Blood pressure and lipid profiles in children born after ART with frozen embryo transfer.

STUDY QUESTION: Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)? SUMMARY ANSWER: Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC. WHAT IS KNOWN ALREADY: Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging. STUDY DESIGN SIZE DURATION: This study was part of the cohort study 'Health in Childhood following Assisted Reproductive Technology' (HiCART), which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lasted from January 2019 to September 2021. PARTICIPANTS/MATERIALS SETTING METHODS: The included children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06-0.64), boys: 0.35, 95% CI (0.03-0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03-0.47), heart rate: 4.53, 95% CI (0.94-8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty. LIMITATIONS REASONS FOR CAUTION: The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely. WIDER IMPLICATIONS OF THE FINDINGS: The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Girls with idiopathic central precocious puberty did not display substatial changes in body mass index after treatment with gonadotropin-releasing hormone analogues.

AIM: To evaluate changes in body mass index (BMI) in girls during and after treatment for idiopathic central precocious puberty (iCPP). METHODS: We studied 123 girls receiving gonadotropin-releasing hormone analogue (GnRHa)treatment for iCPP from 2009 to 2019. Pubertal and anthropometric measurements were monitored at routine clinical visits. BMI standard deviation scores (SDS) were estimated at baseline and followed in two stages from baseline to end of treatment (median 18.9 months) and from end of treatment to end of follow-up (median 18.2 months). The influence of baseline BMI SDS and the frequency and dose of treatment was evaluated using BMI trajectories and latent class mixed models. RESULTS: The median age at treatment initiation was 8.5 years. The median BMI SDS at baseline was 0.7, corresponding to a median BMI of 17.4 kg/m2 . Overall, no changes in BMI SDS were observed during treatment. According to baseline BMI subgroups, an increasing trend in BMI trajectories during treatment was observed for girls in the lowest BMI group. After treatment, most girls maintained stable BMI levels. CONCLUSION: Our retrospective study did not provide evidence that GnRHa treatment for iCPP had a significant impact on BMI trajectories in girls.

Pancreas-related persisting sequelae in ALL survivors with a history of asparaginase-associated pancreatitis: A part of the ALL-STAR study.

OBJECTIVES: Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. METHODS: We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1-45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. RESULTS: We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14-32] and 18 U/L [IQR 10-25] versus 29 [IQR 24-35] and 22 [17-28], p < .001 and p = .002) and community controls (28 U/L [IQR 22-33] and 21 U/L [IQR 17-26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. CONCLUSIONS: ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.

Differentiation of Idiopathic Central Precocious Puberty From Premature Thelarche Using Principal Component Analysis.

CONTEXT: Nonprogressive premature thelarche (PT) is a self-limiting variant of early puberty, while idiopathic central precocious puberty (ICPP) is a disorder that causes progressive development of secondary sexual characteristics and often requires treatment. The diagnostic differentiation between these conditions is important but can be challenging since they often both initially present clinically with isolated breast development. OBJECTIVE: To describe relevant clinical variables in a large cohort of girls referred for early puberty, and to evaluate clinical and biochemical parameters to distinguish between girls with ICPP and PT. METHODS: This retrospective study included 1361 girls referred with signs of early puberty to a single, tertiary center from 2009 to 2019. We evaluated clinical presentation, medical history, growth velocity, bone age, hormonal serum concentrations, and gonadotropin-releasing hormone (GnRH) test results. RESULTS: Central precocious puberty was diagnosed in 11% (ICPP: n = 143, organic CPP: n = 11) girls, whereas 8% (n = 91 girls) presented with PT. Receiver operating characteristic (ROC) analysis showed several biochemical and anthropometric markers as potential parameters to differentiate between ICPP and PT; however, none were individually adequate. Principal component analysis (PCA)-derived clinical and hormone profiles could predict girls with ICPP from girls with PT with a specificity of 90% and sensitivity of 84%, outperforming any single marker. CONCLUSION: Differentiation of girls with ICPP and PT can be supported by individual clinical and biochemical parameters. However, dimension reduction of clinical and hormonal profiles by PCA improved the diagnostic value, which in the future may support the diagnostic process as a supplement to the GnRH test in evaluation of pubertal disorders.

