Aflibercept to treat retinopathy of prematurity: need for more research.

Until recently, the standard care for retinopathy of prematurity (ROP) was destructive treatment of the peripheral avascular retina, most often using laser therapy. Now, intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents have been included in recommendations for treatment-warranted ROP. The three anti-VEGF agents used to treat ROP are bevacizumab, ranibizumab, and aflibercept and clinical trials using, a variety of treatment strategies, have shown all three are efficacious and easy to administer. Intravitreal Bevacizumab is most used in the US, and ranibizumab has been approved for ROP use in Europe. In 2023, the FDA approved aflibercept for treatment of severe ROP. We summarize the clinical trial results and provide a side-by-side comparisons of the three drugs. Despite FDA approval of the use of aflibercept to treat ROP, there is a need for more research as the body of knowledge regarding this agent to treat ROP is limited.

Seizures in Pre-term Infants Less than 29 Weeks: Incidence, Etiology, and Response to Treatment.

INTRODUCTION: Seizures are neurological emergencies with short-and long-term adverse effects in pre-term infants. They may present with or without abnormal movements (clinical versus subclinical). Thus, the true incidence of seizures may be under-reported. Current research indicates that most seizures occur in the first few days of life, are associated with intraventricular hemorrhage (IVH), and show low response to anticonvulsant drugs. The purpose of this study was to evaluate incidence, etiology, clinical antecedents, mortality, and response to treatment of seizures in extremely pre-term infants. METHODS: This is a retrospective cohort study of pre-term infants < 29 weeks gestation from January 2011 to December 2013. Presence or absence of seizure was the outcome. Data extraction included demographics, medications, co-morbidities, mortality, and details of seizures. A multivariable prediction model was developed to evaluate risk for seizures. RESULTS: Analysis included 269 pre-term infants. Incidence of EEG-confirmed seizures was 40% (108/269); 49% were clinical and 51% were subclinical. Seizures occurred in 72% of infants ≤ 24 weeks, 57% of those 25-26 weeks, and 23% of those 27-28 weeks. Most seizures (85%) occurred after day eight of life. Mortality was 14% in those with seizures versus 5% in those without (p = 0.019). The model showed seizures were associated significantly with gestational age and medications, while controlling for sex, APGAR score, and co-morbidities, including IVH. At discharge, anticonvulsants were continued in 66% (72/108) of infants with seizures. CONCLUSION: The incidence of seizures was highest in infants born most premature. Contrary to previous research, nearly two-thirds of pre-term infants with seizures did not have IVH or cystic periventricular leukomalacia; apnea of prematurity was a common presentation of subclinical seizures; and the majority of treated infants responded to Phenobarbital. These findings need be explored in future research.

A Survey of County Health Departments of Kansas Regarding COVID-19.

INTRODUCTION: SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2) causing COVID-19 (Coronavirus Disease 2019) initially was identified in China in December 2019. It has resulted in a pandemic with increasing spread of the virus in the U.S. The county health departments around U.S. are spearheading the response to contain the spread of this virus. METHODS: This project was a survey of county health departments in the state of Kansas with data collection period from April 15 to April 24, 2020. This study evaluated the staffing, resources, and funding of these health departments and how it was affecting the efforts to contain COVID-19. Descriptive statistics were used to summarize the responses. RESULTS: A total of 75% of the county health departments in Kansas responded to the survey. In 89% of locations, the staffing had not increased. Most health departments had an average of five people and the four largest ones had 30 to 98 staff working on COVID-19. Most locations used the Kansas Department of Health and Environment criteria for testing and used a combination of state or private laboratories. The results of the tests were available three days or longer in 62% and after five days in 14% of sites. All locations were active in contact tracing, but most had one to three people for this purpose and in 90% the contact tracing interview was via phone calls. There was no change in funding in 21% and decreased funding in 8.5% of health departments. Most locations had an average of five nasopharyngeal swabs on the day of the survey. The most common needs expressed were help to increase testing capability, more public education, more personal protective equipment, increased personnel, and assistance with contract tracing. CONCLUSION: There is an urgent need in Kansas to increase support to county health departments for testing capability, personal protective equipment, increased number of staff, increased help with contact tracing, and especially increase support for public education.

Strategies to Prevent Severe Retinopathy of Prematurity: A 2020 Update and Meta-analysis.

