Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

OBJECTIVE: To define nomograms of serum cortisol values before 24 hours of postnatal life for extremely preterm infants and determine whether baseline cortisol values affect the benefit/risk ratio of prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: We performed a predefined secondary analysis of the multicenter randomized controlled PREMILOC trial that included inborn infants delivered before 28 weeks of gestation. Nomograms of baseline serum cortisol values measured in 325 enrolled patients were determined for male and female neonates and correlated to perinatal events. BPD-free survival and severe adverse events were analyzed in placebo and hydrocortisone groups according to the cortisol z score in multivariate logistic regression models. RESULTS: Increased cortisol levels measured before 24 hours following birth were associated with a significantly higher chance of BPD-free survival only in placebo-treated infants (aOR [95% CI] 1.57 [1.08-2.27], P = .02) based on sex-specific nomograms for baseline cortisol levels. The cortisol z score for infants treated with prophylactic hydrocortisone predicted a risk of high-grade intraventricular hemorrhage (aOR [95% CI] 1.82 [1.06-3.15], P = .03) and spontaneous intestinal perforation (aOR [95% CI] 4.81 [1.34-17.22], P = .02). CONCLUSIONS: We found no predictive value of baseline cortisol levels for BPD-free survival in infants born extremely preterm treated with hydrocortisone. However, high cortisol levels early after birth were associated with a greater risk of severe intraventricular hemorrhage and spontaneous intestinal perforation in infants treated with hydrocortisone and, therefore, a lower benefit/risk ratio for the treatment. TRIAL REGISTRATION: EudraCT 2007-002041-20, ClinicalTrial.gov: NCT00623740.

Cord blood procalcitonin level and early-onset sepsis in extremely preterm infants.

Early-onset neonatal sepsis (EOS) is observed in 1.7% of extremely preterm infants, with high morbidity and mortality rate. Cord blood procalcitonin (PCT) is a sensitive marker of EOS in full-term newborns, but it has been rarely studied in premature infants. The diagnostic value of cord blood PCT by immunofluorescence has been assessed as an early marker of EOS in a prospective cohort of extremely preterm infants, with a threshold at 0.5 µg/L. EOS was defined by a positive bacterial culture or by the association of postnatal biological/clinical signs of EOS and antibiotic treatment for more than 72 h. Correlation between PCT serum concentrations and postnatal morbidities was also analyzed. Among a total of 186 infants, 45 (24%) were classified as EOS. Blood PCT concentration was ≤ 0.5 µg/L in 114 infants, including 11 EOS (9.6%) and PCT was > 0.5 µg/L in 72 babies including 34 EOS (47.2%). PCT concentration > 0.5 µg/L was associated with higher risk of EOS (OR 2.18; CI95% 1.58-3.02; p < 0.0001). The receiver operating characteristic curve determined a cutoff of 0.7 µg/L as the best compromise, with an area under the curve of 0.75 (sensitivity 69%, specificity 70%). In multivariate analysis, clinical chorioamnionitis was associated with PCT concentration > 0.5 µg/L (OR 2.58; CI95% 1.35-4.94; p = 0.004). Cord blood PCT is a marker significantly associated with EOS in extremely preterm infants, but its sensitivity remains low. Its added value in combination with other early marker of EOS needs to be further investigated in this high-risk population.

Temporal Association Between Rhinovirus Activity and Kingella kingae Osteoarticular Infections.

