| 1. |
- Ginström Ernstad, Erica, et al.
(author)
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Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.
- 2019
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In: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 34:11, s. 2282-2289
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Journal article (peer-reviewed)abstract
- Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts?Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts.Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited.This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa.Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex.A higher risk of PTB (<37weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500g), SGA, macrosomia (≥4500g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower.Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study.The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification.The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71450). There are no conflicts of interest to declare.ISRCTN11780826.
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| 2. |
- H Petersen, Sindre, et al.
(author)
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Risk of Hypertensive Disorders in Pregnancy After Fresh and Frozen Embryo Transfer in Assisted Reproduction: A Population-Based Cohort Study With Within-Sibship Analysis.
- 2022
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In: Hypertension (Dallas, Tex. : 1979). - 1524-4563. ; 80:2
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Journal article (peer-reviewed)abstract
- Frozen embryo transfer (frozen-ET) is increasingly common because of improved cryopreservation methods and elective freezing of all embryos. Frozen-ET is associated with higher risk of hypertensive disorders in pregnancy than both natural conception and fresh embryo transfer (fresh-ET), but whether this is attributable to parental factors or treatment is unknown.Using the Medical Birth Registries of Denmark (1994-2014), Norway, and Sweden (1988-2015), linked to data from national quality registries and databases on assisted reproduction, we designed a population-based cohort study with within-sibship comparison. We included 4426691 naturally conceived, 78300 fresh embryo transfer, and 18037 frozen-ET singleton pregnancies, of which 33209 sibships were conceived using different conception methods. Adjusted odds ratios (aOR) of hypertensive disorders in pregnancy for fresh embryo transfer and frozen-ET versus natural conception with 95% CI were estimated using multilevel logistic regression, where random effects provided conventional population-level estimates and fixed effects gave within-sibship estimates. Main models included adjustment for birth year, maternal age, parity, and country.Risk of hypertensive disorders in pregnancy was higher after frozen-ET compared to natural conception, both at population level (7.4% versus 4.3%, aOR, 1.74 [95% CI, 1.61-1.89]) and within sibships (aOR, 2.02 [95% CI, 1.72-2.39]). For fresh embryo transfer, risk was similar to natural conception, both at population level (aOR, 1.02 [95% CI, 0.98-1.07]) and within sibships (aOR, 0.99 [95% CI, 0.89-1.09]).Frozen-ET was associated with substantially higher risk of hypertensive disorders in pregnancy, even after accounting for shared parental factors within sibships.
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| 3. |
- Henningsen, Anna-Karina A, et al.
(author)
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Infant and maternal health monitoring using a combined Nordic database on ART and safety.
- 2011
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In: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 90:7, s. 683-691
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Journal article (peer-reviewed)abstract
- Objective. To evaluate infant and maternal health after assisted reproductive technology (ART), using data on over 90 000 ART children and their mothers in Denmark, Finland, Norway and Sweden. Data have been combined and will be compared with a control group of spontaneously conceived children and their mothers. The overall aim of this project is to evaluate the safety of ART. The size of the cohort should enable estimation of the prevalence of rare conditions such as birth defects, cancers, neurological impairments and imprinting diseases in the ART population compared to control children. Outcome data on the mothers of ART children can be used to study risks during pregnancy and obstetric complications after ART. Methods. A personal identification number given to all Nordic residents allows cross-linkage of the national health registers and enables long-term follow-up of ART children. The medical birth registers in the Nordic countries make it possible to cross-link data from mother and child. When a child is identified as conceived by ART, we can obtain a list of all International Classification of Diseases (ICD) codes ever registered on that specific child. Conclusion. Combining the Nordic ART and health registers is a complicated but feasible task. The main strengths of this ongoing study are the size of the cohort of ART children and their mothers and the possibility to follow the children through the health registers. The limitations are related to the national differences in reporting and recording of data together with the heterogeneity of data.
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| 4. |
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| 5. |
- Norrman, Emma, et al.
(author)
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Cardiovascular disease, obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study.