The incidence of retinopathy of prematurity (ROP) is showing an increasing trend in the United States. This may be because of increasing survival rates among extremely preterm infants (<25 weeks' gestation) and targeting higher oxygen saturation. Five randomized clinical trials of low versus high oxygen saturation target ranges found increased mortality in the low oxygen saturation target group and an increased incidence of ROP in the high oxygen saturation target group. The American Academy of Pediatrics recommends using an oxygen saturation target range of 90% to 95% in extremely low-birthweight infants. The change of practice to target this higher oxygen saturation range, from admission until discharge, may be contributing to the increasing incidence of ROP in extremely preterm infants. To decrease the incidence of ROP without increasing mortality, 2 new cohort trials suggest gradually increasing oxygen saturation targets as preterm infants mature. There is evidence that human milk, vitamin A, and omega-3 fatty acids can help, in addition to continuous oxygen saturation monitoring, to decrease the risk of ROP. We review this literature and provide a meta-analysis to evaluate the evidence.

Neonatal resuscitation: an update.

Appropriate resuscitation must be available for each of the more than 4 million infants born annually in the United States. Ninety percent of infants transition safely, and it is up to the physician to assess risk factors, identify the nearly 10 percent of infants who need resuscitation, and respond appropriately. A team or persons trained in neonatal resuscitation should be promptly available to provide resuscitation. The Neonatal Resuscitation Program, which was initiated in 1987 to identify infants at risk of needing resuscitation and provide high-quality resuscitation, underwent major updates in 2006 and 2010. Among the most important changes are to not intervene with endotracheal suctioning in vigorous infants born through meconium-stained amniotic fluid (although endotracheal suctioning may be appropriate in nonvigorous infants); to provide positive pressure ventilation with one of three devices when necessary; to begin resuscitation of term infants using room air or blended oxygen; and to have a pulse oximeter readily available in the delivery room. The updated guidelines also provide indications for chest compressions and for the use of intravenous epinephrine, which is the preferred route of administration, and recommend not to use sodium bicarbonate or naloxone during resuscitation. Other recommendations include confirming endotracheal tube placement using an exhaled carbon dioxide detector; using less than 100 percent oxygen and adequate thermal support to resuscitate preterm infants; and using therapeutic hypothermia for infants born at 36 weeks' gestation or later with moderate to severe hypoxic-ischemic encephalopathy.

A paradigm shift in the prevention of retinopathy of prematurity.

For more than 50 years it has been known that oxygen therapy can lead to retinopathy of prematurity (ROP). Recent clinical research has led many neonatologists to lower the target oxygen saturation alarm limits to 85-93% and to titrate the inspired oxygen in small increments. Despite efforts to optimize oxygen therapy, the number of cases of severe ROP remains high as more extremely low birth weight infants survive. Based on new insights into the pathogenesis of ROP, there are multiple interventions, in addition to optimizing oxygen therapy that may help decrease severe ROP. Interventions that have the potential to prevent phase I ROP (birth to ≤32 weeks PMA) include increasing retinal erythropoietin (exogenous rHuEPO) and serum IGF-1 (breast milk and/or exogenous IGF-1), maintaining serum glucose below 120 mg, and providing omega-3 supplements. Interventions with potential to prevent proliferative ROP in phase II (infants >32-34 weeks PMA) include treating anemia with a liberal policy of transfusion in premature infants with stage III ROP, photopic adaptation, vitamin E supplements (>34 weeks PMA), and omega-3 supplements. The WINROP algorithm has shown promise as a biomarker in the early identification of extremely low birth weight infants at high risk for proliferative ROP. As there is interplay of multiple factors in the causation of ROP, we suggest that the simultaneous application of some combination of multiple interventions, mentioned above, may reduce the burden of ROP in the most vulnerable infants. These concepts need study in well-designed randomized clinical trials before being incorporated into clinical practice.

Inborn errors of metabolism in infancy and early childhood: an update.

Recent innovations in medical technology have changed newborn screening programs in the United States. The widespread use of tandem mass spectrometry is helping to identify more inborn errors of metabolism. Primary care physicians often are the first to be contacted by state and reference laboratories when neonatal screening detects the possibility of an inborn error of metabolism. Physicians must take immediate steps to evaluate the infant and should be able to access a regional metabolic disorder subspecialty center. Detailed knowledge of biochemical pathways is not necessary to treat patients during the initial evaluation. Nonspecific metabolic abnormalities (e.g., hypoglycemia, metabolic acidosis, hyperammonemia) must be treated urgently even if the specific underlying metabolic disorder is not yet known. Similarly, physicians still must recognize inborn errors of metabolism that are not detected reliably by tandem mass spectrometry and know when to pursue additional diagnostic testing. The early and specific diagnosis of inborn errors of metabolism and prompt initiation of appropriate therapy are still the best determinants of outcome for these patients.

