Anna-Karina Aaris Henningsen

Infant outcome of 957 singletons born after frozen embryo replacement: The Danish National Cohort Study 1995–2006

OBJECTIVE To examine infant outcome of singletons born after cryopreservation of embryos (Cryo). DESIGN National population-based controlled follow-up study. SETTING Denmark, 1995-2007. PATIENT(S) The study population was 957 Cryo singletons (Cryo-IVF, n=660; Cryo-ICSI, n=244; Cryo-IVF/-ICSI, n=53). The first control group was all singletons born after fresh IVF or intracytoplasmic sperm injection (ICSI) during the same period (IVF, n=6904; ICSI, n=3425). The second control group comprised a random sample of non-assisted reproductive technology (ART) singletons (n=4800). INTERVENTION(S) All observations were obtained from national registers. MAIN OUTCOME MEASURE(S) Low birth weight (LBW; <2500 g), preterm birth (PTB; <37 weeks), congenital malformations, mortality, and morbidity. RESULT(S) Birth weight was higher in Cryo (mean=3578 g, SD=625) versus fresh (mean=3373 g, SD=648) and in Cryo versus non-ART (mean=3537 g, SD=572), and this was also the case for first birth only. Lower adjusted risk of LBW (odds ratio [OR]=0.63; 95% confidence interval [CI], 0.45-0.87) and PTB (OR=0.70; 95% CI, 0.53-0.92) was observed in Cryo versus fresh. Similar LBW and PTB rates were observed when comparing Cryo with non-ART, but the perinatal mortality rate was doubled in Cryo (1.6%) compared with non-ART (0.8%) singletons, and the adjusted risks of very preterm birth (<34 weeks) and neonatal admittance were also significantly increased. No significant differences in the prevalence rates of birth defects, neurological sequelae, malignancies, and imprinting-related diseases were observed between the Cryo and the two control groups. However higher malformation and cerebral palsy rates were observed in the total Fresh vs. non-ART group. CONCLUSION(S) Cryo singletons have better neonatal outcome than offspring after fresh ET but poorer compared with non-ART singletons.

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.

Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?

STUDY QUESTION Are singletons born after frozen embryo transfer (FET) at increased risk of being born large for gestational age (LGA) and if so, is this caused by intrinsic maternal factors or related to the freezing/thawing procedures? SUMMARY ANSWER Singletons after FET have an increased risk of being born LGA. This cannot solely be explained by intrinsic maternal factors as it was also observed in sibling pairs, where the sibling conceived after FET had an increased risk of LGA compared with the sibling born after Fresh embryo transfer. WHAT IS KNOWN ALREADY FET singletons have a higher mean birthweight than singletons born after transfer of fresh embryos, and FET singletons may be at an increased risk of being born LGA. STUDY DESIGN, SIZE, DURATION The national register-based controlled cohort study involves two populations of FET singletons. The first population (A: total FET cohort) consisted of all FET singletons (n = 896) compared with singletons born after Fresh embryo transfer (Fresh) (n = 9480) and also with that born after natural conception (NC; n = 4510) in Denmark from 1997 to 2006. The second population (B: Sibling FET cohort) included all sibling pairs, where one singleton was born after FET and the consecutive sibling born after Fresh embryo transfer or vice versa from 1994 to 2008 (n = 666). The sibling cohort included n = 550 children with the sibling combination first child Fresh/second child FET and n = 116 children with the combination first child FET/second child Fresh. PARTICIPANTS/MATERIALS, SETTING, METHODS Main outcome measures were LGA defined as birthweight of >2 SD from the population mean (z-score >2) according to Marsáls curves. Macrosomia was defined as birthweight of >4500 g. Crude and adjusted odds ratios (AORs) of LGA and macrosomia were calculated for FET versus Fresh and versus NC singletons in the total FET cohort. Similarly, AOR was calculated for FET versus Fresh in the sibling cohort. Adjustments were made for maternal age, parity, child sex, year of birth and birth order in the sibling analyses. Meta-analyses were performed by pooling our data with the previously published cohort studies on LGA and macrosomia. MAIN RESULTS AND THE ROLE OF CHANCE The AORs of LGA (z-score >2) and macrosomia in FET singletons versus singletons conceived after Fresh embryo transfer were 1.34 [95% confidence interval (95% CI) 0.98-1.80] and 1.91 (95% CI 1.40-2.62), respectively. The corresponding risks for FET versus NC singletons were 1.41 (95% CI 1.01-1.98) for LGA and 1.67 (95% CI 1.18-2.37) for macrosomia. The increased risk of LGA and macrosomia in FET singletons was confirmed in the sibling cohort also after adjustment for birth order. Hence, the increased risk of LGA in FET singletons cannot solely be explained by being the second born or by intrinsic maternal factors, but may also partly be related to freezing/thawing procedures per se. In the meta-analysis, the summary effects of LGA and macrosomia in FET versus singletons conceived after Fresh embryo transfer were AOR 1.54 (95% CI 1.31-1.81) and AOR 1.64 (95% CI 1.26-2.12), respectively. The corresponding figures for FET versus NC singletons were for LGA AOR 1.32 (95% CI 1.07-1.61) and macrosomia AOR 1.41 (95% CI 1.11-1.80), respectively. LIMITATIONS, REASONS FOR CAUTION Adjustment for body mass index as a possible confounder was not possible. The size of the FET/Fresh sibling cohort was limited; however, the complete sibling cohort was sufficiently powered to explore the risk of LGA. A bias is very unlikely as data coding was based on national registers. WIDER IMPLICATIONS OF THE FINDINGS Our findings are consistent with the previous Nordic studies and thus can be generalized to the Nordic countries. The causes for LGA in FET singletons should be further explored. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this project. None of the authors have any conflict of interest to declare.