Body Mass Index Trajectories in Children Exposed to Gestational Diabetes in Utero: A Nationwide Register-based Study.

CONTEXT: Children exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing overweight and obesity, but their postnatal growth trajectories and risk profiles remain unclear. OBJECTIVE: We aimed to identify distinct body mass index (BMI) trajectories from birth to 10 years of age in children exposed to GDM and to explore their associations with infant and maternal characteristics. METHODS: This nationwide cohort study linked data from Danish registries on 15 509 children exposed to GDM in utero, born in Denmark from January 2008 to October 2019. We applied latent class trajectory modeling to identify distinct BMI trajectories. Associations of BMI trajectories with infant and maternal characteristics were analyzed using multiple linear regression. RESULTS: We identified 3 distinct BMI trajectories characterized by a "normal" (60%), a "late accelerating" (28%) and an "early accelerating" (12%) BMI trajectory, the 2 latter at risk of overweight and obesity, respectively, at age 10 years, relative to World Health Organization child growth standards. Children in the "late accelerating" BMI trajectory were more often born large for gestational age (P < .001). More children in the "early accelerating" BMI trajectory were boys, born small for gestational age, and had mothers with a higher pre-pregnancy BMI compared to the other groups (P < .001). CONCLUSION: Children exposed to GDM in utero differ widely in their BMI trajectory. The detection of risk profiles based on early BMI growth and infant and maternal characteristics provides an opportunity for future targeted care and prevention.

Childhood BMI after ART with frozen embryo transfer.

STUDY QUESTION: Does BMI at 7-10 years of age differ in children conceived after frozen embryo transfer (FET) compared to children conceived after fresh embryo transfer (fresh-ET) or natural conception (NC)? SUMMARY ANSWER: BMI in childhood does not differ between children conceived after FET compared to children conceived after fresh-ET or NC. WHAT IS KNOWN ALREADY: High childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. Children conceived after FET have a higher risk of being born large for gestational age (LGA) than children conceived after NC. It is well-documented that being born LGA is associated with an increased risk of obesity in childhood, and it has been hypothesized that ART induces epigenetic variations around fertilization, implantation, and early embryonic stages, which influence fetal size at birth as well as BMI and health later in life. STUDY DESIGN, SIZE, DURATION: The study 'Health in Childhood following Assisted Reproductive Technology' (HiCART) is a large retrospective cohort study with 606 singletons aged 7-10 years divided into three groups according to mode of conception: FET (n = 200), fresh-ET (n = 203), and NC (n = 203). All children were born in Eastern Denmark from 2009 to 2013 and the study was conducted from January 2019 to September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We anticipated that the participation rate would differ between the three study groups owing to variation in the motivation to engage. To reach the goal of 200 children in each group, we invited 478 in the FET-group, 661 in the fresh-ET-group, and 1175 in the NC-group. The children underwent clinical examinations including anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan, and pubertal staging. Standard deviation scores (SDS) were calculated for all anthropometric measurements using Danish reference values. Parents completed a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric, and neonatal data were obtained from the Danish IVF Registry and Danish Medical Birth Registry. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, children conceived after FET had a significantly higher birthweight (SDS) compared to both children born after fresh-ET (mean difference 0.42, 95% CI (0.21; 0.62)) and NC (mean difference 0.35, 95% CI (0.14; 0.57)). At follow-up (7-10 years), no differences were found in BMI (SDS) comparing FET to fresh-ET, FET to NC, and fresh-ET to NC. Similar results were also found regarding the secondary outcomes weight (SDS), height (SDS), sitting height, waist circumference, hip circumference, fat, and fat percentage. In the multivariate linear regression analyses, the effect of mode of conception remained non-significant after adjusting for multiple confounders. When stratified on sex, weight (SDS), and height (SDS) were significantly higher for girls born after FET compared to girls born after NC. Further, FET-girls also had significantly higher waist, hip, and fat measurements compared to girls born after fresh-ET. However, for the boys the differences remained insignificant after confounder adjustment. LIMITATIONS, REASONS FOR CAUTION: The sample size was decided in order to detect a difference of 0.3 SDS in childhood BMI (which corresponds to an adult cardiovascular mortality hazard ratio of 1.034). Thus, smaller differences in BMI SDS may be overlooked. As the overall participation rate was 26% (FET: 41%, fresh-ET: 31%, NC: 18%), selection bias cannot be excluded. Regarding the three study groups, many possible confounders have been included but there might be a small risk of selection bias as information regarding cause of infertility is not available in this study. WIDER IMPLICATIONS OF THE FINDINGS: The increased birthweight in children conceived after FET did not translate into differences in BMI, however, for the girls born after FET, we observed increased height (SDS) and weight (SDS) compared to the girls born after NC, while for the boys the results remained insignificant after confounder adjustment. Since body composition in childhood is a strong biomarker of cardiometabolic disease later in life, longitudinal studies of girls and boys born after FET are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Research Foundation. There were no competing interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Reproductive hormones, bone mineral content, body composition, and testosterone therapy in boys and adolescents with Klinefelter syndrome.

Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype, including tall stature, obesity, and hypergonadotropic hypogonadism, as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study, reproductive hormones and whole-body dual-energy x-ray absorptiometry-derived body composition and bone mineral content were standardized to age-related standard deviation scores in 62 patients with KS aged 5.9-20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas luteinizing hormone and follicle-stimulating hormone were high in patients before TRT. Despite normal body mass index, body fat percentage and the ratio between android fat percentage and gynoid fat percentage were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT, a tendency toward a more beneficial body composition with a significant reduction in the ratio between android fat percentage and gynoid fat percentage during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.

Diagnosis and Incidence of Congenital Combined Pituitary Hormone Deficiency in Denmark-A National Observational Study.

CONTEXT: Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors. OBJECTIVE: We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups. METHODS: Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure. RESULTS: We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births. CONCLUSION: cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.

Tracking and Cumulative Lifetime Exposure to IGF-I in 6459 Healthy Individuals and in SGA Children Treated With GH.

CONTEXT: Supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations have been a matter of concern in children treated with GH because high IGF-I levels were associated with risk of later disease in former epidemiological studies. OBJECTIVE: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. METHODS: We included 6459 healthy participants (cross-sectional = 5326; longitudinal = 1133) aged 0-76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment. Intraindividual tracking of IGF-I and IGFBP-3 (SD score [SDS]) was determined by intraclass correlation coefficients (ICCs). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS trajectory from 0 to 76 years. RESULTS: For IGF-I (SDS), ICCs were 0.50 (95% CI, 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12 723 ± 3691 SD) than in male participants (12 563 ± 3393); P = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9512 ± 1889 to 11 271 ± 1689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. CONCLUSION: Because IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.

Neuroimaging in 205 consecutive Children Diagnosed with Central Precocious Puberty in Denmark.

INTRODUCTION: A brain magnetic resonance image (MRI) is considered part of routine evaluation in children diagnosed with central precocious puberty (CPP) to rule out intracranial pathology. We evaluated the occurrence of pathological findings on neuroimaging among children diagnosed with CPP. METHODS: A retrospective study based on an evaluation of 1544 children referred with early signs of puberty from 2009-2019. Of these, 205 children (29 boys) with confirmed CPP had a brain MRI performed, and we report MRI results, pubertal stage, bone age, and hormonal analyses. All abnormal MRI results were re-evaluated by a trained neuroradiologist. RESULTS: A new intracranial pathology was found by brain MRI in 6 out of 205 patients aged 1.5 to 6.1 years. The occurrence of intracranial pathology was 3/162 (1.8%) and 3/24 (12.5 %) in girls and boys respectively. CONCLUSION: Organic causes of precocious puberty are more frequent in boys with CPP than in girls. No cases of organic CPP were seen above age 6.1 years of age. The age cut off value for routine brain MRI could be lowered to seven or perhaps even six years of age for girls, except in rapidly progressing puberty or presence of neurological symptoms. IMPACT: In our study of children with central precocious puberty (CPP), intracranial pathology is a rare cause and occurs only in younger children. It supports the general trend, that younger children are at higher risk of having organic causes to CPP and supports the clinical practice, that only high-risk patients with CPP should undergo routine brain MRI.

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.].

Timing of Puberty, Pubertal Growth, and Adult Height in Short Children Born Small for Gestational Age Treated With Growth Hormone.

