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When should we predict outcomes for extreme prematurity?
June 2016 Volume 173
Aerobic fitness and academic achievement — Stephen R. Daniels, MD, PhD
Math at work: a new neonatal calculator to predict weight loss — Robin H. Steinhorn, MD
Copyright ª 2016 by Elsevier Inc.
T
here has been considerable interest in the relationship between physical activity and academic performance. This has been especially true as schools have adopted increased classroom time in response to the perceived need to improve scores on standardized tests. Often, opportunities for physical activity have been decreased in the process of increasing class time. This may have contributed to the increased prevalence of obesity among children and adolescents. There also has been concern that this approach may be short-sighted because physical activity may improve academic performance. In this issue of The Journal, Pindus et al report on the results of a study to evaluate the relationship of moderate-to-vigorous physical activity and academic achievement. They evaluated this while also including physical fitness measured using a standard exercise test as a covariable, which has not been done in many previous studies. They found that aerobic fitness, rather than daily physical activity, was associated with measures of academic achievement. Although aerobic fitness is related to genetics, it is also related to physical activity. As the authors point out, future research needs to examine these inter-relationships more closely to determine the type and amount of regular physical activity needed to improve aerobic fitness and, ultimately, cognitive function. Article page 136<
C
alculators are used on a daily basis to manage the many numbers required for contemporary newborn practice. Numerous online tools are available to determine the treatment threshold for jaundice, estimate the risk for sepsis, and predict outcomes for prematurity, to name just a few. It is easy to take these ubiquitous calculators for granted, but it is also important to consider how they come into being. In this issue of The Journal, Wilbaux et al provide the detailed methodology and mathematical modeling they used to develop a weight loss calculator for exclusively breastfed infants. They analyzed the weight loss patterns for 1338 healthy term infants while exclusively breastfeeding during the first week of life, and then validated their model in another 300 infants. The weight change patterns proved to be a changing net balance between time-dependent rates of weight gain and weight loss. Gestational age, infant sex, and maternal age emerged as key predictors of weight gain. A particular strength of the analysis by Wilbaux et al is that it incorporates these factors to project weight changes for individual neonates, rather than simply estimate the deviation from the mean, which will be especially helpful in clinical practice. These sophisticated calculations will be accessible to pediatricians and newborn specialists through an online “NeoWeight Prediction” Tool. Meticulous observation and analysis of data from large normal populations is how the best calculators come into being. The weight prediction calculator should help identify those breastfeeding newborns at highest risk for excessive weight loss, and diminish rates of rehospitalization and other complications. Although the analysis may be “math intensive,” it is important to appreciate the solid foundation the math creates for this new online prediction tool. Article page 101<
1
Thyroid screening in trisomy 21 — Thomas R. Welch, MD
Multiplex PCR testing during respiratory infections: good for the patient, good for infection prevention and antimicrobial stewardship — Sarah S. Long, MD
When should we predict outcomes for extreme prematurity? — Robin H. Steinhorn, MD
2
C
hildren with trisomy 21 are at risk for hypothyroidism throughout life. Perhaps most important is their increased incidence of congenital hypothyroidism, because this may add to their burden of cognitive disability. Thus, it is essential to recognize congenital hypothyroidism and institute therapy in a timely way. Most children in developed nations undergo screening for congenital hypothyroidism. The precise protocol for such screening, however, varies by locale. An important question is whether there are important differences in protocols, which may impact the likelihood of making a timely diagnosis of hypothyroidism in newborns with trisomy 21. In this issue of The Journal, Erlichman et al provide the results of a retrospective study of 159 children with trisomy 21, ascertained over a 9-year period. The important take home point from their analysis is that one screening strategy (initial measurement of thyroxine [T4], with secondary thyroid-stimulating hormone measurement for those with T4 <10th percentile) would have failed to recognize congenital hypothyroidism in 10 babies. Those caring for children with trisomy 21 must be familiar with their local screening protocols for congenital hypothyroidism. It is essential that this group of children have screening that includes both T4 and thyroid-stimulating hormone. Simply assuming that a child with trisomy 21 will have had appropriate thyroid screening as part of a standard newborn protocol may miss a very important diagnosis. Article page 165<
T
