Untreated Infants Research Articles

Effects of surfactant treatment in late preterm infants with respiratory distress syndrome

Objective: To evaluate surfactant effectiveness for the treatment of respiratory distress syndrome (RDS) in late preterm infants.Methods: We performed a retrospective cohort study of infants born between 34+0 and 36+6 weeks of gestation admitted for respiratory failure in seven perinatal centers from January 2010 to December 2014. We evaluated changes of FiO2, PaO2 and a/APO2 in surfactant-treated patients, and the need and duration of MV, the duration of noninvasive respiratory support, stay in NICU and in hospital in surfactant-treated and untreated late preterm infants with RDS alone.Results: We studied 562 infants with RDS, 252 (45%) were treated with surfactant and 310 (55%) were not. FiO2, PaO2 and a/APO2 significantly improved after surfactant treatment. The adjusted odds ratio for the need of MV and the adjusted differences of duration of noninvasive respiratory support, and of NICU and hospital stay were not different in the surfactant and non-surfactant groups.Conclusions: Surfactant therapy was followed by a quick and persisting significant improvement of respiratory function in late preterm infants with RDS. Surfactant did not improve short-term outcomes in our population probably because other factors such as the gestational age, occurrence of complications and poor feeding play a relevant role.

Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study

ObjectiveTo compare outcomes at hospital discharge for preterm infants born before 29 weeks of gestation who had at least one episode of isolated hypotension during their first 72 hours of...

Thyroid status of iodine deficient newborn infants living in central region of Turkey: a pilot study.

Iodine deficiency (ID) during the fetal and neonatal periods can lead to neonatal hypothyroidism. This study was conducted to evaluate the effect of ID on the thyroid hormone level of newborns living in Turkey. Between 1998 and 2013, 71 newborns with a urinary iodine concentration <100 μg/L were recruited into the study. Data on thyroid volume, free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroglobulin (Tg) were collected from all newborns, and on breast milk iodine from their mothers. Infants who were classified as having congenital hypothyroidism (TSH >40 mU/L and fT4 <8.5 pmol/L) were treated with levothyroxine (n=26, T group), while the remaining infants remained untreated (n=45, UT group). Thyroid hormones were subsequently measured 7-14 days later in a sub-sample of both treated and untreated infants. The average values at the time of admission were as follows [median (min-max)]. fT3: 5.0 (2.8-7.1) pmol/L, fT4: 7.7 (0.13-19.1) pmol/L, TSH: 75 (14-426) mU/L, Tg: 464 (226-1100) ng/mL, urinary iodine concentration (UIC): 30 (0-61) μg/L, breast milk iodine levels: 21 (10-150) μg/L, thyroid ultrasound (USG): 1.10 (0.24-1.95) mL for the T group; and fT3: 5.7 (1.7-12.7) pmol/L, fT4: 16.2 (9.9-33.5) pmol/L, TSH: 5.4 (0.63-41.8) mU/L, Tg: 171 (15-2124) ng/mL, UIC: 39 (0-90) μg/L, breast milk iodine levels: 47 (10-120) μg/L, thyroid USG: 0.75 (0.35-1.72) mL for the UT group. A significant difference was found between groups in respect to fT3, fT4, TSH and Tg levels. No significant difference in thyroid ultrasonography, UIC, and breast milk iodine levels was found between the two groups. The Tg levels of 50 out of 71 patients were measured, 40 (80%) of whom had Tg levels above the normal range (101 ng/mL). In our country, despite the use of iodized salt, congenital hypothyroidism due to ID remains a problem. The Tg level of newborns can be used as a good indicator of ID.

Effectiveness of Granulocyte Colony-Stimulating Factor in Hospitalized Infants with Neutropenia.

