The risk of Type 1 diabetes in children born after ART: a Nordic cohort study from the CoNARTaS group.

STUDY QUESTION: Do children born after ART have a higher risk of developing Type 1 diabetes (DM1) than children conceived without ART? SUMMARY ANSWER: The risk of DM1 was similar for children conceived with and without ART, and there were no clear differences in risk according to method of fertility treatment. WHAT IS KNOWN ALREADY: ART is associated with a higher risk of adverse perinatal outcomes, and the risk depends on the method of ART. The Developmental Origins of Health and Disease theory proposes that prenatal stress can provoke changes in endocrine processes which impact health later in life. STUDY DESIGN SIZE DURATION: A Nordic register-based cohort study was carried out, including all children born in Denmark (birth years 1994-2014), Finland (1990-2014), and Norway (1984-2015). The study included 76 184 liveborn singletons born after ART and 4 403 419 born without ART. Median follow-up was 8.3 and 13.7 years in the ART and non-ART group, respectively. PARTICIPANTS/MATERIALS SETTING METHODS: The cohort, initiated by the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS), was established by linking national registry data from the medical birth registries and national patient registries available in the Nordic countries. We performed multivariable logistic regression analyses for the birth year intervals 1984-1990, 1991-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015, while adjusting for year of birth within each interval, sex of the child, parity, maternal age, maternal diabetes, and maternal smoking during pregnancy as potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 259 (3.4‰) children born after ART were diagnosed with DM1, while this was the case for 22 209 (5.0‰) born without ART, corresponding to an adjusted odds ratio of 0.98 (95% CI: 0.861.11). Within the different birth year intervals, no significant difference in risk of DM1 between the two groups was found, except for the youngest cohort of children born 2011-2015 where ART was associated with a higher risk of DM1. We found no significant differences in risk of DM1 when comparing children born after IVF versus ICSI or fresh versus frozen embryo transfer, but with only few cases in each group. LIMITATIONS REASONS FOR CAUTION: The main limitation of the study is the relatively short follow-up time. The incidence rate of DM1 peaks during ages 10-14 years, hence a longer follow-up would benefit all analyses and, in particular, the subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Overall, our findings are reassuring especially considering the concomitantly increasing number of children born from ART and the increasing incidence of DM1 globally. STUDY FUNDING/COMPETING INTERESTS: This Nordic registry study has been supported by the Nordic Trial Alliance/NORDFORSK and Rigshospitalets Research Foundation. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. None of the authors has any conflicts of interest to declare regarding this study. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Risk of congenital malformations in live-born singletons conceived after intracytoplasmic sperm injection: a Nordic study from the CoNARTaS group.

OBJECTIVE: To investigate whether the risk of major congenital malformations is higher in live-born singletons conceived with intracytoplasmic sperm injection (ICSI) compared with in vitro fertilization (IVF)? DESIGN: Nordic register-based cohort study. SETTING: Cross-linked data from Medical Birth Registers and National ART and Patient Registers in Denmark, Norway and Sweden. Data were included from the year the first child conceived using ICSI was born: Sweden, 1992; Denmark, 1994; and Norway, 1996. Data were included until 2014 for Denmark and 2015 for Norway and Sweden. PATIENT(S): All live-born singletons conceived using fresh ICSI (n = 32,484); fresh IVF (n = 47,178); without medical assistance (n = 4,804,844); and cryo-ICSI (n = 7,200) during the study period. INTERVENTION(S): Different in vitro conception methods, and cryopreservation of embryos. MAIN OUTCOME MEASURE(S): Risk of major congenital malformations on the basis of International Classification of Diseases codes. The European Concerted Action on Congenital Anomalies and Twins was used to differentiate between major and minor malformations. RESULT(S): Among singletons conceived using fresh ICSI, 6.0% had a major malformation, compared with 5.3% of children conceived using fresh IVF; 4.2% of children conceived without medical assistance; and 4.9% of children conceived using cryo-ICSI; adjusted odds ratio (AOR) 1.07 (95% confidence interval [CI] 1.01-1.14) in ICSI vs. IVF; and AOR 1.28 (95% CI, 1.23-1.35) in ICSI vs. no medical assistance; and AOR 1.11 (95% CI, 0.99-1.26) in ICSI fresh vs. cryo-ICSI. When malformations were grouped by different organ systems, children conceived using ICSI had a higher risk of respiratory and chromosomal malformations compared with children conceived using IVF, but there were very few cases in each group. When categorizing children conceived using ICSI according to treatment indication (male factor infertility only vs. other indications), we found a higher risk of hypospadias when ICSI was performed because of male factor infertility only (AOR 1.85 [95% CI 1.03-332]). The indications for ICSI changed over time, as male factor infertility did not remain the primary indication for ICSI throughout the study period. CONCLUSION(S): In this large cohort study, we found the risk of major malformations in live-born singletons to be slightly higher after fresh ICSI compared with fresh IVF. These findings should be considered when choosing the assisted reproductive technology method for couples without male factor infertility.

