Preimplantation genetic testing and child health: a national register-based study.

STUDY QUESTION: Is preimplantation genetic testing (PGT) associated with adverse perinatal outcome and early childhood health? SUMMARY ANSWER: Children born after PGT had comparable perinatal outcomes to children born after IVF/ICSI and comparable findings regarding early childhood health. WHAT IS KNOWN ALREADY: PGT is offered to couples affected by monogenic disorders (PGT-M) or inherited chromosomal aberrations (PGT-SR), limiting the risk of transferring the disorder to the offspring. PGT, an invasive technique, requires genetic analysis of one or up to ten cells from the embryo and is combined with IVF or ICSI. Several studies, most of them small, have shown comparable results after PGT and IVF/ICSI concerning perinatal outcome. Only a few studies with limited samples have been published on PGT and childhood health. STUDY DESIGN, SIZE, DURATION: We performed a register-based study including all singletons born after PGT (n = 390) in Sweden during 1 January 1996-30 September 2019. Singletons born after PGT were compared with all singletons born after IVF/ICSI (n = 61 060) born during the same period of time and with a matched sample of singletons (n = 42 034) born after spontaneous conception selected from the Medical Birth Register. Perinatal outcomes, early childhood health, and maternal outcomes were compared between pregnancies after PGT and IVF/ICSI as well as between pregnancies after PGT and spontaneous conception. Primary outcomes were preterm birth (PTB) and low birthweight (LBW) whereas childhood morbidity was the secondary outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on women who went through PGT and gave birth were obtained from the local databases at the two PGT centres in Sweden, whereas data on IVF treatment for the IVF/ICSI group were obtained from the national IVF registers. These data were then cross-linked to national health registers; the Medical Birth Register, the Patient Register, and the Cause of Death Register. Logistic multivariable regression analysis and Cox proportional hazards models were performed with adjustment for relevant confounders. MAIN RESULTS AND THE ROLE OF CHANCE: The mean follow-up time was 4.6 years for children born after PGT and 5.1 years for children born after spontaneous conception, whereas the mean follow-up time was 9.0 years for children born after IVF/ICSI. For perinatal outcomes, PTB occurred in 7.7% of children after PGT and in 7.3% of children after IVF/ICSI, whereas the rates were 4.9% and 5.2% for LBW (adjusted odds ratio (AOR) 1.22, 95% CI 0.82-1.81 and AOR 1.17, 95% CI 0.71-1.91, respectively). No differences were observed for birth defects. In comparison to spontaneous conception, children born after PGT had a higher risk for PTB (AOR 1.73, 95% CI 1.17-2.58). Regarding early childhood health, the absolute risk of asthma was 38/390 (9.7%) in children born after PGT and 6980/61 060 (11.4%) in children born after in IVF/ICSI, whereas the corresponding numbers were 34/390 (8.7%) and 7505/61 060 (12.3%) for allergic disorders. Following Cox proportional hazards models, no significant differences were found for these outcomes. Sepsis, hypothyroidism, attention deficit hyperactivity disorder, autism spectrum disorders, mental retardation, cerebral palsy, and epilepsy were diagnosed in a maximum of three PGT children. No PGT children died during the follow-up period. Regarding maternal outcomes, the rates of placenta praevia and caesarean delivery were significantly higher after PGT in comparison to spontaneous conception (AOR 6.46, 95% CI 3.38-12.37 and AOR 1.52, 95% CI 1.20-1.92, respectively), whereas no differences were seen comparing pregnancies after PGT and IVF/ICSI. LIMITATIONS, REASONS FOR CAUTION: The rather small sample size of children born after PGT made it impossible to adjust for all relevant confounders including fertilization method and culture duration. Moreover, the follow-up time was short for most of the children especially in the PGT group, probably lowering the absolute number of diagnoses in early childhood. WIDER IMPLICATIONS OF THE FINDINGS: The results are reassuring and indicate that the embryo biopsy itself has no adverse effect on the perinatal, early childhood, or maternal outcomes. Although the results are comparable to IVF/ICSI also regarding early childhood outcome, they should be taken with caution due to the low number of children with diagnoses and short follow-up time. Long-term follow-up studies on children born after PGT are scarce and should be conducted considering the invasiveness of the technique. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (LUA/ALF 70940), the Board of National Specialised Medical Care at Sahlgrenska University Hospital and Hjalmar Svensson Research Foundation. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

National survey of donor-conceived individuals who requested information about their sperm donor-experiences from 17 years of identity releases in Sweden.

