Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2008, 2009 and 2010.

STUDY QUESTION: What were utilization, outcomes and practices in assisted reproductive technology (ART) globally in 2008, 2009 and 2010? SUMMARY ANSWER: Global utilization and effectiveness remained relatively constant despite marked variations among countries, while the rate of single and frozen embryo transfers (FETs) increased with a concomitant slight reduction in multiple birth rates. WHAT IS KNOWN ALREADY: ART is widely practised in all regions of the world. Monitoring utilization, an approximation of availability and access, as well as effectiveness and safety is an important component of universal access to reproductive health. STUDY DESIGN, SIZE, DURATION: This is a retrospective, cross-sectional survey on utilization, effectiveness and safety of ART procedures performed globally from 2008 to 2010. PARTICIPANTS, SETTING, METHODS: Between 58 and 61 countries submitted data from a total of nearly 2500 ART clinics each year. Aggregate country data were processed and analyzed based on forms and methods developed by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART). Results are presented at country, regional and global level. MAIN RESULTS AND THE ROLE OF CHANCE: For the years 2008, 2009 and 2010, >4 461 309 ART cycles were initiated, resulting in an estimated 1 144 858 babies born. The number of aspirations increased by 6.4% between 2008 and 2010, while FET cycles increased by 27.6%. Globally, ART utilization remained relatively constant at 436 cycles/million in 2008 and 474 cycles/million population in 2010, but with a wide country range of 8-4775 cycles/million population. ICSI remained constant at around 66% of non-donor aspiration cycles. The IVF/ICSI combined delivery rate (DR) per fresh aspiration was 19.8% in 2008; 19.7% in 2009 and 20.0% in 2010, with corresponding DRs for FET of 18.8, 19.7 and 20.7%. In fresh non-donor cycles, single embryo transfer increased from 25.7% in 2008 to 30.0% in 2010, while the average number of embryos transferred fell from 2.1 to 1.9, again with wide regional variation. The rates of twin deliveries following fresh non-donor transfers were, in 2008, 2009 and 2010, 21.8, 20.5 and 20.4%, respectively, with a corresponding triplet rate of 1.3, 1.0 and 1.1%. Fresh IVF and ICSI carried a perinatal mortality rate per 1000 births of 22.8 (2008), 19.2 (2009) and 21.0 (2010), compared with 15.1, 12.8 and 14.6/1000 births following FET in the same periods of observation. The proportion of women aged 40 years or older undergoing non-donor ART increased from 20.8 to 23.2% from 2008 to 2010. LIMITATIONS, REASON FOR CAUTION: The data presented are reliant on the quality and completeness of data submitted by individual countries. This report covers approximately two-thirds of the world ART activity. WIDER IMPLICATIONS OF FINDINGS: The ICMART World Reports provide the most comprehensive global statistical census and review of ART utilization, effectiveness, safety and quality. While ART treatment continues to increase globally, the wide disparities in access to treatment and embryo transfer practices warrant attention by clinicians and policy makers. STUDY FUNDING/COMPETING INTERESTS: The authors declare no conflict of interest and no specific support from any organizations in relation to this manuscript. ICMART acknowledges financial support from the following organizations: American Society for Reproductive Medicine; European Society for Human Reproduction and Embryology; Fertility Society of Australia; Japan Society for Reproductive Medicine; Japan Society of Fertilization and Implantation; Red Latinoamericana de Reproduccion Asistida; Society for Assisted Reproductive Technology; Government of Canada (Research grant), Ferring Pharmaceuticals (Grant unrelated to World Reports). TRIAL REGISTRATION: not applicable.

International Committee for Monitoring Assisted Reproductive Technologies (ICMART) world report: assisted reproductive technology 2004.

