The association between antiretroviral therapy and early placental function: a cohort study.

Objective: To evaluate the association of antiretroviral therapy (ART) type and duration of exposure with early placental function using biomarkers of aneuploidy screening.Study design: Three hundred thirty-eight pregnant women living with HIV were enrolled in two Canadian centers. Multiple linear regressions were performed adjusting for confounding factors (race, age, gestational age, body mass index, parity, smoking, and fetal sex).Results: Women receiving ART had significantly increased second trimester alpha-fetoprotein (AFP) levels (ß = 0.147, 95% CI = [0.067-0.227] for protease inhibitor-based ART and ß = 0.176, 95% CI = [0.080-0.272] for ART without protease inhibitor) compared to women who received no treatment. However, there was no significant association between ART type and the levels of free ß-human chorionic gonadotrophin (ß-hCG), pregnancy-associated plasma protein-A (first trimester), unconjugated estriol, total hCG, and inhibin A (second trimester). No significant association was shown between biomarker levels and duration of ART exposure.Conclusion: Early placental function does not appear to be significantly affected by ART, except for AFP.

Early and Late Postnatal Accelerated Growth Have Distinct Effects on Metabolic Health in Normal Birth Weight Infants.

Accelerated growth in postnatal life in low birth weight infants has been associated with insulin resistance and metabolic syndrome-related disorders in later life. Postnatal accelerated growth in also common in normal birth weight infants, but little is known about the impact on metabolic health. In a prospective cohort study of 203 term normal birth weight infants, we evaluated the impacts of accelerated (Δweight Z score > 0.5) or decelerated (Δweight ΔZ < -0.5) growth during early (0-3 months) and late (3-12 months) postnatal life on metabolic health indicators at age 1-year. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR), ß-cell function [homeostasis model assessment of ß-cell function (HOMA-ß)], and fasting plasma lipids. Adjusting for maternal, paternal, and infant characteristics, accelerated growth during the first 3 months of life was associated with a 41.6% (95% confidence interval 8.9-84.2%) increase in HOMA-ß, and a 8.3% (0.7-15.4%) decrease in fasting plasma total cholesterols, and was not associated with HOMA-IR in infants at age 1-year. Accelerated growth during 3-12 months was associated with a 30.9% (3.3-66.0%) increase in HOMA-IR and was not associated with HOMA-ß. Neither accelerated nor decelerated growth was associated with fasting plasma triglycerides, high-density lipoprotein or low-density lipoprotein cholesterol concentrations in infants at age 1-year. Accelerated growth during early postnatal life may be beneficial for ß-cell function, but during late postnatal life harmful for insulin sensitivity in normal birth weight infants.

Mindfulness-based Intervention for Female Adolescents with Chronic Pain: A Pilot Randomized Trial.

OBJECTIVE: To test the feasibility of a randomized-controlled trial measuring the impact of an adapted mindfulness-based intervention (MBI) in female adolescents with chronic pain. METHODS: This was a single center, single-blind, prospective, experimental, longitudinal trial conducted in a pediatric tertiary care center. Participants had a history of chronic pain during at least three months. They were randomized into an intervention group or a wait-list control group. Both groups successively followed an adapted eight-week MBI designed specifically for adolescents with chronic pain. Pre-determined criteria were established to assess the feasibility, validity and acceptability of the study model. Data evaluating changes in quality of life, depression, anxiety, pain perception, psychological distress and salivary cortisol were collected throughout the 4-month study period. RESULTS: Nineteen female participants completed the study and had a mean age of 15.8 years (range 13.9 -17.8). Attrition rate was low (17%). Attendance to mindfulness sessions (84%) and compliance to study protocol (100%) were high. All participants reported a positive change in the way they coped with pain. No changes in quality of life, depression, anxiety, pain perception, and psychological distress were detected. Significant reductions in pre-and post-mindfulness session salivary cortisol levels were observed (p<0.001). CONCLUSIONS: Mindfulness is a promising therapeutic approach for which limited data exist in adolescents with chronic pain. Our study indicates the feasibility of conducting such interventions in teenage girls. A large trial is needed to demonstrate the efficacy and bio-physiological impacts of MBIs in teenagers with chronic pain.