STUDY QUESTION: What characterizes the group of donor-conceived (DC) individuals who request information about their identity-release sperm donor in Sweden, and what are their experiences of disclosure, information receipt and donor contact? SUMMARY ANSWER: Following three decades of identity-release donation in Sweden, few DC individuals have requested donor information with varying experiences of information receipt and donor contact. WHAT IS KNOWN ALREADY: In 1985, Sweden was the first country worldwide to enact legislation that gave DC individuals the right to obtain identifying information about their donor. Since then, identity-release gamete donation has become available in many countries but there is limited knowledge about the individuals who request donor information. STUDY DESIGN, SIZE, DURATION: A nation-wide cross-sectional survey study was performed at all seven University hospitals that provided donation treatment in Sweden during 1985-2002. During this period only donor insemination to heterosexual couples was permitted. Inclusion criteria were being 18 years of age or older, conceived with donor sperm and having requested information about the donor by December 2020. Recruitment was performed during 2016-2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 60 individuals had requested information about their donor. Of these, 53 were approached and 40 individuals, representing 34 families, accepted study participation (75% response rate). Participants completed a postal survey with the WHO-10 well-being index and study-specific questions about experiences of disclosure, motivations for requesting donor information, receipt of information, as well as intentions and experiences of donor contact. Independent t-test and chi-square tests were used to compare ratings of participants with early and late disclosure. MAIN RESULTS AND ROLE OF CHANCE: Of ∼900 DC individuals who had reached adult age, a total of 60 (≈7%) had requested information about the donor. Most of the 40 study participants (78%) made their requests within 2 years after reaching 18 years of age, or following disclosure at later ages (up to 32 years). Several participants had adult DC siblings in the family who had not requested any donor information. All except five participants received identifying information about the donor from the clinic. However, some donors had died or lacked contact information. Among those participants who were able to contact their donor, 41% had done so at the time of the study, while a third of the participants were unsure about potential contact. Several had met the donor in person and a few were in regular contact. About half of the participants had been informed about their donor conception in adolescence or adulthood (age 12-32), and there were significant differences between participants based on age at disclosure. Compared to those with early disclosure, participants with late disclosure were significantly more likely to be dissatisfied with the timing of their disclosure (P = 0.021), to react with negative emotions (P < 0.001), and to subsequently contact the donor (P = 0.047). LIMITATIONS, REASONS FOR CAUTION: The limited population available for inclusion resulted in a small sample size, despite a high response rate. In addition, men's lower participation rate must be taken into consideration when interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: The small number of individuals requesting information about their identity-release sperm donor is surprising. While not all DC individuals appear to be interested in donor information, it is reasonable to assume that some are unaware of their donor conception and thus unable to make informed decisions regarding their genetic origins. During the coming years, young women and men in many countries will become eligible to access identifying information about their donor. In order to meet the needs of these individuals, and to support positive outcomes for all involved parties, it is essential that adequate protocols and resources are developed. STUDY FUNDING/COMPETING INTEREST: Financial support from The Swedish Research Council. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

A survey of ovarian reserve and quality of life in female survivors of pediatric cancer.

INTRODUCTION: Childhood cancer is rare; the incidence in Sweden is approximately 16 new cases/100 000 children each year. Reduced reproductive function and fertility are well-known side effects of cancer treatment. Anti-Müllerian hormone (AMH) has been shown to correlate well with antral follicle count in healthy women but is currently not recommended as the primary surveillance modality for evaluation of premature ovarian insufficiency in this patient group. Psychological wellbeing related to fertility could affect quality of life and should be included in long-term follow-up. The aim of the study is to present the baseline data from inclusion for a prospective follow-up study of fertility surveillance where both medical and psychological aspects of fertility in female childhood cancer survivors are considered. MATERIAL AND METHODS: These are the first results from this longitudinal follow-up cohort study. Female adolescent and young adult survivors of pediatric cancer in Western Sweden were included from January 2016 to December 2018, a total of 54 participants. Median age at inclusion was 21 (15-29) years and median age at cancer diagnosis was 10 (1-17) years. AMH levels, antral follicle count, and data on fertility were recorded at inclusion and will be prospectively followed up. The study includes questionnaires and interviews concerning quality of life. This study is planned to continue until the participants reach the age of 40 years. RESULTS: Eighteen of 54 (33%) participants had AMH levels below 1.0 µg/L and were considered to have high or very high risk of infertility. Median AMH level was 2.50 µg/L. Six women had immediate need of oocyte cryopreservation. Psychological assessment showed that more than one-third of participants (n = 20) had elevated anxiety scores. CONCLUSIONS: One-third of female survivors of pediatric cancer in the study had high risk of low ovarian reserve, measured by a combination of AMH and antral follicle count, and many had signs of anxiety. The longitudinal study could contribute to better knowledge in the changes of AMH over time for this patient group. Psychological follow-up with questionnaires and interviews evaluating signs of depression and anxiety may serve as a model for future screening programs.

Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.

STUDY QUESTION: How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)? SUMMARY ANSWER: In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not. WHAT IS KNOWN ALREADY: Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs. PARTICIPANTS/MATERIALS, SETTING, METHODS: After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups. LIMITATIONS, REASONS FOR CAUTION: Data on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report.

No effect of weight intervention on perinatal outcomes in obese women scheduled for in vitro fertilization treatment.

