In USA more than 12.5% of all infants are born preterm. Approximately 75% of all perinatal deaths occur among these preterm infants. Preterm infants are frequently very low in birth weight (VLBW) and receive multiple red blood cell (RBC) transfusions. These transfusions pose increased risk of infections and other complications. Since erythropoietin (EPO) stimulates RBC production, EPO treatment of VLBW infants has received attention as a modality for reducing transfusions in this group. The overall hypothesis of this work is that treatment optimization of EPO of anemia in preterm infants requires a comprehensive knowledge of the behavior of RBC and the pharmacokinetic/pharmacodynamics (PK/PD) relationship between EPO and erythropoiesis. Under that overall hypothesis, the specific aims were: 1) To describe erythropoiesis dynamics in preterm infants, 2) To determine and explain the variability in the response to EPO in preterm infants, 3) To evaluate newborn sheep as an experimental model for erythropoiesis in preterm infants, 4) To test the hypothesis that RBC lifespan is shortened under acute hypoxic stress conditions, 5) To test the hypothesis that EPO receptor (EPOR) pool size increases under hypoxic stress conditions and the change in EPOR pool size can be predicted using EPO clearance measurements, 6) To describe the effect of EPOR pool size changes on erythropoiesis kinetics. A model that describes erythropoiesis dynamics in preterm infants as a function of the plasma EPO concentration is presented in Chapter 2. In Chapter 3, several covariates are tested for their ability to identify infants with good EPO responsiveness. The lamb is also tested as an animal model for the erythropoiesis in preterm infants (Chapter 4). In Chapters 5-7, the effect of hypoxic stress conditions on RBC survival was explored defining the relation between the efficacy of EPO and survival of RBC produced as a result of EPO administration. RBC lifespan measurement methods are reviewed in Chapter 5. In Chapter 6, a new methodology for the measurement of RBC lifespan under stress conditions is developed. This new methodology is applied in Chapter 7 to explore the effect of hypoxic stress conditions on the survival of RBC. The study presented in Chapter 8 is undertaken to investigate changes in both EPOR pool size and EPO clearance under hypoxic conditions. An erythropoiesis model that accounts for change in the EPOR pool size under stress conditions is presented in Chapter 9. Analysis of erythropoiesis dynamics in preterm infants demonstrated that a three fold increase in the amount of RBC produced by preterm infants is possible by EPO administration. This emphasizes the potential of using EPO for the management of anemia in preterm infants. Covariate screening identified gestational age as a potential marker for the responsiveness to EPO treatment. PD analysis results in lambs demonstrated similarities between lambs and preterm infants in different erythropoietic characteristics such as sensitivity to EPO in producing RBC, Hb production rate before birth and blood volume. Survival analysis demonstrated that RBC lifespan is not shortened under acute hypoxic conditions Analysis of EPOR mRNA level demonstrated an up regulation of EPOR level under stress conditions accompanied by a parallel increase in EPO clearance. EPOR up regulation under stress conditions level was incorporated in a PD model presented in Chapter 9. The developed model provides a framework for optimizing EPO dosing. Accordingly, an optimal dosing strategy should in general maximize the interaction between EPO and EPOR. Specifically, EPO should be administered when the number of EPOR are close to maximally up-regulated.

