Procedural pain and brain development in premature newborns

Objective: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.

Methods: Infants born very preterm (N ¼ 86; 24–32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were
analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery.

Results: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (b ¼ 0.0002, p ¼ 0.028) and reduced subcortical gray matter NAA/choline (b ¼ 0.0006, p ¼ 0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.

Interpretation: Early procedural pain in very preterm infants may contribute to impaired brain development.

Tractography-based quantitation of corticospinal tract development in premature newborns

To evaluate the impact of early brain injury and neonatal illness on corticospinal tract (CST) development in premature newborns serially studied with diffusion tensor tractography.

Prenatal alcohol exposure alters biobehavioral reactivity to pain in newborns

To examine biobehavioral responses to an acute pain event in a Cape Town, South Africa, cohort consisting of 28 Cape Colored (mixed ancestry) newborns (n = 14) heavily exposed to alcohol during pregnancy (exposed), and born to abstainers (n = 14) or light (<or = 0.5 oz absolute alcohol/d) drinkers (controls).

Morphine pharmacokinetics and pain assessment in premature newborns

To determine morphine pharmacokinetics in premature neonates varying in postconceptional age (PCA) and evaluate behavioral pain response in relationship to serum morphine concentrations.

Judging pain in newborns:facial and cry determinants

Explored the facial and cry characteristics that adults use when judging an infant's pain. Sixteen women viewed videotaped reactions of 36 newborns subjected to noninvasive thigh rubs and vitamin K injections in the course of routine care and rated discomfort. The group mean interrater reliability was high. Detailed descriptions of the infants' facial reactions and cry sounds permitted specification of the determinants of distress judgments. Several facial variables (a brow bulge, eyes squeezed shut, and deepened nasolabial fold constellation, and taut tongue) accounted for 49% of the variance in ratings of affective discomfort after controlling for ratings of discomfort during a noninvasive event. In a separate analysis not including facial activity, several cry variables (formant frequency, latency to cry) also accounted for variance (38%) in ratings. When the facial and cry variables were considered together, cry variables added little to the prediction of ratings in comparison to facial variables. Cry would seem to command attention, but facial activity, rather than cry, can account for the major variations in adults' judgments of neonatal pain.

How well do midwives use skills and knowledge in examining newborns?

Physical examination of the newborn (PEN) was established as part of postnatal care in the late 1960s. The role of discharging babies within the first 72 hours of birth was traditionally undertaken by junior doctors. Currently midwives, nurses, advanced nurse practitioners, and health visitors are being trained to undertake the PEN (NHS Screening Programmes, 2010). However, only a fraction of midwives utilize their acquired skills in clinical practice. A survey by Townsend et al (2004) showed that 2% of babies in England were examined by midwives while 83% were examined by junior doctors.This study aimed to evaluate how well midwives who undertook the PEN course between 2002 and 2005 (n = 40) at a large London University utilized the skills acquired on the course. Questionnaires with a series of open and closed questions were sent out by post followed by phone and email reminders. The eight that responded were midwives. All respondents said they were appropriately trained and felt well prepared for their role to examine babies. However, they felt they were not provided with opportunities to use the skills. Guidelines based on this extended role are available in the workplace but only a few midwives seemed to have negotiated time to implement these and may need greater managerial support for the role.

