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Study Question: Is there an increased risk of unplanned peripartum hysterectomy in pregnancies with assissted reproductive technology compared to those without ART?Summary Answer: Although the absolute risks are low, there is an almost five-fold increased risk of unplanned peripartum hysterectomy and 1.7 more unplanned peripartum hysterectomies occur per 1000 deliveries in pregnancies with ART compared to those without ART.What Is Known Already: It has been reported that pregnancies with ART was associated with increased risk of peripartum hysterectomy in one case-control study and in one cohort study.Study Design, Size, Duration: A retrospective cohort study was conducted using a birth cohort from 2014 and 2015 in the United States, which includes more than 7 million births. Propensity score (PS) matching was used to control for confounding.Participants/materials, Setting, Methods: Subjects were divided into two groups: pregnancies with and without ART. We calculated PSs with demographic, clinical and socioeconomic variables, and subjects were matched using the PS with a 1:1 ratio. Subjects comprised 43868 ART pregnancies and 43868 non-ART pregnancies after PS matching. The primary outcome of interest was the risk of unplanned peripartum hysterectomy which was compared by evaluating the relative risk and the risk difference between the two groups after PS matching.Main Results and the Role Of Chance: Baseline characteristics were similar between groups after PS matching. The risk of peripartum hysterectomy in women with ART was 4.947 times that of those without ART (0.0021 [94/43868] vs 0.0004 [19/43868]; 95% confidence interval [CI] 3.022-8.098). The risk difference between two groups was 0.0017 (95% CI 0.0012-0.0022).Limitations, Reasons For Caution: There is a possibility of bias due to unmeasured confounding such as fibroids, previous history of uterine surgery and intrauterine procedures. Misclassification of the exposure and/or the outcome could also influence the results.Wider Implications Of the Findings: Although we found a five-fold increased risk of unplanned peripartum hysterectomy in pregnancies with ART compared to those without ART, the results should be interpreted with caution in a clinical context as the overall number and the absolute risk of unplanned peripartum hysterectomy are very low in either group (1/2325 in the non-ART group, and 1/468 in the ART group). However, it would be appropriate as future research agenda to explore mechanisms and/or etiology underlying this finding.Study Funding/competing Interest(s): No external funding was used and there are no competing interests.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Study Question: How do the national cumulative (multiple) live birth rates over complete assisted reproduction technology (ART) courses of treatment per woman in Belgium compare to those in other registries?Summary Answer: Cumulative live birth rates (CLBRs) remain high with a low cumulative multiple live birth rate when compared with other registries and publications.What Is Known Already: In ART, a reduction in the multiple live birth rate could be achieved by reducing the number of embryos transferred. It has been shown that by doing so, live birth rates per cycle were maintained, particularly when the augmentation effect of attached frozen-thawed cycles was considered.Study Design, Size, Duration: A retrospective cohort study included all patients with a Belgian national insurance number who were registered in the national ART registry (Belrap) and who started a first fresh ART cycle between 1 July 2009 until 31 December 2011 with follow up until 31 December 2012. We analysed 12 869 patients and 38 008 cycles (both fresh and attached frozen cycles).Participants, Materials, Settings, Methods: CLBRs per patient who started a first ART cycle including fresh and consecutive frozen cycles leading to a live birth. Conservative estimates of cumulative live birth assumed that patients who did not return for treatment had no chance of achieving an ART-related live birth, whereas optimal estimates assumed that women discontinuing treatment would have the same chance of achieving a live birth as those continuing treatment. A maximum of six fresh ART cycles with corresponding frozen cycles was investigated and compared with other registries and publications.Main Results and Role Of Chance: The CLBR was age dependent and declined from 62.9% for women <35 years, to 51.4% for women 35-37 years, to 34.1% for women 38-40 years and 17.7% for women 41-42 years in the conservative analysis after six cycles. In the optimal estimate, the CLBR declined from 85.9% for women <35 years, to 72.0% for women 35-37 years, to 50.4% for women 38-40 years and 36.4% for women 41-42 years. The cumulative multiple live birth rates for the whole population were 5.1 and 8.6% for the conservative and optimal estimate, respectively.Limitations, Reasons For Caution: Conservative and optimal estimates use assumptions for the whole ART population and do not take the individual patient into account.Wider Implications Of the Findings: These data reinforce the validity of the Belgian model of coupling reimbursement of ART costs to a restriction in the number of embryos transferred. Our data can improve decision-making in medical ART practice both on the patient level and for society at large and could provide health care takers and insurance companies with a valid model.Study Funding Competing Interests: none. