OBJECTIVE To develop a model that uses individual and lesion characteristics to help surgeons choose lesions that have a high probability of containing histologically confirmed endometriosis. DESIGN Secondary analysis of prospectively collected information. SETTING Government research hospital in the United States. PATIENT(S) Healthy women 18-45 years of age, with chronic pelvic pain and possible endometriosis, who were enrolled in a clinical trial. INTERVENTION(S) All participants underwent laparoscopy, and information was collected on all visible lesions. Lesion data were randomly allocated to a training and test data set. MAIN OUTCOME MEASURE(S) Predictive logistic regression, with the outcome of interest being histologic diagnosis of endometriosis. RESULT(S) After validation, the model was applied to the complete data set, with a sensitivity of 88.4% and specificity of 24.6%. The positive predictive value was 69.2%, and the negative predictive value was 53.3%, equating to correct classification of a lesion of 66.5%. Mixed color; larger width; and location in the ovarian fossa, colon, or appendix were most strongly associated with the presence of endometriosis. CONCLUSION(S) This model identified characteristics that indicate high and low probabilities of biopsy-proven endometriosis. It is useful as a guide in choosing appropriate lesions for biopsy, but the improvement using the model is not great enough to replace histologic confirmation of endometriosis.