Perinatal outcomes in 375 children born after oocyte donation: a Danish national cohort study

OBJECTIVE To describe perinatal outcomes in children born after oocyte donation (OD) compared with in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and spontaneous conception (SC). DESIGN National cohort study. SETTING Fertility clinics. PATIENT(S) Three hundred seventy-five children born after OD during the period 1995-2010. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Mean birth weight, mean gestational age, risks of low birth weight (LBW), preterm birth (PTB), congenital malformations, cesarean delivery, preeclampsia, and admittance to neonatal intensive care unit. RESULT(S) We found an increased risk of PTB in OD pregnancies. The adjusted odds ratio (AOR) of PTB in OD singletons was 1.8 (95% CI, 1.2-2.69), 2.5 (95% CI, 1.7-3.6), and 3.4 (95% CI, 2.3-4.9) compared with IVF, ICSI, and SC, respectively. The risk of LBW was also increased. The AOR of LBW was 1.4 (95% CI, 0.9-2.2), 1.8 (95% CI, 1.2-2.8), and 2.6 (95% CI, 1.7-4.0) compared with IVF, ICSI, and SC. The risk of preeclampsia was increased in OD pregnancies with an AOR of 2.9 (95% CI, 1.8-4.6), 2.8 (95% CI, 1.7-4.5), and 3.1 (95% CI, 1.9-4.9) compared with IVF, ICSI, and SC. After additional adjustment for preeclampsia, perinatal outcome improved. Among the twins, the difference between the groups was less pronounced. CONCLUSION(S) Pregnancies after OD have a poorer perinatal outcome than those after standard IVF and ICSI mainly because of the high prevalence of preeclampsia.

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.

Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group

STUDY QUESTION Is the risk of hypertensive disorders in pregnancies conceived following specific assisted reproductive technology (ART) procedures different from the risk in spontaneously conceived (SC) pregnancies? SUMMARY ANSWER ART pregnancies had a higher risk of hypertensive disorders, in particular following cryopreservation, with the highest risk seen in twin pregnancies following frozen-thawed cycles. WHAT IS KNOWN ALREADY The risk of hypertensive disorders is higher in ART pregnancies than in SC pregnancies. The increased risk may be partly explained by multiple pregnancies and underlying infertility, but a contribution from specific ART procedures has not been excluded. STUDY DESIGN, SIZE, DURATION Population-based cohort study, including sibling design with nationwide data from health registers in Sweden, Denmark and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS All registered ART pregnancies and a sample of SC pregnancies with gestational age ≥22 weeks from 1988 to 2007 were included. ART singleton pregnancies (n = 47 088) were compared with SC singleton pregnancies (n = 268 599), matched on parity and birth year. ART twin pregnancies (n = 10 918) were compared with SC twin pregnancies (46 674). We used logistic regression to estimate adjusted odds ratios and risk differences for hypertensive disorders in pregnancies following IVF, ICSI and fresh or frozen-thawed cycles. We also compared fresh and frozen-thawed cycles within mothers who had conceived following both procedures using conditional logistic regression (sibling analysis). MAIN RESULTS AND THE ROLE OF CHANCE Hypertensive disorders were reported in 5.9% of ART singleton and 12.6% of ART twin pregnancies. Comparing singleton pregnancies, the risk of hypertensive disorders was higher after all ART procedures. The highest risk in singleton pregnancies was seen after frozen-thawed cycles [risk 7.0%, risk difference 1.8%, 95% confidence interval (CI) 1.2-2.8]. Comparing twin pregnancies, the risk was higher after frozen-thawed cycles (risk 19.6%, risk difference 5.1%, 95% CI 3.0-7.1), but not after fresh cycles. In siblings, the risk was higher after frozen-thawed cycles compared with fresh cycles within the same mother (odds ratio 2.63, 95% CI 1.73-3.99). There were no clear differences in risk for IVF and ICSI. LIMITATIONS, REASONS FOR CAUTION The number of ART siblings in the study was limited. Residual confounding cannot be excluded. In addition, we did not have information on all SC pregnancies in each womans history, and could therefore not compare risk in ART versus SC pregnancies in the same mother. WIDER IMPLICATIONS OF THE FINDINGS Pregnancies following frozen-thawed cycles have a higher risk of hypertensive disorders, also when compared with fresh cycle pregnancies by the same mother. The safety aspects in frozen-thawed cycles merit further attention. STUDY FUNDING/COMPETING INTERESTS Funding was received from the European Society for Human Reproduction and Embryology, the University of Copenhagen, the Danish Agency for Science, Technology and Innovation, the Nordic Federation of Societies of Obstetrics and Gynecology and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. None of the authors has any competing interests to declare.

Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group

STUDY QUESTIONS Has the perinatal outcome of children conceived after assisted reproductive technology (ART) improved over time? SUMMARY ANSWER The perinatal outcomes in children born after ART have improved over the last 20 years, mainly due to the reduction of multiple births. WHAT IS KNOWN AND WHAT THIS PAPER ADDS A Swedish study has shown a reduction in unwanted outcomes over time in children conceived after ART. Our analyses based on data from more than 92 000 ART children born in four Nordic countries confirm these findings. STUDY DESIGN Nordic population-based matched cohort study with ART outcome and health data from Denmark, Finland, Norway and Sweden. PARTICIPANTS, SETTING AND METHODS We analysed the perinatal outcome of 62 379 ART singletons and 29 758 ART twins, born from 1988 to 2007 in four Nordic countries. The ART singletons were compared with a control group of 362 215 spontaneously conceived singletons. Twins conceived after ART were compared with all spontaneously conceived twins (n = 122 763) born in the Nordic countries during the study period. The rates of several adverse perinatal outcomes were stratified into the time periods: 1988-1992; 1993-1997; 1998-2002 and 2003-2007 and presented according to multiplicity. MAIN RESULTS AND ROLE OF CHANCE For singletons conceived after ART, a remarkable decline in the risk of being born preterm and very preterm was observed. The proportion of ART singletons born with a low and very low birthweight also decreased. Finally, the stillbirth and infant death rates have declined among both ART singletons and twins. Throughout the 20 year period, fewer ART twins were stillborn or died during the first year of life compared with spontaneously conceived twins, presumably due to the lower proportion of monozygotic twins among the ART twins. LIMITATIONS, REASONS FOR CAUTION We were not able to adjust for some potential confounders such as BMI, smoking, length or cause of infertility. The Nordic ART populations have changed over time, and in recent years, both less as well as severely reproductive ill couples are being treated. This may have affected the observed trends. WIDER IMPLICATIONS OF THE FINDINGS It is assuring that data from four countries confirm an overall improvement over time in the perinatal outcomes of children conceived after ART. Furthermore, data show the beneficial effect of single embryo transfer, not only in regard to lowering the rate of multiples but also concerning the health of singletons. STUDY FUNDING/COMPETING INTERESTS The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen and the Danish Agency for Science, Technology and Innovation has supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Federation of Obstetrics and Gynecology (NFOG). None of the authors has any competing interests to declare.

