Metabolic bone disease of prematurity screening and individualized enteral mineral supplementation in high-risk neonates: a quality improvement initiative.

OBJECTIVE: Prompted by an alarmingly low screening rate for metabolic bone disease of prematurity (MBDP), we aimed to increase MBDP screening with serum calcium, phosphorous, and alkaline phosphatase at four to six weeks of life in infants born at <1500 g and <32 gestational weeks from a baseline of 27.37% to 90% within one year. STUDY DESIGN: We used the Institute for Healthcare Improvement's Model for Improvement as a framework. A key driver diagram informed the interventions which were carried out through four Plan-Do-Study-Act cycles. RESULTS: There were 129 and 130 neonates in the pre-intervention baseline group and post-intervention MBDP bundle group, respectively. MBDP bundled primary screening rates increased from 27.37% to 95.56% (p < 0.001). Furthermore, 20% of infants had an individualized change in their enteral mineral supplementation after the initiative. CONCLUSIONS: An interdisciplinary team-based quality improvement approach was effective in altering clinical practice to improve screening and subsequent treatment for MBDP.

Prematuridad tardía: recomendaciones para el seguimiento a largo plazo / Late preterm newborn: follow-up recommendations

La tasa de prematuridad global, según laOrganización Mundial de la Salud (OMS),muestra un aumento progresivo; su principal componente es el grupo de prematuros tardíos. Este grupo de pacientes suele tener buen peso al nacer, lo que hace que no se perciba muchas veces el riesgo de presentar un espectro de morbilidades del desarrollo, conductuales einmadurez de diferentes órganos y sistemasque impactan en la evolución a corto y largo plazo y aumentan la morbimortalidad. A su vez, tienen un efecto sustancial en los servicios de atención médica. El objetivo de esta publicación es discutir algunosaspectos relacionados con la salud de este grupo de pacientes y sugerir su seguimiento con un enfoque holístico e interdisciplinario.

The WHO states that prematurity rates have increased mainly due to late preterm births. Since these babies are usually born with appropriate weight for their gestational age, their risk for morbidities such as neurodevelopmental delays, behavioral problems and organ systems immaturity are overlooked. Further, these clinical findings have an impact on short and long term outcomes (i.e., morbidities, mortality, and higher healthcare costs). The aim of this publication is to discuss topics related to late-preterm newborns' health, including a holistic and interdisciplinary approach to follow up care.

[Late preterm newborn: follow-up recommendations]. / Prematuridad tardía: recomendaciones para el seguimiento a largo plazo.

The WHO states that prematurity rates have increased mainly due to late preterm births. Since these babies are usually born with appropriate weight for their gestational age, their risk for morbidities such as neurodevelopmental delays, behavioral problems and organ systems immaturity are overlooked. Further, these clinical findings have an impact on short and long term outcomes (i.e., morbidities, mortality, and higher healthcare costs). The aim of this publication is to discuss topics related to late-preterm newborns' health, including a holistic and interdisciplinary approach to follow up care.

La tasa de prematuridad global, según la Organización Mundial de la Salud (OMS), muestra un aumento progresivo; su principal componente es el grupo de prematuros tardíos. Este grupo de pacientes suele tener buen peso al nacer, lo que hace que no se perciba muchas veces el riesgo de presentar un espectro de morbilidades del desarrollo, conductuales e inmadurez de diferentes órganos y sistemas que impactan en la evolución a corto y largo plazo y aumentan la morbimortalidad. A su vez, tienen un efecto sustancial en los servicios de atención médica. El objetivo de esta publicación es discutir algunos aspectos relacionados con la salud de este grupo de pacientes y sugerir su seguimiento con un enfoque holístico e interdisciplinario.

The incidence of osteopenia of prematurity in preterm infants without phosphate supplementation: A prospective, observational study.