CONTEXT: Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied. OBJECTIVE: To evaluate adult height and peak height velocity in short GH-treated SGA children. METHODS: Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (n = 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data. RESULTS: Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, P = .02) and boys (1.57 [1.13; 2.15] SDS, P < .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, P < .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, P = .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, P = .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, P = .18). CONCLUSION: GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.

Prepubertal and pubertal gonadal morphology, expression of cell lineage markers and hormonal evaluation in two 46,XY siblings with 17ß-hydroxysteroid dehydrogenase 3 deficiency.

OBJECTIVES: 17ß-hydroxysteroid dehydrogenase 3 (17ß-HSD3) deficiency results in insufficient biosynthesis of testosterone and consequently dihydrotestosterone. This is important for the fetal development of male genitalia. Thus, most 46,XY patients with 17ß-HSD3 deficiency have a female appearance at birth and present with virilization at puberty. This study presents the differences in the clinical and hormonal data and analyses of gonadal characteristics in two siblings with 17ß-HSD3 deficiency. CASE PRESENTATION: Patient 1 presented with deepening of the voice and signs of virilization at puberty and increased serum levels of testosterone (T) of 10.9 nmol/L (2.9 SDS) and androstenedione (Δ4) of 27 nmol/L (3.3 SDS) were observed. The T/Δ4-ratio was 0.39. Patient 2 was clinically prepubertal at the time of diagnosis, but she also had increased levels of T at 1.97 nmol/L (2.9 SDS), Δ4 at 5 nmol/L (3.3 SDS), and the T/Δ4-ratio was 0.40, but without signs of virilization. Both siblings were diagnosed as homozygous for the splice-site mutation c.277+4A>T in intron 3 of HSD17B3. They were subsequently gonadectomized and treated with hormone replacement therapy. The gonadal histology was overall in accordance with pubertal status, although with a dysgenetic pattern in both patients, including Sertoli-cell-only tubules, few tubules containing germ cells, and presence of microliths. CONCLUSIONS: Two siblings with 17ß-HSD3 deficiency differed in pubertal development at the time of diagnosis and showed marked differences in their clinical presentation, hormonal profile, gonadal morphology and expression of cell lineage markers. Early diagnosis of 17ß-HSD3 deficiency appears beneficial to ameliorate long-term consequences.

Clinical assessment of blood pressure in 60 girls with Turner syndrome compared to 1888 healthy Danish girls.

OBJECTIVE: Hypertension contributes to increased risk of cardiovascular disease in patients with Turner syndrome (TS). Our objective was to evaluate blood pressure (BP) in girls with TS followed longitudinally through childhood and adolescence compared to a newly established BP reference material. DESIGN: Cohort study with data collected from 1991 to 2019 consisting of a population-based reference cohort and a group of girls with TS followed at a single tertiary centre. PATIENTS/PARTICIPANTS: Reference population of 1888 healthy girls with 4890 BP recordings and 60 girls with TS with 365 BP recordings. MEASUREMENTS: Difference in diastolic BP (DBP) and systolic BP (SBP), expressed in standard deviation scores (SDS), between girls with TS and the reference population, unadjusted and adjusted for BMI. Difference in BP (SDS) between TS subgroups (karyotype, oestrogen treatment, cardiac diagnosis). RESULTS: The girls with TS had significantly higher DBP (mean ± SD, 0.72 SDS ± 0.95; p < .001) and SBP (0.53 SDS ± 1.11; p = .001) than the reference population. Adjusted for BMI, girls with TS had significantly higher DBP (mean ± SE, 0.71 SDS ± 0.12; p < .001) but not SBP (0.17 SDS ± 0.16; p = .29). There was no significant difference in DBP (median, IQR: 0.97 SDS, 0.30-1.58 vs. 0.76 SDS, 0.10-1.20; p = .31) or SBP (0.51 SDS, 0.15-1.30 vs. 0.57 SDS, -0.30 to 1.05; p = .67) between individuals with or without a cardiac diagnosis. In the TS population, 55% (31/56) had at least one BP recording above the hypertension threshold. CONCLUSIONS: Our findings indicate that standardised longitudinal routine monitoring of BP in girls with TS already in childhood is of utmost importance.