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is endometrial thickness measured prior to embryo transfer associated with placenta praevia? SUMMARY ANSWER Following IVF, the risk of placenta praevia is increased 4-fold in women with an endometrial thickness of >12 mm compared with women with an endometrial thickness of <9 mm. WHAT IS KNOWN ALREADY Placenta praevia is a serious complication of pregnancy with adverse maternal and neonatal outcomes. Placenta praevia is 2- to 6-fold more likely to occur following IVF treatment but it remains unknown what factors contribute to that increased risk. STUDY DESIGN, SIZE, DURATION Retrospective cohort study involving 4007 women who had 4537 singleton assisted reproduction technology (ART) births occurring between January 2006 and June 2012 with no loss to follow-up. The primary outcome measure was the diagnosis of placenta praevia, made by the treating obstetrician on a transvaginal ultrasound in the third trimester. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who had singleton births following single embryo transfer performed at Monash IVF in Melbourne, Australia were included. Of the 4537 cycles leading to a singleton ART birth, 2951 were stimulated cycles with fresh embryo transfers; 355 were hormone replacement therapy frozen embryo transfers and 1231 were natural cycles with frozen embryo transfers. The dataset was analysed using binary logistic general estimating equations to calculate odds ratios for placenta praevia adjusted (aOR) for known confounders. MAIN RESULTS AND THE ROLE OF CHANCE The study groups did not differ significantly in age, BMI and aetiologies of infertility prior to IVF treatment. When compared with stimulated cycles, placenta praevia was less common in women undergoing natural cycles with frozen embryo transfers (OR 0.44, 95% confidence interval (CI) 0.27–0.70, P < 0.01) but hormone replacement therapy frozen embryo transfer cycles were not associated with a lower risk (OR 0.89, 95% CI 0.48–1.63). After adjusting for confounders, smoking (aOR 2.58, 95% CI 1.07–6.24, P = 0.04, endometriosis (aOR 2.01, 95% CI 1.21–3.33, P < 0.01) and endometrial thickness remained statistically significant as independent risk factors for placenta praevia. Compared with women with an endometrial thickness of <9 mm, women with an endometrial thickness of 9–12 mm had an aOR of 2.02 (95% CI 1.12–3.65, P = 0.02) and women with an endometrial thickness >12 mm had an aOR of 3.74 (95% CI 1.90–7.34, P < 0.01). These differences remained statistically significant after performing a sensitivity analysis limited to women with no previous births. LIMITATIONS, REASONS FOR CAUTION The study is retrospective in nature, not all confounders may have been accounted for and details on previous intrauterine surgery, a known risk factor, were not available. In addition, ultrasound assessments were carried out by several highly trained operators measuring the endometrial thickness, the main independent variable, in a two-dimensional plane and some inter-observer variability may therefore be present. WIDER IMPLICATIONS OF THE FINDINGS The findings of a higher risk of placenta praevia in patients with endometriosis and in those that smoke are in agreement with the current literature on natural conception. There have so far been no reports of an association between endometrial thickness and placenta praevia after ART. This novel finding warrants further study to elucidate the underlying cause of the association and to assess how to minimize harm to IVF patients and their offspring. The fact that the observed increased risk is not linked to the type of embryo transfer (fresh/frozen) but to the type of endometrial preparation, suggests that the risk of placenta praevia in ART can be reduced by considering an elective frozen embryo ... [ABSTRACT FROM AUTHOR]

STUDY QUESTION What are the mechanisms by which the preparation of spermatozoa on discontinuous density gradients leads to an increase in oxidative DNA damage? SUMMARY ANSWER The colloidal silicon solutions that are commonly used to prepare human spermatozoa for assisted reproduction technology (ART) purposes contain metals in concentrations that promote free radical-mediated DNA damage. WHAT IS KNOWN ALREADY Sporadic reports have already appeared indicating that the use of colloidal silicon-based discontinuous density gradients for sperm preparation is occasionally associated with the induction of oxidative DNA damage. The cause of this damage is however unknown. STUDY DESIGN, SIZE, DURATION This study comprised a series of experiments designed to: (i) confirm the induction of oxidative DNA damage in spermatozoa prepared on commercially available colloidal silicon gradients, (ii) compare the levels of damage observed with alterative sperm preparation techniques including an electrophoretic approach and (iii) determine the cause of the oxidative DNA damage and develop strategies for its prevention. The semen samples employed for this analysis involved a cohort of >50 unselected donors and at least three independent samples were used for each component of the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS The setting was a University biomedical science laboratory. The major techniques employed were: (i) flow cytometry to study reactive oxygen species generation, lipid peroxidation and DNA damage, (ii) computer-aided sperm analysis to measure sperm movement and (iii) inductively coupled mass spectrometry to determine the elemental composition of sperm preparation media. MAIN RESULTS AND THE ROLE OF CHANCE Oxidative DNA damage is induced in spermatozoa prepared on PureSperm® discontinuous colloidal silicon gradients (P < 0.001 versus repeated centrifugation) because this medium contains metals, particularly Fe, Al and Cu, which are known to promote free radical generation in the immediate vicinity of DNA. This damage can be significantly accentuated by reducing agents, such as ascorbate (P < 0.001) and inhibited by selective chelation (P < 0.001). This problem is not confined to PureSperm®; analysis of additional commercial sperm preparation media revealed that metal contamination is a relatively constant feature of such products. LIMITATIONS, REASONS FOR CAUTION While the presence of metals, particularly transition metals, may exacerbate the levels of oxidative DNA damage seen in human spermatozoa, the significance of such damage has not yet been tested in suitably powered clinical trials. WIDER IMPLICATIONS OF THE FINDINGS The results explain why the preparation of spermatozoa on discontinuous colloidal silicon gradients can result in oxidative DNA damage. The results are of immediate relevance to the development of safe, effective protocols for the preparation of spermatozoa for ART purposes. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Australian Health and Medical Research Council. One of the authors (R.J.A.) has had a consultantship with a biotechnology company, NuSep, interested in the development of electrophoretic methods of sperm preparation. He has no current financial interest in this area. None of the other authors have a conflict of interest to declare. [ABSTRACT FROM AUTHOR]

STUDY QUESTION How has the interface between genetics and assisted reproduction technology (ART) evolved since 2005? SUMMARY ANSWER The interface between ART and genetics has become more entwined as we increase our understanding about the genetics of infertility and we are able to perform more comprehensive genetic testing. WHAT IS KNOWN ALREADY In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and ART and published an extended background paper, recommendations and two Editorials. STUDY DESIGN, SIZE, DURATION An interdisciplinary workshop was held, involving representatives of both professional societies and experts from the European Union Eurogentest2 Coordination Action Project. PARTICIPANTS/MATERIALS, SETTING, METHODS In March 2012, a group of experts from the European Society of Human Genetics, the European Society of Human Reproduction and Embryology and the EuroGentest2 Coordination Action Project met to discuss developments at the interface between clinical genetics and ART. MAIN RESULTS AND THE ROLE OF CHANCE As more genetic causes of reproductive failure are now recognized and an increasing number of patients undergo testing of their genome prior to conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and PGD may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from RCTs to substantiate that the technique is both effective and efficient. Whole genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. LIMITATIONS, REASONS FOR CAUTION The legal landscape regarding assisted reproduction is evolving, but still remains very heterogeneous and often contradictory. The lack of legal harmonization and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe, and beyond. WIDER IMPLICATIONS OF THE FINDINGS This continually evolving field requires communication between the clinical genetics and IVF teams and patients to ensure that they are fully informed and can make well-considered choices. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from ESHRE, ESHG and EuroGentest2 European Union Coordination Action project (FP7 – HEALTH-F4-2010-26146) to support attendance at this meeting. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? SUMMARY ANSWER Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. WHAT IS KNOWN ALREADY Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. STUDY DESIGN, SIZE, DURATION We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value ‘B’ is the unstandardized regression coefficient. MAIN RESULTS AND THE ROLE OF CHANCE SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39–22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03–0.53). LIMITATIONS, REASONS FOR CAUTION Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. WIDER IMPLICATIONS OF THE FINDINGS Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the ... [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the impact of the Belgian legislation (1 July 2003), coupling reimbursement of six assisted reproduction technology (ART) cycles per patient to restricted embryo transfer policy, on cumulative delivery rate (CDR) per patient? SUMMARY ANSWER The introduction of Belgian legislation in ART had no negative impact on the CDR per patient based on realistic estimates within six cycles or 36 months. WHAT IS KNOWN ALREADY The introduction of Belgian legislation limiting the number of embryos for transfer resulted in a reduction of the multiple pregnancy rate (MPR) per cycle by 50%. STUDY DESIGN, SIZE, DURATION A retrospective cohort study with a study group after implementation of the new ART legislation (July 2003 to June 2006) and the control group, before legislation (July 1999 to June 2002). PARTICIPANTS/MATERIALS, SETTING, METHODS CDR was compared in an academic tertiary setting between a study group after legislation (n = 795 patients, 1927 fresh and 383 frozen-thawed embryo transfer (FET) cycles) and a control group before legislation (n = 463 patients, 876 fresh and 185 FET cycles) within six cycles or 36 months, delivery or discontinuation of treatment. The CDR was estimated using life table analysis considering pessimistic, optimistic and realistic scenarios and compared after adjustment for confounding variables. In the realistic scenario we included information on embryo quality to define the prognosis of each patient discontinuing treatment. MAIN RESULTS AND THE ROLE OF CHANCE In the realistic scenario, CDR within 36 months was comparable (all ages, P = 0.221) in study group (60.8%) and control group (65.6%), as well as in different age groups (<36 years, P = 0.242; 36–39 years, P = 0.851; 40–42 years, P = 0.840). In the realistic scenario applied to six cycles, we found lower CDRs in the study group than in the control group within the two first cycles (all ages, P = 0.009; <36 years, P = 0.007) but no difference in CDRs between the two groups within the four subsequent cycles (all ages P = 0.232; <36 years, P = 0.198). The CDR within six cycles was 60 and 65.3% for study group and control group, respectively, for