Pregnancy and newborns disorders followed by urine metabolomics

Chapter 1 introduces the scope of the work by identifying the clinically relevant prenatal disorders and presently available diagnostic methods. The methodology followed in this work is presented, along with a brief account of the principles of the analytical and statistical tools employed. A thorough description of the state of the art of metabolomics in prenatal research concludes the chapter, highlighting the merit of this novel strategy to identify robust disease biomarkers. The scarce use of maternal and newborn urine in previous reports enlightens the relevance of this work. Chapter 2 presents a description of all the experimental details involved in the work performed, comprising sampling, sample collection and preparation issues, data acquisition protocols and data analysis procedures. The proton Nuclear Magnetic Resonance (NMR) characterization of maternal urine composition in healthy pregnancies is presented in Chapter 3. The urinary metabolic profile characteristic of each pregnancy trimester was defined and a 21-metabolite signature found descriptive of the metabolic adaptations occurring throughout pregnancy. 8 metabolites were found, for the first time to our knowledge, to vary in connection to pregnancy, while known metabolic effects were confirmed. This chapter includes a study of the effects of non-fasting (used in this work) as a possible confounder. Chapter 4 describes the metabolomic study of 2nd trimester maternal urine for the diagnosis of fetal disorders and prediction of later-developing complications. This was achieved by applying a novel variable selection method developed in the context of this work. It was found that fetal malformations (FM) (and, specifically those of the central nervous system, CNS) and chromosomal disorders (CD) (and, specifically, trisomy 21, T21) are accompanied by changes in energy, amino acids, lipids and nucleotides metabolic pathways, with CD causing a further deregulation in sugars metabolism, urea cycle and/or creatinine biosynthesis. Multivariate analysis models´ validation revealed classification rates (CR) of 84% for FM (87%, CNS) and 85% for CD (94%, T21). For later-diagnosed preterm delivery (PTD), preeclampsia (PE) and intrauterine growth restriction (IUGR), it is found that urinary NMR profiles have early predictive value, with CRs ranging from 84% for PTD (11-20 gestational weeks, g.w., prior to diagnosis), 94% for PE (18-24 g.w. pre-diagnosis) and 94% for IUGR (2-22 g.w. pre-diagnosis). This chapter includes results obtained for an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) study of pre-PTD samples and correlation with NMR data. One possible marker was detected, although its identification was not possible. Chapter 5 relates to the NMR metabolomic study of gestational diabetes mellitus (GDM), establishing a potentially predictive urinary metabolic profile for GDM, 2-21 g.w. prior to diagnosis (CR 83%). Furthermore, the NMR spectrum was shown to carry information on individual phenotypes, able to predict future insulin treatment requirement (CR 94%). Chapter 6 describes results that demonstrate the impact of delivery mode (CR 88%) and gender (CR 76%) on newborn urinary profile. It was also found that newborn prematurity, respiratory depression, large for gestational age growth and malformations induce relevant metabolic perturbations (CR 82-92%), as well as maternal conditions, namely GDM (CR 82%) and maternal psychiatric disorders (CR 91%). Finally, the main conclusions of this thesis are presented in Chapter 7, highlighting the value of maternal or newborn urine metabolomics for pregnancy monitoring and disease prediction, towards the development of new early and non-invasive diagnostic methods.

Use of anti-infective drugs during pregnancy : prevalence, predictors of use and the risk of preterm birth and small-for-gestational-age newborns

