20 years of the European IVF-monitoring Consortium registry: what have we learned? A comparison with registries from two other regions.

STUDY QUESTION: How has the performance of the European regional register of the European IVF-monitoring Consortium (EIM)/European Society of Human Reproduction and Embryology (ESHRE) evolved from 1997 to 2016, as compared to the register of the Centres for Disease Control and Prevention (CDC) of the USA and the Australia and New Zealand Assisted Reproduction Database (ANZARD)? SUMMARY ANSWER: It was found that coherent and analogous changes are recorded in the three regional registers over time, with a different intensity and pace, that new technologies are taken up with considerable delay and that incidental complications and adverse events are only recorded sporadically. WHAT IS KNOWN ALREADY: European data on ART have been collected since 1997 by EIM. Data collection on ART in Europe is particularly difficult due to its fragmented political and legal landscape. In 1997, approximately 78.1% of all known institutions offering ART services in 23 European countries submitted data and in 2016 this number rose to 91.8% in 40 countries. STUDY DESIGN, SIZE, DURATION: We compared the changes in European ART data as published in the EIM reports (2001-2020) with those of the USA, as published by CDC, and with those of Australia and New Zealand, as published by ANZARD. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a retrospective analysis of the published EIM data sets spanning the 20 years observance period from 1997 to 2016, together with the published data sets of the USA as well as of Australia and New Zealand. By comparing the data sets in these three large registers, we analysed differences in the completeness of the recordings together with differences in the time intervals on the occurrence of important trends in each of them. Effects of suspected over- and under-reporting were also compared between the three registers. X2 log-rank analysis was used to assess differences in the data sets. MAIN RESULTS AND THE ROLE OF CHANCE: During the period 1997-2016, the numbers of recorded ART treatments increased considerably (5.3-fold in Europe, 4.6-fold in the USA, 3.0-fold in Australia and New Zealand), while the number of registered treatment modalities rose from 3 to 7 in Europe, from 4 to 10 in the USA and from 5 to 8 in Australia and New Zealand, as published by EIM, CDC and ANZARD, respectively. The uptake of new treatment modalities over time has been very different in the three registers. There is a considerable degree of underreporting of the number of initiated treatment cycles in Europe. The relationship between IVF and ICSI and between fresh and thawing cycles evolved similarly in the three geographical areas. The freeze-all strategy is increasingly being adopted by all areas, but in Europe with much delay. Fewer cycles with the transfer of two or more embryos were reported in all three geographical areas. The delivery rate per embryo transfer in thawing cycles bypassed that in fresh cycles in the USA in 2012, in Australia and New Zealand in 2013, but not yet in Europe. As a result of these changing approaches, fewer multiple deliveries have been reported. Since 2012, the most documented adverse event of ART in all three registers has been premature birth (<37 weeks). Some adverse events, such as maternal death, ovarian hyperstimulation syndrome, haemorrhage and infections, were only recorded by EIM and ANZARD. LIMITATIONS, REASONS FOR CAUTION: The methods of data collection and reporting were very different among European countries, but also among the three registers. The better the legal background on ART surveillance, the more complete are the data sets. Until the legal obligation to report is installed in all European countries together with an appropriate quality control of the submitted data the reported numbers and incidences should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The growing number of reported treatments in ART, the higher variability in treatment modalities and the rising contribution to the birth rates over the last 20 years point towards the increasing impact of ART. High levels of completeness in data reporting have been reached, but inconsistencies and inaccuracies still remain and need to be identified and quantified. The current trend towards a higher diversity in treatment modalities and the rising impact of cryostorage, resulting in improved safety during and after ART treatment, require changes in the organization of surveillance in ART. The present comparison must stimulate all stakeholders in ART to optimize surveillance and data quality assurance in ART. STUDY FUNDING/COMPETING INTEREST(S): This study has no external funding and all costs are covered by ESHRE. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