ABSTRACT: To meet their requirements for bone mineralization, it is recommended that preterm infants receive nutritional support containing calcium and phosphate. There are no clear data on the incidence of osteopenia of prematurity (OFP) in preterm infants without phosphate supplementation.This study aimed to investigate the incidence of OFP in preterm infants without phosphate supplementation and its relationship with the duration of parenteral nutrition (PN).This was a prospective and observational study.This study included 30 infants aged <32 gestational weeks and weighed <1500 g at birth. All infants received PN according to a standard protocol, beginning on day 1 with calcium, without phosphate. Starting from the first day of life, all infants received human milk without fortifiers. Oral vitamin D (400 IU/d) was administered when enteral nutrition reached 100 mL/kg/d.The diagnosis of OFP was based on radiographs that were taken of both wrists. Serum alkaline phosphatase (ALP) was measured 3 times: at the start of PN (ALP 1), at the end of PN (ALP 2), and at discharge or the expected due date (ALP 3). Radiographs were obtained on the same day as ALP 3. The duration of PN was analyzed in the presence of OFP using receiver operating characteristic curve analysis.Among the 30 infants, 13 (43%) were diagnosed with OFP. The duration of PN was significantly longer in the OFP group than in the group without OFP (16 vs 12 days; P < .05). The provision of PN for >15 days significantly increased the risk of OFP (odds ratio, 5.40; 95% confidence interval, 1.12-26.04; P = .035).We found a high incidence of OFP in preterm infants without phosphate supplementation. An association was found between the duration of PN and the incidence of OFP. Further research is needed to prevent the development of osteopenia in preterm infants.

Oropharyngeal colostrum therapy reduces the incidence of ventilator-associated pneumonia in very low birth weight infants: a systematic review and meta-analysis.

BACKGROUND: Oropharyngeal colostrum (OC) is a novel feeding strategy to prevent complications of prematurity. A meta-analysis was conducted to investigate whether very low birth weight infants (VLBWs) can benefit from OC. METHODS: Randomized controlled trials (RCTs) were searched from Embase, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials from the date of inception until May 2019. RCTs were eligible if they used OC therapy on VLBW infants. The primary outcomes included ventilator-associated pneumonia (VAP), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), late-onset sepsis, and death. The secondary outcomes included the time of full enteral feeding and the length of stay. RESULTS: Eight RCTs involving 682 patients (OC group: 332; non-OC group: 350) were included in the meta-analysis. The results suggested that OC was associated with a significantly reduced incidence of VAP [odds ratio (OR) = 0.39, 95% confidence interval (CI): 0.17-0.88, P = 0.02] and full enteral feeding days (mean difference = -2.66, 95% CI: -4.51 to -0.80, P = 0.005), a potential significance of NEC (OR = 0.51, 95% CI: 0.26-0.99, P = 0.05), a trend toward downregulating mortality (OR = 0.60, 95% CI: 0.34-1.08, P = 0.09) and proven sepsis (OR = 0.64, 95% CI: 0.40-1.01, P = 0.06). CONCLUSIONS: OC could significantly reduce the occurrence of VAP, and consequently, its routine use should be considered for VLBWs to prevent infectious diseases. IMPACT: OC significantly reduces the occurrence of VAP and NEC in VLBW infants. OC may reduce the incidence of VAP and NEC by increasing IgA levels. Early OC therapy for mechanical ventilation of low-weight infants may prevent the occurrence of VAP.

The accuracy of transcutaneous bilirubinometry in preterm infants.

OBJECTIVE: To evaluate the correlation between total serum and transcutaneous bilirubin and to determine the reliability of transcutaneous bilirubinometry for screening and monitoring of neonatal jaundice among preterms. STUDY DESIGN: Ninety nine infants with gestational ages ≤34 weeks were prospectively enrolled. Babies were classified into three groups as; 24-28, 29-31, and 32-34 weeks. Total serum bilirubin and simultaneous transcutaneous bilirubin were measured before the onset of phototheraphy, during and at 24 h after discontinuing phototherapy. RESULTS: Total serum bilirubin significantly correlated with transcutaneous bilirubin in the whole cohort (r = 0.867, p < 0.001) and in each group before, during and after phototheraphy. Hypotension was the only variable which effects the difference between two methods at postnatal first day of life (p = 0.039). CONCLUSION: Transcutaneous bilirubin levels were highly correlated with total serum bilirubin levels even in 24-28 GW babies. Transcutaneous bilirubin may be useful for screening and monitoring of jaundice in very preterm newborns.

Accuracy of the Bilicare™ transcutaneous bilirubinometer as the predischarge screening tool for significant hyperbilirubinemia in healthy term and late preterm neonates.