Objective The objective of this study was to determine the time to hematologic recovery and the incidence of secondary sepsis and mortality among neutropenic infants treated or not treated with granulocyte colony-stimulating factor (G-CSF). Study Design We identified all neutropenic infants discharged from 348 neonatal intensive care units from 1997 to 2012. Neutropenia was defined as an absolute neutrophil count ≤ 1,500/µL for ≥ 1 day during the first 120 days of life. Incidence of secondary sepsis and mortality and number of days required to reach an absolute neutrophil count > 1,500/µL for infants exposed to G-CSF were compared with those of unexposed infants. Results We identified 30,705 neutropenic infants, including 2,142 infants (7%) treated with G-CSF. Treated infants had a shorter adjusted time to hematologic recovery (hazard ratio: 1.36, 95% confidence interval [CI]: 1.30-1.44) and higher adjusted odds of secondary sepsis (odds ratio [OR]: 1.50, 95% CI: 1.20-1.87), death (OR: 1.33, 95% CI: 1.05-1.68), and the combined outcome of sepsis or death (OR: 1.41, 95% CI: 1.19-1.67) at day 14 compared with untreated infants. These differences persisted at day 28. Conclusion G-CSF treatment decreased the time to hematologic recovery but was associated with increased odds of secondary sepsis and mortality in neutropenic infants. G-CSF should not routinely be used for infants with neutropenia.

Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy

Infantile hemangiomas involute to some extent, but they often leave sequelae that may cause disfigurement. Factors determining the risk of permanent sequelae after regression are of crucial importance in treatment decision making. To describe the sequelae left by infantile hemangiomas after natural involution and to identify clinical characteristics that could predict the most severe or a particular type of sequelae. Multicentric retrospective cohort study of images from 187 infantile hemangiomas that had not received systemic treatment and had follow-up pictures until regression that were selected from photographic files taken between 2003 and 2013 at 4 university hospitals with large vascular clinics in 3 different countries. Outcome measures were the type of sequelae classified as residual telangiectasia, anetodermal skin, redundant skin, persistent superficial component, and the degree of sequelae ranging from 1 to 4. A total of 184 hemangiomas were included. The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%). The average age at which hemangioma completed involution was 3.5 years. Superficial and deep hemangiomas left significantly fewer sequelae than combined hemangiomas (Mann-Whitney; superficial vs deep, OR, 1.6; 95% CI, 0.6-3.8; P = .81; superficial vs combined, OR, 3.3; 95% CI, 1.7-6.3; P < .001; deep vs combined, OR, 2.1; 95% CI, 0.9-5.1; P < .001). Hemangiomas with a step or abrupt border of the superficial component left more severe sequelae than those with a smooth border (χ2,OR, 3.4; 95% CI, 1.8-6.6; P < .001). Superficial hemangiomas with a cobblestone appearance or rough surface left more severe sequelae than those with a smooth surface (Kruskal-Wallis; α, 0.05; P < .001). Using multivariate analysis, combined hemangiomas with a superficial component and a step border were associated with more sequelae. In this retrospective study of sequelae in a large cohort of untreated infants, we quantified the prevalence of permanent scarring and identified clinical features predictive of permanent sequelae. Our observations provide useful information at a time when the treatment paradigm for hemangiomas has changed. Such knowledge may help primary care physicians predict the risk of sequelae and identify high-risk lesions to implement early treatment.

Point-of-Care Virologic Testing to Improve Outcomes of HIV-Infected Children in Zambia: A Clinical Trial Protocol.

Introduction:In the absence of early infant diagnosis (EID) and immediate antiretroviral therapy (ART), some 50% of untreated HIV-infected infants die before age 2. Conventional EID requires sophisticated instruments that are typically placed in centralized or reference laboratories. In low-resource settings, centralized systems often lead to result turnaround times of several months, long delays in diagnosis, and adverse outcomes for HIV-infected children. Our clinical trial tests the effectiveness of a new point-of-care (POC) diagnostic technology to identify HIV-infected infants and start providing them life-saving ART as soon as possible.Methods and Design:The study uses a randomized, controlled design to test whether the Alere q platform for HIV DNA polymerase chain reaction (PCR) testing improves outcomes of HIV-infected children in Zambia. We aim to enroll 2867 HIV-exposed infants aged 4–12 weeks and to follow those who are HIV infected for 12 months as they receive HIV care at 6 public health facilities in Lusaka. The trial's primary endpoint is the proportion of HIV-infected infants in each study arm who start ART and remain alive, in care, and virally suppressed 12 months after their diagnostic blood draw.Discussion:Our trial will provide evidence for the incremental benefit of implementing a POC EID strategy in low-resource settings where only off-site PCR services are currently available. The results will be useful in guiding future decisions regarding investments in POC virologic testing as part of overall pediatric AIDS mitigation strategies in sub-Saharan Africa.Trial Registration:clinicaltrials.gov NCT02682810.

The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats.

Recently, scientific interest in the brain–gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early-onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2–14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups’ or dams’ anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes.

