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.

Developing a core outcome set for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. 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.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. 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. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. 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 work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study† ‡.

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. 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. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. 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 of 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 work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years.

STUDY QUESTION: Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old singleton IVF children? SUMMARY ANSWER: The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development. WHAT IS KNOWN ALREADY: Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1™ Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life. STUDY DESIGN, SIZE, DURATION: In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1™ Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016. PARTICIPANT/MATERIALS, SETTINGS, METHODS: Parents were invited to attend our clinic with their child for a single visit lasting ~2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m2 (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95%CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm [95% CI: 0.27-6.62]). Both systolic (adj. beta 0.364 [95% CI: -2.129 to 2.856],) and diastolic (adj. beta 0.275 [95% CI: -2.105 to 2.654]) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable. LIMITATIONS, REASONS FOR CAUTION: A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures. WIDER IMPLICATIONS OF THE FINDINGS: This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NTR4220.

Cost-effectiveness of embryo transfer strategies: a decision analytic model using long-term costs and consequences of singletons and multiples born as a consequence of IVF.

STUDY QUESTION: What is the cost-effectiveness of elective single embryo transfer (eSET) versus double embryo transfer (DET) strategies from a societal perspective, when applying a time horizon of 1, 5 and 18 years? SUMMARY ANSWER: From a short-term perspective (1 year) it is cost-effective to replace DET with single embryo transfer; however when intermediate- (5 years) and long-term (18 years) costs and consequences are incorporated, DET becomes the most cost-effective strategy, given a ceiling ratio of €20 000 per quality-adjusted life years (QALY) gained. WHAT IS ALREADY KNOWN: According to previous cost-effectiveness research into embryo transfer strategies, DET is considered cost-effective if society is willing to pay around €20 000 for an extra live birth. However, interpretation of those studies is complicated, as those studies fail to incorporate long-term costs and outcomes and used live birth as a measure of effectiveness instead of QALYs. With this outcome, both multiple and singletons were valued as one live birth, whereas costs of all children of a multiple were incorporated. STUDY DESIGN, SIZE, DURATION: A Markov model (cycle length: 1 year; time horizon: 1, 5 and 18 years) was developed comparing a maximum of: (i) three cycles of eSET in all patients; (ii) four cycles of eSET in all patients; (iii) five cycles of eSET in all patients; (iv) three cycles of standard treatment policy (STP), i.e. eSET in women <38 years with a good quality embryo, and DET in all other women; and (v) three cycles of DET in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Expected life years (LYs), child QALYs and costs were estimated for all comparators. Input parameters were derived from a retrospective cohort study, in which hospital resource data were collected (n=580) and a parental questionnaire was sent out (431 respondents). Probabilistic sensitivity analysis (5000 iterations) was performed. MAIN RESULTS AND THE ROLE OF CHANCE: With a time horizon of 18 years, DETx3 is most effective (0.54 live births, 10.2 LYs and 9.8 QALYs) and expensive (€37 871) per couple starting IVF. Three cycles of eSET are least effective (0.43 live births, 7.1 LYs and 6.8 QALYs) and expensive (€25 563). We assumed that society is willing to pay €20 000 per QALY gained. With a time horizon of 1 year, eSETx3 was the most cost-effective embryo transfer strategy with a probability of being cost-effective of 99.9%. With a time horizon of 5 or 18 years, DETx3 was most cost-effective, with probabilities of being cost-effective of 77.3 and 93.2%, respectively. LIMITATIONS, REASONS FOR CAUTION: This is the first study to use QALYs generated by the children in the economic evaluation of embryo transfer strategies. There remains some disagreement on whether QALYs generated by new life should be used in economic evaluations of fertility treatment. A further limitation is that treatment ends when it results in live birth and that only child QALYs were considered as measure of effectiveness. The results for the time horizon of 18 years might be less solid, as the data beyond the age of 8 years are based on extrapolation. WIDER IMPLICATIONS OF THE FINDINGS: The current Markov model indicates that when child QALYs are used as measure of outcome it is not cost-effective on the long term to replace DET with single embryo transfer strategies. However, for a balanced approach, a family-planning perspective would be preferable, including additional treatment cycles for couples who wish to have another child. Furthermore, the analysis should be extended to include QALYs of family members. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Recurrent miscarriage in translocation carriers: no differences in clinical characteristics between couples who accept and couples who decline PGD.

STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling? SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling. WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision-making after genetic counselling on PGD in these specific couples. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410). LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction.

Hospital costs during the first 5 years of life for multiples compared with singletons born after IVF or ICSI.

STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3-7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to €10 018 and €2093 during the birth admission period (P < 0.001), €1131 and €696 after the birth admission period to the first birthday (not significant (n.s.)) and €1084 and €938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

The wobbly evidence base of reproductive medicine.

In assisted reproduction, there is strong evidence for some things done, but no or only very weak evidence for others. There are several reasons for this. Most assisted reproduction procedures have small signal-to-noise ratios. This means that their treatment effect is sometimes only little better than the spontaneous conception rate, or the conception rate with traditional treatment. Hence, large trials are required. These demand complex multicentre logistics. The latter require substantial funding and funding for reproductive medicine in most countries is notoriously difficult to obtain (as opposed, for example, to oncology research or cardiovascular research). Apart from these funding issues, the creation of embryos specifically for research is only allowed in a limited number of European countries, thus tempting clinicians to skip preclinical studies altogether and go directly for clinical application in their patients, raising an ethical issue. Introducing new treatments into the clinic without proper evidence, however, is perhaps even more of an ethical issue. Subfertile couples are very vulnerable and should not be exploited.

Transperineal ultrasound compared to evacuation proctography for diagnosing enteroceles and intussusceptions.

INTRODUCTION: This study concerns the level of agreement between transperineal ultrasound and evacuation proctography for diagnosing enteroceles and intussusceptions. METHOD: In a prospective observational study, 50 consecutive women who were planned to have an evacuation proctography underwent transperineal ultrasound too. Sensitivity, specificity, positive (PPV) and negative predictive value, as well as the positive and negative likelihood ratio of transperineal ultrasound were assessed in comparison to evacuation proctography. To determine the interobserver agreement of transperineal ultrasound, the quadratic weighted kappa was calculated. Furthermore, receiver operating characteristic curves were generated to show the diagnostic capability of transperineal ultrasound. RESULTS: For diagnosing intussusceptions (PPV 1.00), a positive finding on transperineal ultrasound was predictive of an abnormal evacuation proctography. Sensitivity of transperineal ultrasound was poor for intussusceptions (0.25). For diagnosing enteroceles, the positive likelihood ratio was 2.10 and the negative likelihood ratio, 0.85. There are many false-positive findings of enteroceles on ultrasonography (PPV 0.29). The interobserver agreement of the two ultrasonographers assessed as the quadratic weighted kappa of diagnosing enteroceles was 0.44 and that of diagnosing intussusceptions was 0.23. CONCLUSION: An intussusception on ultrasound is predictive of an abnormal evacuation proctography. For diagnosing enteroceles, the diagnostic quality of transperineal ultrasound was limited compared to evacuation proctography.