Background: The Bilicare™ is a new device that measures transcutaneous bilirubin (TcB) level at the ear pinna. There are only few studies which have evaluated its accuracy in clinical practice.Objective: This study aims to determine the accuracy of Bilicare™ as a predischarge screening tool in late preterm and term neonates and to define the optimal cutoff point for determining the need to measure total serum bilirubin (TSB).Methods: The 35 weeks' gestation or more and healthy neonates who underwent predischarge TSB measurement were enrolled. Bilicare™ TcB was measured within 30 minutes of blood sampling. Paired TcB and TSB data were analyzed.Results: We collected 214 paired samples. Mean age (SD) at TcB measurement was 57.17 (7.47) hours. Mean TSB (SD) was 9.79 (2.83) mg/dL. TcB showed a significant correlation with TSB (r = 0.84, r2 = 0.7). The mean difference (SD) between TcB and TSB was 0.7 (0.21) mg/dL (95%CI 0.49-0.91). TcB tended to overestimate TSB level at the TSB values of <12 mg/dL but underestimate at the higher TSB level. The accuracy of using TcB values to detect neonates who required phototherapy was 92.5%. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 78.3, 94.2, 62.1, and 97.3%, respectively. If TcB +3 mg/dL was applied as a cutoff point, the sensitivity, specificity, PPV, and NPV were 100, 53.9, 20.7, and 100%, respectively.Conclusions: Bilicare™ TcB and TSB measurements were well correlated. The TcB level +3 mg/dL could detect all neonates who had significant hyperbilirubinemia requiring phototherapy during their birth hospitalization.

Severe Hyperkalemia Immediately After Birth.

BACKGROUND Hyperkalemia is an important cause of arrhythmias and a medical emergency that requires urgent treatment. The etiology is usually multifactorial. It is most frequently caused by impaired potassium secretion, followed by transcellular potassium shifts and an increased potassium load. CASE REPORT A male newborn developed monomorphic ventricular tachycardia 2 hours after birth. He was born in the 35th week of gestation by urgent C-section following placental abruption. Laboratory results showed hemolytic anemia (Hb 99 g/L, Hct 0.31) with increased bilirubin levels and reticulocytosis, thrombocytopenia (39×109/L), hypoglycemia (0.8 mmol/L), and severe hyperkalemia (9.8 mmol/L). Umbilical artery blood gas analysis showed hypoxemia with acidosis (pO2 3.8 kPa, pH 7.21, pCO2 7.84 kPa, HCO3 23.3 mmol/L, BE -5 mmol/L). Creatinine (102 µmol/L) and urea (9.8 mmol/L) were mildly elevated. Inflammatory markers were also increased (CRP 26 mg/L, blood leukocyte count 24×109/L). Early-onset sepsis, caused by Candida albicans, was confirmed approximately 24 hours after birth. Non-invasive ventilation with 35-40% O2 was necessary due to transient tachypnea. The neonate received a transfusion of packed red blood cells, a 10% glucose infusion, and empirical antibiotic therapy. Hyperkalemia accompanied by arrhythmias was treated with calcium gluconate, insulin, Sorbisterit enema, and, finally, by exchange transfusion. CONCLUSIONS We report a case of severe hyperkalemia in a newborn immediately after birth. Making a decision as early as possible regarding exchange transfusion is essential in patients with hyperkalemia with electrocardiogram changes and hemodynamic instability.

Trends in reticulocyte hemoglobin equivalent values in critically ill neonates, stratified by gestational age.

OBJECTIVE: The reticulocyte index reticulocyte hemoglobin equivalent (Ret-He) was evaluated as a marker of iron status. STUDY DESIGN: This is a retrospective cohort study of all infants admitted to the University of Washington Neonatal Intensive Care Unit, who received Ret-He measurements as part of routine care within the first 120 days of life. RESULT: A total of 730 Ret-He measurements from 249 infants were analyzed (median gestational age at birth 32.1 weeks; 49 infants <28 weeks and 200 ≥28 weeks). Initial Ret-He measurements were lower in infants <28 weeks (28.24 vs. 33.34 pg). Ret-He values initially decreased, then slowly increased. Infants received an average of 3.9, 6.5, and 8.2 mg/kg/day of enteral iron sulfate at 30, 60, and 90 days, respectively. CONCLUSION: Ret-He values showed a slow uptrend with enteral iron supplementation following an initial decrease, suggesting that neonates are able to improve their iron sufficiency status with supplementation.