Résumé: Les anti-infectieux sont parmi les médicaments les plus utilisés pendant la grossesse. Les indications pour l’utilisation de ces médicaments, telles que les infections bactériennes, figurent parmi les facteurs de risque les plus importants pour la prématurité et les enfants nés petits pour l'âge gestationnel («Small-for-gestational-age », SGA). Ces complications de la grossesse peuvent avoir des incidences sur la santé du nouveau né et sur son développement futur. Compte tenu des impacts sur la santé de la mère et de l’enfant, la prise en charge et le traitement efficace de ces infections sont impératifs. Cependant, l'utilisation des anti-infectieux, pour éviter des issues de grossesse défavorables, fait l’objet d’une controverse dans la littérature. Cette controverse est en partie liée à la qualité méthodologique discutable des études disponibles sur le sujet. Les quatre études présentées dans cette thèse ont donc pour objectif d’investiguer l’utilisation des anti-infectieux durant la grossesse ainsi que d’évaluer le risque de prématurité et de SGA après utilisation de ces médicaments en période gestationnelle. Une révision systématique de la littérature sur l’utilisation du métronidazole durant la grossesse est également présentée. Nous avons utilisé, comme source de données le Registre des Grossesses du Québec, une cohorte longitudinale conçue à partir du jumelage de trois bases de données administratives de la province du Québec (RAMQ, Med-Echo et ISQ). Le registre fournit des informations sur les prescriptions, les services pharmaceutiques et médicaux, ainsi que des donnés sur les soins d’hospitalisation de courte durée et démographiques. Les deux premières études présentées dans cette thèse ont eu pour objectif d’évaluer la prévalence, les tendances, les indications et les prédicteurs de l’utilisation des anti-infectieux dans une cohorte, extraite du registre, de 97 680 femmes enceintes. A l’aide d’un devis cas-témoins, les 2 dernières études ont mesuré l’association entre l’utilisation d’anti-infectieux durant les 2 derniers trimestres de grossesse et le risque de prématurité et de SGA, respectivement. Un cas de prématurité a été défini comme un accouchement survenu avant 37 semaines de gestation. Un cas de SGA a été défini comme l’accouchement d’un enfant dont le poids à la naissance se situe sous le 10ème percentile du poids normalisé à la naissance (compte tenu de l’âge gestationnel et du sexe du bébé). Les données ont été recueillies pour les agents systémiques oraux, ainsi que pour les classes et les agents individuels. Nos résultats ont montré que la prévalence de l’utilisation des anti-infectieux durant la grossesse était comparable à celle d’autres études déjà publiées (25%). Nous avons observé une augmentation de l’utilisation des agents plus anciens et ayant des profils d’innocuité connus. Les prédicteurs de l’usage en début de grossesse identifiés sont : avoir eu plus de deux différentes prescriptions (OR ajusté = 3,83, IC 95% : 3,3-4,3), avoir eu un diagnostic d’infection urinaire (OR= 1,50, IC 95% : 1,3-1,8) et un diagnostic d’infection respiratoire (OR= 1,40, IC 95% : 1,2-1,6). L’utilisation des macrolides a été associée à une diminution du risque de prématurité (OR =0,65, IC 95% : 0,50-0,85). En revanche, les femmes ayant été exposées au métronidazole ont vu leur risque augmenté de 80% (OR=1,81, IC 95% : 1,30-2,54). L’utilisation d’azithromycine a été associée à une diminution importante du risque chez les femmes ayant un diagnostic de rupture prématurée des membranes (OR=0,31, IC 95% : 0,10-0,93). Cependant, l'utilisation de sulfaméthoxazole-triméthoprime (SXT) a été significativement associée à une augmentation du risque de SGA (OR= 1,61, IC 95% : 1,16-2,23), tandis que celle des anti-infectieux urinaires a été associée à une diminution du risque (OR= 0,80, 95%CI : 0.65-0.97). Les conclusions de nos travaux suggèrent que l’utilisation des macrolides et des pénicillines diminuent le risque de prématurité et de SGA. Nous devons considérer l'utilisation de différents choix thérapeutiques tels que l’azithromycine, lors de la prise en charge des infections pouvant induire la prématurité et le SGA.

Tissue- specific DNA methylation profiles in newborns

Experimental and epidemiological studies demonstrate that fetal growth restriction and low birth weight enhance the risk of chronic diseases in adulthood. Derangements in tissue-specific epigenetic programming of fetal and placental tissues are a suggested mechanism of which DNA methylation is best understood. DNA methylation profiles in human tissue are mostly performed in DNA from white blood cells. The objective of this study was to assess DNA methylation profiles of IGF2 DMR and H19 in DNA derived from four tissues of the newborn. We obtained from 6 newborns DNA from fetal placental tissue (n = 5), umbilical cord CD34+ hematopoietic stem cells (HSC) and CD34- mononuclear cells (MNC) (n = 6), and umbilical cord Wharton jelly (n = 5). HCS were isolated using magnetic-activated cell separation. DNA methylation of the imprinted fetal growth genes IGF2 DMR and H19 was measured in all tissues using quantitative mass spectrometry. ANOVA testing showed tissue-specific differences in DNA methylation of IGF2 DMR (p value 0.002) and H19 (p value 0.001) mainly due to a higher methylation of IGF2 DMR in Wharton jelly (mean 0.65, sd 0.14) and a lower methylation of H19 in placental tissue (mean 0.25, sd 0.02) compared to other tissues. This study demonstrates the feasibility of the assessment of differential tissue specific DNA methylation. Although the results have to be confirmed in larger sample sizes, our approach gives opportunities to investigate epigenetic profiles as underlying mechanism of associations between pregnancy exposures and outcome, and disease risks in later life.

Implications of newborn hearing screening: counseling parents of newborns with hearing loss

This paper reviews parental reactions to their newborn newly diagnosed with a hearing loss.