OBJECTIF: Vérifier la faisabilité d'un essai randomisé contrôlé qui mesure l'effet d'une intervention de pleine conscience (IPC) adaptée chez des adolescentes souffrant de douleur chronique. MÉTHODES: Il s'agissait d'un essai monocentrique, à l'insu, prospectif, expérimental, longitudinal mené dans un centre soins tertiaires pédiatriques. Les participantes avaient des antécédents de douleur chronique durant au moins trois mois. Elles ont été randomisées soit dans un groupe d'intervention, soit dans un groupe témoin placé sur une liste d'attente. Les deux groupes ont suivi successivement une IPC adaptée de 8 semaines, conçue spécifiquement pour les adolescentes souffrant de douleur chronique. Des critères prédéterminés ont été établis pour évaluer la faisabilité, la validité et l'acceptabilité du modèle d'étude. Les données évaluant les changements touchant la qualité de vie, la dépression, l'anxiété, la perception de la douleur, la détresse psychologique et le cortisol salivaire ont été recueillies durant la période de 4 mois de l'étude. RÉSULTATS: Dix-neuf participantes ont participé à l'étude et leur âge moyen était de 15,8 ans (écart de 13,9 à 17,8). Le taux d'attrition était faible (17 %). L'assistance aux séances de pleine conscience (84 %) et l'observance du protocole de l'étude (100 %) étaient élevées. Toutes les participantes ont déclaré un changement positif de la façon dont elles traitaient avec la douleur. Aucun changement n'a été détecté en ce qui concerne la qualité de vie, la dépression, l'anxiété, la perception de la douleur, et la détresse psychologique. Des réductions significatives des taux de cortisol salivaire avant et après les séances de pleine conscience ont été observées (p < 0,001). CONCLUSIONS: La pleine conscience est une approche thérapeutique prometteuse pour laquelle il n'existe que des données limitées pour les adolescentes souffrant de douleur chronique. Notre étude indique la faisabilité de mener ces interventions auprès d'adolescentes. Il faut un vaste essai pour démontrer l'efficacité et les effets biophysiologiques des IPC chez les adolescentes souffrant de douleur chronique.

Revisiting Pathological Criteria for Earlier Diagnosis of Coeliac Disease.

OBJECTIVES: The diagnosis of coeliac disease (CD) remains sometimes difficult because the histological criteria are not fully met. The aim of this study was to refine histological diagnostic criteria of CD. METHODS: One hundred seventy-five duodenal bulb D1 (n = 79) and duodenal D2 (n = 96) biopsies of 96 patients with CD (58 girls, mean age 7 years), 135 normal D2 biopsies (69 girls, mean age 12 years), and 64 D2 biopsies of other digestive disorders (DDs) (39 girls, mean age 13 years) obtained from children during a period of 4 years were reviewed. RESULTS: Interobserver agreement was greater for the classification of Corazza-Villanacci than for Marsh-Oberhuber (κ = 0.812 vs κ = 0.409, respectively). Between 40 and 70 intraepithelial lymphocytes (IELs) per 100 epithelial cells (ECs), 32% of patients were CD, whereas 50% had other DD. Above 70 IELs per 100 EC, 53% were CD, and only 6% had other DD. In CD, IELs were significantly located above EC nuclei compared with other DD, (12 IELs/100 EC vs 2 IELs/100 EC, respectively). In 21% of CD cases, D2 were normal and the diagnosis could only be made on D1. Finally, 6% of CD cases showed isolated increase of IELs in D1 without architectural modification. CONCLUSIONS: D1 allowed diagnosis of CD in 21% of cases and IEL >70 per 100 EC correlated strongly with CD. Between 40 and 70 IELs per 100 EC, CD is very likely but other DD must be considered. Finally, the preferential localisation of IELs above EC nuclei favours CD, and increased IEL in D1 may be the sole abnormality.

First-trimester prediction of birth weight.

