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Context Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. Objective We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. Methods This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. Results After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. Conclusion Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.

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.

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 speaker's 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.

Aim The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. Methods Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 – 180 μg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. Results A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m−2); 14% higher in women with a BMI of 18 kg m−2 vs. 32 kg m−2 (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. Conclusions Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label.

Objective: Determine if specific demographic and clinical variables are associated with intra-uterine contraception (IUC) placement by eight weeks postpartum. Methods: This retrospective cohort study included all patients who delivered at Dartmouth-Hitchcock Medical Center (DHMC) (July-December 2008) who identified IUC as their preferred postpartum contraceptive method. Medical records of patients identified from the birth log were reviewed for preferred contraception, demographics, medical, obstetric, and social histories, as well as payer status. Chi-squared analysis was performed for categorical variables, and Mann-Whitney U test was used for continuous variables. Nonparametric continuous variables were categorized for regression modeling. Results: 224 (34%) patients who delivered identified IUC as their preferred method of postpartum contraception. Of these, 94 (49.7%) women had an IUC placed by 8 weeks postpartum. In univariate analyses comparing those who received an IUC versus those patients who did not, only mean interdelivery interval in months (39.7 vs. 35.5, p=0.027) and mean gravidity (2.3 vs. 2.8, p=0.036) were statistically significant. In multivariate regression modeling, no variables were significantly associated with IUC placement. Conclusions: While statically significant interdelivery interval and gravidity are not likely to be clinically significant. Multivariate modeling failed to identify a model associated with IUC placement suggesting that postpartum IUC placement is not well predicted by patient variables. Lack of identifying factors may support offering postplacental IUC placement to all patients who indicate IUC as their preferred contraceptive method.

Objective: To determine the influence of the infertility diagnosis on gestational age (GA) and birth weight (BW) of children conceived using assisted reproductive technology (ART). Design: Retrospective cohort. Setting: University-affiliated infertility clinic. Patients: Women with a singleton live birth following their first fresh ART cycle with autologous oocytes. Interventions: Patients were stratified into groups based on infertility diagnosis. GA and BW of their infants were compared. Main Outcome Measures: GA and BW of children conceived using ART. Results: 397 women were included. Average GA in the cohort was 38.7±2.3 weeks and average BW was 3301.5±633.8 grams. Maternal age, BMI, and parity were significantly different between groups. After controlling for these factors and stratifying by infertility diagnosis, there was no difference in GA or BW in infants conceived with ART. Conclusions: Contrary to previously reported data, there was no difference in GA or BW in infants conceived with ART when stratified by infertility diagnosis. Our results were not different from the national population; however GA was one week longer in our cohort than in the national ART database. These data suggest a difference exists between our cohort and the ART population at large. We propose that the main difference is our institution’s focus on single embryo transfer.

Objective 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. Design Case–control study. Setting Iowa Health in Pregnancy Study (IHIPS), a population-based case–control study of preterm and small-for-gestational-age (SGA) live birth outcomes (from May 2002 through June 2005) in the USA. Sample Women with an intended pregnancy and a history of either one prior cervical surgery (n = 152), colposcopy only (n = 151), or no prior cervical surgery or colposcopy (n = 1021). Methods Cervical treatment history, pregnancy intention, time to pregnancy, and other variables were self-reported by computer-assisted telephone interviews. Odds ratios were calculated using logistic regression to estimate the risk of prolonged time to pregnancy among women with a history of cervical surgery or colposcopy alone, compared with untreated women (control group). Main outcome measure Prolonged time to pregnancy (i.e. >1 year). Results Prolonged time to pregnancy was most prevalent among treated women (16.4%), compared with untreated women (8.4%) and women with colposcopy only (8.6%) (P = 0.039). After adjusting for covariates, women with prior cervical surgery had a more than two-fold higher risk of prolonged time to pregnancy compared with untreated women (aOR 2.09, 95% CI 1.26–3.46). In contrast, women with a history of colposcopy only had a risk equivalent to that found among untreated women (aOR 1.02, 95% CI 0.56–1.89). Conclusions Women with a history of cervical treatment for CIN are at increased risk of subfertility, measured as a time to pregnancy of more than 12 months.

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.