OBJECTIVE: To determine whether the seasonal distribution of Kingella kingae osteoarticular infections is similar to that of common respiratory viruses. STUDY DESIGN: Between October 2009 and September 2016, we extracted the results of K kingae-specific real-time polymerase chain reaction analyses performed for bone or joint specimens in patients from 2 pediatric tertiary care centers in Paris. We used data of respiratory virus detection from the Réseau National des Laboratoires network with coordination with the National Influenza Center of France. The Spearman rank correlation was used to assess a correlation between weekly distributions, with P < .05 denoting a significant correlation. RESULTS: During the 7-year study period, 322 children were diagnosed with K kingae osteoarticular infection, and 317 testing episodes were K kingae-negative. We observed high activity for both K kingae osteoarticular infection and human rhinovirus (HRV) during the fall (98 [30.4%] and 2401 [39.1%] cases, respectively) and low activity during summer (59 [18.3%] and 681 [11.1%] cases, respectively). Weekly distributions of K kingae osteoarticular infection and rhinovirus activity were significantly correlated (r = 0.30; P = .03). In contrast, no significant correlation was found between the weekly distribution of K kingae osteoarticular infection and other respiratory viruses (r = -0.17, P = .34 compared with respiratory syncytial virus; r = -0.13, P = .34 compared with influenza virus; and r = -0.22, P = .11 compared with metapneumovirus). CONCLUSION: A significant temporal association was observed between HRV circulation and K kingae osteoarticular infection, strengthening the hypothesis of a role of viral infections in the pathophysiology of K kingae invasive infection.

Clinical Interest and Economic Impact of Preoperative SMS Reminders before Ambulatory Surgery: A Propensity Score Analysis.

Patient contact by telephone the day before ambulatory surgery is considered as a best practice. The Short Message Service (SMS) could be a suitable alternative. The objective of this prospective study was to evaluate the interest of preoperative instruction (PI) reminders by SMS compared to telephone calls. This was a prospective single center before-and-after study. Patients scheduled in ambulatory surgery were included during 2 consecutive periods of 10 weeks. The "Call" group received a telephone call for preoperative instructions (PI) and the "SMS" group received an automated protocol SMS reminder. The primary endpoint was patient compliance with PI and time of convocation. The two populations were compared with a non-inferiority hypothesis and the impact of the contact modality on compliance with the PI was assessed using a propensity score. The analysis concerned 301 patients in the Call group and 298 in the SMS group. The absence of dysfunction was observed in 75% of patients in the SMS group compared with 61% in the Call group (Risk difference: 14% [95%CI: 7-21]). The use of SMS was associated with a significant improvement in compliance with the PI (Odds ratio: 1.90 [1.48-2.42]; p < 0.0001). Patient satisfaction was similar regardless of the method of PI reminders. The automation of preoperative SMS reminders is associated with a better respect of the PI compared to the conventional calling method. This PI reminder method satisfies the majority of patients and may have a favorable financial impact.

Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.

BACKGROUND: Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants. METHODS: In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740. FINDINGS: 1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02-2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09-3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups. INTERPRETATION: In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. FUNDING: Assistance Publique-Hôpitaux de Paris.

Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age.

Importance: Dexamethasone to prevent bronchopulmonary dysplasia in very preterm neonates was associated with adverse neurodevelopmental events. Early low-dose hydrocortisone treatment has been reported to improve survival without bronchopulmonary dysplasia but its safety with regard to neurodevelopment remains to be assessed. Objective: To assess whether early hydrocortisone therapy in extremely preterm infants is associated with neurodevelopmental impairment at 2 years of age. Design, Setting, and Participants: An exploratory secondary analysis of the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial conducted between 2008 and 2014 in 21 French neonatal intensive care units. Randomization was stratified by gestational age groups. Neurodevelopmental assessments were completed from 2010 to 2016. Interventions: After birth, patients were randomly assigned to receive placebo or hydrocortisone (0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days). Main Outcomes and Measures: The prespecified exploratory secondary outcome of neurodevelopmental impairment was based on a standardized neurological examination and the revised Brunet-Lézine scale (global developmental quotient score and subscores; mean norm, 100 [SD, 15]). The minimal clinically important difference on the global developmental quotient was 5 points. Results: Of 1072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21-23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, -2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups. Conclusions and Relevance: In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants. Trial Registration: clinicaltrials.gov Identifier: NCT00623740.

Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study.

