Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTION: Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER: Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY: Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS: Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE: The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228-338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84-117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with 'male factor' as treatment indication (compared to 'tubal factor'). LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS: Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.

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.

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.

Erratum: Increased blood pressure and impaired endothelial function after accelerated growth in IVF/ICSI children.

[This corrects the article DOI: 10.1093/hropen/hoz037.].

Increased blood pressure and impaired endothelial function after accelerated growth in IVF/ICSI children.

STUDY QUESTION: What is the effect of growth velocity (height and weight) in early infancy on metabolic end-points and endothelial function in children born after ART? SUMMARY ANSWER: Neonatal, infant and childhood growth is positively related to blood pressure in 9-year-old IVF/ICSI offspring, while growth in childhood was negatively associated with endothelial function. WHAT IS KNOWN ALREADY: Offspring of pregnancies conceived after ART are at risk for later cardiometabolic risk factors. It is well established that early growth is related to numerous later cardiometabolic risk factors such as high blood pressure. This concept is known as the Developmental Origin of Health and Disease theory. STUDY DESIGN SIZE DURATION: The relation between early growth and later cardiometabolic risk profile was studied in the MEDIUM-KIDS study, a prospective observational cohort study in children born after an IVF/ICSI treatment. In 131 children (48.1% males) at the average age of 9.4 years, cardiometabolic outcomes were assessed and growth data from birth until age 9 years were collected from child welfare centers. PARTICIPANTS/MATERIALS SETTINGS METHODS: The following cardiometabolic outcomes were assessed: blood pressure, skinfolds, lipid spectrum, hair cortisone and glucose and insulin levels. Data on maximum skin perfusion after transdermal delivery of acetylcholine as a measure of endothelial function were collected.Growth charts were obtained electronically from child welfare centers, which offer free consultations and vaccinations to all Dutch children. At these centers, height and weight are recorded at predefined ages. Growth was defined as z-score difference in weight between two time points. Multivariable linear regression analysis was used to model the relation between growth and cardiometabolic outcomes. The following growth windows were -studied simultaneously in each model: 0-1 month, 1-3 months, 3-6 months, 6-11 months, 11-24 months and 2-6 years. The model was adjusted for height growth in all intervals except for 0-1 month. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable linear regression analyses, multiple growth windows were positively associated with blood pressure, for example growth from 2-6 years was significantly related to systolic blood pressure: B = 4.13, P = 0.005. Maximum skin perfusion after acetylcholine was negatively associated with height-adjusted weight gain from 2 to 6 years: B = -0.09 (log scale), P = 0.03. Several growth windows (weight 1-3 months, 3-6 months, 6-11 months, 11-24 months, 2-6 years) were positively linked with total adiposity. Lipids, glucose tolerance indices and cortisone were not related to growth. LIMITATIONS REASONS FOR CAUTION: This study is of modest size and of observational nature, and we did not include a control group. Therefore, we cannot assess whether the observed associations are causal. It is also not possible to analyze if our observations are specific for, or exacerbated in, the ART population. Ideally, a control group of naturally conceived siblings of IVF/ICSI children should simultaneously be studied to address this limitation and to assess the impact of the ART procedure without the influence of parental (subfertility) characteristics. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study contribute to our understanding of the reported increased risk for hypertension in ART offspring. We speculate that early, accelerated growth may be involved in the reported increased risk for hypertension in ART offspring, with endothelial dysfunction as a possible underlying mechanism. However, additional research into the mechanisms involved is required. STUDY FUNDING/COMPETING INTERESTS: 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 paper. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: NTR4220.

Validation of preimplantation genetic diagnosis by PCR analysis: genotype comparison of the blastomere and corresponding embryo, implications for clinical practice.