Objective To determine a minimum number of procedures required for proficiency in oocyte retrieval and to characterize skill acquisition. Design Retrospective analysis. Setting Reproductive endocrinology and infertility fellowship training program. Subject(s) Fellows in training from 2005 to 2007 and 2008 to 2010. Intervention(s) None. Main Outcome Measure(s) Proficiency scores were calculated by dividing the number of oocytes retrieved by oocytes expected. The 2005 to 2007 trainees were grouped and proficiency scores calculated as an average during specific points in their training. The 2008 to 2010 trainees were compared individually to determine differences in individual skill acquisition. Result(s) A greater number of oocytes were retrieved than expected, 8.6 versus 7.6. A relatively lower proficiency score was noted during the first 10 trainee aspirations (proficiency score=1.1) compared with subsequent aspirations (proficiency score=1.25 for retrievals 11–20, proficiency score=1.21 for retrievals 21–30 and >31). When individual fellows' scores were calculated, the majority achieved proficiency by 20 aspirations, and all but one trainee achieved the mean staff proficiency score by 50 retrievals. Conclusion(s) Regardless of a trainee's initial proficiency in oocyte retrieval, there were no statistically significant differences in the learning curve between trainees. The majority of individual fellows in training demonstrate proficiency in follicular aspirations within 20 procedures; however, a minority may require 50 procedures to achieve the proficiency of an attending physician.

Objective To predict the cost of a delivery following assisted reproductive technologies (ART). Design Cost analysis based on retrospective chart analysis. Setting University-based ART program. Patient(s) Women aged ≥26 and ≤42 years with FSH levels ≤12 IU/L on day 3 undergoing a first cycle of fresh, nondonor ART. Intervention(s) Logit regression using a fractional polynomial model of age and basal FSH was used to estimate the probability of a live birth. Cost analysis was applied to the resulting prediction. Main Outcome Measure(s) The predicted probability of a live birth following ART based on a woman's age and FSH and the associated cost of a live birth. Result(s) Analysis of 1,238 first ART cycles produced a prediction model for live birth rates following ART incorporating both age and FSH. A cost analysis based upon combination of age and FSH revealed the cost of a live birth exceeded $100,000 when the probability of a live birth fell below 15% and the cost rose exponentially at lower probabilities of live birth. Conclusions(s) Based upon a woman's age and FSH and expected cost for a live birth using ART may be calculated. At live birth rates

Background This secondary analysis aimed to identify predictors of low (18 oocytes retrieved) in IVF patients undergoing controlled ovarian stimulation with corifollitropin alfa in a gonadotropin-releasing hormone (GnRH) antagonist protocol. Methods Statistical model building for high and low ovarian response was based on the 150 μg corifollitropin alfa treatment group of the Pursue trial in infertile women aged 35–42 years (n = 694). Results Multivariable logistic regression models were constructed in a stepwise fashion (P

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.

Objective To assess safety in terms of birth defects in infants conceived following ovarian stimulation with corifollitropin alfa (CFA) compared with recombinant FSH (rFSH). Design Incidence of congenital malformations from 379 live-born infants in the Pursue RCT. Analysis of congenital malformations based on integrated data including an additional 794 live-born infants from 2 other RCTs of CFA and rFSH.1 Materials and Methods The Pursue trial included 1390 women aged 35-42 years. Pregnant women having received 150 μg CFA (n=154) or 300 IU/d rFSH (n=167) were enrolled, resulting in 183 and 196 live-born infants, respectively. All congenital malformations were classified blindly by an independent expert according to CDC/Broad criteria. The CFA to rFSH odds ratio (OR) for congenital malformations was calculated based on integrated data from Pursue and 2 RCTs on younger women aged 18-361 using the Cochran-Mantel-Haenszel method (stratified by trial and single or multiple pregnancy). Results In Pursue the percentage of live-born infants with congenital malformations was similar in the CFA and rFSH groups (18.0% and 19.4%, respectively). The incidence of major congenital malformations was also similar in both groups (4.9% and 3.1%, respectively). In the 3 RCTs combined, the percentage of live-born infants with congenital malformations was similar in the CFA and rFSH groups (16.8% and 17.8%, respectively). The CFA to rFSH OR for congenital malformations was 0.93 (95% CI: 0.68-1.25). The OR for major congenital malformations (4.3% in the CFA group vs. 4.6% in the rFSH group) was 0.90 (95% CI: 0.52-1.57). Congenital malformations were more common in infants born from a multiple pregnancy in the rFSH group (24.1% vs. 14.4%), but less so in the CFA group (17.9% vs. 16.1%). Conclusion Across 3 RCTs, with over 1,000 live-born infants, the incidence of congenital malformations was similar following ovarian stimulation with CFA and rFSH.