all ages, and 65.8 and 70.4%, respectively, in the subgroup younger than 36 years. In women ≥36 years, CDR within six cycles was comparable in both groups (36–39 years, 43% in study versus 44.4% in control group, P = 0.730; 40–42 years, 21% in study versus 23% in control group, P = 0.786). LIMITATIONS, REASONS FOR CAUTION A retrospective cohort study design was the only way to study the impact of legislation on CDR. Owing to the retrospective nature of this analysis over a long period of time, our data are potentially influenced by improvements in techniques and therefore improved success rates in ART over time. WIDER IMPLICATIONS OF THE FINDINGS This ‘Belgian model’ can now be considered for application worldwide in countries with the aim to reduce the main ART side effect (high MPR) and its associated costs without a negative effect on the main intended effect (high CDR). STUDY FUNDING/COMPETING INTEREST(S) The authors have no conflict of interest to declare. No funding was obtained for this study. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference −1.5%; 95% confidence interval (CI) −9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference −1.9%; 95% CI −8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference −1.9%; 95% CI −8.0 to 11.7, P = 0.6) in the ‘r-FSH and r-LH’ and ‘r-FSH only’ groups respectively. LIMITATIONS, REASONS FOR CAUTION A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S) Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris®). No conflict of interest to declare. TRIAL REGISTRATION NUMBER The trial was registered in the Dutch trial register (ISRCTN10841210). [ABSTRACT FROM AUTHOR]

STUDY QUESTIONS What are the risks of adverse outcomes in singletons born after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER Singletons born after FET have a better perinatal outcome compared with singletons born after fresh IVF and ICSI as regards low birthweight (LBW) and preterm birth (PTB), but a worse perinatal outcome compared with singletons born after spontaneous conception. WHAT IS KNOWN ALREADY Previous studies have shown a worse perinatal outcome in children born after IVF in general compared with children born after spontaneous conception. In singletons born after FET, a lower rate of PTB and LBW and a higher rate of large for gestational age (LGA) compared with singletons born after fresh IVF have been shown. STUDY DESIGN A retrospective Nordic population-based cohort study of all singletons conceived after FET in Denmark, Norway and Sweden until December 2007 was performed. PARTICIPANTS/MATERIALS, SETTING AND METHODS Singletons born after FET (n = 6647) were compared with a control group of singletons born after fresh IVF and ICSI (n = 42 242) and singletons born after spontaneous conception (n = 288 542). Data on perinatal outcomes were obtained by linkage to the national Medical Birth Registries. Odds ratios were calculated for several perinatal outcomes and adjustments were made for maternal age, parity, year of birth, offspring sex and country of origin. MAIN RESULTS AND THE ROLE OF CHANCE Singletons born after FET had a lower risk of LBW (adjusted odds ratio (aOR) 0.81, 95% confidence interval (CI) 0.71–0.91), PTB (aOR 0.84, 95% CI 0.76–0.92), very PTB (VPTB; aOR 0.79, 95% CI 0.66–0.95) and small for gestational age (SGA; aOR 0.72, 95% CI 0.62–0.83), but a higher risk of post-term birth (aOR 1.40, 95% CI 1.27–1.55), LGA (aOR 1.45, 95% CI 1.27–1.64), macrosomia (aOR 1.58, 95% CI 1.39–1.80) and perinatal mortality (aOR 1.49, 95% CI 1.07–2.07) compared with singletons born after fresh IVF and ICSI. Compared with children conceived after spontaneous conception, singletons born after FET had a higher risk of LBW (aOR 1.27, 95% CI 1.13–1.43), very LBW (aOR 1.69, 95% CI 1.33–2.15), PTB (aOR 1.49, 95% CI 1.35–1.63), VPTB (aOR 2.68, 95% CI 2.24–3.22), SGA (aOR 1.18, 95% CI 1.03–1.35), LGA (aOR 1.29, 95% CI 1.15–1.45), macrosomia (aOR 1.29, 95% CI 1.15–1.45) and perinatal (aOR 1.39, 95% CI 1.03–1.87) neonatal (aOR 1.87, 95% CI 1.23–2.84) and infant mortality (aOR 1.92, 95% CI 1.36–2.72). When analyzing trends over time, the risk of being born LGA increased over time for singletons born after FET compared with singletons born after fresh IVF and ICSI (P = 0.04). LIMITATIONS, REASONS FOR CAUTION As in all observational studies, the possible role of residual confounding factors and bias should be considered. In this study, we were not able to control for confounding factors, such as BMI, smoking and reason for, or length of, infertility. WIDER IMPLICATIONS OF THE FINDINGS Perinatal outcomes in this large population-based cohort of children born after FET from three Nordic countries compared with fresh IVF and ICSI and spontaneous conception were in agreement with the literature. STUDY FUNDING/COMPETING INTEREST (S) No conflict of interest was reported. The study was supported by grants from the ALF agreement at the Sahlgrenska University Hospital, Gothenburg, Sweden. The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen, Denmark, and the Danish Agency for Science, Technology and Innovation have also supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Society of Obstetrics and Gynecology (NFOG). [ABSTRACT FROM PUBLISHER]