- 2021
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In: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 18:9
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Journal article (peer-reviewed)abstract
- Some earlier studies have found indications of significant changes in cardiometabolic risk factors in children born after assisted reproductive technology (ART). Most of these studies are based on small cohorts with high risk of selection bias. In this study, we compared the risk of cardiovascular disease, obesity, and type 2 diabetes between singleton children born after ART and singleton children born after spontaneous conception (SC).This was a large population-based cohort study of individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015. Data were obtained from national ART and medical birth registers and cross-linked with data from national patient registers and other population-based registers in the respective countries. In total, 122,429 children born after ART and 7,574,685 children born after SC were included. Mean (SD) maternal age was 33.9 (4.3) years for ART and 29.7 (5.2) for SC, 67.7% versus 41.8% were primiparous, and 45.2% versus 32.1% had more than 12 years of education. Preterm birth (<37 weeks 0 days) occurred in 7.9% of children born after ART and 4.8% in children born after SC, and 5.7% versus 3.3% had a low birth weight (<2,500 g). Mean (SD) follow-up time was 8.6 (6.2) years for children born after ART and 14.0 (8.6) years for children born after SC. In total, 135 (0.11%), 645 (0.65%), and 18 (0.01%) children born after ART were diagnosed with cardiovascular disease (ischemic heart disease, cardiomyopathy, heart failure, or cerebrovascular disease), obesity or type 2 diabetes, respectively. The corresponding values were 10,702 (0.14%), 30,308 (0.74%), and 2,919 (0.04%) for children born after SC. In the unadjusted analysis, children born after ART had a significantly higher risk of any cardiovascular disease (hazard ratio [HR] 1.24; 95% CI 1.04-1.48; p = 0.02), obesity (HR 1.13; 95% CI 1.05-1.23; p = 0.002), and type 2 diabetes (HR 1.71; 95% CI 1.08-2.73; p = 0.02). After adjustment, there was no significant difference between children born after ART and children born after SC for any cardiovascular disease (adjusted HR [aHR]1.02; 95% CI 0.86-1.22; p = 0.80) or type 2 diabetes (aHR 1.31; 95% CI 0.82-2.09; p = 0.25). For any cardiovascular disease, the 95% CI was reasonably narrow, excluding effects of a substantial magnitude, while the 95% CI for type 2 diabetes was wide, not excluding clinically meaningful effects. For obesity, there was a small but significant increased risk among children born after ART (aHR 1.14; 95% CI 1.06-1.23; p = 0.001). Important limitations of the study were the relatively short follow-up time, the limited number of events for some outcomes, and that the outcome obesity is often not considered as a disease and therefore not caught by registers, likely leading to an underestimation of obesity in both children born after ART and children born after SC.In this study, we observed no difference in the risk of cardiovascular disease or type 2 diabetes between children born after ART and children born after SC. For obesity, there was a small but significant increased risk for children born after ART.ISRCTN11780826.
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| 7. |
- Rodriguez-Wallberg, Kenny A., et al.
(author)
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Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience
- 2016
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In: Acta Obstetricia et Gynecologica Scandinavica. - : WILEY-BLACKWELL. - 0001-6349 .- 1600-0412. ; 95:9, s. 1015-1026
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Journal article (peer-reviewed)abstract
- 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.
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| 8. |
- Sandvei, Marie Søfteland, et al.
(author)
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Risk of ovarian cancer in women who give birth after assisted reproductive technology (ART)-a registry-based Nordic cohort study with follow-up from first pregnancy.
- 2023
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In: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 128:5, s. 825-832
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Journal article (peer-reviewed)abstract
- There is concern that assisted reproductive technology (ART) may increase ovarian cancer risk, but previous studies are inconclusive. We compared ovarian cancer risk for women who gave birth after ART vs natural conception.Through linkage of nationwide registry data, we followed 3,303,880 initially nulliparous women in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015) and Sweden (1985-2015) from first pregnancy ≥22 weeks to ovarian cancer, emigration, death or end of follow-up (2014/2015). We estimated hazard ratios (HRs), adjusting for age, parity, maternal birth year and country, and for body mass index and smoking in subsamples.Mean age at first birth was 27.7 years. During a mean follow-up of 14.4 person-years, 2683 participants (0.08%) developed ovarian cancer; 135 after ART and 2548 after natural conception only (incidence rates 11.6 and 5.5 per 100,000 person-years, respectively). The risk was higher for women who ever gave birth after ART (HR 1.70, 95% confidence interval 1.42-2.03) compared to natural conception. Associations were stronger for conventional in vitro fertilisation than for intracytoplasmic sperm injection.Among parous women, ART-conception was associated with a higher risk of ovarian cancer than natural conception. Further studies should decipher whether this is causal or confounded by infertility or other factors.
