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 stroke the year following a delivery after using assisted reproductive technologies.

BACKGROUND: Studies indicate that individuals who deliver after assisted reproductive technologies (ART) may have an increased risk of cardiovascular disease (CVD). A recent large study from the U.S. showed a higher risk of stroke during the first year after delivery. OBJECTIVES: To compare the risk of stroke during the first year after delivery according to the use of ART in the Nordic countries. METHODS: Registry-based cohort study using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015) and Sweden (1985-2015). Data on ART conception were available from ART quality registries and/or Medical Birth Registries (MBRs). National data on stroke were available from hospital and cause-of-death registries. The risk of stroke during the first year after delivery was estimated with Cox proportional hazard regression, adjusting for age, calendar year of delivery, multiple births, and country. RESULTS: A total of 2,659,272 primiparous individuals had a registered delivery in the MBRs during the study period, and 91,466 (4%) of these gave birth after ART. We observed no overall increased risk of stroke during the first year after delivery among individuals conceiving after ART (adjusted hazard ratio [HR] 1.10, 95% CI 0.77, 1.57). Similarly, there was no convincing evidence that the short-term risk of stroke was higher within 1, 2, 3, or 6 months after delivery, with adjusted HRs ranging between 1.23 and 1.33 and confidence intervals including the null value for all time periods. A secondary analysis also including multiparous individuals (n = 3,335,478) at the start of follow-up yielded similar findings. CONCLUSIONS: We found no evidence of an increased short-term risk of stroke among individuals who delivered after using ART.

Maternal Risk of Cardiovascular Disease After Use of Assisted Reproductive Technologies.

Importance: The use of assisted reproductive technologies (ARTs) is steadily increasing worldwide. The outcomes associated with treatment for an individual's long-term health, including risk of cardiovascular disease (CVD), remain largely unknown, due to the small number of studies and their limited follow-up time. Objective: To study whether the risk of CVD is increased among individuals who have given birth after ART compared with those who have given birth without ART. Design, Setting, and Participants: A registry-based cohort study was conducted using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1985-2015). Data analysis was conducted from January to August 2022. A total of 2 496 441 individuals with a registered delivery in the national birth registries during the study period were included, and 97 474 (4%) of these gave birth after ART. Exposures: Data on ART conception were available from ART quality registries and/or medical birth registries. Main Outcomes and Measures: Information on CVD was available from patient and cause of death registries. The risk of CVD was estimated with Cox proportional hazards regression, adjusting for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country. Results: Median follow-up was 11 (IQR, 5-18) years. The mean (SD) age of women with no use of ART was 29.1 (4.9) years, and the age of those who used ART was 33.8 (4.7) years. The rate of any CVD was 153 per 100 000 person-years. Individuals who gave birth after using ART had no increased risk of CVD (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91-1.02), with evidence of heterogeneity between the countries (I2 = 76%; P = .01 for heterogeneity). No significant differences in the risk of ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, or deep vein thrombosis were noted with use of ART. However, there was a tendency for a modest reduction in the risk of myocardial infarction (AHR, 0.80; 95% CI, 0.65-0.99), with no notable heterogeneity between countries. Conclusions and Relevance: The findings of this study suggest that women who gave birth after ART were not at increased risk of CVD over a median follow-up of 11 years compared with those who conceived without ART. Longer-term studies are needed to further examine whether ART is associated with higher risk of CVD.

Does luteal phase progesterone supplementation affect physical and psychosocial well-being among women undergoing modified natural cycle-FET? A sub-study of a randomized controlled trial.