A Simpler Prediction Rule for Rebound Hyperbilirubinemia.

OBJECTIVES: We previously reported a clinical prediction rule to estimate the probability of rebound hyperbilirubinemia using gestational age (GA), age at phototherapy initiation, and total serum bilirubin (TSB) relative to the treatment threshold at phototherapy termination. We investigated (1) how a simpler 2-variable model would perform and (2) the absolute rebound risk if phototherapy were stopped at 2 mg/dL below the threshold for treatment initiation. METHODS: Subjects for this retrospective cohort study were infants born 2012-2014 at ≥35 weeks' gestation at 1 of 17 Kaiser Permanente hospitals who underwent inpatient phototherapy before age 14 days. TSB reaching the phototherapy threshold within 72 hours of phototherapy termination was considered rebound. We simplified by using the difference between the TSB level at the time of phototherapy termination and the treatment threshold at the time of phototherapy initiation as 1 predictor, and kept GA as the other predictor. RESULTS: Of the 7048 infants treated with phototherapy, 4.6% had rebound hyperbilirubinemia. The area under the receiver operating characteristic curve was 0.876 (95% confidence interval, 0.854 to 0.899) for the 2-variable model versus 0.881 (95% confidence interval, 0.859 to 0.903) for the 3-variable model. The rebound probability after stopping phototherapy at 2 mg/dL below the starting threshold was 2.5% for infants ≥38 weeks' GA and 10.2% for infants <38 weeks' GA. CONCLUSIONS: Rebound hyperbilirubinemia can be predicted by a simpler 2-variable model consisting of GA and the starting threshold-ending TSB difference. Infants <38 weeks' gestation may need longer phototherapy because of their higher rebound risk.

Extrauterine Growth Restriction in Low Birth Weight Infants.

Extrauterine growth restriction (EUGR) affects a significant number of very low birth weight (VLBW) infants and has the potential to impact neurodevelopmental outcome as well as other aspects of long-term health. More aggressive nutritional approaches have reduced the incidence of postnatal growth failure but many questions remain about the expected rate of growth for very preterm infants, the best ways to measure growth velocity, and the optimal approaches to supporting growth. This article examines some of the outstanding issues regarding postnatal growth failure and summarizes current practice recommendations.

Accuracy of transcutaneous bilirubinometry in the preterm infants: a comprehensive meta-analysis.

BACKGROUND: Transcutaneous bilirubin (TcB) measurement is widely used in term babies. But its effectiveness till debated in preterm infants. So, our objective was to pool data to see the accuracy of transcutaneous bilirubinometry in preterm infants. METHOD: MEDLINE, Embase, Cochrane Library database were searched from 2000 to July 2017. The included studies had compared TcB with total serum bilirubin (TSB) in preterm infants before phototherapy and data were presented as correlation coefficients. Data were extracted by two reviewers and checked for accuracy by the third reviewer. The risk bias assessments were done by an assessment quality assessment of diagnostic accuracy studies tool. Pooled correlation coefficient assed after Fisher's z transformation and then converted to r. RESULTS: We included 28 studies; all those studies reported results as correlation coefficients. In combination of both sternal and forehead site measurement, our pooled estimates of r = 0.82 (95% CI: 0.78-0.85) in random effect and r = 0.803 (95% CI: 0.78-0.81) in fixed effect model. For separate sites of measurement of TcB pooled r for forehead and sternum were comparable, r = 0.82 (95% CI: 0.78-0.85), and pooled correlation coefficient for the two devices JM103 and Bilicheck the estimated pooled r were also comparable (Pooled r = 0.83). CONCLUSION: Our study found that TcB measurement is well related with TSB values and can represent a reliable method for evaluating preterm infants with possible hyperbilirubinemia. Our findings support the use of investigated devices at both forehead and sternum sites in preterm infants.

[Hypophosphatemia in preterm infants: a bimodal disorder]. / Hipofosfemia en recién nacidos prematuros: un trastorno bimodal.