STUDY QUESTION Do mothers following assisted reproduction technology (ART) treatment have increased likelihood of gestational diabetes mellitus (GDM) compared with non-ART mothers after controlling for maternal factors and plurality? SUMMARY ANSWER ART mothers had 28% increased likelihood of GDM compared with non-ART mothers. WHAT IS KNOWN ALREADY Advanced maternal age and multiple pregnancies are independently associated with increased likelihood of GDM. Given the average age of mothers having ART treatment is higher than non-ART mothers and the higher multiple pregnancy rate following ART treatment, ART treatment might be expected to be associated with increased risk of GDM. STUDY DESIGN, SIZE, DURATION A population retrospective cohort study of 400 392 mothers who gave birth in Australia between 2007 and 2009, using the Australian National Perinatal Data Collection from five states (Australian Capital Territory, Queensland, Tasmania, Victoria and Western Australia) where a code for ART treatment is available. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included 13 732 ART mothers and 386 660 non-ART mothers. The prevalence of GDM was compared between ART and non-ART mothers. Logistic regressions were used to assess the association between ART treatment and GDM. Odds ratio (OR), adjusted OR (AOR) and 95% confidence interval (CI) were calculated. MAIN RESULTS AND THE ROLE OF CHANCE A larger proportion of ART mothers were aged ≥40 years compared with non-ART counterpart (11.7 versus 3.4%, P < 0.01). The prevalence of GDM was 7.6% for ART mothers and 5.0% for non-ART mothers (P < 0.01). Mothers who had twins had higher prevalence of GDM than those who gave births to singletons (8.8 versus 7.5%, P = 0.06 for ART mothers; and 7.3 versus 5.0%, P < 0.01 for non-ART mothers). Overall, ART mothers had a 28% increased likelihood of GDM compared with non-ART mothers (AOR 1.28, 95% CI 1.20–1.37). Of mothers who had singletons, ART mothers had higher odds of GDM than non-ART mothers (AOR 1.26, 95% CI 1.18–1.36). There was no significant difference in the likelihood of GDM among mothers who had twins between ART and non-ART (AOR 1.18, 95% CI 0.94–1.48). For mothers aged <40 years, the younger the maternal age, the higher the odds of GDM for ART singleton mothers compared with non-ART singleton mothers. LIMITATIONS, REASONS FOR CAUTION It was not possible to investigate which ART procedure is associated with increased risk of GDM and how the risk could have been minimized. The information on BMI and smoking during pregnancy was not stated for a large proportion of mothers. These limitations may have reduced the validity of the study. WIDER IMPLICATIONS OF THE FINDINGS In agreement with other studies, our data suggest that the underlying cause of subfertility and some particular ART procedures might have played an important role in the increased likelihood of GDM. Together with the public education on not delaying motherhood, minimizing multiple pregnancies by applying single embryo transfer may diminish the excess risk of GDM related to ART treatment. STUDY FUNDING/COMPETING INTEREST(S) There is no funding for this study. Authors declare no competing interest related to this study. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION Was the delivery rate of ART cycles negatively affected by the enactment of the Law 40/2004 by the Italian Parliament which imposed a long list of restrictions for ART procedures? SUMMARY ANSWER This large and extensive comparative analysis of ART outcomes prior to and after the introduction of the Law 40 revealed a significant reduction in pregnancy and delivery rates per cycle, independent of age or other clinical variables, once the law went into effect. WHAT IS KNOWN ALREADY Several studies have been published on the effect of Law 40/2004 on ART outcomes, some authors demonstrating a negative impact of the Law in relation to specific etiologies of infertility, other authors showing opposite conclusions. STUDY DESIGN, SIZE, DURATION Retrospective clinical study of 3808 patients treated prior to the enactment of the Law, September 1996–March 2004 (Group I) and 6898 treated during the Law, March 2004–May 2009 (Group II). PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 10 706 ART cycles were analysed, 3808 performed before and 6898 after the application of the Law. An intention-to-treat statistical analysis was performed to detect pregnancy and delivery rates (pregnancies ≥24 weeks) per started cycle. A P value of <0.05 was considered statistically significant. We analysed different outcomes: differences in fertilization, pregnancy and delivery rate, multiple pregnancies and miscarriage rates between the two time periods. MAIN RESULTS AND THE ROLE OF CHANCE The delivery rate for started cycle was 20% before and 16.0% after the introduction of the Law representing a 25% reduction (P < 0.001). The multivariate analysis, corrected by female age of >38 years, duration of infertility, basal FSH level and number of retrieved oocytes, showed a 16% lower delivery rate (odds ratio: 0.84; confidence interval: 0.75–0.94). This statistical approach removed the risk that the observed effects were due to chance and confirmed unequivocally that the Law was an independent factor responsible for the reduced likelihood of a successful outcome. LIMITATIONS, REASONS FOR CAUTION This is a retrospective study. A prospective randomized study, with patients treated in the same time period and randomized to restrictions or not, would have minimized potential limitations due to differences in years of treatments. WIDER IMPLICATIONS OF THE FINDINGS Our findings based on the analysis of such a large number of cycles proved clearly and unequivocally that imposing restrictions on the practice of ART penalized patients. These data represent a relevant clinical contribution for countries still debating the enactment of restrictive limitations of ART. STUDY FUNDING/COMPETING INTEREST This investigation has been supported by a finalized grant from Lombardy County, Italy (DGR 7255, 3 July 2008). [ABSTRACT FROM AUTHOR]