OBJECTIVES: To determine whether the parameters used in first-trimester screening for aneuploidies contribute significantly to the prediction of birth weight. METHODS: In this retrospective cohort study (n = 4110), nuchal translucency (NT), free ß-chorionic gonadotropin (fß-hCG), and pregnancy-associated plasma protein-A (PAPP-A) blood concentrations were measured between 11 + 0 and 13 + 6 weeks. Multiple pregnancies, chromosomal anomalies, major fetal defects, and deliveries before 24 weeks were excluded. RESULTS: NT (0.95 versus 0.98 multiples of the expected median [MoM], p < 0.001) and PAPP-A (0.93 versus 1.06 MoM, p = 0.005) were significantly lower in small-for-gestational-age (SGA) newborns (<10th percentile) than the unaffected group, but not fß-hCG (0.89 versus 0.93 MoM, p = 0.113). NT was significantly higher (1.03 versus 0.98 MoM, p < 0.001) in the large-for-gestational-age (LGA) group (>90th percentile) compared with the unaffected group, and biomarkers did not differ. After controlling for gestational age, maternal weight, smoking status, ethnicity, and fetal sex, first-trimester markers contributed to the prediction of birth weight in a multiple linear model but did not significantly improved the prediction of SGA and LGA compared with maternal characteristics alone. CONCLUSIONS: Parameters used in first-trimester screening for aneuploidies contribute to the prediction of birth weight but their clinical utility to detect women at risk of SGA or LGA baby is limited.

Bioinactive ACTH causing glucocorticoid deficiency.

CONTEXT: A 4-year-old girl and a 4-month-old boy presented with hypoglycemia, normal electrolytes, low cortisol, and high ACTH. A diagnosis of primary adrenal insufficiency was made and initial treatment was with glucocorticoids and mineralocorticoids. The genes known to cause ACTH resistance were normal. Whole exome sequencing revealed that the girl was compound heterozygous for POMC mutations: one previously described null allele and one novel p.R8C mutation in the sequence encoding ACTH and α-MSH. The boy was homozygous for the p.R8C mutation. HYPOTHESIS: The p.R8C ACTH mutant is immunoreactive, but the mutant peptides, ACTH-R8C and α-MSH-R8C, are bioinactive. METHODS: Methods included whole exome sequencing, Sanger sequencing, peptide synthesis, ACTH immunoradiometric assay, hormone binding, and activation assays in cells expressing melanocortin receptors. RESULTS: ACTH-R8C was immunoreactive but failed to bind and activate cAMP production in melanocortin-2 receptor (MC2R)-expressing cells, and α-MSH-R8C failed to bind and stimulate cAMP production in MC1R- and MC4R-expressing cells. CONCLUSION: These are the first documented cases of glucocorticoid deficiency due to the secretion of an ACTH molecule that lacks biological bioactivity but conserves immunoreactivity. POMC mutations should thus be considered in patients presenting with apparent ACTH resistance. Our findings also highlight a limitation to immunoassay-based diagnostics and demonstrate the value of genetic analysis. Establishing the molecular etiology of the disorder in our patients allowed cessation of the unnecessary mineralocorticoids. Finally, discovery of this mutation indicates that in humans, the amino acid sequence His(6)Phe(7)Arg(8)Trp(9) is important not only for cAMP activation but also for ACTH binding to MC2R.

Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes.

CONTEXT: It remains uncertain whether maternal IGF-I is associated with fetal growth. Little is known about the role of maternal IGF-II in fetal growth and whether IGF-I or IGF-II is implicated in fetal hypertrophy in gestational diabetes. OBJECTIVE: The objective of the study was to assess maternal and fetal IGF-I and IGF-II levels in association with fetal growth and gestational diabetes. STUDY DESIGN, POPULATION, AND OUTCOMES: A singleton pregnancy cohort study (n = 307). The primary outcome was birth weight. RESULTS: Maternal plasma concentrations increased by an average of 55.4% for IGF-I and 11.8% for IGF-II between 24-28 and 32-35 weeks of gestation. The maternal IGF-I but not IGF-II level was correlated with birth weight and placental weight. Adjusting for maternal and infant characteristics, each SD increase in maternal IGF-I level at 24-28 weeks was associated with a 75-g (95% confidence intervals 29-120) increase in birth weight, a 20-g (7-33) increase in placental weight, and a 1.91-fold (1.28-2.86) higher odds of macrosomia (birth weight > 90th percentile). Similar associations were observed for the maternal IGF-I level at 32-35 weeks. Maternal and fetal IGF-I (but not IGF-II) levels were significantly higher in gestational diabetic than in nondiabetic pregnancies. The significantly higher birth weight z scores in diabetic pregnancies disappeared after adjusting for maternal and fetal IGF-I levels alone. CONCLUSIONS: Higher maternal IGF-I (but not IGF-II) levels at mid- and late gestation may indicate greater placental and fetal growth. IGF-I (but not IGF-II) may be implicated in fetal hypertrophy in gestational diabetes.