New nutritional approaches to treat extreme premature babies have demonstrated relevant eviden ce of metabolic disturbances with early hypophosphatemia, especially in patients with intrauterine growth restriction (IUGR). They have shown late hypophosphatemia, as well, which is characteristic in the metabolic bone disease. A sytematic search of literature describing metabolic disturbances of phosphorus in preterm newborns is presented, related to the use of early parenteral nutrition and also in the context of metabolic bone disease. The articles were gathered from electronic data bases, such as PubMed and Rima. We include articles in english and spanish which were selected by titles and abstracts. Several strategies for early nutrition have been proposed in order to ensure an adequate amount of nutrients to accomplish the development and growth of preterm babies. Patients with parenteral nutrition support with different doses of phosphate, or inadequate calcium phosphate relation, or an increased amino acid content, may present hypophosphatemia, hypercalcemia, hy pomagnesemia, hypokalemia and hyperglycemia, all of these are additionally noteworthy in the pre sence of intrauterine growth restriction. Furthermore, said alterations are associated with prolonged mechanical ventilation, as well as bronchopulmonary dysplasia and increase in late onset sepsis. The late hypophosphatemia, described several years ago, arises as normocalcemia and as an increment of alkaline phosphatases in the metabolic bone disease in preterm babies, and also with an inadequate mineralization in different grades, secondary to an inadequate supply due to high nutritional requi rements in these patients. When early or late hypophosphatemia appears in preterm babies, it shall require timely control of phosphemia and will need to adjust the nutritional intake in order to correct it. In case of preterm babies with early parenteral nutrition it will also need a control of calcemia in the first week of birth, especially if those belonging to the IUGR group. Adjustment must be made along with metabolic follow up, as well. In late hypophosphatemia, a weekly or every two weeks fo llow up will be a must for all preterm babies in risk and they should be given supplements to get an optimum mineral supply.

Hipofosfemia en recién nacidos prematuros: un trastorno bimodal / Hypophosphatemia in preterm infants: a bimodal disorder

Las estrategias nutricionales para prematuros extremos con alto aporte de proteínas, han mostrado alteraciones metabólicas con hipofosfemia precoz, especialmente en el grupo de pacientes con restricción de crecimiento intrauterino (Rein). También se presenta hipofosfemia tardía, característica de la enfermedad metabólica ósea. En este artículo se revisan y actualizan conceptos en relación a la fisiopatología del metabolismo del fósforo en recién nacidos prematuros y uso de parenterales precoces en el contexto de enfermedad metabólica ósea. Los artículos fueron identificados en base de datos electrónicas como Pubmed y Rima. Fueron incluidos artículos en inglés y español. Fueron filtrados por título y resumen. La literatura actual propone diversas estrategias de nutrición precoz que permitan asegurar una adecuada cantidad de nutrientes para continuar con el crecimiento y desarrollo extrauterino. En pacientes con nutrición parenteral pero con diferentes aportes de fósforo, o relación calcio: fósforo inadecuada, a mayor contenido de aminoácidos, se presenta hipofosfemia, hipercalcemia, hipomagnesemia, hipokalemia e hiperglicemia, especialmente en casos de Rein. Estas alteraciones se asocian a prolongación de ventilación mecánica, mayor riesgo de displasia broncopulmonar y aumento de sepsis tardía. La hipofosfemia tardía, descrita ya hace muchos años, se presenta con normocalcemia y aumento de fosfatasas alcalinas, en la enfermedad metabólica ósea del prematuro, con alteración de la mineralización en distintos grados, secundaria a un inadecuado aporte de este mineral para los altos requerimientos de estos pacientes. Esta presentación de hipofosfemia precoz y tardía en el prematuro alerta sobre el control oportuno de fosfemia para ajustar el aporte nutricional. En el prematuro con nutrición parenteral precoz, el control en conjunto con la calcemia en la primera semana de vida, especialmente en Rein, permite tratar la hipofosfemia y prevenir sus complicaciones. En hipofosfemia tardía, el seguimiento semanal o quincenal desde las 4 semanas a los prematuros con riesgo, permite lograr un aporte óptimo de minerales.