Children with sickle cell disease (SCD) have a significant vascular morbidity, especially cerebral macrovasculopathy (CV), detectable by transcranial Doppler. This study aimed to identify risk factors for CV using longitudinal biological and clinical data in a SCD newborn cohort followed at the Robert Debre Reference centre (n = 375 SS/Sß(0) ). Median follow-up was 6·8 years (2677 patient-years). Among the 59 children presenting with CV, seven had a stroke. Overall, the incidence of CV was 2·20/100 patient-years [95% confidence interval (95% CI): 1·64-2·76] and the incidence of stroke was 0·26/100 patient-years (95% CI: 0·07-0·46). The cumulative risk of CV by age 14 years was 26·0% (95% CI: 20·0-33·3%). Risk factors for CV were assessed by a Cox model encompassing linear multivariate modelling of longitudinal quantitative variables. Years per upper-airway obstruction [Hazard ratio (HR) = 1·47; 95% CI: 1·05-2·06] or bronchial obstruction (HR = 1·76; 95% CI: 1·49-2·08) and reticulocyte count (HR = 1·82 per 50 × 10(9) /l increase; 95% CI: 1·10-3·01) were independent risk factors whereas fetal haemoglobin level (HR = 0·68 per 5% increase; 95% CI: 0·48-0·96) was protective. Alpha-thalassaemia was not protective in multivariate analysis (ancillary analysis n = 209). Specific treatment for upper or lower-airway obstruction and indirect targeting of fetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV.

Identification of a Vulnerable Group for Post-Acute Sequelae of SARS-CoV-2 (PASC): People with Autoimmune Diseases Recover More Slowly from COVID-19.

PURPOSE: Evidence is emerging that a significant percentage of COVID-19 cases experience symptom persistence beyond 30 days and go on to develop post-acute sequelae. Our objective was to compare the risk for COVID-19 symptom persistence by self-reported use of medications for autoimmune disease among participants of an on-line COVID-19 registry. PATIENTS AND METHODS: A community-based online survey collected weekly data on COVID-19 symptom presentation. Participants who completed informed consent online, reported a positive COVID-19 test result within 14 days prior to enrollment and also reported demographics, underlying illnesses, and medication use were included. Symptom presence and severity were evaluated weekly after enrollment and compared between participants reporting use of medications for autoimmune conditions and all others. Logistic regression was used to evaluate the odds of more severe acute illness and symptom persistence approximately 30 days after enrollment. RESULTS: A total of 1,518 COVID-19-positive participants were included. Participants reporting use of medications for autoimmune disease (n=70) were more likely to have experienced symptoms at all time points over a 30-day time period and were more likely to report more severe presentation of COVID-19 during acute illness (adjusted OR (95% CI)=1.32 (0.76-2.29)) compared to those reporting not taking medications for autoimmune disease. At about 30 days after enrollment, users of medications for autoimmune disease were more than twice as likely to report three or more symptoms (adjusted OR (95% CI)=2.53 (1.21-5.29)). In particular, their risk of persistent shortness of breath and fatigue was elevated (adjusted OR (95% CI)=2.66 (1.15-6.18) and 4.73 (2.17-10.34), respectively). CONCLUSION: Individuals with underlying autoimmune conditions appear to be particularly vulnerable to post-acute sequelae from COVID-19; early intervention might be considered.

Variability of Prognostic Results Based on Biological Parameters in Sickle Cell Disease Cohort Studies in Children: What Should Clinicians Know?

BACKGROUND: Many pediatric studies describe the association between biological parameters (BP) and severity of sickle cell disease (SCD) using different methods to collect or to analyze BP. This article assesses the methods used for collection and subsequent statistical analysis of BP, and how these impact prognostic results in SCD children cohort studies. METHODS: Firstly, we identified the collection and statistical methods used in published SCD cohort studies. Secondly, these methods were applied to our cohort of 375 SCD children, to evaluate the association of BP with cerebral vasculopathy (CV). RESULTS: In 16 cohort studies, BP were collected either once or several times during follow-up. The identified methods in the statistical analysis were: (1) one baseline value per patient (2) last known value; (3) mean of all values; (4) modelling of all values in a two-stage approach. Applying these four different statistical methods to our cohort, the results and interpretation of the association between BP and CV were different depending on the method used. CONCLUSION: The BP prognostic value depends on the chosen statistical analysis method. Appropriate statistical analyses of prognostic factors in cohort studies should be considered and should enable valuable and reproducible conclusions.

Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality.

OBJECTIVE: To determine whether early low-dose hydrocortisone treatment in extremely preterm infants is associated with brain damage assessed by MRI at term equivalent of age (TEA). PATIENTS AND OUTCOMES: This is a predefined secondary analysis of brain abnormalities, observed by MRI at TEA, of patients randomly assigned to receive either placebo or hydrocortisone in the PREMILOC trial. Outcomes were based on brain abnormalities graded according to Kidokoro scores. RESULTS: Among 412 survivors at TEA, 300 MRIs were performed and 295 were suitable for analysis. Kidokoro scoring was completed for 119/148 and 110/147 MRIs in the hydrocortisone and placebo groups, respectively. The distribution of the Kidokoro white matter (WM) subscore and other subscores was not significantly different between the two groups. There was, however, a significant association between a higher overall Kidokoro score and hydrocortisone treatment (5.84 (SD 3.51) for hydrocortisone and 4.98 (SD 2.52) for placebo; mean difference, 0.86; 95% CI 0.06 to 1.66; p=0.04). However, hydrocortisone was not statistically associated with moderate-to-severe brain lesions (Kidokoro overall score ≥6) in a multivariate logistic regression model accounting for potential confounding variables (adjusted OR (95% CI) 1.27 (0.75 to 2.14), p=0.38). Bronchopulmonary dysplasia at 36 weeks postmenstrual age significantly predicted both WM damage (adjusted OR (95% CI) 2.70 (1.03 to 7.14), p=0.04) and global brain damage (adjusted OR (95% CI) 2.18 (1.19 to 3.99), p=0.01). CONCLUSIONS: Early hydrocortisone exposure in extremely preterm infants is not statistically associated with either WM brain damage or overall moderate-to-severe brain lesions when adjusted for other neonatal variables. TRIAL REGISTRATION NUMBER: EudraCT number 2007-002041-20, NCT00623740.

Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth.

OBJECTIVE: To determine whether early hydrocortisone treatment in extremely preterm infants affects neurodevelopmental outcomes at 2 years of age according to gestational age at birth. PATIENTS AND METHODS: This is an exploratory analysis of neurodevelopmental outcomes by gestational age strata from the PREMILOC trial, in which patients were randomly assigned to receive either placebo or low-dose hydrocortisone and randomisation was stratified by gestational age groups (24-25 and 26-27 weeks of gestation). Neurodevelopmental impairment (NDI) was assessed using a standardised neurological examination and the revised Brunet-Lézine scale at 22 months of corrected age. RESULTS: A total of 379 of 406 survivors were evaluated, 96/98 in the gestational age group of 24-25 weeks and 283/308 in the gestational age group of 26-27 weeks. Among surviving infants born at 24-25 weeks, significant improvement in global neurological assessment was observed in the hydrocortisone group compared with the placebo group (P=0.02) with a risk of moderate-to-severe NDI of 2% and 18%, respectively (risk difference 16 (95% CI -28% to -5%)). In contrast, no statistically significant difference between treatment groups was observed in infants born at 26-27 weeks (P=0.95) with a similar risk of moderate-to-severe NDI of 9% in both groups. The incidence of cerebral palsy or other major neurological impairments were found similar between treatment groups in each gestational group. CONCLUSIONS: In an exploratory analysis of neurodevelopmental outcomes from the PREMILOC trial, early low-dose hydrocortisone was associated with a statistically significant improvement in neurodevelopmental outcomes in infants born at 24 and 25 weeks of gestation.

Dizziness and Convergence Insufficiency in Children: Screening and Management.