INTRODUCTION: Large observational studies have shown that obstetric and perinatal outcomes are negatively affected in obese women. In contrast, a recent Dutch randomized trial of infertile women and lifestyle weight intervention found no difference between the weight intervention group and the control group in obstetric or neonatal outcomes. We have recently published a large Nordic randomized trial where obese women scheduled for in vitro fertilization (IVF) treatment went through an intensive weight intervention treatment before IVF. No significant effect on live birth rate was found, despite large weight loss in the intervention group. The present study was conducted primarily to find out the effect of weight intervention in obese women scheduled for IVF on mean birthweight and mean deviation from expected birthweight, and secondarily the effect on other perinatal and maternal outcomes. MATERIAL AND METHODS: A secondary analysis of a prospective, randomized controlled trial performed between 2010 and 2016 in the Nordic countries was performed. In all, 317 women were randomized either to weight reduction and IVF treatment (n = 160) or IVF only (n = 157) and the primary end-point was live birth. From this study, all births were analyzed for perinatal and maternal outcomes. Nine infertility clinics participated, including women < 38 years of age planning for IVF, and having a body mass index ≥ 30 and < 35 kg/m2 . Data concerning perinatal and maternal outcomes were gathered from maternal health-care and delivery records for mother and child. All analyses were performed on singletons only. RESULTS: There were 87 live births, 45 singletons in the intervention group and 41 singletons and one twin birth in the control group. The maternal characteristics for the women having a live birth were comparable in the two groups. The primary outcomes, mean birthweight, in the weight intervention and IVF group and the IVF only group were; 3486 g (standard deviation [SD] 523) vs 3584 g (SD 509) (P = 0.46), mean difference -98.6 g (95% confidence interval [CI] -320.3 to 123.2); deviation from expected birthweight 0.25% (SD 10.4) vs 0.87% (SD 12.9), mean difference 1.1% (95% CI -6.1 to 3.9). The estimates of the secondary perinatal and maternal outcomes in the 2 groups were: preterm birth < 37 weeks 2 (4.4%) vs 1 (2.4%) (odds ratio [OR] 1.95; 95% CI 0.17-22.36), small-for-gestational-age 0 (0%) vs 1 (2.4%), mean gestational age (days) 278 vs 280 (P = 0.95), preeclampsia 5 (11.1%) vs 4 (9.8%) (OR 1.19; 95% CI 0.30-4.76), cesarean section 13 (28.9%) vs 10 (24.4%) (OR 1.14; 95% CI 0.45-2.94). CONCLUSIONS: The outcomes in both groups were generally good. There are no indications that weight intervention in this setting, in infertile women with obesity WHO class 1 undergoing IVF, has a negative impact on mean birthweight and deviation from expected birthweight. However, the data are not sufficiently robust to draw firm conclusions concerning other outcomes.

The number of oocytes retrieved during IVF: a balance between efficacy and safety.

STUDY QUESTION: What is the relationship between the number of oocytes collected in fresh IVF treatments and the likelihood of cumulative delivery rate (fresh and frozen) per oocyte aspiration, severe ovarian hyperstimulation syndrome (OHSS) and thromboembolic events? SUMMARY ANSWER: Cumulative delivery rate per aspiration increases up to 20 oocytes retrieved and then evens out while the incidence of severe OHSS increases more rapidly from around 18 oocytes and thromboembolic events, although rare, occurs in particular if 15 or more oocytes are retrieved. WHAT IS KNOWN ALREADY?: Previous studies have shown that the number of oocytes retrieved for IVF is a positive predictor of live birth in fresh cycles. Few studies have investigated cumulative live birth rates and OHSS in relation to the number of aspirated oocytes. STUDY DESIGN, SIZE, DURATION: Retrospective population-based registry study including 39 387 women undergoing 77 956 fresh IVF cycles in the period 2007-2013 and 36 270 consecutive transfers of frozen/thawed embryos in the period 2007-2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from The Swedish National Quality Registry of Assisted Reproduction (Q-IVF) including all IVF cycles with oocyte retrieval performed in public or private infertility clinics during the study period, was cross-linked to the National Patient Register regarding diagnostic codes (ICD 10) for severe (OHSS) and thromboembolic events. Oocyte donation cycles were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth delivery rate in fresh cycles increased up to 11 oocytes retrieved and then evened out, where the live birth rate was 30.3% for a 34-year-old woman. The cumulative delivery rate per aspiration, including fresh transfer and all subsequent transfers of frozen-thawed embryos (FET cycles) per oocyte retrieval, increased up to approximately 20 oocytes where it reached 45.8%. The adjusted odds ratio (AOR) for live birth by the number of oocytes was 1.064 (95% CI: 1.061; 1.067). The incidence of severe OHSS increased significantly by the number of oocytes, particularly if more than 18 oocytes were retrieved. The AOR for OHSS by the number of oocytes was 1.122 (95% CI: 1.08; 1.137). Thromboembolic events were rare, a total of 16 events in 14 patients were observed, and occurred in particular if 15 or more oocytes were retrieved. LIMITATIONS, REASONS FOR CAUTION: All FET cycles might not be included. Some embryos cryopreserved between 2010 and 2013 might still result in additional births until 2018. Furthermore the gonadotrophin dose was not included in the Q-IVF Registry in the study period, thus adjustment for dose was not possible. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest a shift at approximately 18-20 oocytes where the cumulative delivery rate per aspiration levels off and, at the same time, the incidence of severe OHSS increases more rapidly. Thromboembolic events, although rare, should also be taken into consideration at stimulation regimes for IVF. Evaluating data taking both efficacy and the most serious safety aspects into account, is a new approach and of crucial importance both for patients undergoing IVF and their physicians. STUDY FUNDING/COMPETING INTEREST: Financial support was received through an agreement relating to research and the education of doctors (ALFGBG-70 940) and grant from the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