BACKGROUND This 11th European IVF-monitoring report presents the results of assisted reproductive technology (ART) treatments initiated in Europe during 2007. METHODS From 33 countries, 1029 clinics reported 493 184 treatment cycles: IVF (120 761), ICSI (256 642), frozen embryo replacement (91 145), egg donation (15 731), preimplantation genetic diagnosis/preimplantation genetic screening (4638), in vitro maturation (660) and frozen oocytes replacements (3607). Overall, this represents a 7.6% increase since 2006, mostly related to an increase in all registers. IUI using husband/partner's (IUI-H) and donor (IUI-D) semen was reported from 23 countries: 142 609 IUI-H (+6.2%) and 26 088 IUI-D (+7.2%). RESULTS In 18 countries where all clinics reported, 376 971 ART cycles were performed in a population of 425.6million (886 cycles per million). The clinical pregnancy rates per aspiration and per transfer were 29.1 and 32.8% for IVF, and 28.6 and 33.0% for ICSI. Delivery rate after IUI-H was 10.2% in women aged < 40 years. In IVF/ICSI cycles, 1, 2, 3 and ≥4 embryos were transferred in 21.4, 53.4, 22.7 and 2.5% of cycles, with no decline in the number of embryos per transfer since 2006. The proportion of multiple deliveries (22.3: 21.3% twin and 1.0% triplet), did not decrease compared with 2006 (20.8%) and 2005 (21.8%). In women < 40 years undergoing IUI-H, twin deliveries occurred in 11.7% and triplets in 0.5%. CONCLUSIONS In comparison with previous years, the reported number of ART cycles in Europe increased in 2007; pregnancy rates increased marginally, but the earlier decline in the number of embryos transferred and multiple births did not continue. [ABSTRACT FROM PUBLISHER]

BACKGROUND Research has documented that fertility problems can negatively affect the life of infertile patients, by imposing an obstacle to one important life goal: the achievement of parenthood. The Fertility Problem Inventory (FPI) proposes a comprehensive approach in assessing infertility stress, by measuring the impact on social, marital and sexual life dimensions and the importance of parenthood in infertile patients' life. This study examined the factor structure of the FPI, testing two alternative models using confirmatory factor analysis. METHODS A sample of 209 infertile patients was recruited in two public hospital departments of assisted reproduction technology. Measures included the FPI, the Brief Symptom Inventory and the ENRICH Marital Inventory. RESULTS Results confirmed the original measurement model of the instrument but suggested that the inclusion of an intermediate conceptual level resulted in a better fit to the model (χ284= 147.89, P< 0.001) i.e. the instrument assesses infertility stress by assessing two main conceptual domains: the impact of infertility in infertile patients’ life and representations about the importance of parenthood. The instrument revealed measurement and structure invariance and construct validity by correlating with other measures assessing similar constructs. CONCLUSIONS This approach to the FPI has important contributions for research and clinical practice by distinguishing between the impact of infertility on different dimensions of a couple’s' life and representations about the importance of parenthood, therefore extending the utility of the FPI in research and clinical practice. [ABSTRACT FROM PUBLISHER]

BACKGROUND Infants conceived from IVF are at increased risk for low birthweight. Animal studies suggest that embryo culture medium influences birthweight but it is unknown whether this association exists in humans. This study examines the relationship between culture medium and birthweight following IVF. METHODS We identified all IVF cycles with start dates between 1 January 1999 and 31 December 2008 that used autologous oocytes with resulting embryos cultured in G1.3, Global or G1.5 medium. The population was restricted to singleton deliveries following Day 3, fresh single embryo transfer, or twin deliveries following Day 3, fresh double embryo transfer, at a gestational age of ≥34 weeks. Only the first cycle during the study period was included for each woman. Women were excluded if the number of gestational sacs on ultrasound differed from the number of infants born. Variables were evaluated with the χ2-test or analysis of variance. Multiple linear regressions controlled for potential confounders. RESULTS Of the 198 women with singleton deliveries, 102 embryos were cultured in G1.3, 53 in Global and 43 in G1.5 medium. Of the 303 twin deliveries, 172 pairs of embryos were cultured in G1.3, 58 in Global and 73 in G1.5 medium. No significant association between culture medium and birthweight was observed, even when controlling for potential confounders. CONCLUSIONS This retrospective study demonstrated no significant association between embryo culture medium and birthweight following IVF. Although our careful selection of patients minimized the influence of potential confounders, further research is required to elucidate this issue with larger numbers of patients. [ABSTRACT FROM PUBLISHER]

BACKGROUND The higher prevalence of preterm birth (PTB) and low birthweight (LBW) following infertility treatment may relate to the treatment itself or indicate that subfertility predisposes to a higher risk. Our aim was to examine whether basal FSH levels are related to the risk for PTB and LBW among pregnancies resulting from IVF. METHODS We studied a retrospective cohort in the 2008 National Society for Assisted Reproductive Technology Database, including all women who underwent a fresh non-donor IVF cycle resulting in a singleton live birth having a recorded basal serum FSH value (n = 14 262). The FSH value used was either the maximum basal or clomiphene-stimulated serum level. Log binomial models were created to assess the associations between FSH and PTB (<37 weeks), and between FSH and LBW (<2500 g), adjusting for maternal age, ethnicity, gravidity/parity, history of PTB, smoking, BMI and infant gender. RESULTS Data for 14 086 patients were analyzed. FSH levels were inversely related to the risk of PTB and LBW. Women in the highest quartile of FSH levels (≥9 mIU/ml) had the longest adjusted mean gestational age (271.2 days), the lowest adjusted relative risk (RR) of PTB [0.87, 95% confidence interval (CI): 0.76–1.01], the highest adjusted mean birthweight (3249 g) and the lowest adjusted RR of LBW (0.89, 95% CI: 0.73–1.04). CONCLUSIONS The inverse relationship between maximal basal FSH levels and the risk for PTB and LBW in singleton IVF gestations suggests that diminished ovarian reserve is not the primary mediator of the increased prevalence of PTB and LBW in IVF pregnancies. [ABSTRACT FROM AUTHOR]