STUDY QUESTION: Are there any differences in physical and psychosocial well-being among women undergoing modified natural cycle frozen embryo transfer (mNC-FET) with or without vaginal progesterone as luteal phase support (LPS)? SUMMARY ANSWER: Women undergoing mNC-FET with vaginal progesterone supplementation were more likely to experience physical discomfort but there was no difference in psychosocial well-being between the two groups. WHAT IS KNOWN ALREADY: mNC-FET can be carried out with or without vaginal progesterone as LPS, which has several side-effects. It is commonly known that fertility treatment can cause stress and psychosocial strain, however, most studies on this subject are conducted in fresh cycle regimes, which differ from NC-FET and results may not be comparable. STUDY DESIGN, SIZE, DURATION: This is a sub-study of an ongoing RCT investigating whether progesterone supplementation has a positive effect on live birth rate in mNC-FET. The RCT is conducted at eight fertility clinics in Denmark from 2019 and is planned to end primo 2024. The sub-study is based on two questionnaires on physical and psychosocial well-being added to the RCT in August 2019. On the time of data extraction 286 women had answered both questionnaires. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had answered both questionnaires were included in the sub-study. Participants were equally distributed, with 143 in each of the two groups. Participants in both groups received the same questionnaires at two time-points: on cycle day 2-5 (baseline) and after blastocyst transfer. Participants in the progesterone group had administered progesterone for 7 days upon answering the second questionnaire. All items in the questionnaires were validated. Items on psychosocial well-being originate from the Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and from the Mental Health Inventory-5. MAIN RESULTS AND THE ROLE OF CHANCE: Women receiving progesterone experienced more vaginal itching and/or burning than women in the non-progesterone group (P < 0.001). Women in the progesterone group also experienced more self-reported vaginal yeast infection, this was, however, not significant after adjustment for multiple testing (P/adjusted P = 0.049/0.881). No differences regarding psychosocial well-being were found between the two groups. Within the progesterone group, a shift toward feeling less 'downhearted and blue' was found when comparing response distribution at baseline and after blastocyst transfer (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: All items on physical symptoms were self-reported. The item on vaginal yeast infection was therefore not diagnosed by a doctor. Inclusion in the study required a few extra visits to the clinic, participants who felt more burdened by fertility treatment might have been more likely to decline participation. Women who experienced a lot of side-effects to progesterone prior to this FET cycle, might be less likely to participate. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in line with previous known side-effects to progesterone. Physical side-effects of progesterone should be considered before administration. STUDY FUNDING/COMPETING INTEREST(S): The RCT is fully supported by Rigshospitalet's Research Foundation and a grant from Gedeon Richter. Gedeon Richter were not involved in the design of protocol nor in the conduction of the study or analysis of results. A.P., L.P., and N.I.-C.F. report grants from Gedeon Richter, Ferring and Merck with no relations to this study. N.I.-C.F. has received travel support from Ferring, Merck A/S, & Gideon Richter, and is the head of the steering committee for the Danish Fertility Guidelines made by the members of from the Danish Fertility Society. A.P. reports consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, honoraria from Gedeon Richter, Ferring, Merck A/S, Theramex, and Organon, has received travel support from Gedeon Richter (payment to institution), participated on an advisory board for Preglem and was loaned an embryoscope from Gedeon Richter to their institution. A.L.S. has stock options for Novo Nordisk B A/S. B.A. have received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. TRIAL REGISTRATION NUMBER: The RCT is registered on ClinicalTrials. gov (NCT03795220) and in EudraCT (2018-002207-34).

The future of frozen-thawed embryo transfer in hormone replacement therapy cycles.

PURPOSE OF REVIEW: This review focuses on the efficacy of letrozole stimulated frozen-thawed embryo transfer (FET) compared to hormone replacement therapy (HRT) FET in women with polycystic ovarian syndrome (PCOS) and/or oligo-anovulation. Further, obstetric and perinatal risks in HRT FET are summarized. RECENT FINDINGS: The presence of a corpus luteum seems to reduce the risk of pregnancy-related hypertension and preeclampsia after FET. As a natural cycle (NC) FET is not an option for women with oligo-/amenorrhea these women may benefit from FET with mild stimulation compared to HRT FET. The intention of mild stimulation in anovulatory women is to induce (mono) ovulation to mimic the endocrine profiles of the natural cycle and the early pregnancy after natural conception. Mild stimulation by letrozole is patient friendly and cheap compared to gonadotropin stimulated FET and has been increasingly used in recent years. Although the quality of evidence is low, the pregnancy outcomes after letrozole FET seems similar or even better compared to HRT FET in women with PCOS and/or oligo-anovulation. SUMMARY: Natural and modified NC FET should be used whenever possible to mitigate adverse obstetric and perinatal outcomes after HRT FET. For anovulatory women, whenever ovulation can be induced, we advocate the use of mild stimulation FET to create a corpus luteum awaiting results from RCTs limited to oligo-anovulatory women.

Pre- and perinatal exposures associated with developing pediatric-onset immune-mediated inflammatory disease: A Danish nation-wide cohort study.

OBJECTIVES: We aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID). METHODS: This nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: We included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7-4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0-1.3]), and among females (1.5 [95%CI: 1.4-1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6-0.9]). CONCLUSIONS: Our results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID.