The association between the number of oocytes retrieved for IVF, perinatal outcome and obstetric complications.

STUDY QUESTION: Is there an association between the number of oocytes retrieved for IVF, and perinatal and obstetric outcomes? SUMMARY ANSWER: No significant association was found between the number of oocytes retrieved and perinatal outcomes, while an association was found for placenta praevia and male gender. WHAT IS KNOWN ALREADY: Previous studies have shown that between 6 and 15 oocytes retrieved is optimal for the live birth rate in fresh cycles. In a recent study, we showed that the cumulative live birth rate, including fresh and all cryopreservation cycles following one OPU, increases by the number of oocytes retrieved, up to approximately 20 oocytes. However, there was also an increase in serious side effects such as severe ovarian hyperstimulation syndrome (OHSS). A few studies, with contradictory results, have investigated whether the number of oocytes retrieved might also be associated with negative obstetric and perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A retrospective population-based registry study including all singleton babies born after fresh IVF cycles from 2002 to 2015 (n = 27 359) in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on treatment characteristics from the Medical Birth/IVF Registry and the Swedish National Quality Registry of Assisted Reproduction, including all fresh IVF cycles performed in public or private infertility clinics during the study period and resulting in singleton deliveries, were cross-linked to the Medical Birth Registry and the National Patient Registry for maternal and neonatal outcome. Data on educational level, ethnicity and paternal age were obtained through cross-linking to Statistics Sweden. Oocyte donation cycles were excluded. Main perinatal outcome variables were preterm birth (PTB <37 gestational weeks), very PTB (<32 gestational weeks), small for gestational age (SGA: <2 SD), peri/neonatal death and major birth defects. Main obstetric outcome variables were hypertensive disorders of pregnancy and placenta praevia. Univariable and multivariable analyses were used to explore the association between the number of oocytes retrieved and outcome variables. Adjustments were performed for maternal age, parity, smoking, BMI, cause of infertility, maternal educational level, maternal country of birth, treatment period, embryo stage, fertilization method (IVF/ICSI), number of embryos transferred, OHSS and vanishing twin. MAIN RESULTS AND THE ROLE OF CHANCE: The number of oocytes retrieved was analyzed as a continuous variable as well as categorized as <10, 10-14, 15-19 and >20 oocytes. A number of between four and nine oocytes was used as a reference. Single embryo transfer was performed in 20 910 (76.4%) of the cycles. Blastocyst transfer was performed in 3478 (12.7%) and cleavage stage embryo transfer was performed in 23 881 (87.3%) of the cycles. No significant association was observed between the number of oocytes retrieved (continuous variable) and PTB (adjusted odds ratio [AOR] 1.002, 95% CI 0.994-1.011), very PTB (AOR 1.013, 95% CI 0.994-1.032), SGA (AOR 0.998, 95% CI 0.988-1.009), peri/neonatal death (AOR 1.008, 95% CI 0.975-1.043) or major birth defects (AOR 1.009, 95% CI 0.998-1.020). Concerning obstetric outcomes, a significant association was found for placenta praevia (AOR 1.021, 95% CI 1.005-1.037) while no association was found for hypertensive disorders of pregnancy (AOR 0.991, 95% CI 0.981-1.001). Furthermore, a significant association was detected between the number of oocytes retrieved and the secondary outcome variable gender distribution, with a higher rate of males after >20 oocytes (AOR 1.126, 95% CI 1.014-1.249). LIMITATIONS, REASONS FOR CAUTION: As in all observational studies, unknown confounders may affect outcomes. WIDER IMPLICATIONS OF THE FINDINGS: These results are reassuring, indicating that there is no association between adverse neonatal outcomes and the number of oocytes retrieved. The association between the number of oocytes and placenta praevia was significant, though weak. The finding of an association with gender should be interpreted with caution. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received through Sahlgrenska University Hospital (ALFGBG-70 940) and the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

Weight reduction intervention for obese infertile women prior to IVF: a randomized controlled trial.