Dynamic Changes in Serum IGF-I and Growth During Infancy: Associations to Body Fat, Target Height, and PAPPA2 Genotype.

CONTEXT: IGF-I is important for postnatal growth and may be of diagnostic value in infants suspected of pituitary disease; however, little is known about the impact of IGF-I and its determinants on infant growth. Importantly, detailed reference ranges for IGF-I and IGF binding protein-3 (IGFBP-3) concentrations during infancy are lacking. OBJECTIVE: To evaluate the rapid changes in weight and length as well as their determinants in healthy infants, and to establish age- and sex-specific reference curves for IGF-I and IGFBP-3 in children aged 0 to 1 years. DESIGN: Prospective longitudinal study. SETTING: Cohort study. PARTICIPANTS: A total of 233 healthy children (114 girls) with repeated blood samples during the first year of life. MAIN OUTCOME MEASURE(S): Serum concentrations of IGF-I and IGFBP-3, length velocity, weight velocity, and PAPPA2 (rs1325598) genotype. RESULTS: Individual trajectories of length and weight velocities were sex specific. We provide detailed reference curves based on longitudinal data for IGF-I and IGFBP-3 during infancy. In both girls and boys, IGF-I decreased during infancy, whereas IGFBP-3 remained stable. IGF-I and IGFBP-3, but not PAPPA2 genotype, were positively associated with weight gain, but not with longitudinal growth. When stratified by sex, the association between weight gain and IGF-I only remained significant in girls. CONCLUSIONS: Interestingly, we found a significant association between IGF-I and infant weight gain in girls, but not with longitudinal growth in the first year of life. Our findings highlight the role of IGF-I as an important anabolic hormone that is not limited to linear growth.

GAD65 autoantibodies and glucose tolerance in offspring born to women with and without type 1 diabetes (The EPICOM study).

The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab-positive if diagnosed with diabetes or pre-diabetes. This EPICOM study is a prospective follow-up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre-gestational T1D between 1993 and 1999 and matched un-exposed controls (n = 303). Age at the time of follow-up was 16.7 years (13.0-20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR© . An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab-negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab-positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA-IR, HOMA-IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre-diabetes more were GAD65-positive.

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.

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.

Impact of Lean Body Mass and Insulin Sensitivity on the IGF-1-Bone Mass Axis in Adolescence: the EPICOM Study.

CONTEXT: Insulin-like growth factor-1 (IGF-1) is involved in the growth of muscle and bone mass and contributes to glucose homeostasis. The offspring of mothers with diabetes during pregnancy have an increased risk of insulin resistance (IR). OBJECTIVE: We hypothesized that bone mass was decreased in the offspring of mothers with type 1 diabetes (T1D), and that the IGF-1-bone mass relationship would be negatively influenced by IR. DESIGN: Data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study performed from 2012 to 2013 were included. SETTING: This work is a follow-up study of a nationwide register study. PATIENTS: A total of 278 adolescent index offspring whose mothers had T1D and 303 matched controls were studied. MAIN OUTCOME MEASURE: Bone mineral content (BMC) determined by a dual-energy x-ray absorptiometry scan and the interaction with IGF-1 and insulin sensitivity were measured. RESULTS: There was no difference in BMC, bone mineral density, height (SD score [SDS]), or BMC/height between index and control offspring. IGF-1 (SDS) did not differ between the groups but insulin-like growth factor-binding protein 3 (SDS) was higher in index boys compared to controls (B = .31 [95% CI, 0.06-0.57], P = .02). The statistical path analysis showed that IGF-1 predicted BMC/height (B = .24 [95% CI, 0.02-0.45], P = .03), but lean mass was a mediator of this. IGF-1 and the homeostatic model assessment of IR were positively associated (B = .75 [95% CI, 0.37-1.12], P < .001). There was no moderating effect of the interaction between IR and IGF-1 on lean mass in the entire cohort (B = .005 [95% CI, -0.03 to 0.04], P = .81) or when analyzing index cases and controls separately. CONCLUSION: We found that lean mass was an intermediary factor in the IGF-1-bone mass relationship in a large cohort of adolescents, and this relationship was not moderated by IR.