Sonographic Assessment of Hip Swaddling Techniques in Infants With and Without DDH.

The purpose of this single-examination pilot study was to confirm the ability to perform hip sonography while swaddled and to ascertain whether the various swaddling techniques influenced hip position and dynamics. Dynamic sonography was used to evaluate 30 infants in both swaddled and unswaddled positions who were being seen in clinic for suspected or documented developmental dysplasia of the hip. A "treatment group" of 16 infants (32 hips) treated in a Pavlik harness and a "nontreatment group" of 14 untreated infants (28 hips) were studied.Criteria for comparing sonographic results between swaddled and unswaddled hip positions included femoral head position, instability, and range-of-motion restriction. Tight swaddling with a blanket was applied in 11 "nontreatment group" cases (20 hips; in 2 cases, only 1 hip studied) and produced limited flexion and abduction. One unstable left hip dislocated when tightly swaddled. Safe swaddling technique in 12 cases (24 hips) showed no limitation of flexion and abduction of the legs and no change in stability by sonography. Commercial swaddling products appeared to mildly restrict leg motion in 14 hips, but there was no change in hip position in the "nontreatment group." However, the commercial swaddling products changed the hip position in 3 Pavlik harness cases. Swaddling techniques that allow a free range of leg motion may not affect hip stability in normal infants or those being treated with Pavlik harness. Swaddling with restricted leg motion increases potential for hip instability. Tight swaddling dislocated 1 unstable hip, and commercial swaddling products judged to apply only mild restriction of leg motion negatively impacted 3 cases being treated for developmental dysplasia of the hip with Pavlik harness. On the basis of this pilot study, we advise caution when swaddling infants, especially with techniques that restrict leg motion. Further study of the long-term effects of swaddling is warranted. Level II.

Safety of lipid emulsion in very low-birthweight infants according to cytokine level.

The aim of this study was to verify whether lipid emulsion treatment aggravates infection and inflammation in very low-birthweight (VLBW) infants. Very low-birthweight (<1500 g) infants born at <32 weeks gestational age between October 2013 and October 2014 at Dokkyo Medical University Hospital (Mibu, Tochigi, Japan) were treated with or without i.v. nutrition with a lipid emulsion. Infants were excluded who had congenital abnormalities, could not receive i.v. nutrition because of poor general condition, or on physician decision. Lipid emulsion with purified soybean oil was initiated at 0.5 g/kg/day on postnatal day 1. The dose was increased to 1 g/kg/day, and then to 1.5 g/kg/day (maximum dose). Blood tests were performed before (day 1) and after (day 8) initiation of lipid emulsion treatment. Interleukin (IL)-6, IL-8, monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and insulin were measured. Changes in respiratory condition, amount of oxygen used, and phototherapy duration were investigated. A total of 17 treated and 15 untreated VLBW infants were enrolled. IL-6, IL-8, MCP-1, TNF-α, CRP, T-Bil, D-Bil and insulin on days 1 and 8; respirator or surfactant use; amount of oxygen used; and phototherapy duration were not significantly different between the two groups. Lipid emulsion treatment did not increase inflammatory cytokine levels or aggravate respiratory disorders. Lipid emulsions, if proven safe, could be used to treat VLBW infants soon after birth, which may prevent extrauterine growth restriction and improve intellectual development prognosis.

Advances and hope for perinatal HIV remission and cure in children and adolescents.

The known timing of HIV infection in perinatal transmission, combined with the capacity for early antiretroviral therapy (ART) initiation and immune reconstitution, can provide unique insights into HIV persistence. The scientific basis for a pediatric-specific research agenda aimed at HIV remission and cure is discussed. Accumulating evidence supports a favorable biomarker profile for immunotherapeutic interventions in early treated, perinatally infected individuals. HIV DNA concentrations in infected cells of early treated infants decrease over the first few years of life and, after more than 10 years of ART, the overwhelming majority of noninduced proviral genomes are replication-deficient. With early ART initiation, approximately half of perinatally infected individuals become seronegative. Studies of untreated infants and vaccine trials indicate that infected infants can generate HIV-specific humoral responses. Taken together, this evidence suggests that early treatment results in low levels of replication-competent provirus, an absence of HIV-specific immunity, and the capacity to generate immune responses to potential immunotherapeutic interventions. Perinatally HIV-infected individuals require lifelong ART because of the prompt establishment of viral latency in long-lived resting memory CD4 T cells that rekindle viremia upon treatment cessation. However, intense research efforts are ongoing to perturb HIV latency toward reservoir clearance for virologic remission and cure in which perinatally infected individuals can discontinue ART.