Cancer in children born after frozen-thawed embryo transfer: A cohort study.

BACKGROUND: The aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. METHODS AND FINDINGS: We performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale. After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed. The main limitation of this study is the small number of children with cancer in the FET group. CONCLUSIONS: Children born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications. TRIAL REGISTRATION: Trial registration number: ISRCTN 11780826.

The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group.

OBJECTIVE: To assess the risk of neurodevelopmental disorders in singletons born after the use of assisted reproductive technology (ART) compared with singletons born without the use of ART. DESIGN: Nordic register-based study. SETTING: Cross-linked data from Medical Birth Registers and National ART and Patient Registers; liveborn singletons in 1995-2014 in Denmark and Finland, 2005-2015 in Norway, and 1995-2015 in Sweden with follow-up to 2014 (Denmark and Finland) or 2015 (Norway and Sweden). PATIENTS: A total of 5,076,444 singletons: 116,909 (2.3%) born with and 4,959,535 (97.7%) born without the use of ART (non-ART). INTERVENTIONS: In vitro fertilization, intracytoplasmic sperm injection, and fresh and frozen embryo transfer. MAIN OUTCOME MEASURES: The primary outcomes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes) were learning and motor functioning disorders (F80-F83), autism spectrum disorder (F84), attention-deficit/hyperactivity disorder and conduct disorders (F90-F92), and tic disorders (F95). Crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals were calculated. RESULTS: Singletons in the ART cohort had a higher adjusted risk of learning and motor functioning disorders (HR, 1.01 [0.96-1.07]; aHR, 1.17 [1.11-1.24]) and a tendency toward a higher risk of autism spectrum disorder (HR, 1.12 [1.04-1.21]; aHR, 1.07 [0.98-1.16]) and attention-deficit/hyperactivity disorder and conduct disorders (HR, 0.82 [0.77-0.86]; aHR, 1.17 [0.99-1.12]) but not of tic disorders (HR, 1.21 [1.06-1.38]; aHR, 1.17 [0.96-1.27]). No differences in risk were found between children born after in vitro fertilization and intracytoplasmic sperm injection or after fresh and frozen embryo transfer. CONCLUSIONS: Our findings of only small differences in neurodevelopment between ART and non-ART singletons are reassuring and in line with previous studies.

[Children born after assisted reproduction].

This review summarises the knowledge of children born after in vitro fertilization (IVF). They have small increased risk of preterm birth, low birthweight and congenital malformations compared with naturally conceived children. High rates of multiples after IVF have been a major explanation, but with increasing use of frozen embryo transfer, single embryo transfer has facilitated a huge decline in rates of IVF multiples. Attention has been drawn to potential metabolic disturbances and cardiovascular disease in IVF offspring. However, IVF children do not seem to have an increased risk of mental or psychiatric disease, and their school performance is similar to naturally conceived children.

Academic Performance in Adolescents Born to Mothers With Gestational Diabetes-A National Danish Cohort Study.