Orientador: Eliane Chaves Jorge / Resumo: Introdução: A retinopatia da prematuridade (ROP) é uma doença vaso proliferativa multifatorial e uma das principais causas de cegueira infantil no mundo. O exame oftalmológico seriado identifica a forma grave da doença, porém pode causar estresse e instabilidade cardiorrespiratória nos neonatos prematuros. O algoritmo ROPScore, aferido na sexta semana de vida é efetivo em predizer o risco de ROP e diminuir o número de exames necessários para o diagnóstico. No entanto, nos casos em que a doença grave é precoce ou se desenvolve em neonatos mais maduros, o ROPScore seria mais efetivo se aferido antes da sexta semana de vida. Objetivo: avaliar a acurácia do ROPScore aferido na segunda semana de vida quando comparada com a da sexta semana. Métodos: Realizou-se um estudo coorte prospectivo de neonatos pré-termos com peso ao nascimento (PN) ≤1500 g e / ou idade gestacional (IG) ≤ 32 semanas. O ROPScore foi aplicado na 2ª e na 6ª semanas de vida. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade, especificidade e seus valores preditivos positivos (VPP) e negativos (VPN) para o desenvolvimento de ROP em qualquer estágio (RQE) e ROP grave (RG). Resultados: Dos 282 RNPT, 40 (14,2%) desenvolveram ROP e 27 (9,5%) a sua forma grave. A sensibilidade do ROPScore na 2ª semana para prever ROP em qualquer estadiamento foi de 92,5% e de 92,8% na ROP grave. Na 6ª semana foi de 90% e 92,6% respectivamente. O VPN foi alto tanto na 2ª (99%) como na 6ª (98%) semanas, pa... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Retinopathy of prematurity (ROP) is a multifactorial proliferative vessel disease and one of the leading causes of childhood blindness in the world. Serial ophthalmic examination identifies the severe form of the disease but may cause cardiorespiratory stress and instability in preterm infants. The ROPScore algorithm, measured in the sixth week of life, is effective in predicting ROP risk and decreasing the number of tests required for diagnosis. However, in cases where the severe disease is early or develops in more mature neonates, ROPScore would be more effective if measured before the sixth week of life. Objective: to evaluate the accuracy of ROPScore measured in the second week of life when compared to the sixth week. Methods: A prospective cohort study of preterm newborns with birth weight (BW) ≤1500 g and/or gestational age (GA) ≤ 32 weeks was performed. ROPScore was applied in the 2nd and 6th weeks of life. ROC curves were used to determine the best values of sensitivity, specificity and positive predictive values (PPV) and negative predictive value (NPV) for the development of ROP at any stage (RQE) and severe ROP (RG). Results: Of the 282 preterms, 40 (14.2%) developed ROP and 27 (9.5%) developed their severe form. The sensitivity of ROPScore at 2nd week to predict ROP at any stage was 92.5% and 92.8% at ROP. In the 6th week, it was 90% and 92.6% respectively. The NPV was high in both the second (99%) and the sixth (98%) weeks, for ROP in any stage and s... (Complete abstract click electronic access below) / Mestre

Background: Improved neonatal care has resulted in an increasing population of surviving infants. Neonatal morbidity in preterm infants is, however, high, and retinopathy of prematurity (ROP) is one of the major neonatal morbidities. Observations have suggested that ROP might have a different course in extremely preterm compared to more mature infants. Aims: To study the incidence, natural history and treatment of the disease, and the implications regarding screening recommendations for the population of extremely preterm infants. Methods: A national, population-based study of neonatal morbidity in infants born before 27 gestational weeks was performed in Sweden during 2004 to 2007. ROP screening started in the 5th postnatal week and continued until the retina was completely vascularized. Results: Of the 506 infants surviving until the first ROP examination, 73% developed ROP; 38% mild ROP and 35% severe ROP. Ninety-nine infants (20%) were treated. A log-linear relationship was found between severe ROP and gestational age (GA) at birth, and the risk of ROP was reduced by 50% for each week of increase in GA at birth (Paper I). Postmenstrual age (PMA) at onset of ROP was significantly related to GA at birth, as was the site of onset of ROP. ROP had a predilection to start in the nasal retina in the most immature infants. There were significant relations between PMA at onset of ROP and severity of ROP as well as between the site of onset of ROP and severe ROP (Paper III). The most immature infants had a higher risk of reaching treatment criteria for ROP, a higher risk of progression from ROP 3 to treatment criteria, and they reached these criteria at an earlier PMA than the less immature infants (Paper II). According to our results, the first examination can be postponed until a PMA of 31 weeks in infants born before 27 weeks of gestation, since onset of ROP 3 did not occur before this age, and criteria for treatment were not reached before 32 weeks. The majority of infants (75%) were treated during a limited period, i.e. before a PMA of 39 weeks (Paper IV).