STUDY QUESTION: Have changes in assisted reproductive technology (ART) practice and outcomes occurred globally between 2003 and 2004? SUMMARY ANSWER: Globally, ART practice has changed with an increasing prevalence of the use of ICSI rather than conventional IVF. In 2004, a small but increasing number of countries are incorporating single embryo transfer. There remain unacceptably high rates of three or more embryo transfers in select countries resulting in multiple births and adverse perinatal outcomes. WHAT IS KNOWN ALREADY: World data on the availability, effectiveness and safety of ART have been published since 1989. The number of embryos transferred is a major determinant of the iatrogenic increase in multiple pregnancies and is highly correlated with the likelihood of multiple birth and excess perinatal morbidity and mortality. STUDY DESIGN, SIZE, DURATION: Cross-sectional survey of countries and regions undertaking surveillance of ART procedures started in 2004 and their corresponding outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of total, 2184 clinics from 52 reporting countries and regions. Number of ART clinics, types of cycles and procedures, pregnancy, delivery and multiple birth rates and perinatal outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 954 743 initiated cycles resulted in an estimated 237 809 babies born. This was a 2.3% increase in the number of reported cycles from 2003. The availability of ART varied by country and ranged from 14 to 3844 treatment cycles per million population. Over one-third (37.2%) of ART clinics performed <100 cycles per year with only 19.9% performing ≥ 500 cycles per year. Of all cycles, 60.6% were ICSI. Frozen embryo transfers (FETs) represented 31% of the initiated cycles. The overall delivery rate per fresh aspiration for IVF and ICSI was 20.2% compared with 16.6% per FET. The average number of embryos transferred was 2.35. Single (16.3%) and double embryo transfers accounted for 73.2% of cycles. The overall proportion of deliveries with twins and triplets from IVF and ICSI was 25.1 and 1.8%, respectively, but varied widely by country and region. The proportion of premature deliveries per fresh aspiration for IVF and ICSI was 33.7% compared with 26.3% per FET. The perinatal death rate was 25.8 per 1000 births for fresh aspiration for IVF and ICSI compared with 14.2 per 1000 births per FET. LIMITATIONS, REASONS FOR CAUTION: Data are incomplete with seven countries not providing data to the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in 2004 that had in 2003. The validity of data reflects current data collection practice. In 2004, 79.3% of the clinics in participating countries reported to their national or regional registries and to ICMART. In addition, the number of ART cycles per million population is a measure which is affected by a country's government policy, regulation, funding and the number of service providers. WIDER IMPLICATIONS OF THE FINDINGS: ART practice, effectiveness and outcomes vary markedly internationally. Notably, the increasing proportion of cycles that are FET, the change in practice to single embryo transfer and the cessation of the transfer of three or more embryos in some countries has resulted in improved perinatal outcomes with minimal impact on pregnancy rates. STUDY FUNDING/COMPETING INTEREST(S): ICMART receives financial support from ASRM, ESHRE, FSA, Japan Society for Reproductive Medicine, REDLARA, MEFS and SART.

Top 10 priorities for future infertility research: an international consensus development study.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/ COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Not applicable.

EQUSUM: Endometriosis QUality and grading instrument for SUrgical performance: proof of concept study for automatic digital registration and classification scoring for r-ASRM, EFI and Enzian.