CONTEXT: The prevalence of gestational diabetes mellitus (GDM) is increasing, and intrauterine hyperglycemia is suspected to affect offspring cognitive function. OBJECTIVE: We assessed academic performance by grade point average (GPA) in children aged 15 to 16 years at compulsory school graduation, comparing offspring exposed to GDM (O-GDM) with offspring from the background population (O-BP). METHODS: This register-based, cohort study comprised all singletons born in Denmark between 1994 and 2001 (O-GDM: n = 4286; O-BP: n = 501 045). Standardized and internationally comparable GPAs were compared in univariate and multivariable linear models. Main outcome measures included the adjusted mean difference in GPA. We also analyzed the probability of having a high GPA, a GPA below passing, and no GPA registered. RESULTS: O-GDM had a GPA of 6.29 (SD 2.52), whereas O-BP had a GPA of 6.78 (SD 2.50). The adjusted mean difference was -0.36 (95% CI, -0.44 to -0.29), corresponding to a Cohen's D of 0.14. O-GDM had a lower probability of obtaining a high GPA (adjusted odds ratio [aOR] 0.68; 95% CI, 0.59 to 0.79), while their risk of obtaining a GPA below passing was similar to O-BP (aOR 1.20; 95% CI, 0.96 to 1.50). O-GDM had a higher risk of not having a GPA registered (aOR 1.38; 95% CI, 1.24 to 1.53). CONCLUSION: Academic performance in O-GDM was marginally lower than in O-BP. However, this difference is unlikely to be of clinical importance.

Cerebral palsy in ART children has declined substantially over time: a Nordic study from the CoNARTaS group.

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.

Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.

STUDY QUESTION: Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: A higher risk of PTB (<37 weeks) 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 (<2500 g), SGA, macrosomia (≥4500 g) 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 (≥4500 g) 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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 71 450). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Perinatal outcomes in 6,338 singletons born after intrauterine insemination in Denmark, 2007 to 2012: the influence of ovarian stimulation.

OBJECTIVE: To study perinatal outcomes in singletons born after intrauterine insemination (IUI) compared with children born after in vitro fertilization (IVF), intracytoplasmic sperm injection, and spontaneous conception (SC), and to assess predictors of poor outcome in singletons born after IUI, exploring the effect of ovarian stimulation. DESIGN: National cohort study, 2007-2012. SETTING: Danish national registries. PATIENT(S): Four thousand two hundred twenty-eight singletons born after insemination with partner semen (IUI-H) and 1,881 singletons born after insemination with donor semen. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA). RESULT(S): Children born after IUI-H had higher risks of PTB, LBW, and SGA vs. SC singletons (adjusted odds ratios [aOR] 1.3; 95% confidence interval (CI), 1.1-1.5; 1.4; 95% CI, 1.2-1.7; and 1.4; 95% CI, 1.2-1.6), respectively. Compared with IVF, risk of SGA was similar, but risks of PTB and LBW were lower (aOR 0.6; 95% CI, 0.5-0.8; and 0.8; 95% CI, 0.6-0.9). Compared with intracytoplasmic sperm injection, no differences were found. For children born after IUI with donor semen, results were similar to those for IUI-H. Risks of LBW and SGA were higher in IUI singletons born after ovarian stimulation with clomiphene citrate, compared with natural-cycle IUI (aOR 1.5; 95% CI, 1.1-2.1 and 1.6; 95% CI, 1.1-2.4). Treatment with follicle-stimulating hormone vs. natural-cycle IUI did not seem to affect perinatal outcomes. CONCLUSION(S): Singletons born after IUI had higher risk of adverse perinatal outcomes compared with SC children, similar to ICSI, but favorable outcomes compared with IVF. Stimulation with clomiphene citrate was associated with higher risk of SGA compared with natural-cycle IUI, but follicle-stimulating hormone treatment did not seem to be associated with adverse outcomes.

Birth and perinatal outcomes and complications for babies conceived following ART.