he evaluation and application of molecular techniques to diagnoses of infectious diseases have been phenomenal, both in scope and pace. In this month’s issue of The Journal, Subramony et al report a retrospective “before–after” study to evaluate the impact of multiplex polymerase chain reaction (PCR) testing of respiratory tract specimens on healthcare utilization in a children’s hospital. They compared performance of chest radiograph, respiratory isolation precautions, and antibiotic use in patients whose respiratory specimens were tested by predominantly antigen detection/culture techniques (available in 2010-2012) vs multiplex PCR testing for 10 viral and bacterial pathogen groups (available 2012-2014). PCR testing detected pathogen(s) in 42% of patients compared with 14% of patients tested by older methods. In patients tested by PCR compared with others, performance of chest radiograph and prescription of $2 days of an antibiotic each was reduced $50%, and care under isolation precautions was doubled. PCR testing in the clinical arena represents 90% progress, 10% pitfall. Similar to all other tests in medicine, interpretation in context of the clinical problem is essential. Longitudinal studies of children during health show frequent and sometimes lengthy shedding of respiratory viruses while remaining symptom free. The detection of a virus does not necessarily prove causation of the patient’s illness. Additionally, because viral respiratory tract infections predispose to bacterial infections, virus detection has the potential risk of identifying the trigger but detracting attention from a secondary major bacterial threat. On the whole, PCR confirmation of the clinically suspect viral illness is reassuring, should drive use of appropriate antiviral therapy when it is indicated, and help restrict use of antibiotic therapy when it is unnecessary. Article page 196<
T
he birth of an extremely preterm infant presents a crisis in decision making for families and their caregivers. On one hand, babies who will do well should be given a chance to do just that. On the other hand, unnecessary intensive care should be avoided for those infants who are destined to die or survive with severe handicaps. This dilemma has led to the widely used Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) calculator that
Volume 173
estimates outcomes for a pregnancy at 22-25 weeks gestation based on risk factors such as gestation, estimated fetal weight, and use of betamethasone. In this issue of The Journal, Andrews et al asked whether outcomes for extreme prematurity could be predicted after birth and during therapy in the neonatal intensive care unit (NICU). They used the surprisingly simple approach of analyzing only two items in 89 ventilated extremely preterm infants—the results of head ultrasound scans and the clinical intuitions of medical caretakers predicting death before NICU discharge. Predictions for survival proved to be similar for the NICHD calculator vs the postnatal “trial of therapy” model, particularly for the infants who died before NICU discharge or survived with neurologic disability. Furthermore, even though almost all of the 35 infants who survived without neurodevelopmental impairment were predicted to do well by the “trial of therapy” model, many had predictions of worse outcomes from the NICHD calculator. Prenatal predictive models are excellent for analyzing and predicting outcomes for large populations, but provide little guidance for any individual infant after birth. The tool proposed by Andrews et al may help fill this important gap and encourage caregivers to trust in their ability to make early and valid predictions for extremely preterm infants. Even though this predictive tool still needs to be validated beyond a single NICU, the ability to provide prognostic information before and after birth will be of tremendous help to families facing difficult choices. Article page 96<
Are neonatal stroke and hypoxic-ischemic encephalopathy related? — Paul G. Fisher, MD
The Barker hypothesis revisited — Stephen R. Daniels, MD, PhD
June 2016
P
erinatal asphyxia is known to be a risk factor for neonatal arterial ischemic stroke (NAIS) and hypoxic-ischemic encephalopathy (HIE), and HIE can play a role in the pathogenesis of NAIS. Do NAIS and HIE share antepartum or intrapartum risk factors and perhaps causal pathways? In this issue of The Journal, Martinez-Biarge et al report their results from a retrospective cohort study comparing 79 infants who experienced NAIS with 239 controls and 405 babies with HIE. Male sex, as well as family history of seizures or neurologic diseases, were significantly associated with NAIS, and a number of intrapartum risk factors were associated with both NAIS and HIE: prolonged rupture of membranes, maternal fever, prolonged second stage of labor, failed vacuum delivery, and tight nuchal cord. Although newborns with NAIS and HIE both experienced higher rates, when compared with controls, of sentinel events (uterine rupture, placental abruption, cord prolapse, and maternal collapse), abnormal fetal tracing patterns, thick meconium, and shoulder dystocia, these findings were significantly more common in HIE. The findings of this study point to our pressing need to understand better the pathophysiology underlying those intrapartum events common to NAIS and stroke. More research is needed to clarify the roles of infection and other triggers of thromboinflammatory responses in the placenta and fetus that might lead to adverse intrapartum events and poor neonatal outcomes. Article page 62<
T
he Barker hypothesis focuses on the role of fetal factors and growth on subsequent life course outcomes, such as the development of obesity, diabetes, and cardiovascular disease. As the hypothesis has been further developed into a developmental origin of disease concept, the impact of postnatal growth and other factors has become apparent. In this issue of The Journal, Perng et al evaluated the impact of birth size and early weight gain on obesity and cardiometabolic health in midchildhood. They found that gain in body mass index after 1 year appears to work independent of size at birth, whereas the influence of weight gain during the first year of life may differ depending on size at birth. This creates a more complicated set of relationships but also may help to clarify how we may identify groups at higher risk of developing obesity in the future. Article page 122< 3
Aerobic fitness and academic achievement — Stephen R. Daniels, MD, PhD
Math at work: a new neonatal calculator to predict weight loss — Robin H. Steinhorn, MD
Copyright ª 2016 by Elsevier Inc.