Cancer in children and young adults born after assisted reproductive technology: a Nordic cohort study from the Committee of Nordic ART and Safety (CoNARTaS).

STUDY QUESTION Do children and young adults born after assisted reproductive technology (ART) have an increased risk of cancer? SUMMARY ANSWER Children born after ART showed no overall increase in the rate of cancer when compared with children born as a result of spontaneous conception. WHAT IS KNOWN ALREADY Children born after ART have more adverse perinatal outcomes, i.e. preterm births, low birthweights and birth defects. Previous studies have shown divergent results regarding the risk of cancer among children born after ART. STUDY DESIGN, SIZE, DURATION A retrospective Nordic population-based cohort study was performed, comprising all children born after ART in Sweden, Denmark, Finland and Norway between 1982 and 2007. The mean (±standard deviation) follow-up time was 9.5 (4.8) years. PARTICIPANTS/MATERIALS, SETTING, METHODS Children born after ART (n = 91 796) were compared with a control group of children born after spontaneous conception. This control group was almost 4-fold the size of the ART group (n = 358 419) and matched for parity, year of birth and country. Data on perinatal outcomes and cancer were obtained from the National Medical Birth Registries, the Cancer Registries, the Patient Registries and the Cause of Death Registries. The cancer diagnoses were divided into 12 main groups. Hazard ratios (HRs) and adjusted HR were calculated. Adjustments were carried out for country, maternal age, parity, sex, gestational age and birth defects. MAIN RESULTS AND THE ROLE OF CHANCE There was no significant increase in overall cancer rates among children born after ART when compared with children born after spontaneous conception (adjusted HR 1.08; 95% CI 0.91-1.27). Cancer, of any form, was found among 181 children born after ART (2.0/1000 children, 21.0/100 000 person-years) compared with 638 children born after spontaneous conception (1.8/1000 children, 18.8/100 000 person-years). Leukaemia was the most common type of cancer (n = 278, 0.62/1000 children) but no significantly increased incidence was found among children born after ART. An increased risk was observed for 2 of 12 cancer groups. They were central nervous system tumours (adjusted HR 1.44; 95% CI 1.01-2.05) and malignant epithelial neoplasms (adjusted HR 2.03; 95% CI 1.06-3.89); the absolute risks were 0.46/1000 and 0.15/1000 children, respectively, corresponding to an absolute increased risk of 0.14/1000 and 0.08/1000 children, respectively. LIMITATIONS, REASONS FOR CAUTION As this is an observational study, the main limitation is the fact that it is not possible to adjust for all potential confounders. We were not able to control for confounders such as socio-economic status and perinatal factors, such as Apgar score, which other studies have suggested affect cancer rates. WIDER IMPLICATIONS OF THE FINDINGS The results of this large population-based cohort study are in agreement with most previously published studies. The main findings are reassuring for couples undergoing ART, children born after ART and clinicians working with ART. STUDY FUNDING/COMPETING INTERESTS No conflict of interest was reported. The study was supported by grants from The European Society for Human Reproduction and Embryology (ESHRE), Sahlgrenska University Hospital, Gothenburg, Sweden, the University of Copenhagen, Denmark, the Danish Agency of Science, Technology and Innovation and the Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

Infant and maternal health monitoring using a combined Nordic database on ART and safety

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.

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

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