Although very low birth weight preterm (VLBW) infants with grade 3,4 retinopathy of prematurity (ROP) are at high risk for unfavorable visual outcomes, the middle school vision motor integration (VMI) skills and cognitive outcome scores of these children remain largely unknown. Data for 323 very VLBW survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial (BW 600 1250 g) were analyzed to test the hypothesis that grades 3, 4 ROP would be an important predictor of cognitive and VMI skills. 3 subgroups were evaluated: ROP negative (N = 163), ROP grades 1,2 (N = 137) and ROP grades 3,4 (N = 23) were evaluated prospectively at 12 years of age with a neurocognitive battery. High-resolution volumetric MRI scans were quantified for 40 of the study subjects, and occipital brain volumes were correlated with Beery VMI scores. Children with ROP 3-4 had [arrow up - increased] vision impairment and lower test scores. Whole brain volumes were significantly less for children with any grade of ROP (p = 0.02), occipital white matter volumes tended to be less for the same study subjects (p = 0.08) and both total occipital brain volumes and occipital white matter volumes were significantly correlated with Beery VMI scores (r=0.610, p = 0.009 and r = 0.652, p =0.005, respectively). Prematurely-born children with a history of grade 3-4 ROP continue to have [arrow up - increased] vision impairment, special needs and lower performance on cognitive, language and visual motor integration scores at age 12 years. Both whole occipital brain volumes and occipital white matter volumes were predictive of VMI scores for children with ROP. (supp by NS 27116)

This retrospective cohort study examined risk factors associated with RSV-associated hospitalization (RSV-H) among infants born 32 to 35 weeks gestational age in Nova Scotia. Results were used to develop a clinical instrument (RSV-H scoring tool) that would discriminate between infants at high, moderate and low risk for RSV-H. Identifying the highest-risk infants, (using baseline information to predict RSV-H in the first year of life), would help target cost effective prophylaxis by Palivizumab (Pz), an expensive RSV-specific monoclonal antibody. Significant risk factors, determined by multivariate logistics, included infants born in December, January or February, passive household smoke exposure and household crowding. The scoring tool produced similar RSV-H post-test probabilities (3.1% pre-test probability) between risk groups (5.5% vs. 5.8%) and was unable to target highest risk infants. The tool could be used as an educational guideline for health professionals, outlining the importance of significant risk factors for RSV-H to parents and caregivers.

Very premature infants often experience high blood sugar levels as a result of incomplete metabolic development, illness, and stress. High blood sugar levels have been associated with a range of worsened outcomes and increased mortality, but debate exists as to whether high blood sugar levels are a cause of, or marker for, these worsened outcomes. Insulin can be used to lower blood sugar levels, but there is no standard protocol for its use in neonates, and the few clinical studies of insulin use in neonatal intensive care are relatively small and/or have resulted in high incidence of dangerously low blood sugar levels. Hence, there is a need for a safe and effective protocol for controlling blood sugar levels to a normal range in order that potential clinical benefits can be successfully studied in this clinical cohort. This thesis adapted a glucose-insulin model successfully used in adult intensive care for the unique physiology and situation of the very premature infant. The model aims to reflect known physiology. As such, sources and disposal of glucose and insulin within the body are examined using both published data and unique data sets from a study here in New Zealand. In addition, the absorption of glucose from milk feeds is examined. This glucose-insulin physiological model is then used alongside statistical forecasting to develop a protocol for selecting an appropriate insulin dose based on targeting of likely outcomes to a specified target normal range. The protocol is tested in silico using virtual trials, and then clinically implemented, with results showing improved performance over current clinical practice and other published studies. In particular, ~77% of blood glucose is observed within the specified target range across the cohort, and there has been no incidence of dangerously low blood glucose levels. This protocol is thus safe and effective, accounting for inter- and intra- patient variability, and thus enabling patient-specific care.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Introdução: A retinopatia da prematuridade (ROP) é uma das principais causas de cegueira e morbidade visual na infância. É uma doença ocular vasoproliferativa secundária à vascularização inadequada da retina dos recém-nascidos (RNs) prematuros (PMTs), cuja etiologia é multifatorial e não está completamente elucidada. Dentre os fatores implicados na sua patogênese estão a exposição da retina em desenvolvimento a níveis anormais de oxigênio e a deficiência do fator de crescimento insulínico-1 (insulin-like growth factor-1, IGF-1). O leite materno (LM) contém IGF-1 e pode ter um efeito protetor contra o desenvolvimento da ROP. Objetivos: Avaliar o possível efeito protetor do LM contra a ROP, através da comparação da quantidade de LM recebida entre os pacientes que desenvolveram ROP e aqueles livres da doença. Tentar determinar a quantidade mínima necessária e o momento em que o RN precisa receber o LM para que esse efeito seja significativo. Pacientes e métodos: Estudo de coorte observacional incluindo RNs com peso de nascimento (PN) inferior a 1500 gramas e / ou com idade gestacional (IG) inferior a 32 semanas, nascidos no período de janeiro de 2011 a outubro de 2014 e internados nas primeiras 24 horas de vida na UTI Neonatal do Hospital da Criança Conceição (HCC) em Porto Alegre. Resultados: A prevalência da ROP em