The aim of this study was to validate the overall preimplantation genetic diagnosis (PGD)-PCR procedure and to determine the diagnostic value. Genotyped embryos not selected for embryo transfer (ET) and unsuitable for cryopreservation after PGD were used for confirmatory analysis. The PGD genotyped blastomeres and corresponding embryos were compared, and morphology was scored on Day 4 post fertilization. To establish the validity of the PGD-PCR procedure and the diagnostic value, misdiagnosis rate, false-negative rate and negative predictive value were calculated. Moreover, comparison on the validity was made for the biopsy of one or two blastomeres. For the total embryo group (n = 422), a misdiagnosis rate of 7.1% and a false-negative rate of 3.1% were found. The negative predictive value was 96.1%. Poor morphology Day 4 embryos (Class 1) were over-represented in the embryo group in which the blastomere genotype was not confirmed by the whole embryo genotype. The misdiagnosis rate of Class 1 embryos was 12.5% and the false-negative rate 17.1%. Exclusion of these embryos resulted in a misdiagnosis rate of 6.1%, a false-negative rate of 0.5% and a negative predictive value of 99.3%. The two blastomere biopsies revealed a significant higher positive predictive value, lowering the misdiagnosis rate, whereas the negative predictive value remained the same. In conclusion, the PGD-PCR procedure is a valid diagnostic method to select unaffected embryos for ET. The misdiagnosis and false-negative rates decrease by rejecting Class 1 embryos for ET. The biopsy of a second blastomere improves the positive predictive value, lowering the misdiagnosis rate.

What is the most accurate estimate of pregnancy rates in IVF dropouts?

BACKGROUND: Dropouts in IVF-programmes affect cumulative pregnancy rates (CPRs), but it is unknown what the impact of loss to follow-up is. METHODS: Data were obtained from 588 couples starting IVF treatment ('as treated group'). Cycle-based and real-time-based CPRs were calculated using three assumptions for dropouts: dropouts having no probability of pregnancy, dropouts having the same probability of pregnancy as those continuing treatment and dropouts stopping because of medical reasons having no chance of pregnancy and those stopping because of other reasons having the same probability of pregnancy as those continuing treatment. CPRs obtained in the 'as treated group' were compared with CPRs calculated using the data set including the follow-up data of the dropouts ('completed group'). RESULTS: In 1.7% of couples, no follow-up could be obtained. The cycle-based CPR after three IVF-cycles ranged from 63% to 71% in the 'as treated group' and was 65% in the 'completed group'. The real-time-based CPR after 9 months ranged from 54% to 59% in the 'as treated group' and was 55% in the 'completed group'. The PR in dropouts was 14% (95% confidence interval 8.22%). CONCLUSIONS: In IVF programmes, outcome data of dropouts remain unknown, and CPRs should be calculated by assuming dropouts to have a PR between no probability and the same probability as those who continue treatment. Our study shows that the most accurate estimate for the PR in dropouts is 14%.

No effect of IVF culture medium on cognitive development of 9-year-old children.

STUDY QUESTION: Do embryo culture media used during an IVF/ICSI treatment have an effect on cognitive development of singleton IVF children at 9 years of age? SUMMARY ANSWER: Cognitive development of children born after culture in two different embryo culture media is comparable. WHAT IS KNOWN ALREADY: Previously, we have shown that the culture medium used in an IVF/ICSI treatment affects birthweight and weight at 2 years of age after alternating assignment to embryo culture in either K-SCICM (Cook) or G1™ Version 3 (Vitrolife). Children with low birthweight are known to have an increased risk for learning disabilities. Data on cognitive development in general of children born after ART are still conflicting, and the only study reporting on the effects of culture medium on cognitive development shows significant differences in cognitive development between two culture medium groups. STUDY DESIGN SIZE DURATION: In this observational cohort follow-up study (MEDIUM-KIDS), parents of all singletons from our abovementioned study were approached after the ninth birthday of their child to participate in an additional follow-up study. Of the 294 eligible children included in the original study, 119 children (70 Vitrolife and 49 Cook) participated in the current study. PARTICIPANTS/MATERIALS SETTING METHODS: All follow-up measurements were performed between March 2014 and December 2016. CITO (Dutch Central Institute for Test Development) developed the Dutch pupil monitoring system, which involves nationwide independent, standardized, academic achievement score tests to monitor the child's school performance twice a year at fixed time points from third grade onward. The tests include language skills (vocabulary and orthography), mathematics and reading capability and comprehension. Results from the tests performed between third and sixth grades, expressed as ability scores, were obtained from the school. To investigate school performance development over the years, we used a mixed effects multilevel model. The least complex model with the best fit was selected to analyze whether culture medium affects cognitive development in our cohort. The study had enough power to detect a difference in ability score that reflects at least one performance category between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: No differences were seen in baseline characteristics between participants and non-participants (both parental and children characteristics). For all domains, the random intercept model was used. All analyses showed comparable results for the two culture medium groups. No significant differences were observed for any of the cognitive development domains, even after correction for potential confounders. Parental level of education was higher in the IVF group (45%) if compared to the national average level of education (35%), which most likely explains the higher CITO scores for the IVF children if compared to the National ability scores. LIMITATIONS REASONS FOR CAUTION: A limitation of the study was its pseudo-randomized design and the relatively low participation rate of 40.5%. This and the number of missing data prevent us from drawing robust causal conclusions. However, as this is the first and therewith oldest cohort of children where culture medium was allocated alternatingly and used in a blinded setting, in the same period, with all other conditions identical this study gives up until now the best available evidence. WIDER IMPLICATIONS OF THE FINDINGS: Our study analyzes the effects of culture medium on school performance of children born after IVF/ICSI in a prospective cohort study. Although further research on long-term academic skills and also on behavior is essential, our results are reassuring and should make parents of children born after IVF/ICSI feel comfortable with their children's cognitive development. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the March of Dimes (Grant no. #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.