BACKGROUND As in many advanced societies, the age at first birth and the rate of post-menopausal pregnancies in Israel are constantly increasing. Since Israeli university students are the most likely population to postpone parenthood, this study aims at evaluating their awareness of: (i) women's age-related fertility decline; (ii) age-dependent success rates of IVF technology and (iii) medical procedures allowing late and post-menopausal pregnancies. METHODS Israeli undergraduate students (n= 410), attending four academic institutions and studying in different fields, completed a structured questionnaire in the 2009/2010 academic year. RESULTS Students overestimated women's chances of spontaneous pregnancy in all age groups, whereas women's chances of achieving a live birth following IVF treatment were overestimated only for ages 40 years and above. Regarding both spontaneous and IVF pregnancies, success rates of very late pregnancies (beyond 45 years and after menopause) were greatly overestimated. Only 11% of the students knew that genetic motherhood is unlikely to be achieved from the mid-40s onward, unless using oocytes frozen in advance. CONCLUSIONS The findings demonstrate entrenched fertility myths among Israeli students, particularly the false belief in the possibility of late (beyond 35 years) and very late genetic motherhood. This can be explained by technological ‘hype’ and favorable media coverage of very late pregnancies. Since this may culminate in involuntary childlessness, it is highly important to increase the awareness of the Israeli public on the subject of fertility. However, as our sample is not representative of the Israeli student population, our findings should be tested in future studies. [ABSTRACT FROM PUBLISHER]

BACKGROUND Debate exists regarding the effect of raised BMI on the outcome of pregnancies after assisted reproduction technology. We assessed the effect of BMI on the risk of miscarriage in women conceiving following single blastocyst transfer (SBT) after controlling for confounding factors. METHODS Fresh and cryo-thawed cycles of SBT that resulted in a pregnancy between January 2006 and March 2010 were included. Patients with BMI < 18.5 kg/m2 or older than 40 years were excluded. Patients were grouped according to their BMI at the start of treatment cycle. The main outcome measure was the miscarriage rate before 23 weeks gestation. Confounding variables examined included female age, duration and cause of infertility, previous miscarriage, smoking status and quality of blastocyst replaced. RESULTS A total of 413 women conceived following SBT in fresh (n= 325) or cryo-thawed (n= 88) IVF cycles, of whom 244 had a normal BMI (18.5–24.9) and 169 had a raised BMI of ≥25. Overall, 27% (113/413) of women miscarried before 23 weeks gestation. Women with a BMI of ≥25 had more than double the risk of miscarriage compared with women who had normal BMI [38 versus 20%, odds ratio (OR): 2.4, 95% confidence interval (CI) 1.6–3.8, P < 0.001, respectively]. After adjusting for confounding variables, having a BMI of ≥25 significantly increased the risk of clinical miscarriage before 23 weeks gestation in both fresh (adjusted OR = 2.7, 95% CI 1.5–4.9, P= 0.001) and cryo-thawed IVF cycles (OR = 6.8, 95% CI 1.5–31.1, P= 0.012). CONCLUSIONS Raised BMI is independently associated with higher miscarriage rate after IVF treatment. [ABSTRACT FROM PUBLISHER]

BACKGROUND Although assisted reproductive technology (ART) is reported to result in abnormal genomic imprinting and/or altered genomic methylation, few if any studies have used high-throughput methods to analyze genomic methylation in ART embryos. We hypothesized that a microarray-based assessment of genomic methylation could be used to reveal differences between ART and normal preimplantation embryos. METHODS In this pilot study, we performed methylation-sensitive amplification of genomic DNA from preimplantation mouse blastocysts, obtained by natural mating and either maintained in vivo until E3.5 (n= 4) or cultured in vitro (n= 4) from E0.5 until E3.5. An oligonucleotide microarray was then used to perform comparative hybridization of amplified DNA, allowing us to assess relative methylation at ∼16 000 loci on mouse chromosome 7. RESULTS We show that for in vivo derived embryos, the methylation/microarray results were strikingly consistent. In contrast, all four in vitro cultured embryos showed evidence of generalized hypermethylation as well as greater locus-to-locus variability, when compared with in vivo derived embryos. Genomic segments that overlapped exons and CpG islands were most likely to be hypomethylated in both normal and experimental blastocysts. Other sequence features, such as repetitive elements, were not associated with the presence of or the degree of methylation. CONCLUSIONS We conclude that a general assessment of genomic methylation in blastocyst stage embryos is technically feasible. Data from this small sample suggest that in vitro embryo culture is associated with generalized hypermethylation as well as increased locus-to-locus variability in methylation. However, it is premature to conclude that this is a general property of in vitro cultured blastocysts. [ABSTRACT FROM AUTHOR]