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

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

Risk of stillbirth and infant deaths after assisted reproductive technology: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of stillbirth and perinatal deaths increased after assisted reproductive technology (ART) compared with pregnancies established by spontaneous conception (SC)? SUMMARY ANSWER: A significantly increased risk of stillbirth in ART singletons was only observed before 28 + 0 gestational weeks. WHAT IS KNOWN ALREADY: The current literature indicates that children born after ART have an increased risk of perinatal death. The knowledge on stillbirth in ART pregnancies is limited. STUDY DESIGN, SIZE, DURATION: A population based case-control study. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A total of 62 485 singletons and 29 793 twins born after ART in Denmark, Finland, Norway and Sweden, from 1982 to 2007, were compared with 362 798 spontaneously conceived (SC) singletons and 132 181 twins. MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted rate ratio for stillbirth at gestational weeks 22 + 0 to 27 + 6 was 2.08 [95% confidence interval (CI) 1.55-2.78] for ART versus SC singletons. After 28 + 0 gestational weeks there was no significant difference in the risk of stillbirth between ART and SC singletons. ART twins had a lower risk of stillbirth compared with SC twins, but when restricting the analysis to opposite-sex twins and excluding all monozygotic twins, there was no significant difference between the groups. Singletons conceived by ART had an overall increased risk of early neonatal death (adjusted odds ratio 1.54, 95% CI 1.28-1.85) and death within the first year after birth (1.45, 1.26-1.68). No difference regarding these two parameters was found when further adjusting for the gestational age [(0.97, 0.80-1.18) and (0.99, 0.85-1.16), respectively]. ART twins had a lower risk of early neonatal and infant deaths than SC twins, but no difference was found when restricting the analyses to opposite-sex twins. LIMITATIONS, REASON FOR CAUTION: We were not able to adjust for potential confounders, such as a prior history of stillbirth, induction of labour, body mass index or smoking. WIDER IMPLICATIONS OF THE FINDINGS: The risk of stillbirth in ART versus SC singletons was only increased for very early gestational ages (before 28 weeks). This might indicate that the current clinical management of ART pregnancies is sufficient regarding prevention of stillbirth during the third trimester. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest was reported. The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen, Denmark, the Danish Agency for Science, Technology and Innovation and Sahlgrenska University Hospital, Gothenburg, Sweden supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Society of Obstetrics and Gynecology (NFOG).

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

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

Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE.

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 425.6 million (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.

Assisted reproductive technology in Europe, 2008: results generated from European registers by ESHRE.

BACKGROUND: This 12th European IVF-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2008. METHODS: From 36 countries (3 more compared with 2007), 1051 clinics reported 532 260 treatment cycles including: IVF (124 539), ICSI (280 552), frozen embryo replacements (FER, 97 120), egg donation (ED, 13 609), in vitro maturation (IVM, 562), preimplantation genetic diagnosis/screening (PGD/PGS, 2875) and frozen oocyte replacements (FOR, 4080). Overall, this represents a 7.9% increase in the activity since 2007, which is mainly related to an increase in cycles from almost all registers and only partially to the new countries entering EIM (Estonia, Kazakhstan, Moldova and Romania, 5480 cycles in total). European data on intrauterine insemination using husband/partner's (IUI-H) and donor (IUI-D) semen were reported from 27 and 21 countries, respectively. A total of 144 509 IUI-H (+1.5%) and 24 960 IUI-D (-4.3%) cycles were included. RESULTS: In 19 countries where all clinics reported to the ART register, a total of 350 143 ART cycles were performed in a population of 369.8 million, corresponding to 947 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 28.5 and 32.5%, respectively, and for ICSI the corresponding rates were 28.7 and 31.9%. In FER cycles, the pregnancy rate per thawing was 19.3%. The delivery rate after IUI was 9.1% for IUI-H and 13.8% for IUI-D. In IVF and ICSI cycles, one, two, three and four or more embryos were transferred in 22.4, 53.2, 22.3 and 2.1%, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (combined) were 78.3, 20.7 and 1.0%, respectively, resulting in a total multiple delivery rate of 21.7%, compared with 22.3% in 2007, 20.8% in 2006 and 21.8% in 2005. In FER cycles, the multiple delivery rate was 13.7% (13.4% twins and 0.3% triplets). In women undergoing IUI, twin and triplet deliveries occurred in 10.6% and 0.7% with IUI-H and in 9.4 and 0.3% with IUI-D, respectively. CONCLUSIONS: In comparison with previous years, there was an increase in the reported number of ART cycles in Europe. For the first time in 5 years, the pregnancy rates failed to show a year-on-year increase. Compared with 2007, the number of transfers of multiple embryos (3+) and a multiple delivery rate showed a marginal decline.