[The effects of inhaled steroids withdrawal in COPD]. / Impact du sevrage des corticostéroïdes inhalés dans la BPCO.

The key pathophysiological feature of chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory bronchial reaction after inhalation of toxic substances. The priority is the avoidance of such toxic inhalations, but the use of anti-inflammatory drugs also seems appropriate, especially corticosteroids that are the sole anti-inflammatory drug available for this purpose in France. The risks associated with the prolonged use of these parenteral drugs are well known. Inhalation is therefore the optimal route, but inhaled drugs may also lead to adverse consequences. In COPD, there is an inhaled corticosteroids overuse, and a non-satisfactory respect of the guidelines. Consequently, their withdrawal should be considered. We reviewed seven clinical studies dealing with inhaled corticosteroids withdrawal in patients with COPD and found that included populations were heterogenous with different concomitant treatments. In non-frequent exacerbators receiving inhaled corticosteroids outside the recommendations, withdrawal appears to be safe under a well-managed bronchodilator treatment. In patients with severe COPD and frequent exacerbations, the risk of acute respiratory event is low when they receive concomitant optimal inhaled bronchodilators. However, other risks may be observed (declining lung function, quality of life) and a discussion of each case should be performed, especially in case of COPD and asthma overlap.

[Miliary cerebral carcinomatosis secondary to EGFR mutation-positive lung adenocarcinoma]. / Miliaire cérébrale carcinomateuse secondaire a un adénocarcinome pulmonaire muté EGFR.

INTRODUCTION: Miliary brain metastases are a rare form of brain metastatic lesions. CASE REPORT: We report the case of a 58-year-old patient with lung adenocarcinoma and an EGFR mutation, who had metastatic lesions in the bones, pleura and pericardia at the time of diagnosis. The patient was treated with tyrosine kinase inhibitor. A few months later, he presented with progressive neuropsychiatric symptoms, which were attributed to miliary brain metastases based on the radiological pattern (micronodules, some of which were calcified) and the elimination of alternative possible diagnoses. Despite tumour stability in the thorax and metastatic sites other than the brain, his neurological condition deteriorated, even after cerebral radiotherapy, leading to his death eight months after the diagnosis of lung cancer. CONCLUSION: Miliary brain metastases are a rare form of brain metastases with unusual clinical presentation. The diagnosis is based on the radiological pattern of cerebral miliary dissemination, with sometimes calcified tumor nodules. Despite its rarity, several cases have been reported in lung adenocarcinoma in the presence of EGFR mutations.

[The place of inhaled corticosteroids in COPD]. / Place des corticostéroïdes inhalés dans la BPCO.

INTRODUCTION: Clinical trials have provided some evidence of a favorable effect of inhaled corticosteroids on the frequency of exacerbations and on the quality of life of patients with chronic obstructive pulmonary disease (COPD). In contrast, ICS have little or no impact on lung function decline and on mortality. STATE OF THE ART: Inhaled corticosteroids are recommended only in a minority of COPD patients, those with severe disease and repeated exacerbations and probably those with the COPD and asthma overlap syndrome. However, surveys indicate that these drugs are inappropriately prescribed in a large population of patients with COPD. Overtreatment with inhaled corticosteroids exposes these patients to an increased risk of potentially severe side-effects such as pneumonia, osteoporosis, and oropharyngeal candidiasis. Moreover, it represents a major waste of health-care spending. CONCLUSION: Primary care physicians as well as pulmonologists should be better aware of the benefits as well as the side-effects and costs of inhaled corticosteroids.

Microbiological evaluation of central venous catheter administration hubs.