STUDY QUESTION: Does an intensive weight reduction programme prior to IVF increase live birth rates for infertile obese women? SUMMARY ANSWER: An intensive weight reduction programme resulted in a large weight loss but did not substantially affect live birth rates in obese women scheduled for IVF. WHAT IS ALREADY KNOWN: Among obese women, fertility and obstetric outcomes are influenced negatively with increased risk of miscarriage and a higher risk of maternal and neonatal complications. A recent large randomized controlled trial found no effect of lifestyle intervention on live birth in infertile obese women. STUDY DESIGN, SIZE, DURATION: A prospective, multicentre, randomized controlled trial was performed between 2010 and 2016 in the Nordic countries. In total, 962 women were assessed for eligibility and 317 women were randomized. Computerized randomization with concealed allocation was performed in the proportions 1:1 to one of two groups: weight reduction intervention followed by IVF-treatment or IVF-treatment only. One cycle per patient was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine infertility clinics in Sweden, Denmark and Iceland participated. Women under 38 years of age planning IVF, and having a BMI ≥30 and <35 kg/m2 were randomized to two groups: an intervention group (160 patients) with weight reduction before IVF, starting with 12 weeks of a low calorie liquid formula diet (LCD) of 880 kcal/day and thereafter weight stabilization for 2-5 weeks, or a control group (157 patients) with IVF only. MAIN RESULTS AND ROLE OF CHANCE: In the full analysis set (FAS), the live birth rate was 29.6% (45/152) in the weight reduction and IVF group and 27.5% (42/153) in the IVF only group. The difference was not statistically significant (difference 2.2%, 95% CI: 12.9 to -8.6, P = 0.77). The mean weight change was -9.44 (6.57) kg in the weight reduction and IVF group as compared to +1.19 (1.95) kg in the IVF only group, being highly significant (P < 0.0001). Significantly more live births were achieved through spontaneous pregnancies in the weight reduction and IVF group, 10.5% (16) as compared to the IVF only group 2.6% (4) (P = 0.009). Miscarriage rates and gonadotropin dose used for IVF stimulation did not differ between groups. Two subgroup analyses were performed. The first compared women with PCOS in the two randomized groups, and the second compared women in the weight reduction group reaching BMI ≤ 25 kg/m2 or reaching a weight loss of at least five BMI units to the IVF only group. No statistical differences in live birth rates between the groups in either subgroup analysis were found. LIMITATIONS, REASON FOR CAUTION: The study was not powered to detect a small increase in live births due to weight reduction and was not blinded for the patients or physician. Further, the intervention group had a longer time to achieve a spontaneous pregnancy, but were therefore slightly older than the control group at IVF. The study only included women with a BMI lower than 35 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that weight loss for obese women (BMI: 30-34.9 kg/m2) may not rectify the outcome in IVF cycles, although a significant higher number of spontaneous conceptions occurred in the weight loss group. Also, the study suggests that intensive weight reduction with LCD treatment does not negatively affects the results. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB, Solna, Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation and Jane and Dan Olsson Foundation. Dr Thurin-Kjellberg reports grants from Merck, non-financial support from Impolin AB, during the conduct of the study, and personal fees from Merck outside the submitted work. Dr Friberg reports personal fees from Ferring, Merck, MSD, Finox and personal fees from Studentlitteratur, outside the submitted work. Dr Englund reports personal fees from Ferring, and non-financial support from Merck, outside the submitted work. Dr Bergh reports and has been reimbursed for: writing a newsletter twice a year (Ferring), lectures (Ferring, MSD, Merck), and Nordic working group meetings (Finox). Dr Karlström reports lectures (Ferring, Finox, Merck, MSD) and Nordic working group meetings (Ferring). Ms Kluge, Dr Einarsson, Dr Pinborg, Dr Klajnbard, Dr Stenlöf, Dr Larsson, Dr Loft and Dr Wistrand have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01566929. TRIAL REGISTRATION DATE: 23-03-2012. DATE OF FIRST PATIENT'S ENROLMENT: 05-10-2010.

Experiences of Pre-Implantation Genetic Diagnosis (PGD) in Sweden: a Three-Year Follow-Up of Men and Women.

Men and women with a hereditary genetic disease are faced with different options when they wish to become parents. One is pre-implantation genetic diagnosis (PGD) which is a combination of in vitro fertilization (IVF) and genetic analysis of the embryo before implantation. The present study focused on men and women's psychological experiences of PGD three years after applying for PGD. Nineteen women and seventeen men (i.e. seventeen couples and two women) participated. The interviews were analysed by thematic method. It is better to have tried was identified as a master theme, under which came three underlying sub-themes, which had the following headings: Practical experience of PGD, Psychological experience of PGD and Goals of PGD. The results show that men and women three years after PGD are still psychologically affected by their experience. The men and women raised concerns that their relationship had been affected, both positively and negatively, and feelings of anxiety and depression still remained. Healthcare services should recognize the heterogeneous nature of the group being studied and therefore the need for counselling can arise at different times and in relation to different areas, regardless of the outcome of the PGD.