Objective To examine the efficacy and safety of frozen-thawed embryo transfer (FTET) cycles with supernumerary embryos cryopreserved during a randomized clinical trial (PURSUE). Design Follow-up clinical study. Setting In vitro fertilization (IVF) centers. Patient(s) Infertile women 35 to 42 years of age. Intervention(s) In PURSUE, women were randomized to a single injection of 150 μg of corifollitropin alfa (n = 694) or daily 300 IU of recombinant follicle-stimulating hormone (recombinant FSH; n=696) for the first 7 days of controlled ovarian stimulation (COS) in a gonadotropin-releasing hormone (GnRH) antagonist protocol. Main Outcome Measure(s) Cumulative vital pregnancy rate per-patient by treatment group, cumulative live-birth rate per-patient by treatment group, and occurrence of adverse events in (pregnant) women and their fetuses/infants and the incidence of congenital malformations in the infants. Result(s) Of the 1,390 treated women in PURSUE, 307 were enrolled in the FTET study. In PURSUE or a subsequent FTET cycle, the cumulative vital pregnancy rate (per patient) was 31.1% (95% confidence interval [CI], 27.7%; 34.7%) with corifollitropin alfa versus 33.0% (95% CI: 29.6%; 36.7%) with recombinant FSH; treatment difference, −1.8% (95% CI, −6.5%; 3.0%), and the cumulative live-birth rate (per patient) was 28.2% (95% CI, 24.9%; 31.8%) with corifollitropin alfa versus 29.5% (95% CI, 26.1%; 33.0%) with recombinant FSH; treatment difference, −1.2% (95% CI, −5.7%; 3.4%). There were no clinically relevant differences in safety outcomes collected from pregnant women or their infants after transfer of cryopreserved embryos obtained by treatment with corifollitropin alfa or recombinant FSH. Conclusion(s) The cumulative vital pregnancy and live-birth rates (from fresh cycles and FTET) were similar in women treated with corifollitropin alfa and recombinant FSH. No new safety signals were detected in this follow-up FTET study. Clinical Trial Registration Number NCT01146418.

Objective And Study Design: Ovarian needle diathermy was used in the treatment of clomiphene-resistant polycystic ovarian syndrome (PCOS). Factors predictive of pregnancy in our study group included younger age, lower body weight, and surgery before 1998. Results And Conclusion: Insulin resistance and adhesions at surgery were negatively associated with pregnancy. Sixty-six percent of the study group cycled spontaneously after surgery and 50% became pregnant. (Am J Obstet Gynecol 2003;188:1171-3.)

Introduction: The aim of this study was to determine if laterality of an absent umbilical artery (AUA) is associated with specific sonographic findings, chromosomal defects or postpartum birth defects. Materials and Methods: In this retrospective cohort study, ultrasound reports and medical records of patients who received an obstetric ultrasound at the University of Iowa Hospitals and Clinics with an identified laterality of the AUA from 1989 to 2007 (n = 405) were reviewed. Rates of sonographic abnormalities between fetuses with a right versus left AUA were compared using Fisher’s exact test. Adjustments for confounding were made using logistic regression modeling. The significance level was set at 0.05. Results: Right AUAs on ultrasound demonstrate higher unadjusted rates of ultrasound abnormalities with a higher percentage of fetuses with >1 additional abnormality (51.1 vs. 37.0%; p = 0.0043). The left AUA group had a significantly higher percentage of isolated AUA (63.0 vs. 48.8%; p = 0.004). In a multivariate analysis, a sonographic right AUA was significantly associated with gastrointestinal (GI) and genitourinary (GU) abnormalities. No other ultrasonographic and umbilical artery Doppler abnormalities, chromosomal defects or postpartum birth defects were significantly associated with a specific laterality of the AUA. Discussion: Our study identified a significant association between a right AUA and concomitant fetal GI and GU abnormalities. Contrary to previous reports, we conclude that laterality of the AUA may prove to be an easily identified early marker of fetal abnormalities.

Objective The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. Study Design A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. Results The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55–17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually. Conclusion Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors.

To report the outcomes of a program policy instituted in 2004 mandating single-embryo transfer (mSET) for all women aged38 years, with at least seven zygotes, no prior failed fresh cycle at our center, and at least one good-quality blastocyst.Retrospective cohort study.Academic medical center.All women38 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).mSET policy implementation.Live-birth rate, multiple pregnancy rate, clinical volume, and outcomes of all mSET fresh IVF transfers were analyzed.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%.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.