STUDY QUESTION: Is electronic digital classification/staging of endometriosis by the EQUSUM application more accurate in calculating the scores/stages and is it easier to use compared to non-digital classification? SUMMARY ANSWER: We developed the first digital visual classification system in endometriosis (EQUSUM). This merges the three currently most frequently used separate endometriosis classification/scoring systems (i.e. revised American Society for Reproductive Medicine (rASRM), Enzian and Endometriosis Fertility Index (EFI)) to allow uniform and adequate classification and registration, which is easy to use. The EQUSUM showed significant improvement in correctly classifying/scoring endometriosis and is more user-friendly compared to non-digital classification. WHAT IS KNOWN ALREADY: Endometriosis classification is complex and until better classification systems are developed and validated, ideally all women with endometriosis undergoing surgery should have a correct rASRM score and stage, while women with deep endometriosis (DE) should have an Enzian classification and if there is a fertility wish, the EFI score should be calculated. STUDY DESIGN SIZE DURATION: A prospective endometriosis classification proof of concept study under experts in deep endometriosis was conducted. A comparison was made between currently used non-digital classification formats for endometriosis versus a newly developed digital classification application (EQUSUM). PARTICIPANTS/MATERIALS SETTING METHODS: A hypothetical operative endometriosis case was created and summarized in both non-digital and digital form. During European endometriosis expert meetings, 45 DE experts were randomly assigned to the classic group versus the digital group to provide a proper classification of this DE case. Each expert was asked to provide the rASRM score and stage, Enzian and EFI score. Twenty classic forms and 20 digital forms were analysed. Questions about the user-friendliness (system usability scale (SUS) and subjective mental effort questionnaire (SMEQ)) of both systems were collected. MAIN RESULTS AND THE ROLE OF CHANCE: The rASRM stage was scored completely correctly by 10% of the experts in the classic group compared to 75% in the EQUSUM group (P < 0. 01). The rASRM numerical score was calculated correctly by none of the experts in the classic group compared with 70% in the EQUSUM group (P < 0.01). The Enzian score was correct in 60% of the classic group compared to 90% in the EQUSUM group (P = 0.03). EFI scores were calculated correctly in 25% of the classic group versus 85% in the EQUSUM group (P < 0.01). Finally, the usability measured with the SUS was significantly better in the EQUSUM group compared to the classic group: 80.8 ± 11.4 and 61.3 ± 20.5 (P < 0.01). Also the mental effort measured with the SMEQ was significant lower in the EQUSUM group compared to the classic group: 52.1 ± 18.7 and 71.0 ± 29.1 (P = 0.04). Future research should further develop and confirm these initial findings by conducting similar studies with larger study groups, to limit the possible role of chance. LIMITATIONS REASONS FOR CAUTION: These first results are promising, however it is important to note that this is a preliminary result of experts in DE and needs further testing in daily practice with different types (complex and easy) of endometriosis cases and less experienced gynaecologists in endometriosis surgery. WIDER IMPLICATIONS OF THE FINDINGS: This is the first time that the rASRM, Enzian and EFI are combined in one web-based application to simplify correct and automatic endometriosis classification/scoring and surgical registration through infographics. Collection of standardized data with the EQUSUM could improve endometriosis reporting and increase the uniformity of scientific output. However, this requires a broad implementation. STUDY FUNDING/COMPETING INTERESTS: To launch the EQUSUM application, a one-time financial support was provided by Medtronic to cover the implementation cost. No competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009.

BACKGROUND: Many definitions used in medically assisted reproduction (MAR) vary in different settings, making it difficult to standardize and compare procedures in different countries and regions. With the expansion of infertility interventions worldwide, including lower resource settings, the importance and value of a common nomenclature is critical. The objective is to develop an internationally accepted and continually updated set of definitions, which would be utilized to standardize and harmonize international data collection, and to assist in monitoring the availability, efficacy, and safety of assisted reproductive technology (ART) being practiced worldwide. METHOD: Seventy-two clinicians, basic scientists, epidemiologists and social scientists gathered together at the WHO headquarters in Geneva, Switzerland in December, 2008. Several months in advance, three working groups were established which were responsible for terminology in three specific areas: clinical conditions and procedures, laboratory procedures and outcome measures. Each group reviewed the existing ICMART glossary, made recommendations for revisions and introduced new terms to be considered for glossary expansion. RESULTS: A consensus was reached on 87 terms, expanding the original glossary by 34 terms, which included definitions for numerous clinical and laboratory procedures. Special emphasis was placed in describing outcome measures such as cumulative delivery rates and other markers of safety and efficacy in ART. CONCLUSIONS: Standardized terminology should assist in analysis of worldwide trends in MAR interventions and in the comparison of ART outcomes across countries and regions. This glossary will contribute to a more standardized communication among professionals responsible for ART practice, as well as those responsible for national, regional and international registries.

Multimedia article. Laparoscopic transection choledochoduodenostomy.