T
here has been considerable interest in the relationship between physical activity and academic performance. This has been especially true as schools have adopted increased classroom time in response to the perceived need to improve scores on standardized tests. Often, opportunities for physical activity have been decreased in the process of increasing class time. This may have contributed to the increased prevalence of obesity among children and adolescents. There also has been concern that this approach may be short-sighted because physical activity may improve academic performance. In this issue of The Journal, Pindus et al report on the results of a study to evaluate the relationship of moderate-to-vigorous physical activity and academic achievement. They evaluated this while also including physical fitness measured using a standard exercise test as a covariable, which has not been done in many previous studies. They found that aerobic fitness, rather than daily physical activity, was associated with measures of academic achievement. Although aerobic fitness is related to genetics, it is also related to physical activity. As the authors point out, future research needs to examine these inter-relationships more closely to determine the type and amount of regular physical activity needed to improve aerobic fitness and, ultimately, cognitive function. Article page 136<
C
alculators are used on a daily basis to manage the many numbers required for contemporary newborn practice. Numerous online tools are available to determine the treatment threshold for jaundice, estimate the risk for sepsis, and predict outcomes for prematurity, to name just a few. It is easy to take these ubiquitous calculators for granted, but it is also important to consider how they come into being. In this issue of The Journal, Wilbaux et al provide the detailed methodology and mathematical modeling they used to develop a weight loss calculator for exclusively breastfed infants. They analyzed the weight loss patterns for 1338 healthy term infants while exclusively breastfeeding during the first week of life, and then validated their model in another 300 infants. The weight change patterns proved to be a changing net balance between time-dependent rates of weight gain and weight loss. Gestational age, infant sex, and maternal age emerged as key predictors of weight gain. A particular strength of the analysis by Wilbaux et al is that it incorporates these factors to project weight changes for individual neonates, rather than simply estimate the deviation from the mean, which will be especially helpful in clinical practice. These sophisticated calculations will be accessible to pediatricians and newborn specialists through an online “NeoWeight Prediction” Tool. Meticulous observation and analysis of data from large normal populations is how the best calculators come into being. The weight prediction calculator should help identify those breastfeeding newborns at highest risk for excessive weight loss, and diminish rates of rehospitalization and other complications. Although the analysis may be “math intensive,” it is important to appreciate the solid foundation the math creates for this new online prediction tool. Article page 101<
1
Thyroid screening in trisomy 21 — Thomas R. Welch, MD
Multiplex PCR testing during respiratory infections: good for the patient, good for infection prevention and antimicrobial stewardship — Sarah S. Long, MD
When should we predict outcomes for extreme prematurity? — Robin H. Steinhorn, MD
2
C
hildren with trisomy 21 are at risk for hypothyroidism throughout life. Perhaps most important is their increased incidence of congenital hypothyroidism, because this may add to their burden of cognitive disability. Thus, it is essential to recognize congenital hypothyroidism and institute therapy in a timely way. Most children in developed nations undergo screening for congenital hypothyroidism. The precise protocol for such screening, however, varies by locale. An important question is whether there are important differences in protocols, which may impact the likelihood of making a timely diagnosis of hypothyroidism in newborns with trisomy 21. In this issue of The Journal, Erlichman et al provide the results of a retrospective study of 159 children with trisomy 21, ascertained over a 9-year period. The important take home point from their analysis is that one screening strategy (initial measurement of thyroxine [T4], with secondary thyroid-stimulating hormone measurement for those with T4 <10th percentile) would have failed to recognize congenital hypothyroidism in 10 babies. Those caring for children with trisomy 21 must be familiar with their local screening protocols for congenital hypothyroidism. It is essential that this group of children have screening that includes both T4 and thyroid-stimulating hormone. Simply assuming that a child with trisomy 21 will have had appropriate thyroid screening as part of a standard newborn protocol may miss a very important diagnosis. Article page 165<
