Survey on ART and IUI: legislation, regulation, funding, and registries in European countries-an update.

STUDY QUESTION: How are ART and IUI regulated, funded, and registered in European countries, and how has the situation changed since 2018? SUMMARY ANSWER: Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding varies across and sometimes within countries (and is lacking or minimal in four countries), and national registries are in place in 33 countries; only a small number of changes were identified, most of them in the direction of improving accessibility, through increased public financial support and/or opening access to additional subgroups. WHAT IS KNOWN ALREADY: The annual reports of the European IVF-Monitoring Consortium (EIM) clearly show the existence of different approaches across Europe regarding accessibility to and efficacy of ART and IUI treatments. In a previous survey, some coherent information was gathered about how those techniques were regulated, funded, and registered in European countries, showing that diversity is the paradigm in this medical field. STUDY DESIGN, SIZE, DURATION: A survey was designed using the SurveyMonkey tool consisting of 90 questions covering several domains (legal, funding, and registry) and considering specific details on the situation of third-party donations. New questions widened the scope of the previous survey. Answers refer to the situation of countries on 31 December 2022. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: All members of the EIM were invited to participate. The received answers were checked and initial responders were asked to address unclear answers and to provide any additional information considered relevant. Tables resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, requesting a second check. Conflicting information was clarified by direct contact. MAIN RESULTS AND THE ROLE OF CHANCE: Information was received from 43 out of the 45 European countries where ART and IUI are performed. There were 39 countries with specific legislation on ART, and artificial insemination was considered an ART technique in 33 of them. Accessibility is limited to infertile couples only in 8 of the 43 countries. In 5 countries, ART and IUI are permitted also for treatments of single women and all same sex couples, while a total of 33 offer treatment to single women and 19 offer treatment to female couples. Use of donated sperm is allowed in all except 2 countries, oocyte donation is allowed in 38, simultaneous donation of sperm and oocyte is allowed in 32, and embryo donation is allowed in 29 countries. Preimplantation genetic testing (PGT)-M/SR (for monogenetic disorders, structural rearrangements) is not allowed in 3 countries and PGT-A (for aneuploidy) is not allowed in 10; surrogacy is accepted in 15 countries. Except for marital/sexual situation, female age is the most frequently reported limiting criterion for legal access to ART: minimal age is usually set at 18 years and the maximum ranges from 42 to 54 with some countries not using numeric definition. Male maximum age is set in very few countries. Where third-party donors are permitted, age is frequently a limiting criterion (male maximum age ranging from 35 to 50; female maximum age from 30 to 37). Other legal restrictions in third-party donation are the number of children born from the same donor (or, in some countries, the number of families with children from the same donor) and, in 12 countries, there is a maximum number of oocyte donations. How countries deal with the anonymity is diverse: strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), a mixed system (anonymous and non-anonymous donations), and strict non-anonymity. Inquiring about donors' genetic screening showed that most countries have enforced either mandatory or scientific recommendations that exclude the most prevalent genetic diseases, although, again, diversity is evident. Reimbursement/compensation systems exist in more than 30 European countries, with around 10 describing clearly defined maximum amounts considered acceptable. Public funding systems are extremely variable. One country provides no financial assistance to ART/IUI patients and three offer only minimal support. Limits to the provision of funding are defined in the others i.e. age (female maximum age is the most used), existence of previous children, BMI, maximum number of treatments publicly supported, and techniques not entitled for funding. In a few countries reimbursement is linked to a clinical policy. The definitions of the type of expenses covered within an IVF/ICSI cycle, up to which limit, and the proportion of out-of-pocket costs for patients are also extremely dissimilar. National registries of ART are in place in 33 out of the 43 countries contributing to the survey and a registry of donors exists in 19 of them. When comparing with the results of the previous survey, the main changes are: (i) an extension of the beneficiaries of ART techniques (and IUI), evident in nine countries; (ii) public financial support exists now in Albania and Armenia; (iii) in Luxembourg, the only ART centre expanded its on-site activities; (iv) donor-conceived children are entitled to know the donor identity in six countries more than in 2018; and (v) four more countries have set a maximum number of oocyte donations. LIMITATIONS, REASONS FOR CAUTION: Although the responses were provided by well-informed and committed individuals and submitted to double checking, no formal validation by official bodies was in place. Therefore, possible inaccuracies cannot be excluded. The results presented are a cross-section in time, and ART and IUI frameworks within European countries undergo continuous modification. Finally, some domains of ART activity were deliberately left out of the scope of this survey. WIDER IMPLICATIONS OF THE FINDINGS: Our results offer a detailed updated view of the ART and IUI situation in European countries. It provides extensive answers to many relevant questions related to ART usage at the national level and could be used by institutions and policymakers at both national and European levels. STUDY FUNDING/COMPETING INTEREST(S): The study has no external funding, and all costs were covered by ESHRE. There were no competing interests.