Risk of stillbirth and neonatal death in singletons born after fresh and frozen embryo transfer: cohort study from the Committee of Nordic Assisted Reproduction Technology and Safety.

OBJECTIVES: To investigate whether risks of stillbirth and neonatal death differ after fresh embryo transfers (fresh-ETs) and frozen embryo transfers (frozen-ETs) compared with singletons conceived without medical assistance. DESIGN: A population-based cohort study. SETTING: Not applicable. PATIENT(S): Data linkage between the nationwide Medical Birth Registries in Denmark (1994-2014), Norway and Sweden (1988-2015), and national quality registries and databases on assisted reproductive technology identified a total of 4,590,853 singletons, including 78,642 conceived by fresh-ET and 18,084 by frozen-ET. INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Stillbirth (fetal death before and during delivery) and neonatal death (live born with death 0-27 days postpartum). RESULT(S): Overall, 17,123 (0.37%) singletons were stillborn and 7,685 (0.17%) died neonatally. Compared with singletons conceived without medical assistance, the odds of stillbirth were similar after fresh-ET and frozen-ET, whereas the odds of neonatal death were high after fresh-ET (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.46-1.95) and frozen-ET (OR, 1.51; 95% CI, 1.08-2.10). Preterm birth (<37 gestational weeks) was more common after fresh-ET (8.0%) and frozen-ET (6.6%) compared with singletons conceived without medical assistance (5.0%), and strongly associated with neonatal mortality across all conception methods. Within gestational age categories, risk of stillbirth and neonatal death was similar for all conception methods, except that singletons from fresh-ET had a higher risk of stillbirth during gestational week 22-27 (OR, 1.85; 95% CI, 1.51-2.26). CONCLUSION(S): Overall, the risk of stillbirth was similar after fresh-ET and frozen-ET compared with singletons conceived without medical assistance, whereas neonatal mortality was high, possibly mediated by the high risk of preterm birth when compared with singletons conceived without medical assistance. Our results gave no clear support for choosing one treatment over the other.

Risk of Hypertensive Disorders in Pregnancy After Fresh and Frozen Embryo Transfer in Assisted Reproduction: A Population-Based Cohort Study With Within-Sibship Analysis.

BACKGROUND: 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. METHODS: 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 4 426 691 naturally conceived, 78 300 fresh-ET, and 18 037 frozen-ET singleton pregnancies, of which 33 209 sibships were conceived using different conception methods. Adjusted odds ratios (aOR) of hypertensive disorders in pregnancy for fresh-ET 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. RESULTS: 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-ET, 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]). CONCLUSIONS: Frozen-ET was associated with substantially higher risk of hypertensive disorders in pregnancy, even after accounting for shared parental factors within sibships.

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.

Correction: School performance in Danish children exposed to maternal type 1 diabetes in utero: A nationwide retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003977.].

School performance in Danish children exposed to maternal type 1 diabetes in utero: A nationwide retrospective cohort study.

BACKGROUND: Conflicting results have been reported concerning possible adverse effects on the cognitive function of offspring of mothers with type 1 diabetes (O-mT1D). Previous studies have included offspring of parents from the background population (O-BP), but not offspring of fathers with type 1 diabetes (O-fT1D) as the unexposed reference group. METHODS AND FINDINGS: This is a population-based retrospective cohort study from 2010 to 2016. Nationally standardized school test scores (range, 1 to 100) were obtained for public school grades 2, 3, 4, 6, and 8 in O-mT1D and compared with those in O-fT1D and O-BP. Of the 622,073 included children, 2,144 were O-mT1D, and 3,474 were O-fT1D. Multiple linear regression models were used to compare outcomes, including the covariates offspring with type 1 diabetes, parity, number of siblings, offspring sex, smoking during pregnancy, parental age, and socioeconomic factors. Mean test scores were 54.2 (standard deviation, SD 24.8) in O-mT1D, 54.4 (SD 24.8) in O-fT1D, and 56.4 (SD 24.7) in O-BP. In adjusted analyses, the mean differences in test scores were -1.59 (95% CI -2.48 to -0.71, p < 0.001) between O-mT1D and O-BP and -0.78 (95% CI -1.48 to -0.08, p = 0.03) between O-fT1D and O-BP. No significant difference in the adjusted mean test scores was found between O-mT1D and O-fT1D (p = 0.16). The study's limitation was no access to measures of glycemic control during pregnancy. CONCLUSIONS: O-mT1D achieved lower test scores than O-BP but similar test scores compared with O-fT1D. Glycemic control during pregnancy is essential to prevent various adverse pregnancy outcomes in women with type 1 diabetes. However, the present study reduces previous concerns regarding adverse effects of in utero hyperglycemia on offspring cognitive function.