BACKGROUND Previous studies have measured cytokines expressed within follicular fluid and compared the profiles with the aetiology of infertility and/or successful or unsuccessful assisted reproduction technology (ART) outcomes. METHODS In this study, 71 paired follicular fluid and vaginal secretions collected from ART patients were cultured to detect microorganisms and tested for the presence of cytokines. Patient specimens were selected for assay based on two criteria: whether the follicular fluid specimen was colonized (with microorganisms prior to oocyte retrieval) or contaminated by vaginal flora and; the aetiology of infertility. Patients included fertile women (with infertile male partners; n = 18), women with endometriosis (n = 16) or polycystic ovary syndrome (PCOS, n = 14), or couples with a history of genital tract infection (n = 9) or idiopathic infertility (n = 14). RESULTS Microorganisms and cytokines were detected within all tested specimens. Colonizing microorganisms in follicular fluid were associated with: decreased fertilization rates for fertile women (P = 0.005), women with endometriosis (P = 0.0002) or PCOS (P = 0.002) compared with women whose follicular fluid was contaminated at the time of oocyte retrieval and with decreased pregnancy rates for couples with idiopathic infertility (P = 0.001). A single cytokine was discriminatory for women with an idiopathic aetiology of infertility (follicular fluid interleukin (IL)-18). Unique cytokine profiles were also associated with successful fertilization (IL-1α, IL-1β, IL-18 and vascular endothelial growth factor). CONCLUSIONS Follicular fluid is not sterile. Microorganisms colonizing follicular fluid and the ensuing cytokine response could be a further as yet unrecognized cause and/or predictor of adverse ART outcomes and infertility. [ABSTRACT FROM PUBLISHER]

BACKGROUND In May 2009, the Italian Constitutional Court banned most of the limitations of a restrictive law regulating assisted reproduction technology on the grounds that it limited a couple's right to have access to the best possible medical treatment and reduce any possible higher risk of complications. The aim of the study was to compare our results in fresh cycles before and after this change. MATERIALS AND METHODS We analysed retrospectively 3274 IVF cycles: 2248 before and 1026 after the law was modified. RESULTS There was no significant difference between the two groups in terms of age, basal FSH levels, years of infertility, the number of previous cycles or the number of oocytes retrieved but the number of oocytes used (2.7 ± 0.6 versus 4.6 ± 1.8; P = <0.001), the number of embryos obtained (2.0 ± 0.9 versus 3.3 ± 1.8; P = <0.001) and transferred (2.2 ± 0.7 versus 2.3 ± 0.7; P = <0.001) were all higher after the removal of the previous restrictions, as was the pregnancy rate per started cycle (23.49% versus 20.42%; P = 0.047). Before modification of the law, the pregnancies were single in 74.11% of the cases (versus 71.43% afterwards), twins in 23.44% (versus 26.89%; P = 0.318) and triplets in 2.46% (versus 1.68%; P = 0.594). CONCLUSIONS Our preliminary results after the removal of the previous legal restrictions show a higher pregnancy rate per started cycle (3.7% represents a 15% difference) and a positive (albeit non-significant) trend towards a reduction in the number of multiple pregnancies. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this qualitative, phenomenological study was to explore the subjective experiences of infertile women who conceived through the use of assisted reproduction technology—ovarian stimulation, intrauterine insemination or IVF—only to lose their pregnancy at 2–16 weeks gestation. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Previous studies have suggested that assisted reproduction technology (ART) is associated with increased risk of breech presentation. We investigated whether factors that tend to differ between ART and spontaneously conceived pregnancies may explain the higher risk of breech deliveries associated with ART. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Endometriosis, a common gynaecological disease, is characterized by local and systemic inflammation, which may cause infertility and consequently, increased utilization of assisted reproduction technology (ART). We aimed to estimate the risk for preterm birth, small-for-gestational-age (SGA) birth, stillbirth, Caesarean section, pre-eclampsia and antepartal haemorrhage among women with a previous diagnosis of endometriosis compared with women with no previous diagnosis of endometriosis. [ABSTRACT FROM PUBLISHER]

This report describes the ethical and legal aspects of assisted reproduction technology (ART) that have been instituted in Asian countries. The data were collected by a questionnaire circulated to ART units in Asia. These are Taiwan, Singapore, Korea, Indonesia, Thailand, Japan, Iran, India, Jordan, Malaysia, China, Israel, Hong Kong, Pakistan, Lebanon, Saudi Arabia, and Persian Gulf countries. According to the survey, there are approximately 260 ART centers in Asia (half of which are in Japan). On a global basis each ART centre in Asia serves an average population of 13 million people. On the other hand, in those Asian countries where the standards of living are relatively high, the availability of ART services, including the more sophisticated and costly ART procedures like micromanipulation, is similar to that in the Western world. In most of the Asian countries practising ART, however, no state registry exists. Taiwan is the only country that has specific legislation, and in six other countries some kind of ministerial regulations are practised. We conclude that ART is now practised in 20 countries in Asia. The prevailing rules and cultural heritage in many of these Asian countries has a major influence on the implementation of ART in Asia. However, in view of the complicated and sensitive issues involved, and as no supervision on ART clinics exists in most of these Asian countries, we advocate that some kind of quality control should be urgently instituted in all centres practising ART. In this way, it is hoped that the highest standards be attained for all parties concerned. [ABSTRACT FROM PUBLISHER]