No major differences in perinatal and maternal outcomes between uninterrupted embryo culture in time-lapse system and conventional embryo culture.

STUDY QUESTION: Is embryo culture in a closed time-lapse system associated with any differences in perinatal and maternal outcomes in comparison to conventional culture and spontaneous conception? SUMMARY ANSWER: There were no significant differences between time-lapse and conventional embryo culture in preterm birth (PTB, <37 weeks), low birth weight (LBW, >2500 g) and hypertensive disorders of pregnancy for singleton deliveries, the primary outcomes of this study. WHAT IS KNOWN ALREADY: Evidence from prospective trials evaluating the safety of time-lapse incubation for clinical use show similar embryo development rates, implantation rates, and ongoing pregnancy and live birth rates when compared to conventional incubation. Few studies have investigated if uninterrupted culture can alter risks of adverse perinatal outcomes presently associated with IVF when compared to conventional culture and spontaneous conceptions. STUDY DESIGN, SIZE, DURATION: This study is a Swedish population-based retrospective registry study, including 7379 singleton deliveries after fresh embryo transfer between 2013 and 2018 from selected IVF clinics. Perinatal outcomes of singletons born from time-lapse-cultured embryos were compared to singletons from embryos cultured in conventional incubators and 71 300 singletons from spontaneous conceptions. Main perinatal outcomes included PTB and LBW. Main maternal outcomes included hypertensive disorders of pregnancy (pregnancy hypertension and preeclampsia). PARTICIPANTS/MATERIALS, SETTING, METHODS: From nine IVF clinics, 2683 singletons born after fresh embryo transfer in a time-lapse system were compared to 4696 singletons born after culture in a conventional incubator and 71 300 singletons born after spontaneous conception matched for year of birth, parity, and maternal age. Patient and treatment characteristics from IVF deliveries were cross-linked with the Swedish Medical Birth Register, Register of Birth Defects, National Patient Register and Statistics Sweden. Children born after sperm and oocyte donation cycles and after Preimplantation Genetic testing cycles were excluded. Odds ratio (OR) and adjusted OR were calculated, adjusting for relevant confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In the adjusted analyses, no significant differences were found for risk of PTB (adjusted OR 1.11, 95% CI 0.87-1.41) and LBW (adjusted OR 0.86, 95% CI 0.66-1.14) or hypertensive disorders of pregnancy; preeclampsia and hypertension (adjusted OR 0.99, 95% CI 0.67-1.45 and adjusted OR 0.98, 95% CI 0.62-1.53, respectively) between time-lapse and conventional incubation systems. A significantly increased risk of PTB (adjusted OR 1.31, 95% CI 1.08-1.60) and LBW (adjusted OR 1.36, 95% CI 1.08-1.72) was found for singletons born after time-lapse incubation compared to singletons born after spontaneous conceptions. In addition, a lower risk for pregnancy hypertension (adjusted OR 0.72 95% CI 0.53-0.99) but no significant difference for preeclampsia (adjusted OR 0.87, 95% CI 0.68-1.12) was found compared to spontaneous conceptions. Subgroup analyses showed that some risks were related to the day of embryo transfer, with more adverse outcomes after blastocyst transfer in comparison to cleavage stage transfer. LIMITATIONS, REASONS FOR CAUTION: This study is retrospective in design and different clinical strategies may have been used to select specific patient groups for time-lapse versus conventional incubation. The number of patients is limited and larger datasets are required to obtain more precise estimates and adjust for possible effect of additional embryo culture variables. WIDER IMPLICATIONS OF THE FINDINGS: Embryo culture in time-lapse systems is not associated with major differences in perinatal and maternal outcomes, compared to conventional embryo culture, suggesting that this technology is an acceptable alternative for embryo incubation. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by a research grant from Gedeon Richter. There are no conflicts of interest for all authors to declare. TRIAL REGISTRATION NUMBER: N/A.