We compared, in three intensive care units, colonization of hubs with hub protection boxes or hubs with needleless closed connectors; 137 central venous catheters and 451 hubs were randomized in two groups with similar characteristics. Catheter and hub colonization were not different between the two groups. Among 30 colonized catheters, the same isolate was found in only two hubs; hub contamination rarely is responsible for catheter colonization in short-term catheters. Further studies are required to evaluate the benefit of protected hubs compared with unprotected hubs.

Elevated levels of basal estradiol-17beta predict poor response in patients with normal basal levels of follicle-stimulating hormone undergoing in vitro fertilization.

OBJECTIVE: To evaluate whether the predictive ability of a normal FSH level on cycle day 3 can be enhanced by levels of estradiol-17beta (E2) on cycle day 3. DESIGN: Prospective cohort study. SETTING: University hospital-based, tertiary care infertility center. PATIENT(S): Two hundred thirty-one consecutively seen patients who attended the center for their first IVF attempt. INTERVENTION(S): Blood samples were collected on day 3 of the cycle preceding IVF; IVF was performed in all patients. MAIN OUTCOME MEASURE(S): Patient's age, number of ampules of hMG, cancellation rate, number of oocytes, fertilization rate, and clinical pregnancy rate. RESULT(S): In patients with elevated FSH levels on cycle day 3, a low oocyte yield was achieved (7 versus 11) and a high number of ampules of hMG was necessary (56 versus 33). Their cancellation rate was high (67% versus 16%). In patients with normal basal FSH levels, high E2 levels predicted a high cancellation rate (56%, versus 13% in patients with low E2 levels) and a low oocyte yield (9, versus 11 in patients with low E2 levels). Patients with both normal FSH levels and low E2 levels on cycle day 3 fared best. CONCLUSION(S): The basal E2 level on cycle day 3 is a useful prognosticator of response to stimulation in IVF patients with normal basal FSH levels.

High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome.

OBJECTIVE: To study the outcome in poor responders to three ampules (225 IU) of hMG per day in subsequent IVF treatment cycles in which six ampules (450 IU)of hMG per day were administered. DESIGN: Retrospective chart review. SETTING: Academic tertiary center. PATIENTS: Between January 1988 and May 1995, 126 poor response patients had a first treatment cycle on three ampules and a second cycle on six ampules of hMG per day. MAIN OUTCOME MEASURES: Numbers of follicles, oocytes, and embryos, and pregnancy rates. RESULTS: On six ampules, patients had significantly more follicles and oocytes. The number of embryos did not differ significantly. The pregnancy rate on six ampules were low (3.2% pregnancies per cycle started). CONCLUSION: Poor responders do not benefit from high-dose hMG stimulation; their reproduction outcome is poor.

Lack of effect of peritoneal endometriosis on fertility in the rabbit model.

STUDY OBJECTIVE: To study the isolated influence of peritoneal endometrial implants on fertility in an adhesion-free rabbit model. STUDY DESIGN: Thirty-two rabbits with endometrium implants were used; 31 rabbits with fat implants served as controls. In these rabbits parameters of early embryonic development were investigated. RESULTS: No significant differences were noted in ovulation, ovum pick-up, fertilization, tubal transport, and embryonic and fetal development. CONCLUSION: In the adhesion-free rabbit model, peritoneal implants of endometriosis do not have an effect on fertility. This supports the contention that therapies focused toward the implants are unlikely to change the pregnancy outcomes. Alternatively, it may cast doubts onto the relevance of animal models in studying this disease.

Immaturity and aneuploidy in human oocytes after different stimulation protocols.

OBJECTIVE: To study immaturity and aneuploidy in human oocytes after two different stimulation protocols. DESIGN: Retrospective. SETTING: Outpatient IVF clinic/laboratory. PATIENTS: One hundred forty-three patients of whom 65 were stimulated with clomiphene citrate (CC)/human menopausal gonadotropin (hMG) and 78 were stimulated with gonadotropin-releasing hormone agonist (GnRH-a)/hMG. Only patients with at least one oocyte unfertilized were included in this study. RESULTS: Stimulation with GnRH-a/hMG, as compared with CC/hMG stimulation, resulted in larger numbers of oocytes (P less than 0.00001), a higher fertilization rate (P less than 0.02), and oocyte retrieval at a later average cycle day (P less than 0.000005). Cytogenetic findings of immaturity were observed in 33.9% of unfertilized oocytes after CC/hMG stimulation, compared with only 17.8% after GnRH-a/hMG stimulation (P less than 0.0005). Aneuploidy findings were the same for both groups. CONCLUSION: In GnRH-a/hMG stimulation, oocytes approach the normal day of ovulation more closely. This may allow for better oocyte maturation and higher fertilization and pregnancy rates.