Choledochoduodenostomy is a well-established procedure and is indicated in patients with multiple ductal calculi and dilated common bile duct (>or=2.0 cm) because these patients require drainage for good long-term results without recurrence of jaundice or cholangitis. The technique most commonly used is that of a side-to-side hand-sutured anastomosis between the supraduodenal common bile duct and the duodenum. The merit of this technique is its simplicity, although it is prone to duodenobiliary reflux and to occasional symptomatic inspissation with food debris causing cholangitis (sump syndrome). It is the technique that has been adopted by most centers for laparoscopic choledochoduodelaostomy. The alternative operation, transection choledochoduodenostomy, excludes the distal (transpancreatic) segment of the bile duct from the end-to-side anastomosis of the transected common bile duct with the second part of the duodenum. The long-term results of this procedure are excellent, and for this reason we have used it for laparoscopic drainage of the common bile duct in six elderly patients (four females and two males; age range, 61-72 years) with multiple occluding ductal calculi and grossly dilated bile duct. Three of these patients (including the one shown in the multimedia video) were admitted acutely with bacterial cholangitis and required emergency insertion of pigtail stent to overcome the acute septic illness. There were no conversions. The first operation lasted 4 h but the operating times in the last two patients were 2.0 and 2.5 h. The results have been excellent, with no deaths and a low postoperative morbidity (chest infection in one patient) and median postoperative hospital stay of 5 days.

Somatomedins in pregnancy: a cross-sectional study of insulin-like growth factors I and II and somatomedin peptide content in normal human pregnancies.

To explore the role of the somatomedins (SM) during human pregnancy, we have measured plasma levels of insulin-like growth factor I (IGF-I), IGF-II, and SM peptide content (SMPC) in 79 women in various stages of normal pregnancies. IGF-I and IGF-II were measured by specific RIAs, and SMPC was measured by a radioreceptor assay using human placental membranes. IGF-I and SMPC rose during pregnancy, showing a significant positive correlation with the length of gestation. Plasma levels of IGF-I in the third trimester averaged 324 ng/ml, a 33% increase over the first trimester average of 243 ng/ml (P less than 0.05). Although IGF-II did not correlate with the length of gestation, the third trimester average was significantly higher than the first trimester average (780 vs. 630 ng/ml; P less than 0.05). After delivery, both IGF-I and IGF-II levels rapidly dropped to levels significantly below those seen in the third trimester. The gestational rise in SMPC and plasma levels of both IGF-I and IGF-II supports the hypothesis that SM play a role in the regulation of fetal growth.

13CO2 isotopic laser used through the operating channel of laser laparoscopes: a comparative study of power and energy density losses.

OBJECTIVE: To evaluate the power transmission, spot size, power density, and energy density of a new isotopic carbon dioxide (13CO2) laser compared with a conventional CO2 laser. METHODS: Experiments were performed in a laboratory using a conventional CO2 laser and an isotopic 13CO2 laser. Two laparoscopes with 5-mm and 7.5-mm operating channels were connected to a standard coupler and to each of the lasers. Standardized measurements were made of power transmission and spot size using both nitrogen purge gas and CO2 purge gas at rates of 1-20 L/minute. Power density and energy density were calculated for continuous mode and ultrapulse mode transmission, respectively. RESULTS: The isotopic 13CO2 laser power transmission was higher and proportional to input power, while spot size was smaller compared with the conventional laser and was insensitive to power level or purge rate. Power density and energy density were markedly higher with the isotopic 13CO2 laser, reaching the threshold for complete ablation, and were much more predictable. The 7.5-mm operating channel generally had superior operating results compared with the 5-mm channel because of the smaller spot size and higher power transmission. CONCLUSIONS: The isotopic 13CO2 laser is associated with much higher power density and energy density capabilities than are conventional CO2 lasers. At surgery, we have noted less thermal injury, faster ablation, more precise and predictable tissue effects, and greater control of tissue effect with the isotopic 13CO2 laser than with other CO2 lasers. These results are attributed to the improved beam propagation through CO2 insufflation gas measured in the laboratory. Thermal injury can be varied according to the required surgical situation and can be kept to an absolute minimum at high-pulse energy.