New nutritional approaches to treat extreme premature babies have demonstrated relevant eviden ce of metabolic disturbances with early hypophosphatemia, especially in patients with intrauterine growth restriction (IUGR). They have shown late hypophosphatemia, as well, which is characteristic in the metabolic bone disease. A sytematic search of literature describing metabolic disturbances of phosphorus in preterm newborns is presented, related to the use of early parenteral nutrition and also in the context of metabolic bone disease. The articles were gathered from electronic data bases, such as PubMed and Rima. We include articles in english and spanish which were selected by titles and abstracts. Several strategies for early nutrition have been proposed in order to ensure an adequate amount of nutrients to accomplish the development and growth of preterm babies. Patients with parenteral nutrition support with different doses of phosphate, or inadequate calcium phosphate relation, or an increased amino acid content, may present hypophosphatemia, hypercalcemia, hy pomagnesemia, hypokalemia and hyperglycemia, all of these are additionally noteworthy in the pre sence of intrauterine growth restriction. Furthermore, said alterations are associated with prolonged mechanical ventilation, as well as bronchopulmonary dysplasia and increase in late onset sepsis. The late hypophosphatemia, described several years ago, arises as normocalcemia and as an increment of alkaline phosphatases in the metabolic bone disease in preterm babies, and also with an inadequate mineralization in different grades, secondary to an inadequate supply due to high nutritional requi rements in these patients. When early or late hypophosphatemia appears in preterm babies, it shall require timely control of phosphemia and will need to adjust the nutritional intake in order to correct it. In case of preterm babies with early parenteral nutrition it will also need a control of calcemia in the first week of birth, especially if those belonging to the IUGR group. Adjustment must be made along with metabolic follow up, as well. In late hypophosphatemia, a weekly or every two weeks fo llow up will be a must for all preterm babies in risk and they should be given supplements to get an optimum mineral supply.

Carnitine deficiency in preterm infants: A national survey of knowledge and practices.

OBJECTIVE: Lipid supplementation improves developmental outcomes in preterm infants. Carnitine is essential for lipid metabolism; however, despite high risk for carnitine deficiency, there are no standards for carnitine supplementation in preterm infants receiving total parenteral nutrition (TPN). Our objective was to assess knowledge, beliefs and practices regarding preterm carnitine deficiency and supplementation among neonatal practitioners. METHODS: Cross-sectional electronic survey administered via a nationally representative listserv of neonatal practitioners. RESULTS: 492 respondents participated in the survey. Only 21% of respondents were aware that carnitine is secreted by the placenta. 72% believed that carnitine deficiency was common, and 60% believed deficiency could have serious consequences. Five percent routinely screened for deficiency, and 40% routinely provided carnitine supplementation. Respondents with >5 years' experience were more likely to report using carnitine supplementation (50% vs. 38%). CONCLUSIONS: Although most respondents believed that carnitine deficiency is common and could have serious consequences, few screened for deficiency and fewer than half routinely supplemented. Thus, many preterm infants remain at risk for carnitine deficiency. Further research is needed to elucidate the risks of carnitine deficiency in these vulnerable infants.

Prematurity and biliary atresia: a 30-year observational study.

AIM OF STUDY: The diagnosis of biliary atresia (BA) remains challenging and delay can lead to significant morbidity with time to surgery a key factor in determining outcome. Prematurity may impact on outcome potentially delaying diagnosis. We sought to assess whether the premature BA infants (PBA) have a delayed time to surgery and as such, worse outcomes? METHODS: Review of a single-centre prospectively maintained database. Prematurity was defined as delivery < 37/40 gestation. PBA was compared with date-matched term biliary atresia controls on a 2:1 basis. Primary outcomes were clearance of jaundice (< 20 µmol/L) and native liver survival. A retrospective assessment of liver fibrosis was made on biopsies at diagnosis and at Kasai portoenterostomy (KPE) in both premature and term cohorts. Data are quoted as median (range) unless indicated. A P value of ≤ 0.05 was considered statistically significant. RESULTS: 21 (female n = 14, 67%) premature infants with BA were treated in the period Jan. 1988-Dec. 2016 and compared with 41 contemporaneous term BA controls. Median gestation was 33 (29-36) weeks and birth weight 1930 (948-4230)g. Twin pregnancy (n = 10) was the leading cause for prematurity and significantly higher than the controls (48 vs. 0%; P < 0.0001). Maternal co-morbidity was high (n = 10, 48%) including pre-eclampsia (19%) and diabetes (14%). Liver biopsy was performed in 19 (90%) patients (all diagnostic) at a median of 57 (4-266) days. Delayed diagnosis (> 50 days) was seen in n = 13 but not associated with parenteral nutrition use (46 vs. 33%, P = 0.59) or phototherapy (50 vs. 83%, P = 0.19). Both BASM (33 vs. 7.5%; P = 0.01) and duodenal atresia (19 vs. 0%; P = 0.01) were seen more frequently in the PBA cohort. Mean fibrosis scores (Ishak) from diagnostic biopsies were lower in the premature group than the control group (2.71 vs. 3.53, P = 0.043) indicating less fibrosis but this equalized by time of subsequent KPE (P = 0.17). Primary surgery was Kasai portoenterostomy (n = 20) at an older median age than controls (65 vs. 56 days; P = 0.06). Liver transplantation was the primary procedure in one late-presenting child. There was an increased but non-significant clearance of jaundice in the PBA group [n = 12/20 (60%) vs 20/41 (48%); P = 0.23] post-KPE. Native liver survival and true survival were not different (P = 0.58 and 0.23). CONCLUSIONS: PBA infants have similar outcomes to term infants, despite delayed diagnosis and higher frequency of the syndromic form. The high incidence of discordant twins supports the theory that epigenetic modifications could contribute to the pathogenesis of BA. LEVEL OF EVIDENCE: IIIc Retrospective Matched Cohort Study.