qualquer grau foi de 31% (100 casos em 323 pacientes) e a de ROP grave foi de 9% (29 casos em 323 pacientes). A mediana da quantidade de LM recebida pelos pacientes foi de 10,2mL/kg/dia entre os pacientes sem ROP (amplitude interquartil 1,5-25,5) e de 4,9 mL/kg/dia entre os pacientes com ROP (0,3-15,4). A quantidade de LM recebida nas primeiras seis semanas de vida foi inversamente associada à incidência de ROP em qualquer grau e de ROP grave nas análises univariadas, mas a significância estatística não se manteve após análise multivariada para controle de fatores confundidores na maioria dos períodos avaliados, exceto na sexta semana de vida. Conclusão: Pequenas quantidades de LM não são suficientes para prevenção de ROP em PMTs de risco para a doença. / Introduction: Retinopathy of prematurity (ROP) is one of the major causes of blindness and visual morbidity in childhood. It is a vasoproliferative eye disease secondary to inad-equate vascularization of the retina in premature neonates. Its etiology is multifactorial and it is not completely elucidated. The exposure of the developing retina to abnormal oxygen levels and the deficiency of insulin-like growth factor-1 (IGF-1) are among the factors involved in its pathogenesis. Breast milk (BM) contains IGF-1 and may have a protective effect against the development of ROP. Objectives: To evaluate the possible protective effect of BM against ROP by comparing the amount of breast milk received among patients who developed ROP and those who were disease-free. To attempt to determine both the required minimum amount and the time in which a neonate needs to receive BM for this effect to be significant. Patients and methods: Observational cohort study of newborns with a birth weight be-low 1500 grams and/or gestational age less than 32 weeks, born from January 2011 to October 2014 and hospitalized within their first 24 hours of life in the Neonatal Intensive Care Unit (NICU) at the Hospital da Criança Conceição (HCC), in Porto Alegre- RS- Brazil. Results: The prevalence of ROP at any degree was of 31% (100 cases in 323 patients) and of severe ROP was of 9% (29 cases in 323 patients). The median amount of BM received by patients was 10.2 mL/kg/day among patients without ROP (interquartile range 1.5-25.5) and 4.9 mL/kg/day among patients with ROP (0.3-15.4). The amount of breast milk received in the first six weeks of life was inversely associated with the inci-dence of ROP in any degree and of severe ROP in the univariate analyses. The statistical significance was not maintained after a multivariate analysis to control for confounding factors in the majority of the periods evaluated, except in the sixth week of life. Conclusion: Small amounts of BM are not enough to prevent ROP in premature new-borns at risk of the disease.

Justificativa do estudo: Existem evidências crescentes de redução de fluxos expiratórios em crianças nascidas pré-termo sem doenças respiratórias neonatais. O seguimento destes pacientes sugere que haja um catch-up de função pulmonar durante os primeiros anos de vida. Objetivos: Medir a função pulmonar de lactentes pré-termo sadios (sem patologias respiratórias neonatais) durante os primeiros dois anos de vida e analisar o efeito de dados perinatais no crescimento pulmonar destes pacientes. Delineamento: Estudo de coorte prospectivo com controles históricos. Pacientes e métodos: Foram recrutados neonatos pré-termo menores de 34 semanas de idade gestacional que não necessitaram de ventilação mecânica ou oxigenoterapia prolongada no período neonatal. O grupo controle consistiu de lactentes normais a termo menores de três anos. Duas medidas longitudinais de função pulmonar foram realizadas após 40 semanas e após os 12 meses de idade corrigida., através da técnica de Compressão Torácica Rápida Os principais testes estatísticos utilizados na análise dos dados foram a análise de covariância e a regressão linear. Resultados: Os lactentes pré-termo apresentaram redução nos fluxos expiratórios forçados, com volumes pulmonares normais, em ambos os testes. A melhora da função pulmonar entre os testes foi semelhante entre os dois grupos. O uso breve de oxigênio no período neonatal foi associado a uma melhora nos fluxos e a exposição ao tabagismo antes do nascimento, a fluxos mais reduzidos. Conclusões: Fluxos expiratórios persistentemente reduzidos na presença de capacidades vitais normais e a ausência de catch-up no crescimento pulmonar dos pacientes pré-termo sugerem que o nascimento pré-termo per se está relacionado a um desenvolvimento pulmonar alterado. / Rationale: There is growing evidence of reduced expiratory flows in preterm infants without respiratory troubles at birth. Longitudinal follow-up of these children suggests there is a catch-up of lung function in the first years of life. Objectives: To measure lung function in healthy preterm infants (without neonatal respiratory disease) in the first two years of life, and analyze the effect of perinatal variables in lung growth of these group. Study: Prospective cohort study with historic controls. Patients and methods: Preterm infants less than 34 gestational weeks and with no need for mechanical ventilation or prolonged oxygen support after birth were recruited. Controls consisted of less than three year-old healthy term infants. Longitudinal lung function measures were carried out after 40 weeks and 12 months of corrected gestational age, through the Rapid Thoracic Compression Technique. The main statistical tests used were covariance analysis and linear regression. Results: Preterm infants showed reduced expiratory flows and normal lung volumes in both tests. The improvement of lung function between the two tests were similar in both groups. Brief oxygen use in the neonatal period was associated with better flows, and antenatal smoking exposure was associated to more reduced flows. Conclusions: Persistently reduced flows in the presence of normal forced vital capacity and the absence of catch-up growth in airway function suggest that premature birth is associated with altered lung development.