Threshold intrauterine perfusion pressures for intraperitoneal spill during hydrotubation and correlation with tubal adhesive disease.

OBJECTIVE: To determine the minimum intrauterine perfusion pressure that will produce spill from the fallopian tubes into the peritoneal cavity and to correlate this pressure with the extent of tubal adhesive disease. DESIGN: Hydrotubation was performed at laparoscopy and intrauterine perfusion pressure was measured. The extent of peritubal and fimbrial adhesions was graded at laparoscopy. SETTING: Ambulatory surgery suites. PATIENTS: Ten patients with infertility and/or pelvic pain were enrolled in the study. Data from nine patients were analyzed. INTERVENTIONS: Measurement of intrauterine perfusion pressures. MAIN OUTCOME MEASURES: The minimum pressure that produced spill of dye from each fallopian tube and the correlation between extent of external tubal pathology and this threshold pressure. RESULTS: The median threshold pressure at which dye spilled from at least one fallopian tube was 100 mm Hg, and no spill occurred at pressures < 70 mm Hg. The threshold pressure was correlated negatively with the extent of tubal disease. CONCLUSIONS: Fluid with the same viscosity as hydrotubation dye will not spill into the peritoneal cavity through normal fallopian tubes until the intrauterine perfusion pressure exceeds 70 mm Hg. The threshold pressure is higher when tubal adhesive disease that can be visualized by laparoscopy is present.

Laparoscopic CO2 laser vaporization of endometriosis compared with traditional treatments.

This study reports on 108 infertile patients with endometriosis diagnosed at laparoscopy. Sixty-four patients had endometriosis and adhesions vaporized with a CO2 laser (LAS) and were prospectively compared with a control group (CON) of 44 patients who had laparoscopy. The 6- and 12-month estimated cumulative pregnancy rates for LAS were 0.32 +/- 0.07 and 0.55 +/- 0.09 respectively, and for CON 0.17 +/- 0.06 and 0.43 +/- 0.09 (Breslow P = 0.10). Monthly fecundity rates were 6.7% in LAS and 4.5% in CON. Survival analysis with fixed covariates showed that pregnancy rates were increased in patients with adhesions (P = 0.002) and other pelvic disease (P = 0.0001). Pregnancy rates were reduced by age (P = 0.02), previous adhesiolysis (P = 0.0000) and post-laparoscopy medical treatment (P = 0.0002). Our findings indicate that CO2 laser laparoscopy vaporization of endometriosis can be a safe, effective, and possibly improved modality for treating endometriosis.

Endometriosis: studies of a method for the design of a surgical staging system.

This study develops a method of identifying factors that predict pregnancy rates in patients with endometriosis. In 123 women, 60% had adhesions, 89% had implants, and 29% had endometriomas. The most common lesions were cul-de-sac implants (60%), ovarian implants (58%), and ovarian adhesions (55%). With no treatment, the life-table-estimated 3-year pregnancy rate was 40%; with oral contraceptives, 33%; and with surgery, 53%. Clustering techniques suggested new combinations of variables to be tested. We identified structures commonly involved simultaneously in a given patient, defined subgroups based on type of lesion, and developed a method to determine which factors were important in predicting outcome. In our patients, neither of two current methods of endometriosis staging predicted outcome. Further testing of the model systems suggested by the data may enable us to develop a staging system more predictive of pregnancy rates in endometriosis patients.

Stability of in vitro fertilization-embryo transfer success rates from the 1989, 1990, and 1991 Clinic-Specific Outcome Assessments.

OBJECTIVE: To determine if the differences in IVF-ET success rates among clinics are due to chance alone. DESIGN: Retrospective analysis of data reported by individual clinics. SETTING: One hundred seventy-five clinics in 1989, 192 clinics in 1990, and 208 clinics in 1991 that reported IVF-ET success rates to the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine (formerly The American Fertility Society). PATIENTS: Women < 40 years of age with no male factor. INTERVENTION: In vitro fertilization-ET. MAIN OUTCOME MEASURE: Delivery rate per retrieval and delivery rate per transfer. RESULTS: The hypothesis that the differences among IVF-ET success rates for clinics is due to chance alone can be rejected. Seven clinics were found to have pregnancy rates significantly higher than average and six clinics were found to have pregnancy rates significantly lower than average. Significant correlations were found between different years in the success rates for individual clinics but not for success as a function of the number of patients treated. CONCLUSIONS: Success rates for a few clinics are significantly different from the average success rate, but success rates must be used with caution in selecting a clinic.