OBJECTIVE: In children screened for dizziness with vergence disorders, we tested short and long term efficacy of orthoptic vergence training (OVT) and instructions to reduce screen usage. METHODS: Prospective study: Of the 179 children referred for vertigo or dizziness (over 3 years) with ophthalmological disorder as the only problem after complete oto-neuro-vestibular testing, 69 presented vergence insufficiency, and 49 accepted to participate in this study. 109 healthy children served as controls. All subjects had classic orthoptic evaluation and video binocular movement recordings during various oculomotor tasks. Patients were evaluated before OVT (M0), 3 months after the end of OVT (M3) and 9 months after the end of OVT (M9). Statistics compared orthoptic and oculomotor parameters between patients and controls over time with one-way ANCOVA, and mixed models, controlling for age and gender. RESULTS: Patients reported vertigo that was usually rotatory, lasting <15 min, associated with or alternating with headache (50%). Their exposure to small video screens and TV was intensive (∼3.6 h per day). At M0, all orthoptic and oculomotor parameters were statistically different in patients relative to controls (p < 0.0001) except for divergence. At M3, vertigo symptoms had disappeared in all of the patients, and all eye movement parameters improved significantly (p < 0.0001). At M9, this improvement remained stable or continued. CONCLUSION: Vergence disorders (assessed by abnormal orthoptic and oculomotor parameters) can generate symptoms of dizziness in children. Orthoptic treatment and instruction to reduce screen usage has a significant and long term effect on vertigo symptoms as well as oculomotor performances. Dizzy children should be screened for vergence disorders. WHAT THIS STUDY ADDS: Dizziness in children can be associated exclusively with insufficient convergence. Orthoptic training and instructions to reduce screen exposure made dizziness symptoms disappear and improved all eye movement parameters for 6 months. Vergence disorders should be screened for in dizzy children.

Placental Findings and Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

OBJECTIVES: To investigate the relationship between histologic findings of the placenta and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary dysplasia (BPD) in extremely preterm infants. METHODS: In an exploratory analysis of the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, detailed placental analyses were performed on the basis of standardized macroscopic and histologic examinations. Placental histology, categorized into 3 groups, was correlated to neonatal outcomes and response to hydrocortisone treatment. RESULTS: Of 523 randomly assigned patients, 457 placentas were analyzed. In total, 125 out of 457 (27%) placentas were classified as normal, 236 out of 457 (52%) placentas were classified as inflammatory, and 96 out of 457 (21%) placentas were classified as vascular. Placental inflammation was associated with a significant, increased rate of BPD-free survival at 36 weeks' postmenstrual age, independent of gestational age, treatment group, and sex (adjusted odds ratio: 1.72, 95% confidence interval [CI]: 1.05 to 2.82, P = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06). Adjusted to gestational age and treatment groups, placental inflammation was associated with significantly fewer patent ductus arteriosus ligation (adjusted hazard ratio: 0.58, 95% CI: 0.36 to 0.95, P = .03). Placental histology was not found to be associated with other adverse events related to preterm birth. CONCLUSIONS: With these findings, we confirm that early low-dose hydrocortisone confers benefits in extremely preterm infants overall and we suggest there is a higher treatment effect in those born after placental vascular disease.

Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study.

BACKGROUND: An increase in the incidence of congenital hypothyroidism (CH) with a normally located gland has been reported worldwide. Affected individuals display transient or permanent CH during follow-up in childhood. This study aimed to determine the prevalence of transient CH and to investigate the possibility of distinguishing between transient and permanent CH in early infancy. METHODS: This observational cohort study included all patients identified by systematic neonatal screening for CH in the northern Parisian region between 2002 and 2012 and treated for CH with a normally sited gland. A standardized data collection form was completed prospectively at diagnosis. Patients were classified during follow-up as having transient or permanent CH. RESULTS: Of the 92 patients initially treated for CH with a normally located gland during the neonatal period, 49 (54%) had a transient form of CH after the cessation of levothyroxine (LT4) treatment at 1.5 (0.6-3.2) years of age. Multivariate analysis revealed that transient CH was associated with a lower likelihood of having a first-degree family history of CH (p = 0.03) and a lower LT4 dose at six months of age (p = 0.03) than permanent CH. Sex, ethnicity, neonatal problems (e.g., prematurity, being small for gestational age, and/or neonatal distress), iodine status, coexisting malformations, initial CH severity, and thyroid morphology at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 3.2 µg/kg/day for LT4 dose requirement at six months of age had a sensitivity of 71% and a specificity of 79% for predicting transient CH, with values below this threshold considered predictive of transient CH. CONCLUSION: In patients with CH and a normally located gland, these findings highlight the need to evaluate LT4 dose requirements early, at six months of age, particularly in patients with no family history of CH, for early identification of the approximately 50% of patients for whom treatment should be stopped.

Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children.

CONTEXT: Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety. OBJECTIVE: To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels. DESIGN, PATIENTS AND METHODS: This observational cohort study included all patients (n = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data. RESULTS: Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose (P < 0.01), etiological group (P < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect. CONCLUSIONS: These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.

Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.

Insulin treatment of maternal diabetes mellitus and respiratory outcome in late-preterm and term singletons.

OBJECTIVES: While the incidence of diabetes mellitus (DM) during pregnancy has been steadily increasing in recent years, the link between gestational DM and respiratory outcome in neonates has not been definitely established. We asked the question whether DM status and its treatment during pregnancy could influence the risk of neonatal respiratory distress. DESIGN: We studied in a large retrospective cohort the relationship between maternal DM status (non-DM, insulin-treated DM (IT-DM) and non-insulin-treated DM (NIT-DM)), and respiratory distress in term and near-term inborn singletons. RESULTS: Among 18,095 singletons delivered at 34 weeks of gestation or later, 412 (2.3%) were admitted to the neonatal intensive care unit (NICU) for respiratory distress within the first hours of life. The incidence of NICU admission due to respiratory distress groups was 2.2%, 5.7% and 2.1% in the non-DM, IT-DM and NIT-DM groups, respectively. Insulin treatment of DM, together with several other perinatal factors, was associated with a significant increased risk for respiratory distress. Several markers of the severity of respiratory illness, including durations of mechanical ventilation and supplemental oxygen, and hypertrophic cardiomyopathy were also found increased following IT-DM as compared with NIT-DM. In a multivariate model, we found that IT-DM, but not NIT-DM, was significantly associated with respiratory distress independent of gestational age and caesarean section, with an incidence rate ratio of 1.44 (1.00-2.08). CONCLUSIONS: This study shows that the treatment of maternal DM with insulin during pregnancy is an independent risk factor for respiratory distress in term and near-term newborns.

Fetal growth restriction is worse than extreme prematurity for the developing lung.

BACKGROUND: Perinatal lung growth is highly vulnerable to inflammation and intrauterine growth restriction (IUGR), two major risk factors for chronic lung disease (CLD) in preterm neonates. However, the balance between extremely low gestational age (ELGA) and IUGR in very preterm infants as risk factors for CLD and co-morbidities remains poorly explored. OBJECTIVES: This single-center study aims to compare neonatal morbidity (including CLD) and mortality among ELGA infants with normal birth weight (ELGA-AGA), very preterm infants with IUGR <3rd percentile (VLGA-IUGR) and very preterm infants with a birth weight appropriate for gestational age (VLGA-AGA), matched with VLGA-IUGR infants. METHODS: Selected characteristics of the perinatal and neonatal periods were recorded and retrospectively compared among the three groups. Infants with major congenital anomalies were excluded. The diagnosis of CLD was based on whether the infant was receiving supplemental oxygen and/or non-invasive ventilation at a postmenstrual age of 36 weeks. RESULTS: We found that, despite a median difference of 3 weeks in gestational age at birth between VLGA-IUGR and ELGA-AGA infants, neonatal mortality was 35% higher in neonates who had experienced fetal growth restriction, and that VLGA- IUGR was five times more predictive of CLD than was ELGA-AGA. These differences persisted after adjustment for confounding factors such as antenatal steroids, gender and respiratory distress syndrome. CONCLUSIONS: This study reports that VLGA-IUGR infants are at higher risk of neonatal mortality and CLD than both ELGA-AGA and VLGA-AGA infants.