Puberty disorders among ART-conceived singletons: a Nordic register study from the CoNARTaS group.

STUDY QUESTION: Do ART-conceived children have an increased risk for puberty disorders? SUMMARY ANSWER: Both ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys. WHAT IS KNOWN ALREADY: Some physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited. STUDY DESIGN, SIZE, DURATION: A register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994-2014), Finland (1990-2014), Norway (2002-2015) and Sweden (1985-2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: There were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29-1.64) and late puberty (aHR 1.47, 95% CI: 1.21-1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29-1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24-1.95). LIMITATIONS, REASONS FOR CAUTION: Using reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers' own puberty characteristics and BMI, as well as children's BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility. WIDER IMPLICATIONS OF THE FINDINGS: This large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway's Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium 'Family Formation in Flux-Causes, Consequences and Possible Futures', funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group.

STUDY QUESTION: When do the differences in birth weights become apparent between singletons born after frozen embryo transfer (FET) and fresh embryo transfer (fresh ET)? SUMMARY ANSWER: Mean birth weights after FET become significantly higher starting from gestational week (GW) 33 among boys and from GW 34 among girls. WHAT IS KNOWN ALREADY: In recent years, there has been a steep rise in recorded FET treatments, enabling widespread use of elective single embryo transfer, thus reducing the risks associated with multiple gestations. However, singletons born after FET are heavier and there is a higher risk of large-for-gestational-age (LGA) (birth weight > 90 percentiles) compared to fresh ET. In contrast, risk of small-for-gestational-age (SGA, birth weight < 10 percentiles) is lower in singletons born after FET compared to fresh ET. The reasons, timing and consequences of these differences remain largely unclear. There is limited evidence about whether this difference in growth develops before the last trimester of pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective Nordic register-based cohort study compared singletons born after FET (n = 17 500) to singletons born after fresh ET (n = 69 510) and natural conception (NC, n = 3 311 588). All live born singletons born between the years 2000 and 2015 in Denmark, Norway and Sweden at gestational age ≥22 weeks were included from the population-based Committee of Nordic ART and Safety (CoNARTaS) study population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children born after FET were compared to those born after fresh ET and NC for mean birth weight and proportion of LGA and SGA for each GW at birth. Chi-square test and tests for relative proportions were used to compare categorical variables and Student's t-test was used to compare continuous variables. Adjusted odds ratios (aORs) for LGA and SGA were calculated using logistic regressions, adjusting for year of birth, maternal age, parity, BMI, chronic hypertension, diabetes, smoking and offspring sex. MAIN RESULTS AND THE ROLE OF CHANCE: Mean birth weights were significantly higher after FET compared to fresh ET starting from GW 33 (range from 75 g to 228 g by week) for boys and starting from GW 34 (range from 90 g to 236 g by week) for girls. Boys born after FET had a significantly higher proportion of LGA (11.0-15.1%) at birth between GW 36 and 42, compared to those born after fresh ET (7.1-9.4%) (range from P < 0.001 to P = 0.048 by week). For girls born after FET, the difference was seen between GW 37 and 42 (10.6-13.4%) compared to those born after fresh ET (6.6-8.0%) (range from P < 0.001 to P = 0.009 by week).The proportion of SGA was significantly lower among boys born after FET (7.6-8.7%) compared to fresh ET (11.9-13.6%) between GW 36 and 42 (range from P < 0.001 to P = 0.016 by week). For girls born after FET, the difference was seen between GW 38 and 42 (7.0-9.3%) compared to those born after fresh ET (13.0-14.6%) (P < 0.001). The proportion of LGA (12.3-15.1%) was significantly higher for boys born after FET between GW 38 and 41 (P < 0.001) and for girls born after FET (12.6-13.4%) between GW 37 and 40 (range from P < 0.001 to P = 0.018 by week), compared to naturally conceived boys (9.7-9.9%) and girls (9.0-10.0%). All singletons born after FET had a higher risk of LGA compared to singletons born after fresh ET (aOR 1.87, 95% CI 1.76-1.98) and singletons born after NC (aOR 1.28, 95% CI 1.22-1.35). LIMITATIONS, REASONS FOR CAUTION: There