Introdução: A retinopatia da prematuridade (ROP) é uma das principais causas de cegueira e morbidade visual na infância. É uma doença ocular vasoproliferativa secundária à vascularização inadequada da retina dos recém-nascidos (RNs) prematuros (PMTs), cuja etiologia é multifatorial e não está completamente elucidada. Dentre os fatores implicados na sua patogênese estão a exposição da retina em desenvolvimento a níveis anormais de oxigênio e a deficiência do fator de crescimento insulínico-1 (insulin-like growth factor-1, IGF-1). O leite materno (LM) contém IGF-1 e pode ter um efeito protetor contra o desenvolvimento da ROP. Objetivos: Avaliar o possível efeito protetor do LM contra a ROP, através da comparação da quantidade de LM recebida entre os pacientes que desenvolveram ROP e aqueles livres da doença. Tentar determinar a quantidade mínima necessária e o momento em que o RN precisa receber o LM para que esse efeito seja significativo. Pacientes e métodos: Estudo de coorte observacional incluindo RNs com peso de nascimento (PN) inferior a 1500 gramas e / ou com idade gestacional (IG) inferior a 32 semanas, nascidos no período de janeiro de 2011 a outubro de 2014 e internados nas primeiras 24 horas de vida na UTI Neonatal do Hospital da Criança Conceição (HCC) em Porto Alegre. Resultados: A prevalência da ROP em qualquer grau foi de 31% (100 casos em 323 pacientes) e a de ROP grave foi de 9% (29 casos em 323 pacientes). A mediana da quantidade de LM recebida pelos pacientes foi de 10,2mL/kg/dia entre os pacientes sem ROP (amplitude interquartil 1,5-25,5) e de 4,9 mL/kg/dia entre os pacientes com ROP (0,3-15,4). A quantidade de LM recebida nas primeiras seis semanas de vida foi inversamente associada à incidência de ROP em qualquer grau e de ROP grave nas análises univariadas, mas a significância estatística não se manteve após análise multivariada para controle de fatores confundidores na maioria dos períodos avaliados, exceto na sexta semana de vida. Conclusão: Pequenas quantidades de LM não são suficientes para prevenção de ROP em PMTs de risco para a doença. / Introduction: Retinopathy of prematurity (ROP) is one of the major causes of blindness and visual morbidity in childhood. It is a vasoproliferative eye disease secondary to inad-equate vascularization of the retina in premature neonates. Its etiology is multifactorial and it is not completely elucidated. The exposure of the developing retina to abnormal oxygen levels and the deficiency of insulin-like growth factor-1 (IGF-1) are among the factors involved in its pathogenesis. Breast milk (BM) contains IGF-1 and may have a protective effect against the development of ROP. Objectives: To evaluate the possible protective effect of BM against ROP by comparing the amount of breast milk received among patients who developed ROP and those who were disease-free. To attempt to determine both the required minimum amount and the time in which a neonate needs to receive BM for this effect to be significant. Patients and methods: Observational cohort study of newborns with a birth weight be-low 1500 grams and/or gestational age less than 32 weeks, born from January 2011 to October 2014 and hospitalized within their first 24 hours of life in the Neonatal Intensive Care Unit (NICU) at the Hospital da Criança Conceição (HCC), in Porto Alegre- RS- Brazil. Results: The prevalence of ROP at any degree was of 31% (100 cases in 323 patients) and of severe ROP was of 9% (29 cases in 323 patients). The median amount of BM received by patients was 10.2 mL/kg/day among patients without ROP (interquartile range 1.5-25.5) and 4.9 mL/kg/day among patients with ROP (0.3-15.4). The amount of breast milk received in the first six weeks of life was inversely associated with the inci-dence of ROP in any degree and of severe ROP in the univariate analyses. The statistical significance was not maintained after a multivariate analysis to control for confounding factors in the majority of the periods evaluated, except in the sixth week of life. Conclusion: Small amounts of BM are not enough to prevent ROP in premature new-borns at risk of the disease.