Objective To determine whether patients support a mandatory single blastocyst transfer (mSBT) policy in IVF. Design Prospective survey study. Setting Academic hospital–based infertility center. Patient(s) Two hundred sixty-two female patients presenting for fresh or cryopreserved/thawed ET after IVF. Intervention(s) Internet-based in-clinic survey after ET. Follow-up at-home survey after pregnancy test results. Main Outcome Measure(s) Patient support for an mSBT policy and attitudes regarding patient input into IVF treatment. Logistic regression analyses tested associations among main outcome measures, patient characteristics, and treatment results. Result(s) Ninety-four percent of patients endorsed support for our mSBT policy; 95% and 87% felt they had the right amount of input in their IVF treatment and number of embryos transferred, respectively, and these subjects were more likely to support the mSBT policy. Other factors associated with stronger support were concern for multiples, availability of extra cryopreserved embryos, and shorter duration of infertility. Receiving a single blastocyst during treatment did not change the level of support. A negative pregnancy outcome decreased support, however. Conclusion(s) Policies restricting the number of embryos transferred may find wide patient acceptance.

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 ¼ 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.

Objective To examine ovarian response in infertile women undergoing ovarian stimulation after abdominal myomectomy. Design Case report. Setting Academic medical research center. Patient(s) Four infertile women with known fibroids who had a failed assisted reproductive technology (ART) cycle followed by an abdominal myomectomy. Intervention(s) Infertile women with known fibroids who had a failed ART cycle, from January 2000 to December 2006, followed by an abdominal myomectomy and a subsequent ART cycle. Main Outcome Measure(s) Ovarian function before (baseline) and after myomectomy was assessed by age, day 3 and day 10 FSH levels, days of stimulation, total gonadotropins used, peak E 2 level, the number of oocytes retrieved and embryos obtained, the number of high-grade embryos, and pregnancy outcome. Result(s) The mean age was 35 and 36 years before and after myomectomy, respectively. All subjects had uterine factor infertility. Two of these women also had tubal factor infertility, and one had endometriosis and male factor infertility. There was no difference in ovarian response before and after myomectomy. Conclusion(s) As expected, abdominal myomectomy did not adversely affect ovarian response in infertile women undergoing ovarian stimulation after a failed ART cycle. Larger randomized prospective studies are needed to accurately assess whether myomectomy has a negative impact on ovarian response.

Objective To correlate histology with endometriosis characteristics. Design Secondary data analysis. Setting Government research hospital. Patient(s) One hundred thirty-three women with chronic pelvic pain and endometriosis who underwent laparoscopic surgery between 1999 and 2004. Intervention(s) Laparoscopic excision of lesions, including recording of lesion characteristics and surgical impression of the lesions. Main Outcome Measure(s) All biopsies were sent for histological examination for endometriosis, and surgical and histological findings were compared. Result(s) Three hundred fifty-seven of 544 lesions believed to be endometriosis by the surgeon had positive histology. Mixed-color lesions most commonly contained endometriosis (76%), with the percentage of positive lesions being similar between single-color groups. Among subtle (red or white) lesions, 58% (164/283) were positive for endometriosis. Thirty women had only red or white lesions, and 18 (60%) had at least one lesion positive for endometriosis. Lesions were most commonly located in the cul-de-sac (64%), utero-sacral ligaments (68%), and ovarian fossa (70%). Conclusion(s) Wide, deep, mixed-color lesions in the cul-de-sac, the ovarian fossa, or the utero-sacral ligaments had the highest frequency of endometriosis. More than half of subtle lesions had endometriosis. These results should be considered when diagnosing endometriosis.

A retrospective cohort study examining all completed nondonor first ART cycles was performed to evaluate the ultrasonographic appearance of the endometrial pattern and thickness at time of hCG administration among precycle screened patients with uterine fibroids compared with patients without fibroids. There was no difference in the endometrial thickness (10.3 +/- 2.0 mm vs. 10.0 +/- 2.6 mm) between those with fibroids and controls; however, the rate of nonproliferative endometrial pattern (3.1% vs. 1.0%) and live birth rates (34.4% vs. 43.0%) were significantly different, most notably among those patients with intramural fibroids.