Normalization of brain morphology after surgery in sagittal craniosynostosis.

OBJECT Nonsyndromic craniosynostosis (NSC) is associated with significant learning disability later in life. Surgical reconstruction is typically performed before 1 year of age to correct the cranial vault morphology and to allow for normalized brain growth with the goal of improving cognitive function. Yet, no studies have assessed to what extent normalized brain growth is actually achieved. Recent advances in MRI have allowed for automated methods of objectively assessing subtle and pronounced brain morphological differences. The authors used one such technique, deformation-based morphometry (DBM) Jacobian mapping, to determine how previously treated adolescents with sagittal NSC (sNSC) significantly differ in brain anatomy compared with healthy matched controls up to 11.5 years after surgery. METHODS Eight adolescent patients with sNSC, previously treated via whole-vault cranioplasty at a mean age of 7 months, and 8 age- and IQ-matched control subjects without craniosynostosis (mean age for both groups = 12.3 years), underwent functional 3-T MRI. Statistically significant group tissue-volume differences were assessed using DBM, a whole-brain technique that estimates morphological differences between 2 groups at each voxel (p < 0.01). Group-wise Jacobian volume maps were generated using a spacing of 1.5 mm and a resolution of 1.05 × 1.05 × 1.05 mm(3). RESULTS There were no significant areas of volume reduction or expansion in any brain areas in adolescents with sNSC compared with controls at a significance level of p < 0.01. At the more liberal threshold of p < 0.05, two areas of brain expansion extending anteroposteriorly in the right temporooccipital and left frontoparietal regions appeared in patients with sNSC compared with controls. CONCLUSIONS Compared with previous reports on untreated infants with sNSC, adolescents with sNSC in this cohort had few areas of brain dysmorphology many years after surgery. This result suggests that comprehensive cranioplasty performed at an early age offers substantial brain normalization by adolescence, but also that some effects of vault constriction may still persist after treatment. Specifically, few areas of expansion in frontoparietal and temporooccipital regions may persist. Overall, data from this small cohort support the primary goal of surgery in allowing for more normalized brain growth. Larger samples, and correlating degree of normalization with cognitive performance in NSC, are warranted.

Diagnosis of 21-hydroxylase deficiency by urinary metabolite ratios using gas chromatography–mass spectrometry analysis: Reference values for neonates and infants

One major issue of newborn screening programs for 21-hydroxylase deficiency (21OHD) is the high rate of false-positive results, especially in preterm neonates. Urinary steroid metabolite analysis using gas chromatography–mass spectrometry (GC–MS) is suitable as a confirmatory diagnostic tool.The objective of this study was to analyze retrospectively diagnostic metabolite ratios in neonates and infants with and without 21OHD using GC–MS with emphasis on glucocorticoid metabolism, and to develop reference values for the steroid metabolite ratios for the diagnosis of 21OHD.We retrospectively analyzed urinary steroid hormone metabolites determined by GC–MS of 95 untreated neonates and infants with 21OHD (1–148 days), and 261 neonates and infants (100 preterms) without 21OHD (0–217 days).Metabolites of 17α-hydroxyprogesterone showed specificities below 98%, whereas the 21-deoxycortisol metabolite pregnanetriolone clearly separated 21OHD from non-21OHD subjects. The best diagnostic ratio for 21OHD was pregnanetriolone to 6α-hydroxy-tetrahydrocortisone. The lowest value of this ratio in the 21OHD group (0.47) was at least eight times higher than the highest values in the non-21OHD group (0.055).We have given appropriate reference values for steroid metabolite ratios in the largest 21OHD cohort so far described. Consideration of glucocorticoid metabolism, especially the use of typical neonatal 6α-hydroxylates metabolites, leads to improvement of diagnostic metabolite ratios.

Effect of vitamin A supplementation on the urinary retinol excretion in very low birth weight infants.