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.

Maternal first trimester iron status and its association with obstetric and perinatal outcomes.

PURPOSE: To assess the following in singleton pregnant women: (1) associations between first trimester iron deficiency and obstetric and perinatal outcomes, (2) overall first trimester iron status and (3) post-treatment iron status after intensified iron supplementation. METHODS: A prospective cohort study was conducted with linkage of first trimester hemoglobin and plasma ferritin with obstetric and perinatal data from a hospital database. Blood sample data were obtained from a Danish University Hospital. The cohort was divided into groups according to ferritin and hemoglobin: (1) iron-deficient anemic (ferritin < 30 ng/mL and Hb < 110 g/L), (2) iron-deficient non-anemic (ferritin < 30 ng/mL and Hb ≥ 110 g/L), and (3) iron-replete non-anemic (ferritin 30-200 ng/mL and Hb ≥ 110 g/L). Obstetric and perinatal outcomes in each iron-deficient group were compared to the iron-replete non-anemic group using multivariable logistic regression. The effect of 4 weeks intensified iron supplementation on hemoglobin and ferritin was assessed by groupwise comparisons. RESULTS: The cohort comprised 5763 singleton pregnant women, of which 14.2% had non-anemic iron deficiency, and 1.2% had iron-deficiency anemia. Compared to iron-replete non-anemic women, iron-deficient anemic women had a higher risk of gestational diabetes (aOR 3.8, 95% CI 1.4-9.0), and iron-deficient non-anemic women had a higher risk of stillbirth (aOR 4.0, 95% CI 1.0-14.3). In group 1 and 2, 81.5% and 67.7% remained iron-deficient after intensified iron supplementation. CONCLUSION: Iron-deficiency anemia was associated with gestational diabetes, and non-anemic iron deficiency with stillbirth, although risk estimates were imprecise due to few events. Iron deficiency was present in 15.4% and often persisted despite 4 weeks intensified iron supplementation.

[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.

Cardiovascular disease, obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study.

BACKGROUND: 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). METHODS AND FINDINGS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

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.

Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET.

OBJECTIVE: To investigate whether obstetric and perinatal outcomes in pregnancies differ after different frozen embryo transfer (FET) protocols. DESIGN: Register-based cohort study. SETTING: Not applicable. PATIENT(S): All singleton deliveries after assisted reproductive technology in Denmark from 2006 to 2014. Data consisted of 1,136 deliveries after frozen in vitro fertilization. Frozen embryo transfer cycles were grouped by type of FET protocol: programmed FET (n = 357); modified natural cycle FET (n = 611); and true natural cycle FET (n = 168). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Obstetric outcomes (hypertensive disorders in pregnancy, preterm prelabor rupture of membranes, placenta previa, placental abruption, induction of labor, postpartum hemorrhage, and cesarean section) and perinatal outcomes (post-term birth, preterm birth, birth weight, small for gestational age, large for gestational age). RESULT(S): The risk of hypertensive disorders in pregnancy, postpartum hemorrhage, and cesarean section was significantly higher after programmed FET compared with natural cycle FET (modified natural cycle FET and true natural cycle FET). A higher risk of birth weight > 4,500 g was observed in the programmed FET group compared with natural cycle FET. CONCLUSION(S): This study shows that obstetric and perinatal outcomes are adversely affected in programmed FET cycles. Hence, when possible, an endometrial preparation with the creation of a corpus luteum should be considered. Properly sized randomized controlled trials of FET in programmed cycle versus natural cycle including perinatal outcomes are warranted in the future. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

OBJECTIVE: To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment. DESIGN: Multicentre, randomised controlled superiority trial. SETTING: Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain. PARTICIPANTS: 460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection. INTERVENTIONS: Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure. MAIN OUTCOME MEASURES: The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle. RESULTS: Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group. CONCLUSIONS: In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present. TRIAL REGISTRATION: Clinicaltrials.gov NCT02746562.