High risks of maternal and perinatal complications in singletons born after oocyte donation.

INTRODUCTION: Previous studies have shown an increased risk of obstetric complications in pregnancies after oocyte donation (OD). The present study includes all singletons born after OD over 10 years in Sweden. MATERIAL AND METHODS: This was a retrospective population-based cohort study. Data from all Swedish in vitro fertilization (IVF) clinics between 2003 and 2012 were collected. Data were cross-linked with the Swedish Medical Birth Registry. The study included 388 OD singletons, 26 696 IVF/ICSI singletons and 999 804 spontaneously conceived (SC) singletons. An adjusted odds ratio (aOR) was calculated with adjustment for relevant confounders. RESULTS: Singleton OD pregnancies had a significantly increased risk of preeclampsia compared with IVF (aOR 3.05; 95% CI 2.23-4.16) and SC (aOR 2.84; 95% CI 2.10-3.84), and increased risk of postpartum hemorrhage (>1000 mL) compared with IVF (aOR 2.66; 95% CI 2.04-3.49) and SC (aOR 2.87; 95% CI 2.20-3.71), a higher risk of preterm birth (<37 weeks) compared with IVF (aOR 1.79; 95% CI 1.30-2.46) and SC (aOR 1.58; 95% CI 1.15-2.16) and a higher risk of low birthweight (<2500 g) compared with IVF (aOR 1.67; 95% CI 1.15-2.42) and SC (aOR 1.46; 95% CI 1.01-2.11). The rate of large-for-gestational age was significantly increased in singletons born after OD with frozen cycles than with fresh cycles (odds ratio 5.29, 95% CI 1.30-21.54). CONCLUSIONS: Singleton pregnancies conceived after OD are associated with increased maternal and perinatal risks compared with IVF/ICSI pregnancies using the woman's own oocytes and with SC.

Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience.

INTRODUCTION: The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. MATERIAL AND METHODS: A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. RESULTS: Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1:3). CONCLUSIONS: Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.

The association between body mass index and live birth and maternal and perinatal outcomes after in-vitro fertilization: a national cohort study.

Objective: To investigate the association between female body mass index (BMI) and live birth rates and maternal and perinatal outcomes after in-vitro fertilization (IVF). Methods: We performed a national, population-based cohort study including women undergoing IVF between 2002 and 2020. The cohort included 126,620 fresh cycles and subsequent frozen embryo transfers between 2007 and 2019 (subpopulation 1) and 58,187 singleton deliveries between 2002 and 2020 (subpopulation 2). Exposure was female BMI (kg/m2) categorized according to the World Health Organization as underweight (<18.5), normal weight (18.5-24.9, reference), overweight (25.0-29.9), class I obesity (30.0-34.9), class II obesity (35.0-39.9), and class III obesity (≥40.0). The primary outcome in subpopulation 1 was cumulative live birth per started fresh IVF cycle, including fresh and subsequent frozen embryo transfers. Primary outcomes in subpopulation 2 were hypertensive disorders of pregnancy and preterm birth at less than 37 weeks. Risk ratios (RRs) with 95% confidence intervals (CIs) for the association between BMI class and outcomes were calculated using generalized linear models after adjustment for relevant confounders. Results: The cumulative live birth rate decreased significantly with increasing BMI from 32.6% in normal-weight women to 29.4% in overweight women, 27.0% in women in obesity class I, 21.8% in women in obesity class II, and 7.6% in women in obesity class III. The risk of hypertensive disorders of pregnancy increased significantly and progressively with increasing BMI, from 4.6% in normal-weight women to 7.8% in overweight women and 12.5%, 17.9%, and 20.3% in women in obesity classes I, II, and III. The risk of preterm birth followed a similar pattern, from 6.3% in normal-weight women to 7.5% in overweight women and 8.9%, 9.9%, and 15.3% in women in obesity classes I, II, and III. The risks of other perinatal complications, such as perinatal death, showed an even more pronounced increase. Conclusion: Using a large and complete national cohort of women undergoing IVF, we demonstrate a dose-dependent decrease in live birth rate and a substantial increase in maternal and perinatal complications with increasing BMI. Strategies to improve this situation are warranted.

Prevalence of Vitamin D Insufficiency and Its Determinants among Women Undergoing In Vitro Fertilization Treatment for Infertility in Sweden.