Despite high-dose vitamin A supplementation of very low birth weight infants (VLBW, <1500 g), their vitamin A status does not improve substantially. Unknown is the impact of urinary retinol excretion on the serum retinol concentration in these infants. Therefore, the effect of high-dose vitamin A supplementation on the urinary vitamin A excretion in VLBW infants was investigated. Sixty-three VLBW infants were treated with vitamin A (5000 IU intramuscular, 3 times/week for 4 weeks); 38 untreated infants were classified as control group. On days 3 and 28 of life, retinol, retinol-binding protein 4 (RBP4), glomerular filtration rate, proteinuria, and Tamm-Horsfall protein were quantified in urine. On day 3 of life, substantial retinol and RBP4 losses were found in both groups, which significantly decreased until day 28. Notwithstanding, the retinol excretion was higher (P < 0.01) under vitamin A supplementation as compared to infants of the control group. On day 28 of life, the urinary retinol concentrations were predictive for serum retinol concentrations in the vitamin A treated (P < 0.01), but not in the control group (P = 0.570). High urinary retinol excretion may limit the vitamin A supplementation efficacy in VLBW infants. Advanced age and thus postnatal kidney maturation seems to be an important contributor in the prevention of urinary retinol losses.

Redox cycling and generation of reactive oxygen species in commercial infant formulas

Three nationally prominent commercial powdered infant formulas generated hydrogen peroxide, ranging from 10.46 to 11.62μM, when prepared according to the manufacturer’s instructions. Treating infant formulas with the chelating agent diethylene triamine pentaacetic acid (DTPA) significantly reduced H2O2 generation. In contrast, the addition of disodium ethylenediaminetetraacetic acid (EDTA) elevated the level of H2O2 generated in the same infant formulas by approximately 3- to 4-fold above the untreated infant formulas. The infant formulas contained ascorbate radicals ranging from about 138nM to 40nM. Treatment with catalase reduced the ascorbate radical contents by as much as 67%. Treatment with DTPA further reduced ascorbate radical signals to below quantifiable levels in most samples, further implicating the involvement of transition metal redox cycling in reactive oxygen species (ROS) formation. Supportive evidence of the generation of ROS is provided using luminol-enhanced luminescence (LEL) in both model mixtures of ascorbic acid and in commercial infant formulas.

Examining the nature and directionality of the relationship between children's anxiety symptoms and the immunoendocrine systems

Background: Preterm birth is strongly associated with mortality, morbidity and lifetime difficulties including neurodevelopmental deficits. Immaturity of the lungs at birth is a major underlying cause, thus antenatal corticosteroid therapy (ACT) is administered to pregnant women in cases of threatened preterm birth to accelerate fetal lung development in hope of lessening infant mortality and morbidity. However, ACT has become controversial due to potential side-effects of exposure to excessive corticoids for the fetus. Objective: To study the associations between antenatal exposure to corticosteroids and infant size at birth. Design, setting, and participants: Population-based cohort study of women with live singleton births in Finland from 2006 through 2010. Maternal, pregnancy, and obstetric data came from the nationwide Finnish Medical Birth Register. Methods: Two analytic strategies were compared. First, traditional multiple regression analysis was employed to test the associationsadjusted forpotential confounders. Second,propensity scorematching (PSM)was used to take into account pre-treatment factors that could influence treatment allocation and outcome. Because PSM analysis closely matches participants on treatment characteristics results are akin to a randomized control trial although observational data are used. Results: We obtained data for 278508 women and their liveborn singletons (4887 treated and 273621 untreated). Results of adjusted multiple regression analyses and PSM converged. There were no differences by treatment in birth size for infants born very early (gestational age 24-29 weeks). Preterm infants born between 30 and 37 weeks exposed to ACT were smaller than untreated infants of the samegestational age in all respects: 518g lighter birth weight, 2.68 cm shorter birth length, 0.12 lower ponderal index, and 1.77 cm smaller head circumference, according to PSM.Deficits were also statistically significant among term born infants (gestational weeks 38-41) though differences were of lower magnitude. Post-term infants were of similar size regardless of ACT exposure. Conclusions and relevance: We were able to capitalize on the clinical practice of ACT during pregnancy to test whether synthetic glucocorticoids impact on the growth potential of the developing fetus. The results showed that infantswere smaller at birth and that head circumference, indicative of brain volume,was compromised. These results lend support to the hypothesis that prenatal exposure to excessive cortisol affects infant size and neurodevelopment.