may be residual confounding factors that we were not able to control for, most importantly the causes of preterm birth, which may also influence foetal growth. A further limitation is that we have no knowledge on growth patterns between implantation and GW 22. Finally, the number of children born extremely preterm or post-term was limited even in this large study population. WIDER IMPLICATIONS OF THE FINDINGS: This is, to date, the largest study on birth weights among preterm and term ART singletons with a population-based design and NC control group. The results suggest that the freeze-thaw process is associated with higher birthweights and greater risk of LGA at least in the last trimester of pregnancy. This is an important aspect of the safety profile of ART. More research is needed on the long-term outcome of these children. STUDY FUNDING/COMPETING INTEREST(S): The CoNARTaS collaboration has received the following funding: the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk [71450], the Central Norway Regional Health Authorities [46045000], the Norwegian Cancer Society [182356-2016], the Nordic Federation of Obstetrics and Gynaecology [NF13041, NF15058, NF16026 and NF17043], the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) and the Research Council of Norway's Centre of Excellence funding scheme [262700]. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Type 1 diabetes in children born after assisted reproductive technology: a register-based national cohort study.

STUDY QUESTION: Do children born after assisted reproductive technology (ART) have an increased risk of developing type 1 diabetes? SUMMARY ANSWER: Children born after ART were found to have an increased risk of type 1 diabetes in the unadjusted analysis, while after adjustment this association was only significant in children born after frozen embryo transfer. WHAT IS KNOWN ALREADY?: Some studies raise concerns as to whether fertility treatments may influence long-term morbidity in children born after ART. Elevated blood pressure and altered glucose metabolism have been found after ART in a few studies. STUDY DESIGN, SIZE, DURATION: A register-based national cohort study that included all children born in Sweden between 1985 and 2015-in total, 3 138 540 children-was carried out. PARTICIPANTS/MATERIAL, SETTING, METHODS: The study was population-based and all live-born singleton children born after ART (n = 47 938) or spontaneous conception (SC) (n = 3 090 602) were included. The ART cohort comprised 36 727 children born after fresh embryo transfer and 11 211 children born after frozen embryo transfer. Several national registries were used together with data from Statistics Sweden. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 202 children born after ART and 17 916 children born after SC developed type 1 diabetes, corresponding to 43.4 and 35.5 per 100 000 person-years at risk (hazard ratio [HR] 1.23; 95% confidence interval [CI], 1.07 to 1.42). Mean follow-up was 9.7 (SD 6.4) years for ART children and 16.3 (SD 9.2) years for SC children. After adjustment for calendar year of birth, HR for type 1 diabetes was 1.13; 95% CI, 0.98-1.30. After further adjustment for sex, maternal age, country of birth, educational level, smoking and parental diabetes, HR was 1.07; 95% CI, 0.93-1.23. In subgroup analyses, an association was found between frozen embryo transfer and type 1 diabetes (adjusted HR 1.52; 95% CI, 1.08-2.14 and 1.41; 95% CI, 1.05-1.89 for frozen versus fresh and frozen versus SC, respectively). When comparing intracytoplasmic sperm injection to in vitro fertilization, no difference was found (adjusted HR 1.08; 95% CI, 0.77-1.51). LIMITATIONS, REASONS FOR CAUTION: Limitations were the missing data and residual confounding caused by unknown confounders. Furthermore, the control group consisted of all children not conceived by ART and not non-ART children from subfertile mothers. The study was also performed in only singletons and not in the total ART population. WIDER IMPLICATIONS OF THE FINDINGS: Type 1 diabetes is a serious disease, affecting human life in several ways, including risk of serious complications, reduced life span and a life-long treatment. Our results are generally reassuring, showing no increase in diabetes in ART children compared to children born after SC after adjustment for relevant confounders. The observation of an association between children born after frozen embryo transfer and type 1 diabetes, although based on subgroup analyses with a limited number of children and modest in size, is however a reason for concern. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Nordforsk 71450, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement 70940, and the Hjalmar Svensson Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER: ISRCTN 11780826.