There is a lack of research on women with infertility in the northern latitudes, where vitamin D insufficiency is high. Therefore, this study aimed to assess the prevalence and determinants of vitamin D insufficiency (serum 25(OH)D concentration < 50 nmol/L) among women undergoing in vitro fertilization (IVF) treatment. Thus, 265 women scheduled for IVF/intracytoplasmic sperm injection (ICSI) between September 2020 and August 2021 at Sahlgrenska University Hospital in Gothenburg, Sweden, were included. Data on serum 25(OH)D concentration, vitamin D intake, and sun exposure were collected via questionnaires and blood samples. Approximately 27% of the women had 25(OH)D insufficiency, which was associated with longer infertility duration. The likelihood of insufficiency was higher among women from non-Nordic European countries (OR 2.92, 95% CI 1.03-8.26, adjusted p = 0.043), the Middle East (OR 9.90, 95% CI 3.32-29.41, adjusted p < 0.001), and Asia (OR 5.49, 95% CI 1.30-23.25, adjusted p = 0.020) than among women from Nordic countries. Women who did not use vitamin D supplements were more likely to have insufficiency compared with supplement users (OR 3.32, 95% CI 1.55-7.10, adjusted p = 0.002), and those who avoided sun exposure had higher odds of insufficiency compared to those who stayed "in the sun all the time" (OR 3.24, 95% CI 1.22-8.62, adjusted p = 0.018). Women with infertility in northern latitudes and those from non-Nordic countries who avoid sun exposure and do not take vitamin supplements have a higher prevalence of 25(OH)D insufficiency and longer infertility duration.

Patient preferences for characteristics differentiating ovarian stimulation treatments.

BACKGROUND: Little is known concerning patient preferences for IVF treatments. The objective of this study was to elicit patient preferences for characteristics differentiating ovarian stimulation treatments. METHODS: Women undergoing IVF were recruited from six clinics in Sweden between May 2010 and December 2010. Included patients completed a study questionnaire consisting of one contingent valuation (CV) question (with six different bids) and 16 conjoint analysis (CA) questions formulated as discrete choices between two hypothetical ovarian stimulation treatments (defined in terms of manufacturing method, method of administration, time required for administration, dose variability and hypothetical price). Patient preferences were derived using multinomial logit modelling. RESULTS: The final study population consisted of 294 women (mean age of 35). Respondents were willing to pay €360 [95% confidence interval (CI): €340-€390] to receive FSH derived from DNA technology instead of highly purified extract from urine from post-menopausal women, €300 (95% CI: €280-€320) to administer the FSH using a prefilled injection pen instead of a conventional syringe, €30 (95% CI: €20-€40) per saved minute required for administration and €530 (95% CI: €500-€570) to reduce the dose variability from 10-20% to 1-2% (P< 0.001 for all estimates). The result from the CV was similar to the CA. CONCLUSIONS: Women undergoing IVF place significant value on characteristics differentiating ovarian stimulation treatments. Product-specific aspects should be taken into account by decision-makers when discriminating between commercial gonadotrophins in clinical practice to align health-care decision-making with patient preferences and potentially improve the effectiveness of IVF interventions through enhanced patient satisfaction and treatment compliance. Preferences for treatment characteristics should also be considered in evaluations of ovarian stimulation products to capture their true value from a patient perspective.

Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.

BACKGROUND: There is increasing use of cryopreservation in IVF. This study compared singletons born after cryopreservation with singletons born after fresh IVF cycles and singletons born to women in the general population. METHODS: Data were collected for Swedish IVF treatments during the years 2002-2006. All singletons from single embryo transfer (SET) and double embryo transfer (DET) after cryopreserved (n = 2348) and fresh cycles (n = 8944) were included and cross-linked with the Swedish Medical Birth Registry and compared with all singletons born after spontaneous conception (n = 571 914). Main outcomes were preterm and very preterm birth and low and very low birthweight (VLBW). Other outcomes were small for gestational age, large for gestational age (LGA), perinatal mortality and maternal outcomes. RESULTS: Singletons from cryopreserved SET/DET or cryopreserved SET had increased rates of extreme preterm birth compared with singletons from the general population. A lower rate of LBW was found for cryopreserved SET/DET singletons compared with singletons from fresh cycles; however, a higher rate of perinatal mortality was detected. The rates of LGA and macrosomia were increased for cryopreserved SET/DET singletons when compared with those from fresh cycles and the general population. For maternal outcomes, a higher rate of pre-eclampsia was noted for pregnancies from cryopreserved cycles compared with those from fresh cycles or the general population, but the rate of placenta praevia was lower in pregnancies from cryopreserved cycles compared with those from fresh cycles. CONCLUSIONS: The obstetric outcome of singletons after cryopreservation was slightly poorer when compared with the general population. In comparison with fresh cycles, the outcome varied. The finding of an increased rate of LGA after cryopreservation requires further study.

[Gamete donation]. / Donation av ägg och spermier.

Since 1985 only non-anonymous sperm donation  (where a child born as a result of treatment can recieve information about the identity of the donor at a mature age) is performed in Sweden, and from 2003 the same applies to egg donation. Treatment is legal for different groups of patients; man-woman couples, female same sex couples and single women. Treatment can be performed at publicly funded and at private clinics, and for sperm donation it is possible using either insemination or IVF. Treatment with donated gametes is steadily increasing.

Inflammatory and metabolic markers in relation to outcome of in vitro fertilization in a cohort of predominantly overweight and obese women.