Sonohysterographic screening before in vitro fertilization.

OBJECTIVE: To evaluate the use of sonohysterography for uterine screening before IVF. DESIGN: Prospective screening with sonohysterography and comparison with available hysterosalpingographic and hysteroscopic evaluations. SETTING: Private practice. PATIENT(S): Seventy-two women undergoing IVF-ET using their own or donor eggs. INTERVENTION(S): Sonohysterography was performed by instilling saline into the uterine cavity through an intracervical balloon catheter; there was concurrent vaginal sonographic visualization in all cases. MAIN OUTCOME MEASURE(S): Sonohysterographic findings and pregnancy rates. RESULT(S): Cavitary lesions were detected in 8 (11.1%) of 72 sonohysterographic examinations. Six of 8 cases were confirmed and treated by hysteroscopy. After sonohysterographic evaluation, 35 (48.6%) of 72 patients conceived, resulting in 25 ongoing or delivered pregnancies, 5 chemical pregnancies, and 5 spontaneous abortions. No statistically significant difference was observed in the pregnancy outcome for patients undergoing IVF who had sonohysterography compared with that for patients undergoing IVF during the same period who previously had a uterine evaluation by a different method. The estimated cost savings per patient undergoing sonohysterography instead of in-office hysteroscopy was $275. CONCLUSION(S): Sonohysterography offers advantages over in-office hysteroscopy and hysterosalpingography for evaluation of the uterus before IVF.

Improved prediction of postovulatory day using temperature recording, endometrial biopsy, and serum progesterone.

The use of basal body temperature (BBT) recording and a single progesterone (P) level at the time of the endometrial biopsy in the late luteal phase improved our ability to predict the onset of the next menstrual period (NMP) and determine the postovulatory day (POD) in 124 regularly menstruating infertile women. We determined BBT shift using a microcomputer program, analyzed P levels by radioimmunoassay, and evaluated endometrial biopsies both prospectively (blinded) and retrospectively (with knowledge of the other variables). Serum P levels were within the normal range for the luteal phase and prospective and retrospective histological diagnoses closely agreed (82% within 2 days). The best correlation with the NMP was the BBT shift (r = 0.493) followed by P (r = 0.426) and prospective histologic dating (r = 0.390). Multiple regression analysis confirmed that use of all of the variables markedly improved the ability to estimate the POD (R2 = 0.51).

Laparoscopic endometriosis treatment: is it better?

OBJECTIVE: To assess the hypothesis that pregnancy rates (PRs) after operative laparoscopy (Laparoscopy Group) for endometriosis treatment would be equal to or greater than diagnostic laparoscopy only (No Treatment Group), diagnostic laparoscopy with medical treatment (Medical Treatment Group), and laparotomy (Laparotomy Group). DESIGN: Prospectively recorded data were analyzed to identify significant variables affecting PRs. These variables were statistically controlled for using survival analysis with multiple fixed covariates to compare operative laparoscopy PRs versus other treatment PRs. SETTING: Treatment was performed by the senior author in a referral reproductive endocrinology and surgery private practice. PATIENTS: Five hundred seventy-nine infertile women were diagnosed with endometriosis. A subset (n = 258) considered to have endometriosis only was evaluated separately (Endometriosis-Only Subset). INTERVENTIONS: Treatment groups included: No Treatment Group, Medical Treatment Group, Laparoscopy Group, and Laparotomy Group. MAIN OUTCOME MEASURE(S): Pregnancy was used as the indicator of treatment success. RESULTS: Laparoscopy Group PRs were at least equal to all other treatment groups and were significantly higher than some other treatment groups in some comparisons. CONCLUSIONS: Operative laparoscopy is the treatment of choice for infertile women with endometriosis unless they have severe tubal and/or fimbrial disease.