Children born after assisted reproductive techniques (ART) have an increased risk of several adverse perinatal outcomes compared with their naturally conceived peers. This has various causes such as higher multiple birth rates, parental characteristics and higher maternal age, with more being nulliparous. Furthermore the in-vitro techniques, the controlled ovarian stimulation, culture media, and possibly additional freezing or vitrification procedures seem to play a role. However, when analyzing the perinatal trends over time, the differences between ART and naturally conceived children appear to have diminished. This is probably due to ART being more accessible and therefore couples have shorter duration of infertility before referral to ART; hence couples are nowadays less reproductively ill than in the past. A refinement of both clinical and laboratory skills during the past three decades of assisted reproduction may be another explanation. However, caution should be taken, as we do not yet know the full consequences of the observed increase in fetal growth and potential epigenetic changes in the early embryonic stages of fetal development.

Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.

STUDY QUESTIONS: What are the risks of adverse outcomes in singletons born after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Singletons born after FET have a better perinatal outcome compared with singletons born after fresh IVF and ICSI as regards low birthweight (LBW) and preterm birth (PTB), but a worse perinatal outcome compared with singletons born after spontaneous conception. WHAT IS KNOWN ALREADY: Previous studies have shown a worse perinatal outcome in children born after IVF in general compared with children born after spontaneous conception. In singletons born after FET, a lower rate of PTB and LBW and a higher rate of large for gestational age (LGA) compared with singletons born after fresh IVF have been shown. STUDY DESIGN: A retrospective Nordic population-based cohort study of all singletons conceived after FET in Denmark, Norway and Sweden until December 2007 was performed. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Singletons born after FET (n = 6647) were compared with a control group of singletons born after fresh IVF and ICSI (n = 42 242) and singletons born after spontaneous conception (n = 288 542). Data on perinatal outcomes were obtained by linkage to the national Medical Birth Registries. Odds ratios were calculated for several perinatal outcomes and adjustments were made for maternal age, parity, year of birth, offspring sex and country of origin. MAIN RESULTS AND THE ROLE OF CHANCE: Singletons born after FET had a lower risk of LBW (adjusted odds ratio (aOR) 0.81, 95% confidence interval (CI) 0.71-0.91), PTB (aOR 0.84, 95% CI 0.76-0.92), very PTB (VPTB; aOR 0.79, 95% CI 0.66-0.95) and small for gestational age (SGA; aOR 0.72, 95% CI 0.62-0.83), but a higher risk of post-term birth (aOR 1.40, 95% CI 1.27-1.55), LGA (aOR 1.45, 95% CI 1.27-1.64), macrosomia (aOR 1.58, 95% CI 1.39-1.80) and perinatal mortality (aOR 1.49, 95% CI 1.07-2.07) compared with singletons born after fresh IVF and ICSI. Compared with children conceived after spontaneous conception, singletons born after FET had a higher risk of LBW (aOR 1.27, 95% CI 1.13-1.43), very LBW (aOR 1.69, 95% CI 1.33-2.15), PTB (aOR 1.49, 95% CI 1.35-1.63), VPTB (aOR 2.68, 95% CI 2.24-3.22), SGA (aOR 1.18, 95% CI 1.03-1.35), LGA (aOR 1.29, 95% CI 1.15-1.45), macrosomia (aOR 1.29, 95% CI 1.15-1.45) and perinatal (aOR 1.39, 95% CI 1.03-1.87) neonatal (aOR 1.87, 95% CI 1.23-2.84) and infant mortality (aOR 1.92, 95% CI 1.36-2.72). When analyzing trends over time, the risk of being born LGA increased over time for singletons born after FET compared with singletons born after fresh IVF and ICSI (P = 0.04). LIMITATIONS, REASONS FOR CAUTION: As in all observational studies, the possible role of residual confounding factors and bias should be considered. In this study, we were not able to control for confounding factors, such as BMI, smoking and reason for, or length of, infertility. WIDER IMPLICATIONS OF THE FINDINGS: Perinatal outcomes in this large population-based cohort of children born after FET from three Nordic countries compared with fresh IVF and ICSI and spontaneous conception were in agreement with the literature.