Undetectable AMH at 3 days of age: a clue to bilateral anorchia.

We report the case of a newborn boy who presented with micropenis and bilateral cryptorchidism at birth. The determination of AMH level strongly suggested a diagnosis of bilateral anorchia at 3 days of age whereas FSH and LH levels at the same time were not informative. The rapidity and reliability of results can reduce parental anxiety and avoid more invasive explorations.

Contingent use of fetal fibronectin testing and cervical length measurement in women with preterm labour.

OBJECTIVE: To evaluate the contingent use of fetal fibronectin (fFN) testing and cervical length (CL) measurement to predict preterm delivery, and to validate the use of phosphorylated IGFBP-1 as a predictor of preterm delivery. METHODS: We recruited 71 women with a clinical diagnosis of preterm labour between 24 and 34 weeks, and tested for the presence of fFN and IGFBP-1 in the cervicovaginal secretions of all women immediately before CL measurement. RESULTS: Among the 66 women with complete outcome, four were excluded from the final analysis as two had assessment for fFN but no CL measurement, and another two had CL measured but no screening for fFN. Among 62 women with complete results, the mean gestational age at recruitment was 29.4 +/- 2.5 weeks. Six women (9.6%) delivered within two weeks of assessment, and 14 (22.5%) delivered before 34 weeks. A positive fFN test resulted in a sensitivity of 83%, a specificity of 84%, a positive predictive value of 36%, and a negative predictive value of 98% for delivery within two weeks; for CL < 25 mm, these figures were 50%, 52%, 10%, and 91%, respectively, and for a positive IGFBP-1, they were 17%, 93%, 20%, and 91%, respectively. A policy of contingent use of fFN (in which the test was assumed to be positive if CL < or = 15 mm, and fFN was only measured if the CL was between 16 and 30 mm) gave sensitivity, specificity, positive and negative predictive values of 80%, 61%, 17%, and 97%, respectively for delivery within two weeks. Using this contingent use protocol, only one third of women needed fFN screening after CL measurement. CONCLUSION: In this study, IGFBP-1 screening did not predict preterm delivery and fFN screening provided the best predictive capacity. A policy of contingent use of testing for fFN after CL measurement, or contingent use of CL measurement after fFN screening (depending on available resources) is a promising approach to limit use of resources.

Pericardial effusion in severe hypothyroidism in children.

Pleural and pericardial effusion is a rare complication of severe hypothyroidism in children but can be present in 10 to 30% of adults. Most pediatric cases have been in children with Down syndrome. In this report, six cases of pericardial effusion in children with severe hypothyroidism with and without trisomy 21 are presented. In all patients, the pericardial effusion was managed successfully without pericardiocentesis. The effusions resolved completely in 2 to 12 months after initiation of thyroxin replacement. In conclusion, hypothyroidism should be considered in any child with unexplained pericardial or pleural effusions. Early recognition and treatment with thyroid hormone replacement could eliminate the need for unnecessary diagnostic procedures and invasive treatment measures and reduce the risk of progression to cardiac tamponade.

Congenital hypothyroidism: from paracelsus to molecular diagnosis.

Endemic cretinism was noted in alpine Europe as early as the 13th century. However, it was only in 1848 that a commission, sponsored by the King of Sardinia, first formally demonstrated its link to goiter. An important landmark was the publication of a report in 1871 describing several cases of nongoitrous hypothyroidism that were clearly distinguished from the endemic form of the disease, for which the author suggested the designation of "sporadic cretinism." Classification of the hypothyroid status was for a long time solely based on clinical observation. In the second half of the 20th century, the use of radionuclides (iodine radioisotope and technetium pertechnetate) allowed a more precise diagnosis and taxonomy into thyroid dysgenesis and dyshormonogenesis. This brief review summarizes the progress that has been achieved during the last 40 years in diagnosing the multiple variants of congenital hypothyroidism (CH). It becomes evident that while accurate diagnosis for CH is readily available, its exact etiology requires a precise molecular investigation as different genes are implicated in the differentiation, migration and growth of the thyroid gland.