Malignancies among women who gave birth after in vitro fertilization.

BACKGROUND: Relatively few studies published to date have investigated IVF and cancer risk. In this study we compared the occurrence of cancer in women who gave birth after IVF with all other women who gave birth in the study period. METHODS: All women who were treated with IVF and gave birth during the years 1982-2006 in Sweden were identified from all IVF clinics, and the occurrence of cancer in these women was identified by linkage with the nationwide Swedish cancer register. Comparison was made with Mantel-Haenszel odds ratios (ORs), adjusting for year of delivery and maternal age, parity and smoking. Cancer before IVF was only studied in first parity women. Specific cancer forms were also studied. RESULTS: Among 24058 women who had been treated with IVF, 1279 appeared in the cancer register. The total number of women studied in the population was 1 394 061, and 95 775 of these were registered in the cancer register. The risk for cancer before IVF was increased [OR 1.37, 95% confidence interval (CI) 1.27-1.48] and was especially high for ovarian cancer (3.93). The risk for cancer after IVF was significantly lower (OR 0.74, 95% CI 0.67-0.82), mainly due to a lower than expected risk for breast and cervical cancer. The risk for ovarian cancer was increased but lower than the risk before IVF (2.13). CONCLUSIONS: Cancer or cancer treatment may increase the risk for infertility leading to IVF. After IVF, in most cases with treatment with fertility hormones, a significantly low cancer risk was found. Ovarian cancer showed an increased risk, although lower than before IVF. One possible reason is ovarian pathology causing both infertility and an increased cancer risk.

Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years.

BACKGROUND: Marked changes have occurred in in vitro fertilization (IVF) methodology during the past 25 years but also in characteristics of couples undergoing treatment. METHODS: This study was based on 27 386 women undergoing IVF treatment from 1982 to 2006 and giving birth to 31 850 infants. Outcomes of deliveries were studied using Swedish health registers. Comparisons were made with all deliveries in the population (n = 2 603 601). Adjusted odds ratios were calculated when important changes in background rates had occurred. RESULTS: There was a substantial increase in the use of intracytoplasmatic sperm injection (ICSI) and the transfer of cryopreserved embryos. Among all ICSI cases, the proportion using epididymal or testicular sperm varied between 5 and 10%. Maternal characteristics changed during the observation period but the median age remained relatively constant in spite of the increasing maternal age in the population. There was a decline in the rate of some maternal pregnancy diagnoses (notably pre-eclampsia, premature rupture of membranes) and some neonatal diagnoses (notably preterm births, low birthweight, cerebral hemorrhage, respiratory diagnoses, use of continuous positive airway pressure and mechanical ventilation, sepsis/pneumonia). Up till 1992, the twinning rate increased to a maximum of about 30% and then declined to 5% towards the end of the period whereas higher order multiples nearly disappeared. The total rate of infants with congenital malformations changed only little. CONCLUSIONS: The decrease in unwanted outcomes can, to a large extent, be explained by the reduced rate of multiple births but was seen also among singletons. Other explanations can be sought in changes in the characteristics of patients undergoing IVF.

Assisted reproductive technology in Europe, 2006: results generated from European registers by ESHRE.

BACKGROUND: In this 10th European IVF-monitoring (EIM) report, the results of assisted reproductive techniques from treatments initiated in Europe during 2006 are presented. Data were mainly collected from existing national registers. METHODS: From 32 countries, 998 clinics reported 458 759 treatment cycles including: IVF (117 318), ICSI (232 844), frozen embryo replacement (FER, 86 059), egg donation (ED, 12 685), preimplantation genetic diagnosis/screening (6561), in vitro maturation (247) and frozen oocytes replacements (3498). Overall this represents a 9.7% increase in activity since 2005, which is partly due to an increase in registers (seven more countries with complete coverage). European data on intrauterine insemination using husband/partner's (IUI-H) and donor (IUI-D) semen were reported from 22 countries. A total of 134 261 IUI-H and 24 339 IUI-D cycles were included. RESULTS: In 20 countries, where all clinics reported to the IVF register, a total of 359 110 assisted reproductive technology (ART) cycles were performed in a population of 422.5 million, corresponding to 850 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 29.0 and 32.4%, respectively. For ICSI, the corresponding rates were 29.9 and 33.0%. After IUI-H the delivery rate was 9.2% in women below 40. After IVF and ICSI the distribution of transfer of one, two, three and four or more embryos was 22.1, 57.3, 19.0 and 1.6%, respectively. Compared with 2005, fewer embryos were replaced per transfer, but significant national differences in practice were apparent. The proportion of singleton, twin and triplet deliveries after IVF and ICSI combined was 79.2, 19.9 and 0.9%, respectively. This gives a total multiple delivery rates of 20.8% compared with 21.8% in 2005 and 22.7% in 2004. IUI-H in women below 40 years of age resulted in 10.6% twin and 0.6% triplet pregnancies. CONCLUSIONS: Compared with previous years, the reported number of ART cycles in Europe has increased, pregnancy rates have increased marginally, even though fewer embryos were transferred and the multiple delivery rates have declined.