Failure of intrauterine insemination in a refractory infertility population.

Intrauterine insemination by itself for multiple and/or severe infertility factors had no benefit over cervical cap with whole ejaculate or coitus in this study. The PRs for IUI and cervical cap with whole ejaculate or coitus were similar and low, suggesting that IUI by itself has limited, if any, utility in enhancing PRs in this type of infertility population. Couples attempting IUI should be advised about the low probability of achieving pregnancy. Ovulation stimulation and/or heterologous donor insemination, IVF, or gamete intrafallopian transfer may be beneficial therapeutic options.

Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine's revised classification of endometriosis.

OBJECTIVE: To estimate the empirical relationship between the revised American Society for Reproductive Medicine's classification of endometriosis and pregnancy rates after treatment. DESIGN: Retrospective analysis. PATIENT(S): Patients seen by four practicing physicians. INTERVENTION(S): Medical and/or surgical therapy for endometriosis. MAIN OUTCOME MEASURE(S): Pregnancy defined as ongoing or delivered. RESULT(S): There were no significant differences in pregnancy rates across stages of endometriosis. There was a slight decline in pregnancy rates among patients with Stage IV endometriosis, but statistical significance was not achieved. CONCLUSION(S): The use of an arbitrary weighted system for assigning scores to individual categories of disease, or for computing a total score, has limited the overall effectiveness of the classification system to predict pregnancy.

Comparison of CO2 laser laparoscopy with laparotomy for treatment of endometriomata.

OBJECTIVE: To assess the effectiveness of laparoscopy versus laparotomy in the treatment of endometriomata. DESIGN: Controlled study using data prospectively tabulated. SETTING: Treatment performed by senior author in a referral reproductive endocrinology and surgery private practice. PATIENTS: One hundred infertile women were diagnosed with endometriomata. INTERVENTION: Forty-eight women were treated with CO2 laser laparoscopy (laparoscopy group) and 52 women were treated with CO2 laser or nonlaser laparotomy (laparotomy group). MAIN OUTCOME MEASURE: The hypothesis that laparoscopy group pregnancy rates (PRs) would be equal to or greater than laparotomy group was formulated before data analysis but after data tabulation. RESULTS: The 1 and 3-year life table estimated cumulative PRs +/- SE were 0.30 +/- 0.07 and 0.52 +/- 0.09 for laparoscopy group and 0.23 +/- 0.06 and 0.46 +/- 0.09 for laparotomy group (Breslow P = 0.48). Monthly fecundity over 3 years was 2.4% for laparoscopy group and 2.0% for laparotomy group. CONCLUSIONS: Laparoscopy with CO2 laser can be a safe and effective modality for treating endometriomata.

Efficacy of treatment for unexplained infertility.

OBJECTIVE: To analyze the efficacy and cost-effectiveness of alternative treatments for unexplained infertility. DESIGN: Retrospective analysis of 45 published reports. SETTING: Clinical practices. PATIENT(S): Couples who met criteria for unexplained infertility. Women with Stage I or Stage II endometriosis were included. INTERVENTION(S): Observation; clomiphene citrate (CC); gonadotropins (hMG); IUI; and GIFT and IVF. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): Combined pregnancy rates per initiated cycle, adjusted for study quality, were as follows: no treatment = 1.3%-4.1%; IUI = 3.8%; CC = 5.6%; CC + IUI = 8.3%; hMG = 7.7%; hMG + IUI = 17.1%; IVF = 20.7%; GIFT = 27.0%. The estimated cost per pregnancy was $10,000 for CC + IUI, $17,000 for hMG + IUI, and $50,000 for IVF. CONCLUSION(S): Clomiphene citrate + IUI is a cost-effective treatment for unexplained infertility. If this treatment fails, hMG + IUI and assisted reproduction are efficacious therapeutic options.