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| 9. |
- Spangmose, Anne Lærke, et al.
(author)
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Cerebral palsy in ART children has declined substantially over time: a Nordic study from the CoNARTaS group
- 2021
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In: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 36:8, s. 2358-2370
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Journal article (peer-reviewed)abstract
- STUDY QUESTION: Are the decreasing multiple birth rates after ART associated with a simultaneous drop in the incidence of cerebral palsy (CP) in ART children over time? SUMMARY ANSWER: The relative odds of CP in ART children have declined in the Nordic countries over the past two decades concurrently with declining multiple birth rates. WHAT IS KNOWN ALREADY: In the Nordic countries, the rate of twin pregnancies after ART has decreased from 30% in the early 1990s to 4-13% in 2014, following the implementation of elective single embryo transfer (SET). Consequently, preterm birth rates have declined substantially in ART pregnancies. However, whether the risk of CP, a known consequence of preterm birth, has decreased correspondingly is still unknown. STUDY DESIGN, SIZE, DURATION: Retrospective register-based cohort study based on data on all singletons, twins, and higher-order multiples born in Denmark (birth year 1994-2010), Finland (1990-2010), and Sweden (1990-2014), corresponding to 111 844 ART children and 4 679 351 spontaneously conceived children. PARTICIPANTS/MATERIAL, SETTING, METHODS: Data were obtained from a large Nordic cohort of children born after ART and spontaneous conception initiated by the Committee of Nordic ART and Safety-CoNARTaS. The CoNARTaS cohort was established by cross-linking national register data using the unique personal identification number, allocated to every citizen in the Nordic countries. Data from the National Medical Birth Registers, where information on maternal, obstetric, and perinatal outcomes is recorded, were cross-linked to data from the National ART- and Patients Registers to obtain information on fertility treatments and CP diagnoses. Relative risks of CP for ART compared to spontaneous conception were estimated as odds ratios from multivariate logistic regression analyses across all birth years, as well as for the following birth year categories: 1990-1993, 1994-1998, 1999-2002, 2003-2006, 2007-2010, and 2011-2014. Analyses were made for all children and for singletons and twins, separately. MAIN RESULTS AND THE ROLE OF CHANCE: The main outcome measure was the relative odds of CP in different time periods for ART versus spontaneously conceived children. CP was diagnosed in 661 ART children and 16 478 spontaneously conceived children born between 1990 and 2014. In 1990-1993, the relative odds of CP were substantially higher in all ART children (adjusted odds ratio (aOR) 2.76 (95% CI 2.03-3.67)) compared with all spontaneously conceived children, while in 2011-2014, it was only moderately higher (aOR 1.39 (95% CI 1.01-1.87)). In singletons, the higher relative odds of CP in ART children diminished over time from 1990 to 1993 (aOR 2.02 (95% CI 1.22-3.14)) to 2003-2006 (aOR 1.18 (95% CI 0.91-1. 49)) and was not significantly increased for birth cohorts 2007-2010 and 2011-2014. For ART twins versus spontaneously conceived twins, the relative odds of CP was not statistically significantly increased throughout the study period. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study was a shorter follow-up time and younger age at first CP diagnosis for ART children compared with spontaneously conceived children. However, analyses ensuring a minimum of bias from differences in age at CP diagnosis and follow-up time confirmed the results, hence, we do not consider this to cause substantial bias. WIDER IMPLICATIONS OF THE FINDINGS: A SET policy in ART treatments has the potential to reduce the increased risk of cerebral palsy in the ART population due to lower rates of multiple deliveries. At a time with high survival rates of frozen/thawed embryos, this study provides a strong argument against the continued use of multiple embryo transfer in most ART settings. Larger cohort studies including also the number of gestational sacs in early pregnancy will be preferable to show an effect of vanishing twins on the risk of CP in the ART population. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by grants from NordForsk (grant number 71450), Elsass Foundation (19-3-0444), the ALF-agreement (ALFGBG 70940), and The Research Fund of Rigshospitalet, Copenhagen University Hospital. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.
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| 11. |
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| 12. |
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| 13. |
- Westvik-Johari, Kjersti, et al.
(author)
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Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis.
- 2021
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In: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 18:6
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Journal article (peer-reviewed)abstract
- Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (-51 g, 95% CI -58 to -45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI -1.2 to -0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.ClinicalTrials.gov ISRCTN11780826.
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