Selected neonatal outcomes in dizygotic twins after IVF versus non-IVF pregnancies.

OBJECTIVE: To compare neonatal outcome among twins conceived after in vitro fertilisation (IVF) with that of spontaneously conceived twins. DESIGN: Comparison of different-sex (dizygotic) twins born after IVF with non-IVF dizygotic twins. SETTING: National health registers in Sweden. POPULATION: All births in Sweden during the period 1982-2007. METHODS: We studied gestational duration, lowest birthweight and birthweight difference in the twin pair, presence of one or two twins with a respiratory complication, and with jaundice in one or both twins. Risk estimates were calculated as odds ratios with adjustments for year of birth, maternal age, parity and smoking in pregnancy. MAIN OUTCOME MEASURES: Gestational duration, birth weight, respiratory complications, jaundice. RESULTS: We studied 1545 pairs of dizygotic twins born after IVF, and 8675 pairs of dizygotic twins where IVF was not known to have occurred. The risk for preterm delivery before 32 weeks of gestation was significantly increased among dizygotic twin pairs born after IVF compared with non-IVF dizygotic twin pairs. No significant difference in low birthweight or birthweight difference within twin pairs was seen. There was an increased occurrence of twin pairs with respiratory problems or jaundice, but only the latter diagnosis occurred in a statistically significant excess. CONCLUSIONS: The study confirms recent findings that IVF is associated with an increased risk for some neonatal complications, not only among singletons but also among twins.

Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE).

BACKGROUND: Results of assisted reproductive techniques from treatments initiated in Europe during 2005 are presented in this ninth report. Data were mainly collected from existing national registers. METHODS: From 30 countries, 923 clinics reported 418 111 treatment cycles including: IVF (118 074), ICSI (203 329), frozen embryo replacement (79 140), oocyte donation (ED, 11 475), preimplantation genetic diagnosis/screening (5846) and in vitro maturation (247). Overall, this represents a 13.6% increase since 2004, partly due to inclusion of 28 417 cycles from Turkey. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 21 countries and included 128 908 IUI-H and 20 568 IUI-D cycles. RESULTS: In 16 countries where all clinics reported to the IVF register, 1115 cycles were performed per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.9% and 30.3%, respectively. For ICSI, the corresponding rates were 28.5% and 30.9%. After IUI-H, the clinical pregnancy rate was 12.6% per insemination in women <40. After IVF and ICSI, the distribution of transfer of one, two, three and four or more embryos was 20.0%, 56.1%, 21.5% and 2.3%, respectively. Huge differences exist between countries. The distribution of singleton, twin and triplet deliveries after IVF and ICSI was 78.2%, 21.0% and 0.8%, respectively. This gives a total multiple delivery rate of 21.8% compared with 22.7% in 2004 and 23.1% in 2003. In women <40 years of age, IUI-H was associated with a twin and triplet pregnancy rate of 11.0% and 1.1%, respectively. CONCLUSIONS: Compared with earlier years, there was an increase in the reported number of ART cycles in Europe. Although fewer embryos were transferred per treatment, there was a marginal increase in pregnancy rates and a reduction in multiple deliveries.

Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data.