Congenital anomalies after assisted reproductive technology.

Worldwide, more than 5 million children have been born after assisted reproductive technology (ART), and in many developed countries ART infants represent more than 1% of the birth cohorts. It is well known that ART children are at increased risk of congenital malformations even after adjustment for known confounders such as maternal age. The proportion of ART children is not negligible, and knowledge about the causes of the higher risk of congenital malformations is crucial to develop prevention strategies to reduce the future risk in ART children. The aim of this review is to summarize the literature on the association between ART and congenital anomalies with respect to subfertility, fertility treatment other than ART, and different ART methods including intracytoplasmic sperm injection, blastocyst culture, and cryotechniques. Trends over time in ART and congenital anomalies will also be discussed.

[The prognosis for children born after assisted reproduction]. / Prognosen for børn født efter assisteret reproduktion.

Children who are born after assisted reproduction (ART) have a slightly increased risk of being born preterm, of having low birthweight and a higher perinatal mortality than spontaneously conceived children. The higher rate of multiple births among women having had ART can to some extent explain this. However, adverse outcomes persist even in ART singletons. The characteristics of the infertile parents have negative effects on the outcome, but also the hormone stimulation and the in vitro techniques are thought to play a role. A milder hormone stimulation and elective single embryo transfer, which reduces the number of multiples after ART, have improved the overall health of children born as a result of ART.

Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study.

OBJECTIVE: To compare the perinatal outcome of singleton siblings conceived differently. DESIGN: National population-based registry study. SETTING: Denmark, from 1994 to 2008. PATIENT(S): Pairs of siblings (13,692 pairs; n = 27,384 children) conceived after IVF, intracytoplasmatic sperm injection (ICSI), frozen embryo replacement (FER), or spontaneous conception subcategorized into five groups according to succession: [1] IVF-ICSI vs. spontaneous conception (n = 7,758), [2] IVF-ICSI vs. FER (n = 716), [3] FER vs. FER (n = 34), [4] IVF-ICSI vs. IVF-ICSI (n = 2,876), and [5] spontaneous conception vs. spontaneous conception (n = 16,000). INTERVENTION(S): Observations were obtained from national registries. MAIN OUTCOME MEASURE(S): Birth weight, gestational age, low birth weight (<2,500 g), preterm birth (<37 weeks' gestation) and perinatal deaths. RESULT(S): Mean birth weight was 65 g (95% confidence interval [CI], 41-89] lower in all assisted reproductive technology children compared with their spontaneously conceived siblings. FER children were 167 g (95% CI, 90-244] heavier than siblings born after replacement of fresh embryos. The difference in birth weight between firstborn and second born sibling depended on order of conception method. Higher risk of low birth weight with (odds ratio [OR], 1.4; 95%CI, 1.1-1.7] and preterm birth (OR, 1.3; 95% CI, 1.1-1.6] was observed in IVF/ICSI compared with spontaneous conception. CONCLUSION(S): When differentiating between order and mode of conception, it seems that assisted reproductive technology plays a role in mean birth weight and risk of low birth weight and preterm birth. Birth weight was higher in siblings born after FER compared with fresh embryos replacement.

Massive fetomaternal hemorrhage caused by an intraplacental choriocarcinoma: a case report.

Background. Intraplacental choriocarcinoma is a rare but highly malignant trophoblastic neoplasm. When found near term the risk of maternal metastasis is high because of the late diagnosis. Case. We describe a case of an intraplacental choriocarcinoma diagnosed postpartum after a near-term delivery of a severely anemic infant. A fetomaternal hemorrhage resulted in a hemoglobin concentration in the infant of only 2,1 g/dL. Neither mother nor child showed signs of metastatic disease. The macroscopic examination showed a hydropic placenta weighing more than 1 kilogram. Microscopy showed an intraplacental choriocarcinoma 3 cm in diameter. The tumor had infiltrated the maternal basal plate. Conclusion. Fetomaternal bleeding is a rare form of presentation of choriocarcinoma but its presence should always warrant detailed examination of placenta, mother, and infant.