Obstetric and perinatal risks in 4601 singletons and 884 twins conceived after fresh blastocyst transfers: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Are obstetric and perinatal outcomes in pregnancies after fresh blastocyst transfer (BT) comparable with those born after fresh cleavage stage transfer (CT) and spontaneous conception (SC)? SUMMARY ANSWER: Fresh BT is associated with a higher risk of placental and perinatal complications. WHAT IS KNOWN ALREADY: BT optimizes the selection of top-quality embryos and increases pregnancy and live birth rates per transfer compared to CT. However, concerns have been raised as extended culture duration may increase obstetric complications and impair perinatal outcomes. Previous studies have shown a higher risk of preterm birth (PTB) among infants born after BT compared with CT. Pregnancies after BT are also prone to a higher risk of same-sex twins after single embryo transfer (SET). STUDY DESIGN, SIZE, DURATION: A retrospective register-based cohort study used data from Denmark, Norway and Sweden including three cohorts: 56 557 singletons and 16 315 twins born after fresh IVF/ICSI cycles and 2 808 323 SC singletons in Denmark (birth years 1997-2014), Norway (2010-2015) and Sweden (2002-2015). Of the fresh IVF/ICSI singletons, 4601 were born after BT and 51 956 after CT. The twin cohort consisted of 884 fresh IVF/ICSI children born after BT and 15 431 fresh IVF/ICSI children born after CT. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from a large Nordic cohort of children born after ART and SC initiated by the Committee of Nordic ART and Safety (CoNARTaS). The CoNARTaS cohort was established by cross-linking National ART-, Medical Birth-, and National Patients Registers using the unique personal identification number, allocated to every citizen in the Nordic countries. Obstetric and perinatal outcomes after BT, CT and SC were compared using logistic regression analysis. For perinatal outcomes, we calculated gestational age based on the date of oocyte pick-up (OPU) and in sensitivity analyses on data from Denmark and Norway, we also calculated gestational age based on the second-trimester ultrasonography (US) scan. Risk of pregnancies with same-sex twins after SET was used as a proxy for risk of monozygotic twins. Adjustments were made for child's sex, birth year, parity (0 or >1), maternal age, body mass index, smoking, educational level, fertilization method (IVF/ICSI), the number of aspirated oocytes, SET and country. Information on educational level and the number of aspirated oocytes was not available for Norway. Children born after frozen embryo transfer were not included. The birth cohorts were restricted according to the year in which BT was introduced in the different countries. MAIN RESULTS AND THE ROLE OF CHANCE: A higher risk of placenta previa was found in singleton pregnancies after BT compared with CT (adjusted odds ratio [aOR] 2.11 [95% CI 1.76; 2.52]). Singletons born after BT had a higher risk of PTB (aOR 1.14 [95% CI 1.01; 1.29]) compared with CT singletons, when estimated based on OPU. Furthermore, an altered male/female ratio (aOR 1.13 [95% CI 1.06; 1.21]) with more males following BT compared with CT was seen. Risk of same-sex twins after SET was higher after single BT compared with single CT (aOR 1.94 [95% CI 1.42; 2.60]). LIMITATIONS, REASONS FOR CAUTION: Residual confounding cannot be excluded, in particular related to duration and cause of infertility that we could not adjust for due to lack of reliable data. WIDER IMPLICATIONS OF THE FINDINGS: Extended embryo culture to the blastocyst stage has the potential to compromise obstetric and perinatal outcomes in fresh cycles. These results are important since an increasing number of IVF/ICSI treatments are performed as BT. STUDY FUNDING/COMPETING INTEREST(S): NORDFORSK (project no: 71450). The Research Fund of Rigshospitalet, Copenhagen University Hospital. ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. Grants from Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation. The Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. None of the authors has any conflicts of interests to declare regarding this study. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of imprinting disorders increased in children conceived after ART? SUMMARY ANSWER: We found an adjusted odds ratio (AOR) of 2.84 [95% CI: 1.34-6.01] for Beckwith-Wiedemann syndrome in ART children, while the risk of Prader-Willi syndrome, Silver-Russell syndrome or Angelman syndrome was not increased in children conceived after ART. WHAT IS KNOWN ALREADY: Earlier studies, most of them small, have suggested an association between ART and imprinting disorders. STUDY DESIGN, SIZE, DURATION: This was a binational register-based cohort study. All children conceived by ART in Denmark (n = 45 393, born between 1994 and 2014) and in Finland (n = 29 244, born between 1990 and 2014) were identified. The full background populations born during the same time periods in the two countries were included as controls. Odds ratios of imprinting disorders in ART children compared with naturally conceived (NC) children were calculated. The median follow-up time was 8 years and 9 months for ART children and 11 years and 9 months for NC children. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the national health registries in Denmark and Finland, we identified all children diagnosed with Prader-Willi syndrome (n = 143), Silver-Russell syndrome (n = 69), Beckwith-Wiedemann syndrome (n = 105) and Angelman syndrome (n = 72) born between 1994/1990 and 2014, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a total of 388 children diagnosed with imprinting disorders; 16 of these were conceived after ART. The overall AOR for the four imprinting disorders in ART children compared with NC children was 1.35 [95% CI: 0.80-2.29], but since eight ART children were diagnosed with Beckwith-Wiedemann syndrome, the AOR for this specific imprinting disorder was 2.84 [95% CI: 1.34-6.01]. The absolute risk of Beckwith-Wiedemann syndrome in children conceived after ART was still low: 10.7 out of 100 000 newborns. The risks of Prader-Willi syndrome, Silver-Russell syndrome and Angelman syndrome were not increased in children conceived after ART. LIMITATIONS, REASONS FOR CAUTION: Imprinting disorders are rare events and our results are based on few ART children with imprinting disorders. The aetiology is complex and only partly clarified, and the clinical diagnoses are challenged by a broad phenotypic spectrum. WIDER IMPLICATIONS OF THE FINDINGS: In the existing studies, results on the risk of imprinting disorders in children conceived after ART are ambiguous. This study adds that the risk of imprinting disorders in ART children is very small and perhaps restricted to Beckwith-Wiedemann syndrome. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (grant number: 71450), the Nordic Federation of Obstetrics and Gynecology (grant numbers: NF13041, NF15058, NF16026 and NF17043) and the Interreg Öresund-Kattegat-Skagerak European Regional Development Fund (ReproUnion project). The authors have no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER: N/A.

The addition of anti-Müllerian hormone in an algorithm for individualized hormone dosage did not improve the prediction of ovarian response-a randomized, controlled trial.

Study question: Does the addition of anti-Müllerian hormone (AMH) to a conventional dosage regimen, including age, antral follicle count (AFC) and BMI, improve the rate of targeted ovarian response, defined as 5-12 oocytes after IVF? Summary answer: The addition of AMH did not alter the rate of targeted ovarian response, 5-12 oocytes, or decreased the rate of ovarian hyperstimulation syndrome (OHSS) or cancelled cycles due to poor ovarian response. What is known already: Controlled ovarian hyperstimulation (COH) in connection with IVF is sometimes associated with poor ovarian response resulting in low pregnancy and live birth rates or leading to cycle cancellations, but also associated with excessive ovarian response, causing an increased risk of OHSS. Even though it is well-established that both AMH and AFC are strong predictors of ovarian response in IVF, few randomized trials have investigated their impact on achieving an optimal number of oocytes. Study design, size and duration: Between January 2013 and May 2016, 308 patients starting their first IVF treatment were randomly assigned, using a computerized randomization program with concealed allocation of patients and in the proportions of 1:1, to one of two dosage algorithms for decisions on hormone starting dose, an algorithm, including AMH, AFC, age and BMI (intervention group), or an algorithm, including only AFC, age and BMI (control group). The study was blinded to patients and treating physicians. Participants/materials, setting, methods: Women aged >18 and <40 years, with a BMI above 18.0 and below 35.0 kg/m2 