The prevalence of hyperbilirubinemia as a risk ractor for hearing loss in newborns

This paper examines hyperbilirubinemia as a risk factor for hearing loss in newborns. Even though it is not a prevalent risk factor compared with other risk factors, low levels of bilirubin toxicity have been determined to have significant effects on hearing.

Potential roles and clinical utility of prebiotics in newborns, infants, and children: proceedings from a global prebiotic summit meeting, New York City, June 27-28, 2008

Initial bacterial colonization, including colonization with health-positive bacteria, such as bifidobacteria and lactobacilli, is necessary for the normal development of intestinal innate and adaptive immune defenses. The predominance of beneficial bacteria in the gut microflora of breast-fed infants is thought to be, at least in part, supported by the metabolism of the complex mixture of oligosaccharides present in human breast milk, and a more adult-type intestinal microbiota is found in formula-fed infants. Inadequate gut colonization, dysbiosis, may lead to an increased risk of infectious, allergic, and autoimmune disorders later in life. The addition of appropriate amounts of selected prebiotics to infant formulas can enhance the growth of bifidobacteria or lactobacilli in the colonic microbiota and, thereby, might produce beneficial effects. Among the substrates considered as prebiotics are the oligosaccharides inulin, fructo-oligosaccharides, galacto-oligosaccharides, and lactulose. There are some reports that such prebiotics have beneficial effects on various markers of health. For example, primary prevention trials in infants have provided promising data on prevention of infections and atopic dermatitis. Additional well-designed prospective clinical trials and mechanistic studies are needed to advance knowledge further in this promising field. (J Pediatr 2009;155:S61-70).

Non-nutritive sucking scoring system for preterm newborns

Aim: To validate a non-nutritive sucking (NNS) scoring system for oral feeding in preterm newborns (PTNB). Methods: A cohort study was carried out in two phases. In phase one of the study, 22 mastered speech-language pathologists received the protocol and procedure for a NNS scoring system to evaluate the content and presentation of the form and to define the grading scale. In phase two, six speech-language pathologists evaluated 51 PTNBs weekly, using the defined scoring system. Setting: This study was carried out in the Nursery Annex to the Maternity at the Intensive and Neonatal Pediatrics Service, Instituto da Crianca, Hospital das Clinicas, School of Medicine, University of Sao Paulo (FMUSP) during the period from May 2004 to May 2006. Participants: A total of 28 speech-language pathologist experts and 51 PTNBs. Results: In the first phase of the study, 22 speech-language pathologists selected the criteria, utilized in the NNS evaluation with 80% agreement. In the second phase of the study, the NNS evaluation was carried out on 51 PTNB, and a scoring system of 50 points was proposed, which corresponds to the smallest number of false positive and negative results regarding oral feeding ability. Conclusion: An NNS evaluation system was validated that was able to indicate when oral feeding could safely begin in PTNBs with a high level of agreement among the speech-language pathologists who have participated.

Body mass index values for newborns according to gestational age

Objective: The combination of twho anthropometric parameters has been more appropriate to assess body composition and proportions in children, with special attention to the Body Mass Index (BMI), as it relates weight and length. However the BMI values for the neonatal period have not been determined yet. This study shows the BMI for newborns at different gestational ages represented in a normal smoothed percentile curve. Methods: Retrospective study including 2,406 appropriate for gestational age newborns following the Alexander et al curve (1996) from 29 to 42 weeks of gestational age. Weight and lenght were measured following standard procedures. For the construction aof a normal smoothed percentile curve, the 3(rd) 5(th), 10(th), 25(th), 5(th), 75(th), 90(th) and 95(th) percentiles were determined and a statistical procedure based on the mathematical model ""sinosuoidal fit"" was applied to establish a curve that estimates biological growth parameters. Results: The Body Mass Index values for gestational age in all percentiles shows a steady increase up to 38 weeks, levels off up to the 40(th) week, followed by a slight decrease to the 42(nd) week in both genders. Conclusion: The results show a direct correlation between gestational age and Body Mass Index for both genders in the nine percentiles, and can provide a useful reference to assess intra-uterine proportional growth.