BACKGROUND: An estimated 3.5 million children have been born to date using assisted reproduction technologies. We reviewed the data in order to evaluate current knowledge of medical outcome for IVF/ICSI children born after cryopreservation, slow freezing and vitrification of early cleavage stage embryos, blastocysts and oocytes. METHODS: A systematic review was performed. We searched the PubMed, Cochrane and Embase databases from 1984 to September 2008. Inclusion criteria for slow freezing of early cleavage stage embryos were controlled studies reporting perinatal or child outcomes. For slow freezing and vitrification of blastocysts and oocytes, and vitrification of early cleavage stage embryos, case reports on perinatal or child outcomes were also included. Three reviewers independently read and evaluated all selected studies. RESULTS: For early cleavage embryos, data from controlled studies indicated a better or at least as good obstetric outcome, measured as preterm birth and low birthweight for children born after cryopreservation, as compared with children born after fresh cycles. Most studies found comparable malformation rates between frozen and fresh IVF/ICSI. For slow freezing of blastocysts and for vitrification of early cleavage stage embryos, blastocysts and oocytes, limited neonatal data was reported. We found no long-term child follow-up data for any cryopreservation technique. CONCLUSION: Data concerning infant outcome after slow freezing of embryos was reassuring. Properly controlled follow-up studies of neonatal outcome are needed after slow freezing of blastocysts and after vitrification of early cleavage stage embryos, blastocysts and oocytes. In addition, child long-term follow-up studies for all cryopreservation techniques are essential.

Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE.

BACKGROUND: European results of assisted reproductive techniques from treatments initiated during 2004 are presented in this eighth report. METHODS: Data were mainly collected from existing national registers. From 29 countries, 785 clinics reported 367,066 treatment cycles including: IVF (114,672), ICSI (167,192), frozen embryo replacement (FER, 71,997), egg donation (ED, 10 334), preimplantation genetic diagnosis/screening (PGD/PGS, 2701) and in vitro maturation (IVM, 170). Overall, this represents only a marginal increase since 2003, due to a huge reduction in treatments in Germany. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 20 countries. A total of 115,980 cycles (IUI-H, 98,388; IUI-D, 17,592) were included. RESULTS: In 14 countries where all clinics reported to the IVF register, a total of 248,937 ART cycles were performed in a population of 261.6 million, corresponding to 1095 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.6% and 30.1%, respectively. For ICSI, the corresponding rates were 27.1% and 29.8%. After IUI-H, the clinical pregnancy rate was 12.6% in women below 40. After IVF and ICSI, the distribution of transfer of 1, 2, 3 and 4 or more embryos was 19.2%, 55.3%, 22.1% and 3.3%, respectively. Compared with 2003, fewer embryos were transferred, but huge differences still existed between countries. The distribution of singleton, twin and triplet deliveries after IVF and ICSI combined was 77.2%, 21.7% and 1.0%, respectively. This gives a total multiple delivery rate of 22.7% compared with 23.1% in 2003 and 24.5% in 2002. After IUI-H in women below 40 years of age, 11.9% were twin and 1.3% triplet gestations. CONCLUSIONS: Compared with earlier years, the reported number of ART cycles in Europe increased and the pregnancy rates increased marginally, even though fewer embryos were transferred and the multiple delivery rates were reduced.

The methodological quality of clinical guidelines of the European Society of Human Reproduction and Embryology (ESHRE).

BACKGROUND: Clinical practice guidelines bridge the gap between the evidence from literature and clinical practice, and they may provide guidance in ethical, legal and societal dilemmas. To explore the potentials for future international guideline development within the field of human reproduction and embryology, we assessed the quality of existing guidelines produced by the European Society of Human Reproduction and Embryology (ESHRE). METHODS: We systematically searched for the ESHRE guidelines produced after 1996 in electronic databases and on the Internet. Subsequently, we assessed the methodological quality of these guidelines using the validated Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument. RESULTS: The overall methodological quality of most of the 11 selected ESHRE guidelines was poor. Most of the guidelines scored <30% in the domains of 'stakeholder involvement', 'rigour of development', 'applicability' and 'editorial independence'. Only one guideline was rated 'strongly recommended'. CONCLUSIONS: The methodological quality of the guidelines produced under the auspices of ESHRE can be improved. We suggest a systematic, up-to-date methodology, investment in guideline development specialists, systematic quality control and the incorporation of indicator development. Furthermore, attention should be paid to the document nomenclature, and an ESHRE guidelines' summary on a special part of the ESHRE website would be a good initiative.

Avoidance of multiple pregnancy by use of single embryo transfer.