Fetal Valproate Syndrome - Still a Problem Today!

Introduction Fetal exposition to valproate can lead to a cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. Case Report In this report we describe 2 cases of fetal valproate syndrome. In the first case, the gravida had a valproate medication before and during pregnancy with additional folic acid. She delivered a male premature infant at 25+2 weeks of gestation due to preterm labor and rupture of the membranes. Physical examination showed even in the premature infant typical signs of fetal valproate syndrome with trigonocephaly, epicanthal folds, broad root of the nose, low-set ears, thin upper lip and anteverted nares. In the second case, the gravida was under antiepileptic therapy with valproate and lamotrigine before and during pregnancy without any prophylaxis with folic acid. Sonographic examination during pregnancy diagnosed a spina bifida, Chiari II malformation and clubfeet. A female newborn was delivered at 39+4 weeks of gestation. Besides the prenatally detected anomalies, facial dysmorphism including microcephaly, low-set ears, thin upper lip and shallow philtrum were seen after birth. Conclusion Valproate, a widely used anticonvulsant medication, is known for its teratogenic effects. The risk of congenital anomalies is even higher in combination with other antiepileptic drugs. Therefore, the avoidance of valproate or at least supplementation with a high dose prophylactic folic acid before and during pregnancy is highly recommended for women with epilepsy.

Necrotizing enterocolitis - classification and two initial steps towards prevention.