Effect of oxygen concentration on in vitro fertilization and embryo culture in the human and the mouse.

OBJECTIVE: To compare the effect of culturing oocytes, zygotes and embryos under low (5%) versus ambient (20%) oxygen conditions on human IVF results and on mouse blastocyst formation. DESIGN: A prospective, randomized study of 257 consecutive IVF treatment cycles in 186 couples undergoing oocyte retrieval for various reasons of infertility. Gametes and resulting embryos after IVF were alternately allocated to fertilization and culture either under a gas phase of 5% CO2/90% N2/5% O2, or 5% CO2/95% air (20% O2). Oocytes and embryos from randomly bred and hybrid mouse strains were randomly allocated to culture under either of the two gas phases. SETTING: A university hospital-based IVF-ET program. MAIN OUTCOME MEASURE: In the human, rates of fertilization, embryonic development at the time of embryo replacement (42 to 46 hours after insemination), pregnancy, and implantation were compared. In the mouse, the rates of blastocyst formation were compared. RESULTS: Clinical pregnancies occurred in 24.2% versus 19.4% of retrievals when culture took place under low oxygen versus ambient oxygen conditions. Fertilization, embryonic development, pregnancy, and implantation rates did not differ significantly between the groups. Slightly higher blastocyst rates occurred when mouse embryos from hybrid strains were cultured under low oxygen compared with culture under ambient oxygen conditions, whereas no such difference in blastocyst rates was found in randomly bred mouse embryos. CONCLUSIONS: This study failed to demonstrate any improvement in human IVF results associated with the use of a gas mixture of 5% CO2/90% N2/5% O2 during the first two days of development compared with the use of 5% CO2 in air.

The protective effects of polymers in the cryopreservation of human and mouse zonae pellucidae and embryos.

OBJECTIVES: To evaluate the occurrence of injury due to physical factors in embryo cryopreservation and the effect of the polymers dextran, polyvinylpyrrolidone (PVP), and Ficoll on this mechanical damage. DESIGN: Damage to the zona pellucida (ZP) observed after cryopreservation was taken as indication of cryoinjury caused exclusively by physical factors. Human and mouse ZPs from oocytes remaining unfertilized after previous IVF attempts and mouse two-cell embryos were frozen in the presence of different polymers. After thawing, they were checked carefully for signs of physical damage (cracks). A possible toxicity of the use of the polymers in cryoprotection was evaluated by development to the blastocyst stage of mouse two-cell embryos that survived the freezing and thawing process. RESULTS: Incidences of damaged ZPs in groups of human and mouse ZPs and two-cell embryos frozen without polymers were found to vary between 20% and 29%. The use of any of the tested polymers resulted in significantly lower incidences of damaged ZPs (0% to 15%). Damage to the ZP after freezing and thawing in mouse embryos was accompanied by low survival rates of the embryo itself. Of mouse embryos that survived the cryopreservation process, blastocyst formation was not significantly different in groups frozen without polymer (80%) or in the presence of either dextran (90%) or Ficoll (82%); however, embryos frozen in the presence of PVP showed low blastocyst formation (12%). CONCLUSIONS: Polymers can protect embryos against cryoinjury by avoiding mechanical strain occurring during cryopreservation. Polyvinylpyrrolidine is toxic to mouse two-cell embryos when present during freezing and thawing.

Representations used for health planning: naivety and crisis in the concepts and methods.

This article supports the theory that one of the causes underlying the crisis in the health services in the crisis in the concepts and methods used. Examples from a Third-World country (Congo) and from an industrialized country (France) are given in which problems of the same nature are met. Epidemiology is of little use in defining health action save in the case of accurately-identified diseases for which efficient technical means are available. Detailed epidemiological data is of no use in establishing priorities for larger-scale action, since operational and political criteria are beyond its scope as a discipline. The infra-medical magma which constitutes the bulk of health problems has to be tackled from a point of view broader than the purely medical, since a great number of risk factors must be acted upon. Relations between different administrations and different professions founder on linguistic and power conflicts. Some of the administrative criteria recommended for the organization of the medical side of health care are neither practised nor practicable, since they take no account of the functional logic of such systems, particularly the balance of power between interest groups.