Neonatal abstinence syndrome: Historical perspective, current focus, future directions

BackgroundNeonatal abstinence syndrome (NAS) occurs following prenatal opioid exposure. It is characterized by signs and symptoms indicating central nervous system hyperirritability and autonomic nervous system, gastrointestinal tract, and respiratory system dysfunction. ObjectiveThis article: (1) briefly reviews NAS history, including initial identification, assessment, and treatment efforts; (2) summarizes the current status of and current issues surrounding recent NAS assessment and treatment, and (3) details future directions in NAS conceptualization, measurement, and treatment. ResultsMortality rate estimates in neonates treated for NAS exceeded 33%, and surpassed 90% for un-treated infants during the late-1800s until the mid-1900s. The focus of both assessment and treatment over the past 50years is predominantly due to two forces. First, methadone pharmacotherapy for “heroin addiction” led to women in methadone maintenance programs who were, or became pregnant. The second was defining NAS and developing a measure of neonatal withdrawal, the Neonatal Abstinence Scoring System (NASS). Various NAS treatment protocols were based on the NASS as well as other NAS measures. ConclusionsFuture research must focus on psychometrically sound screening and assessment measures of neonatal opioid withdrawal for premature, term and older infants, measuring and treating possible withdrawal from non-opioids, particularly benzodiazepines, integrated non-pharmacological treatment of NAS, weight-based versus symptom-based treatment of NAS, and second-line treatment for NAS.

Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies.

ObjectivesThe objectives of this study were to summarize antiretroviral drug concentrations in breast milk (BM) and exposure of breast-fed infants.MethodsThis was a systematic review of pharmacokinetic studies of HIV-positive women taking antiretrovirals that measured drugs in BM. The quality of pharmacokinetic and laboratory methods was assessed using pre-defined criteria. Pooled ratios and 95% CIs were calculated using the generalized inverse variance method and heterogeneity was estimated by the I2 statistic. PubMed Central, SCOPUS and LactMed databases were searched. No date or language restrictions were applied. Searches were conducted up to 10 November 2014. Clinical relevance was estimated by comparing ingested dose with the recommended therapeutic dose for each drug.ResultsTwenty-four studies were included. There was substantial variability in the clinical and laboratory methods used and in reported results. Relative to maternal plasma (MP), NRTIs accumulate in BM, with BM : MP ratios (95% CI estimates) from 0.89 to 1.21 (14 studies, 1159 paired BM and MP samples). NNRTI estimates were from 0.71 to 0.94 (17 studies, 965 paired samples) and PI estimates were from 0.17 to 0.21 (8 studies, 477 paired samples). Relative to the recommended paediatric doses, a breast-fed infant may ingest 8.4% (95% CI 1.9–15.0), 12.5% (95% CI 2.6–22.3) and 1.1% (95% CI 0–3.6) of lamivudine, nevirapine and efavirenz, respectively, via BM.ConclusionsTransfer to untreated infants appears quantitatively important for some NRTIs and NNRTIs. The pharmacokinetic methods varied widely and we propose standards for the design, analysis and reporting of future pharmacokinetic studies of drug transfer during breastfeeding.

Infantile hepatic hemangioendothelioma presenting as early heart failure: An autopsy case report

Infantile hepatic hemangioendothelioma (IHHE) is the most common type of hepatic vascular tumor in infancy, but is rarely reported because of the low incidence estimated to be about 1/20,000. We report an autopsy case of IHHE in a 20-day-old female who came with an initial manifestation of abdominal distension and congestive heart failure (CHF). Symptoms of cardiac decompensation gradually worsened in spite of treatment and child died within 2 days. On autopsy, grossly enlarged liver showed microscopy of large ecstatic vascular channels lined by single layer of plump endothelial cells and diagnosis was given as Type I IHHE. CHF is common complication due to arteriovenous shunts within the tumor and contributes to high morbidity and mortality in up to 70% of untreated infants with median age of presentation of 1-month. Therefore, if symptoms develop, aggressive treatments are warranted.