Sexual dimorphism of thyroid function in newborns with congenital hypothyroidism.

Several characteristics of congenital hypothyroidism (CH) from thyroid dysgenesis (ectopy and athyreosis) are sexually dimorphic: girls are more often affected, and boys are twice more likely than girls to have absent knee epiphysis at diagnosis, an indicator of severity of CH. Whether the biochemical severity of CH is sexually dimorphic is unknown. We therefore reviewed the charts of all newborns referred to our clinic from 1990 to 2004 because of a TSH greater than 15 mU/liter on newborn screening. In ectopy (24 boys, 78 girls) at screening, median TSH was lower in boys than girls (75 vs. 135 mU/liter, P = 0.017), whereas total T4 was higher (123 vs. 68 mmol/liter, P = 0.003); the same differences were present at diagnosis: TSH was 90 and 284 mU/liter (P = 0.001) and free T4 10 and 7 pmol/liter (P = 0.049) in boys and girls, respectively. The log-linear relationships between TSH and T4 at screening and diagnosis were similar in both sexes. In athyreosis (10 boys, 14 girls) at screening and diagnosis, TSH was higher in boys [308 vs. 207 (P = 0.053) and 712 vs. 555 mU/liter (P = 0.0057)]. In infants with an orthotopic gland (dyshormonogenesis, nine boys, 13 girls), there was no sex difference in biochemical severity of CH. In conclusion, sexual dimorphism in biochemical severity of CH from thyroid dysgenesis is apparent but differs according to etiology. These novel findings suggest that sexual dimorphism should be considered as a modulator of the mechanisms underlying the fate and function of ectopic thyroid cells.

Twenty years later: a reevaluation of the contribution of plasma thyroglobulin to the diagnosis of thyroid dysgenesis in infants with congenital hypothyroidism.

BACKGROUND: The definition of the type of thyroid dysgenesis in congenital hypothyroidism (CH), ectopy, or athyreosis is important for monitoring patients and for genetic investigations. We have recently encountered infants who in spite of undetectable Technetium uptake on scintigraphy had biochemical results making athyreosis unlikely. OBJECTIVE: To reevaluate the utility of plasma thyroglobulin (Tg) in this clinical context using new sensitive Tg assays. SUBJECTS AND METHODS: Plasma Tg was retrospectively determined by two immunoassay systems on specimens obtained at diagnosis in 31 hypothyroid infants with thyroid dysgenesis. RESULTS: Scintigraphy led to the diagnosis of ectopy in 19 infants and of athyreosis in 12. Seven (58%) of the infants classified as athyreotic by scintigraphy had detectable plasma Tg (>0.2 microg/l), indicating that they had functional thyroid tissue. CONCLUSIONS: An undetectable plasma Tg should be documented to validate a scintigraphic diagnosis of athyreosis. Conversely, when plasma Tg is undetectable, scintigraphy could be avoided.

Reference intervals for free thyroxine, total triiodothyronine, thyrotropin and thyroglobulin for Quebec newborns, children and teenagers.

OBJECTIVE: Paediatric reference values, although essential for interpreting patients' results, are scarce. Moreover, they are often population- and instrument-dependent. We have measured free thyroxine (Free T(4)), total triiodothyronine (Total T(3)), thyroglobulin (Tg) and thyrotropin (TSH) in samples obtained from groups of newborns, children and adolescents. SUBJECTS AND METHODS: Blood samples collected from healthy children and teenagers (100 girls and 100 boys) of age groups ranging between 9-10, 11-14 and 15-17 years and selected randomly from a cohort representative of the Quebec population, were used. Samples from infants of age ranging between 1 day and 2 years (n = 99) were obtained from a hospital-based population with benign conditions unlikely to affect thyroid function. Variables were measured on the Access 2 immunosystem. RESULTS: Free T(4), Tg and TSH levels declined significantly with age. However, Total T(3) level presented a nonlinear variation with age, being lower in the first month of life.