Variability in the dose of intravenous vitamin E given to very low birth weight infants.

OBJECTIVE: Vitamin E is required by very low birth weight (VLBW) infants to prevent vitamin E deficiency. However, prolonged intravenous intakes of vitamin E >4 international units (IU)/kg/day often yield potentially toxic serum tocopherol levels. This study was designed to assess the frequency of potentially inadequate or excessive doses of intravenous vitamin E in parenteral nutrition for VLBW infants in the US. STUDY DESIGN: A questionnaire was sent to the 100 neonatal-perinatal training program centers listed in the 2003 directory (American Academy of Pediatrics (AAP)). Using the information provided for each neonatal unit, we calculated the doses of vitamin E (IU/kg/day) that would have been given to infants with body weights of 0.5, 1.0 and 1.5 kg in that unit. The doses were then recoded as inadequate if less than recommended (2.8 IU/kg/day, maximum 7 IU/day) by the American Society for Clinical Nutrition and the AAP, and excessive if >4 IU/kg/day, and frequencies were compared using chi2 analysis. RESULTS: The 65 centers that responded were predominantly among those that offered the highest level of subspecialty neonatal intensive care (level IIID). The predicted dose of vitamin E had a median value of 2.8 IU/kg/day for all three weights, and was no significantly different among the three weights. VLBW infants with weights of 0.5, 1.0 and 1.5 kg were predicted to receive doses <2.8 IU/kg/day in 12, 12 and 19% of the neonatal intensive care units (NICUs), respectively, and doses >4 IU/kg/day in 40, 31 and 10% of the NICUs, respectively. Excessive doses were significantly associated with body weight, with more frequent excessive doses at lower weight (p=0.0008). CONCLUSION: This survey showed a lack of uniformity of dosing of intravenous vitamin E in VLBW infants. The smallest infants (<1.0 kg) were receiving excessive, potentially toxic doses of vitamin E in a significant number of NICUs in the US in 2003.

Craniosynostosis.

Skull deformity in infants continues to be a diagnostic and therapeutic challenge. Deformational plagiocephaly is a common and somewhat benign cause of skull deformity in infants that must be distinguished from the more serious craniosynostosis, which occurs alone or as a syndrome. Examining an infant's head from above can help the physician distinguish true lambdoid synostosis from deformational plagiocephaly. In infants with lambdoid synostosis, the posterior bossing is in the parietal area contralateral to the flat part of the head. Deformational plagiocephaly causes frontal bossing ipsilateral to the flat part of the head. In infants with lambdoid synostosis, the ear is displaced posteriorly toward the fused suture. In infants with deformational plagiocephaly, the ear is displaced anteriorly. Isolated sagittal synostosis is the most common type of craniosynostosis. Of the more than 150 craniosynostosis syndromes, Crouzon's disease and Apert's syndrome account for the majority of cases. The diagnosis of craniosynostosis relies on physical examination, plain radiography, and computed tomography. Untreated progressive craniosynostosis leads to inhibition of brain growth, and an increase in intracranial and intraorbital pressure. Infants should be evaluated as soon as they are diagnosed.

What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants?

The Committee on Fetus and Newborn of the American Academy of Pediatrics (AAP) has endorsed 1 to 2 mg/dl as the normal range of serum tocopherol level. Our Cochrane review has shown that vitamin E supplementation resulting in levels >3.5 mg/dl, but not < or =3.5 mg/dl, significantly reduces the risk for severe retinopathy among very-low-birth-weight (VLBW) infants examined but increases the risks of sepsis and of necrotizing enterocolitis among infants treated for >1 week. As a fixed daily intravenous dose of vitamin E results in an inverse relationship between serum level and birth weight and is a risk for both low and high serum tocopherol levels, a dose adjusted for current weight appears more judicious than a fixed dose per day. Based on currently available data the AAP and the American Society for Clinical Nutrition currently recommend a routine intake of 2 ml/kg/day of MVI Pediatric (2.8 IU/kg/day) in VLBW infants (maximum of 5 ml/day or 7 IU/day).