For overweight and obese women undergoing in vitro fertilization (IVF) the pregnancy and live birth rates are compromised while the underlying mechanisms and predictors are unclear. The aim was to explore the association between adipose tissue-related inflammatory and metabolic markers and the pregnancy and live birth outcome of IVF in a cohort of predominantly overweight and obese women. Serum samples, fulfilling standardizing criteria, were identified from 195 women having participated in either the control (n = 131) or intervention (n = 64) group of a randomized controlled trial (RCT), seeking to evaluate the effect of a weight reduction intervention on IVF outcome in obese women. Serum high-sensitivity C-reactive protein (hsCRP) and the adipokines leptin and adipocyte fatty acid-binding protein (AFABP) were analyzed for the whole cohort (n = 195) in samples collected shortly before IVF [at randomization (control group), after intervention (intervention group)]. Information on age, anthropometry [BMI, waist circumference, waist-to-height ratio (WHtR)], pregnancy and live birth rates after IVF, as well as the spontaneous pregnancy rate, was extracted or calculated from collected data. The women of the original intervention group were also characterized at randomization regarding all variables. Eight women [n = 3 original control group (2.3%), n = 5 original intervention group (7.8%)] conceived spontaneously before starting IVF. BMI category proportions in the cohort undergoing IVF (n = 187) were 1.6/20.1/78.3% (normal weight/overweight/obese). The pregnancy and live birth rates after IVF for the cohort were 35.8% (n = 67) and 24.6% (n = 46), respectively. Multivariable logistic regression revealed that none of the variables (age, hsCRP, leptin, AFABP, BMI, waist circumference, WHtR) were predictive factors of pregnancy or live birth after IVF. Women of the original intervention group displayed reductions in hsCRP, leptin, and anthropometric variables after intervention while AFABP was unchanged. In this cohort of predominantly overweight and obese women undergoing IVF, neither low-grade inflammation, in terms of hsCRP, other circulating inflammatory and metabolic markers released from adipose tissue (leptin, AFABP), nor anthropometric measures of adiposity or adipose tissue distribution (BMI, waist, WHtR) were identified as predictive factors of pregnancy or live birth rate.Trial registration: ClinicalTrials.gov number, NCT01566929. Trial registration date 30-03-2012, retrospectively registered.

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis.

INTRODUCTION: Dietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the effectiveness and safety of dietary and/or physical activity interventions in women with infertility and overweight or obesity on reproductive, maternal and perinatal outcomes and to explore if there are subgroup(s) of women who benefit from each specific intervention or their combination (treatment-covariate interactions). METHODS AND ANALYSIS: We will include RCTs with dietary and/or physical activity interventions as core interventions prior to fertility treatment in women with infertility and overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify eligible studies. We will approach authors of eligible trials to contribute individual participant data (IPD). We will perform risk of bias assessments according to the Risk of Bias 2 tool and a random-effects IPDMA. We will then explore treatment-covariate interactions for important participant-level characteristics. ETHICS AND DISSEMINATION: Formal ethical approval for the project (Venus-IPD) was exempted by the medical ethics committee of the University Medical Center Groningen (METc code: 2021/563, date: 17 November 2021). Data transfer agreement will be obtained from each participating institute/hospital. Outcomes will be disseminated internationally through the collaborative group, conference presentations and peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42021266201.

Obstetric outcome after in vitro fertilization with single or double embryo transfer.

BACKGROUND: IVF children, including singletons, are known to have a poorer obstetric outcome than children born after spontaneous conception. With a broad introduction of single embryo transfer (SET), this scenario might change. This study compares the obstetric outcome after IVF with SET, elective SET (eSET), non elective SET (non-eSET) and double embryo transfer (DET) with outcomes in the general population. METHODS: All IVF children born in Sweden after IVF treatment during the years 2002-2006 (n = 13 544 children) were included and compared with all non-IVF children born during the same time period (n = 587 009 children). Data were collected from all 16 Swedish IVF clinics and cross-linked with the Swedish Medical Birth Registry. Main outcomes were preterm birth (<28, <32 and <37 w), very-low-birthweight (VLBW) and low-birthweight (LBW). Adjusted odds ratios were calculated. RESULTS: In total, 7763 children were born after SET and 5724 children after DET. Comparing all SET children, irrespective of multiplicity, with all children in the general population, significantly higher rates of <28 w was found for the IVF children. Comparing IVF singletons, irrespective of SET and DET with non-IVF singletons from the general population, significantly higher rates of <28 w, <37 w, LBW and VLBW were found. eSET singletons, compared with singletons in the general population, had a significantly higher rate of <37 w and non-eSET singletons had significantly higher rates of <28 w and <2500 g births. CONCLUSIONS: Children born after IVF had a poorer obstetric outcome compared with children from the general population. Singletons, when analysed as one group, irrespective of whether the children were born after eSET, non-eSET or DET, also had a poorer obstetric outcome with higher rates of preterm and LBW compared with singletons in the general population.