Exome Sequencing Identifies Pxdn and DSP As Recurrently Mutated Genes in Infant ALL Patients Carrying a MLL-AF4 Translocation

Background and purpose: Acute lymphoblastic leukemia (ALL) in infants (<1 year of age) carrying MLL translocations represent a highly aggressive subtype of leukemia with an exceedingly poor prognosis. Although MLL rearrangements have been considered to be causative for this type of leukemia, recent studies using mouse models suggest that the expression of chimeric MLL fusion genes alone may not be sufficient to induce leukemia. In an attempt to identify additional mutations that synergize with MLLfusion genes in driving leukemogenesis, we performed exome-sequencing in primary infant ALL patient samples (n=13) carrying the t(4;11)-translocation, giving rise to the MLL-AF4 fusion protein.Materials and Methods: Bone marrow or peripheral blood samples from untreated infants diagnosed with t(4;11)+ ALL were collected at our laboratory as part of the international collaborative INTERFANT treatment protocols. Genomic DNA was extracted from ~5×106leukemic cells. Exome capture has been performed using the Sure Select Human All Exon v2 kit (Agilent Technologies). The samples were prepped for sequencing according to the TruSeq v3 protocol (Illumina) prior to sequencing on the Hiseq2000 with a v3 flowcell for 100bp = 7bp index (Illumina). The reads have been aligned against the human reference genome build 19 (hg19) using a BWA and NARWHAL based pipeline. Sequential filtering selected for single nucleotide variations (SNVs) in canonical splice sites, insertions/deletions (indels) providing frameshifts, indels involving regions conserved between species (phyloP >3), nonsense mutations and nonsynonymous missense mutations involving regions conserved between species. All known annotated single nucleotide polymorphisms according to dbSNP build 138 and an in-house database of 1354 sequenced exomes were excluded. Recurrent mutations were validated by Sanger sequencing on an extended infant ALL patient cohort (n=122).Results: The sequenced exomes had an average coverage depth of 102.5 reads per region or 109 per base. Exome sequencing revealed that, after filtering, t(4;11)+ infant ALL patients on average carried 71 variants (range 58-98, including rare germline variants and somatic mutations). To identify recurrent mutations we selected 23 genes in which two or more patients carried a mutation for further validation by Sanger sequencing. Although all 23 genes were successfully validated, no additional patients carrying these mutations were found. However, recurrent secondary mutations within the same functional region as the initial mutations were found in two genes: PXDN and DSP. The average incidences of the PXDN and DSP mutations amongst MLL-rearranged infant ALL patients were 32% and 20%, respectively. Interestingly, MLL-rearranged infant ALL patients carrying a PXDN mutation had a significantly (p=0.013) better prognosis compared with patients not carrying a PXDNmutation, with mean EFS rates of 6.4 vs. 3.2 years, respectively. Both gene products are involved in intracellular interactions, desmosome formation, extracellular matrix consolidation and phagocytosis and no prior associations with ALL have been made before.Conclusion: We identified 23 genes with two or more mutations in our initial exome sequencing cohort. None of these mutations were found in additional patients in our validation cohort. Despite an average of 71 variations per patient, no recurrent mutations were identified and our study provides evidence supporting previous observations that infant ALL has one of the lowest mutation rates observed in human cancer. However, we identified additional mutations within the same functional region as the initial mutation in DSP and PXDN. Interestingly, PXDN mutations show an association with a favorable prognosis in MLL-R patients. DisclosuresNo relevant conflicts of interest to declare.

Nonsynostotic Cranial Deformity: A Six-Month Matched-Pair Photogrammetric Comparison of Treated and Untreated Infants

Objective : To photogrammetrically objectify changes in nonsynostotic craniofacial deformity in orthotically treated versus untreated infants. Design : A statistical retrospective pairwise comparison of two respective three-dimensional (3D) photo scans of 80 children performed in a 6-month time lag. Patients : Two comparable samples of children (40 treated, 40 untreated) with nonsynostotic cranial deformity. Interventions : Respective 3D photo scans were matched using Cranioform Analytics 4.0 software. Main Outcome Measures : Median change of 30° Cranial Vault Asymmetry Index (CVAI), modified CVAI (CVAImod), Cranial Index (CI), and posterior symmetry ratio (PSR). Results : We found an improvement in Δ30° CVAI by 3.3% (treated) and by 1.31% (untreated), respectively. CVAImod improved by 3.46% in the treated group and by 1.55% in the untreated group. CI improved by 4.41% in the treated group and by 3.68% in the untreated group, and PSR improved by 0.71 in the treated group and 0.49 in the untreated group. Although improvement of cranial asymmetry was higher in those children treated with an individual molding orthosis, we could not document a statistically significant difference between the two groups. Conclusions : Helmet therapy may be less appropriate for the correction of brachycephaly than for cranial asymmetry. Nonsynostotic cranial deformity shows some spontaneous correction. Photogrammetry presents an accurate method to objectify craniofacial changes in early infancy.