starting their first IVF cycle where standard IVF was planned, were eligible. All patients were treated with a GnRH agonist protocol and recombinant FSH was used for stimulation. The study was performed as a single-centre study at a large IVF unit at a university hospital. Main results and the role of chance: The rate of patients having the targeted number of oocytes retrieved was 81/152 (53.3%) in the intervention group versus 96/155 (61.9%) in the control group (P = 0.16, difference: -8.6, 95% CI: -20.3; 3.0). Cycles with poor response (<5 oocytes) were more frequent in the AMH group, 39/152 (25.7%) versus the non-AMH group, 17/155 (11.0%) (P < 0.01), while the number of cancelled cycles due to poor ovarian response did not differ 7/152 (4.6%) and 4/155 (2.6%) (P = 0.52). An excessive response (>12 oocytes) was seen in 32/152 (21.1%) and 42/155 (27.1%) patients, respectively (P = 0.27). Moderate or severe OHSS was observed among 5/152 (3.3%) and 6/155 (3.9%) patients, respectively (P = 1.0). Live birth rates were 48/152 (31.6%) and 42/155 (27.1%) per started cycle. Limitations, reasons for caution: The categorization of AMH values in predicted low, normal and high responders was originally established using the Diagnostic Systems Laboratories assay and was translated to more recently released assays, lacking international standards and well-established reference intervals. The interpretation of AMH values between different assays should therefore be made with some caution. Wider implications of the findings: An individualised dosage regimen including AMH compared with a non-AMH dosage regimen in an unselected patient population did not alter the number of women achieving the targeted number of oocytes, or the cancellation rate due to poor response or the occurrence of moderate/severe OHSS. However, this study cannot answer the question if using an algorithm for dose decision of FSH is superior to a standard dose and neither which ovarian reserve test is the most effective. Study funding/competing interest: Financial support was received through Sahlgrenska University Hospital (ALFGBG-70 940) and unrestricted grants from Ferring Pharmaceuticals and the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest. Trial registration: The study was registered at www.clinicaltrials.gov NCT02013973. Trial registration date: 6 December 2013. DATE OF FIRST PATIENT RANDOMIZED: 14 January 2013.

Obstetric and neonatal complications in pregnancies conceived after oocyte donation: a systematic review and meta-analysis.

BACKGROUND: Approximately 50 000 oocyte donation (OD) treatment cycles are now performed annually in Europe and the US. OBJECTIVES: To ascertain whether the risk of adverse obstetric and perinatal/neonatal outcomes is higher in pregnancies conceived by OD than in pregnancies conceived by conventional in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) or spontaneously. SEARCH STRATEGY: A systematic search was performed in the PubMed, Cochrane and Embase databases from 1982-2016. Primary outcomes were hypertensive disorders of pregnancy, pre-eclampsia (PE), gestational diabetes mellitus, postpartum haemorrhage, caesarean section, preterm birth, low birthweight and small for gestational age. SELECTION CRITERIA: Inclusion criteria were original studies including at least five OD pregnancies with a control group of pregnancies conceived by conventional IVF/ICSI or spontaneous conception, and case series with >500 cases reporting one or more of the selected complications. Studies not adjusting for plurality were excluded. DATA COLLECTION AND ANALYSIS: Thirty-five studies met the inclusion criteria. A random-effects model was used for the meta-analyses. MAIN RESULTS: For OD pregnancies versus conventional IVF/ICSI pregnancies the risk of PE was adjusted odds ratio (AOR) 2.11 (95% CI, 1.42-3.15) in singleton and AOR 3.31 (95% CI, 1.61-6.80) in multiple pregnancies. The risks of preterm birth and low birthweight in singletons were AOR 1.75 (95% CI, 1.39-2.20) and 1.53 (95% CI, 1.16-2.01), respectively. CONCLUSIONS: OD conceptions are associated with adverse obstetric and neonatal outcomes. To avoid the additional increase in risk from multiplicity, single-embryo transfer should be the choice of option in OD cycles. TWEETABLE ABSTRACT: Oocyte donation pregnancies have increased risk of a range of obstetric and neonatal complications.

Classification of pregnancies of unknown location according to four different hCG-based protocols.