Objective To determine the association of preterm birth with antimullerian hormone (AMH) levels both in isolation and in combination with other markers of fetoplacental health commonly measured during integrated prenatal screening (IPS) for aneuploidy. Design Retrospective case-control study. Setting Not applicable. Patient(s) Pregnant women in Iowa who elected to undergo IPS and who subsequently delivered in Iowa, including women giving birth at Intervention(s) None. Main Outcome Measure(s) Probability of a preterm birth. Result(s) Second trimester AMH levels were not associated with preterm birth, either independently or after controlling for other markers of fetoplacental health. The AMH difference was not associated with preterm birth when modeled alone, but a statistically significant association was found after adjusting for maternal serum α-fetoprotein (MSAFP) and maternal weight change between the first and second trimesters. After stratifying the model by MSAFP level, most of the risk for preterm birth was identified in women with an MSAFP >1 multiple of the median and who had a stable or rising AMH level in early pregnancy. Conclusion(s) A lack of decline in the AMH level in early pregnancy can be used to identify women with a high probability for preterm birth, especially when MSAFP levels are >1 multiple of the median. Monitoring changes in the AMH level between the first and second trimesters of pregnancy may help identify women who would benefit from interventional therapies such as supplemental progesterone.

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.

Objective To critically examine ovarian reserve testing before assisted reproduction. Design A PUBMED computer search to identify relevant literature. Setting Multiple sites. Patient(s) Patients undergoing assisted reproduction. Intervention(s) Testing for ovarian reserve. Main Outcome Measure(s) Assisted reproductive technology (ART) and pregnancy outcomes. Result(s) The prevalence of ovarian insufficiency varies significantly for women aged 30–45 years. Generalization or averaging of threshold values across different aged women leads to very poor sensitivity, specificity, and positive predictive value for all tests of ovarian reserve. Because of the changing prevalence of ovarian insufficiency, there is no single, suitable threshold value for any screening test of ovarian reserve. Our analysis supports dividing impaired ovarian reserve into two groups: age-dependent ovarian aging (physiologic) and premature (nonphysiologic) reductions in the oocyte pool. Interpretation of any screening test used requires that age is considered as a variable. To guide clinical interpretation of test results, we suggest using a nomogram of FSH values versus expected delivery rate-per-cycle-start with ART for a given age. Conclusion(s) Proper interpretation of screening tests for ovarian insufficiency in couples considering ART is important as the presence of impaired ovarian reserve is associated with a low likelihood of pregnancy. The condition of premature (nonphysiologic) ovarian insufficiency warrants additional research.

Maternal anti-mullerian hormone declines sharply between 13-15 weeks, likely as a result of feto-placental signaling. Fetal AMH levels are known to be widely disparate after the first trimester, with high levels in male and absent levels in female. However, it is unclear as to whether differing fetal AMH levels influence the pattern of change of maternal AMH. Our objective was to examine AMH throughout gestation to determine if the maternal concentration varies according to the gender of the fetus.

Perinatal infections account for 2% to 3% of all congenital anomalies. TORCH, which includes Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes infections, are some of the most common infections associated with congenital anomalies. Most of the TORCH infections cause mild maternal morbidity, but have serious fetal consequences, and treatment of maternal infection frequently has no impact on fetal outcome. Therefore, recognition of maternal disease and fetal monitoring once disease is recognized are important for all clinicians. Knowledge of these diseases will help the clinician appropriately counsel mothers on preventive measures to avoid these infections, and will aid in counseling parents on the potential for adverse fetal outcomes when these infections are present.

Clearly, more research is required to fully evaluate the impact of stress on both fertile and infertile women, and discovery of a biomarker that correlates well with psychosocial stress would be a great advantage to researchers. This article is a first step toward that goal, but it may be premature to assign these findings to stress alone.

Follicle-Stimulating Hormone (FSH) drops rapidly in pregnancy but Anti-Mullerian Hormone (AMH) has not been shown to drop until about 12 weeks. Since the follicles that secrete AMH are thought to be FSH independent, AMH levels should slowly decline in the absence of FSH because when the follicles reach FSH dependence, they would die off. A study has presented data that suggests a decline in AMH levels suddenly starts at 12 weeks gestation. The present study agrees with a decline in AMH after the first trimester. There is a sharp decline in AMH at 12-16 weeks gestation indicating that the follicular development is actively suppressed, not passively lost because of a drop in FSH. It appears that pregnancy may be a unique situation in regards to AMH.