The benefits of single embryo transfer (SET) for both mother and child are evident. Already twin pregnancies constitute a relatively serious problem exemplified by the incidence of cerebral palsy, which will increase significantly as well as a risk for premature birth. Selective embryo reduction in countries where this is allowed may be one way to acutely solve the situation. In the beginning the use of natural cycle in vitro fertilization (IVF) avoided the problem, but with the introduction of controlled ovarian hyperstimulation predominantly by use of gonadotrophins in the early 1980ies the temptation to replace more than 1 embryo at a time became too strong. SET with maintenance of acceptable pregnancy rates can only be achieved if tools (improved morphological criteria, biomarkers, preimplantation genetic screening) to select the most viable/normal embryos are at hand together with improved cryopreservation procedures. In reports from Finland and Belgium already 5 years ago, elective single embryo transfer (eSET) was shown to reach almost the same success rates as double embryo transfer (DET) in selective patient groups (age under 37, good quality embryos). The indications for eSET have increased during the last years. In Finland the initiative came from the IVF clinics while in Sweden a legislative process (in act from January 2003) resulted in the recommendation that eSET should be used in the vast majority of the IVF cycles. In both these Nordic countries around 60% of the transfers are today eSET and the multiple pregnancy rate below 10% with no triplets. From an economical point of view, it is of course evident that multiple pregnancies with the numerous potential complications should be avoided altogether. Countries where IVF is included in the government health insurance will thus most likely show the way towards an even more successful, safer and cheaper treatment of infertile couples in the future.

Vitamin A transporting plasma proteins and female sex hormones.

Retinol-binding protein, prealbumin, and sex steroid plasma levels have been estimated daily in four women during the course of a normal menstrual cycle and in three women during treatment with combined oral contraceptives. The retinol-binding protein level showed a bicyclic variation during the menstrual cycle, whereas for prealbumin no consistent pattern of variation was observed. Oral contraceptive therapy induced a significant increase of retinol-binding protein which was correlated with the increase of vitamin A. The increase was about 35% for the formulation containing synthetic estrogen as compared with 15% for the one with natural estrogen. In relation to retinol-binding protein, the plasma level of prealbumin showed a less rapid increase but the final increment after oral contraceptive therapy appeared to be of the same magnitude for both proteins.

Neonatal outcome in pregnancies from ovarian stimulation.

OBJECTIVE: To study the neonatal outcome in pregnancies after ovarian stimulation, not including in vitro fertilization. The outcomes studied were multiple birth, preterm birth, and low birth weight among singletons, congenital malformations, and infant death. METHODS: We identified 4029 women who delivered between 1995-1999 after ovarian stimulation alone and compared them with 438,582 women who neither had ovarian stimulation nor in vitro fertilization. We controlled for the confounding effect of year of birth, maternal age, parity, and length of subfertility before the pregnancy. RESULTS: The twinning rate was 5.9% in the study group and 1.2% in the control group. The triplet rate was 0.5% in the study group and 0.02% in the control group. A nearly doubling of the rate of monozygotic twinning was indicated in the study group compared with the control group. There was an excess of singleton preterm births and low birth weight infants in the study group, but this was mainly explainable by confounding of maternal age, parity, and subfertility. The rates of congenital malformations and perinatal deaths were increased, also mainly explainable by maternal characteristics. No increase in specific types of congenital malformations was seen. CONCLUSION: As the deviations in neonatal outcome after ovarian stimulation alone were reduced or disappeared when the confounding of maternal age, parity, and subfertility was taken into consideration, there is probably little direct effect of the stimulation procedure as such.

Factors affecting the clinical performance of Nova T and Copper T 200.

In a randomized comparative use-effectiveness study of the copper-releasing intrauterine devices (IUDs), Nova T and Copper T 200, an analysis was made of the differences in women between the participating countries and of the influence of various factors on pregnancy rate and rates of terminations. In a cohort of 1865 women the five-year gross cumulative pregnancy rates were 3.4 per 100 women for Nova T and 8.7 per 100 women for Copper T 200. The rate of unwanted pregnancy was significantly related to the type of IUD, the country, and the age of the women. Prognostic factors for expulsion or removal of the device were age, country, parity, previous use of IUD, previous vaginal delivery, and previous abortion. The differences among the results for the participating countries may reflect the effects of different policies in clinics.