STUDY QUESTION: How do four protocols based on serial human chorionic gonadotropin (hCG) measurements perform when classifying pregnancies of unknown location (PULs) as low or high risk of being an ectopic pregnancy (EP)? SUMMARY ANSWER: The use of cut-offs in hCG level changes published by NICE, and a logistic regression model, M4, correctly classify more PULs as high risk, compared with two other protocols. WHAT IS KNOWN ALREADY: A logistic regression model, M4, based on the mean of two consecutive hCG values and the hCG ratio (hCG 48 h/hCG 0 h) that classify PULs into low- and high-risk groups for triage purposes, identifies more EPs than a protocol using the cut-offs between a 13% decline and a 66% rise in hCG levels over 48 h. STUDY DESIGN, SIZE, DURATION: A retrospective comparative study of four different hCG-based protocols classifying PULs as low or high risk of being an EP was performed at a gynaecological emergency unit over 3 years. PARTICIPANTS/MATERIALS, SETTING, METHOD: We identified 915 women with a PUL. Initial transvaginal ultrasonography (TVS) findings categorised 187 of the PULs as probable intrauterine pregnancies (IUPs) and 16 as probable EPs. The rate of change in hCG levels over 48 h was calculated for each patient and subjected to three different hCG threshold intervals and a logistic regression model for outcome prediction. Each PUL was subsequently dichotomised to either low-risk (i.e. failed PUL/IUP) or high-risk (i.e. EP) classification, which allowed us to compare the diagnostic performance. In 'Protocol A', a PUL was classified as low risk if >13% hCG level decline or >66% hCG level rise was achieved; otherwise, the PUL was classified as high risk of being an EP. 'Protocol B' classified a PUL as low or high risk using cut-offs of 35-50% declining hCG levels and of 53% rising hCG levels. Similarly, 'Protocol C' used hCG level cut-offs published by NICE, 50% for declining hCG levels and 63% for rising hCG levels. Finally, if a logistic regression model 'Protocol M4' calculated a ≥5% risk of the PUL being an EP, it was classified as high risk, and otherwise the PUL was classified as low risk. When the time interval between two hCG measurements failed to meet an exact 48 h, extrapolation and interpolation of hCG values was made, using log linear transformation. MAIN RESULTS AND THE ROLE OF CHANCE: Protocols A, B, C and M4 classified 73, 66, 55 and 56% of PULs as low risk. The sensitivity for protocols A, B, C and M4 was 68% (95% confidence interval (CI) 61-75%), 81% (74-86%), 87% (82-92%) and 88% (83-93%), respectively. The specificity was 82% (80-85%), 77% (74-80%), 66% (62-69%) and 67% (63-70%) for protocols A, B, C and M4, respectively. All comparisons of sensitivity and specificity between the protocols were statistically significant except for protocol C versus protocol M4. In protocol C, 87% (66-97%) of misclassified EPs had rising hCG levels, compared with 19% (6-41%) for protocol M4 (P < 0.01). In a secondary analysis excluding probable IUPs and probable EPs, the results for 712 PULs were analysed. The sensitivity subsequently remained stable for all protocols. Protocol M4 reached a 78% (74-81%) specificity, which was significantly higher than 70% (66-74%) for protocol C (P = 0.01) and protocol M4 classified 63% of PULs as low risk compared with 58% for protocol C. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of the study is a limitation. The results are derived from a population where laparoscopy played an important role in PUL management and diagnosis of EPs, although it did reflect real clinical practice. Although we tried to adhere to definitions of PUL and final outcomes as in previous studies and a recent consensus statement, potential differences in this regard must be acknowledged. Where the time interval between two serial hCG measurements deviated from 48 h we estimated 48 h hCG values. WIDER IMPLICATIONS OF THE FINDINGS: A logistic regression model, M4, classifies more PULs correctly as low risk in a selected PUL population without probable IUPs and EPs and identifies as many EPs, in comparison with the cut-offs available in the NICE guideline. This advantage for model M4 may result in a reduction of unnecessary follow-up visits, when fewer low-risk PULs are misclassified as high risk. These findings, however, ought to be clarified in a randomised controlled trial. STUDY FUNDING/COMPETING INTERESTS: The study was supported by LUA/ALF grant No. 70940. There are no competing interests.