The premature infant suffers from immaturity of all organ systems, one of them being the gastrointestinal tract. When the infant is born, the immature gastrointestinal tract is exposed to milk and simultaneously colonized by high densities of bacteria. The combination of milk, microbiota and an immature gut, leaves the infant vulnerable to developing the dreaded intestinal emergency necrotizing enterocolitis (NEC). NEC is often very aggressive and no cure exists, which means that prevention is an utmost important topic to researchers, physicians, parents - and infants.   Despite immense research during the last decades, no specific test to determine if an infant suffers from NEC exists. Most neonatal units use Bell's staging criteria, which are based on clinical and radiographic findings, as a diagnostic tool; however the diagnosis given according to Bell's stages has not been validated. In study I, we aimed to determine the validity of the NEC diagnosis given at discharge. An expert panel consisting of a neonatologist, a paediatric surgeon and a paediatric radiologist served as the golden standard. We found that the diagnosis given at discharge had a poor validity which significantly affected the reported incidence of NEC in the neonatal department at Rigshospitalet, Denmark. The validity of the NEC diagnosis was worse than the validity of most other paediatric diagnoses that had been investigated.   In studies II and III, we aimed to explore possible means of NEC prevention. The role of nutrition in NEC development is well established with mother's milk as the best option to avoid NEC in the preterm infant. Maternal milk is, however, most often not available in sufficient amounts during the first days of life, and preterm infant formula or human donor milk is used in its absence. Studies in preterm piglets showed that bovine colostrum equally to human donor milk protected against NEC compared to infant formula. Furthermore, bovine colostrum was superior to human donor milk in stimulating gut immunity and digestive functions.   Hence, in study II we aimed to design a pilot study of bovine colostrum used as a supplement to maternal milk in the first days of life and to determine if the study was feasible. In the paper, we present the protocol and the results of the first two phases of the Precolos study in which 12 infants were included and received pasteurized, spray-dried and reconstituted bovine colostrum during the first days of life as the first infants in the world. We found that the infants tolerated bovine colostrum without clinical adverse effects, but we also observed a transient hypertyrosinemia on day seven of life in five infants. The results were evaluated by a safety management board which encouraged us to continue the pilot study with the last phase, which was a randomized controlled trial of 20+20 infants comparing supplementation with bovine colostrum to supplementation with standard nutrition. The randomized trial has just finished recruitment.   At last, we wanted to shed light on a possible microbiological angle of NEC prevention. Dysbiosis and bacterial translocation are believed to play a crucial role in the development of NEC as intestinal pneumatosis, which occurs when bacteria produce gas inside the intestinal wall, is a pathognomonic radiographic finding. In a quality improvement study from the US published in 2014, NEC incidence was significantly reduced after the implementation of several quality improvement interventions. Standardized weekly exchange of nasogastric feeding tubes was suggested as one of the potential NEC-reducing interventions.   In the neonatal unit at Rigshospitalet, Denmark, preterm infants are fed 8-12 times daily through a resident nasogastric feeding tube which is exposed to body temperature, contains milk residuals from the last meal and is handled by both parents and personnel. Since bacterial pollution of milk given through the nasogastric feeding tube might be NEC-inducing, we aimed in study III to determine the bacterial load given to the infants when feeding them through a tube. We collected 92 used nasogastric feeding tubes and flushed them with one ml saline each to imitate a meal given through them. Eighty-nine percent of the tubes contaminated the meals with more than 1000 colony-forming units of bacteria and fifty-five percent contaminated the meals with the possible pathogens Enterobacteriaceae or Staphylococcus aureus. The concentration of bacteria in the saline flushed through the tubes was as high as 109 colony-forming units per ml; however, neither the risk of contamination nor the concentration of bacteria in the flush was associated with the duration of use. Implementation of standardized weekly exchange of feeding tubes would therefore not prevent the contamination of meals.   In conclusion, the studies included in this thesis serve as a base for future studies investigating the prevention of NEC. We found a poor validity of the NEC diagnosis given at discharge. This should be kept in mind when conducting epidemiological studies of NEC and especially when conducting interventional trials with NEC as an outcome. If the findings of the randomized part of the Precolos study indicate a positive effect of bovine colostrum and do not give rise to concerns regarding feasibility, safety or tolerability, a large-scale randomized controlled study with NEC as the primary outcome will be planned. Based on the high concentrations of bacteria found in the nasogastric feeding tubes, a randomized controlled trial investigating whether the frequency of feeding tube exchange affects the early colonization has been commenced in the neonatal department at Rigshospitalet. Hopefully, the results of these studies will bring us closer to preventing NEC in the future.

Bovine Colostrum in Prevention of Necrotizing Enterocolitis and Sepsis in Very Low Birth Weight Neonates: A Randomized, Double-blind, Placebo-controlled Pilot Trial.

OBJECTIVE: To study the efficacy of bovine colostrum in prevention of necrotizing enterocolitis (NEC) and sepsis in very low birth weight (VLBW) infants. STUDY DESIGN: Randomized, double-blind, placebo-controlled pilot trial. PARTICIPANTS: Neonates with birth weight ≤1500 g, gestation ≤32 weeks and postnatal age ≤96 h. INTERVENTION: Enteral bovine colostrum or placebo, four times a day, till 21 days of life or discharge or death. MAIN OUTCOME MEASURES: Definite NEC. Secondary outcomes included sepsis, mortality and stool interleukin-6 (IL-6) levels. RESULTS: Of the total 86 subjects (43 in each group), there were no statistically significant in the main outcome measures. In the colostrum group, there were trends toward higher stool IL-6 values and higher incidence of ileus and radiological signs of NEC. CONCLUSION: The use of prophylactic enteral bovine colostrum in VLBW infants shows a trend toward increased stool IL-6 and features of NEC. We were unable to detect clinical benefits.