T
he evaluation and application of molecular techniques to diagnoses of infectious diseases have been phenomenal, both in scope and pace. In this month’s issue of The Journal, Subramony et al report a retrospective “before–after” study to evaluate the impact of multiplex polymerase chain reaction (PCR) testing of respiratory tract specimens on healthcare utilization in a children’s hospital. They compared performance of chest radiograph, respiratory isolation precautions, and antibiotic use in patients whose respiratory specimens were tested by predominantly antigen detection/culture techniques (available in 2010-2012) vs multiplex PCR testing for 10 viral and bacterial pathogen groups (available 2012-2014). PCR testing detected pathogen(s) in 42% of patients compared with 14% of patients tested by older methods. In patients tested by PCR compared with others, performance of chest radiograph and prescription of $2 days of an antibiotic each was reduced $50%, and care under isolation precautions was doubled. PCR testing in the clinical arena represents 90% progress, 10% pitfall. Similar to all other tests in medicine, interpretation in context of the clinical problem is essential. Longitudinal studies of children during health show frequent and sometimes lengthy shedding of respiratory viruses while remaining symptom free. The detection of a virus does not necessarily prove causation of the patient’s illness. Additionally, because viral respiratory tract infections predispose to bacterial infections, virus detection has the potential risk of identifying the trigger but detracting attention from a secondary major bacterial threat. On the whole, PCR confirmation of the clinically suspect viral illness is reassuring, should drive use of appropriate antiviral therapy when it is indicated, and help restrict use of antibiotic therapy when it is unnecessary. Article page 196<
T
he birth of an extremely preterm infant presents a crisis in decision making for families and their caregivers. On one hand, babies who will do well should be given a chance to do just that. On the other hand, unnecessary intensive care should be avoided for those infants who are destined to die or survive with severe handicaps. This dilemma has led to the widely used Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) calculator that
Volume 173
estimates outcomes for a pregnancy at 22-25 weeks gestation based on risk factors such as gestation, estimated fetal weight, and use of betamethasone. In this issue of The Journal, Andrews et al asked whether outcomes for extreme prematurity could be predicted after birth and during therapy in the neonatal intensive care unit (NICU). They used the surprisingly simple approach of analyzing only two items in 89 ventilated extremely preterm infants—the results of head ultrasound scans and the clinical intuitions of medical caretakers predicting death before NICU discharge. Predictions for survival proved to be similar for the NICHD calculator vs the postnatal “trial of therapy” model, particularly for the infants who died before NICU discharge or survived with neurologic disability. Furthermore, even though almost all of the 35 infants who survived without neurodevelopmental impairment were predicted to do well by the “trial of therapy” model, many had predictions of worse outcomes from the NICHD calculator. Prenatal predictive models are excellent for analyzing and predicting outcomes for large populations, but provide little guidance for any individual infant after birth. The tool proposed by Andrews et al may help fill this important gap and encourage caregivers to trust in their ability to make early and valid predictions for extremely preterm infants. Even though this predictive tool still needs to be validated beyond a single NICU, the ability to provide prognostic information before and after birth will be of tremendous help to families facing difficult choices. Article page 96<
Are neonatal stroke and hypoxic-ischemic encephalopathy related? — Paul G. Fisher, MD
The Barker hypothesis revisited — Stephen R. Daniels, MD, PhD
June 2016
P
erinatal asphyxia is known to be a risk factor for neonatal arterial ischemic stroke (NAIS) and hypoxic-ischemic encephalopathy (HIE), and HIE can play a role in the pathogenesis of NAIS. Do NAIS and HIE share antepartum or intrapartum risk factors and perhaps causal pathways? In this issue of The Journal, Martinez-Biarge et al report their results from a retrospective cohort study comparing 79 infants who experienced NAIS with 239 controls and 405 babies with HIE. Male sex, as well as family history of seizures or neurologic diseases, were significantly associated with NAIS, and a number of intrapartum risk factors were associated with both NAIS and HIE: prolonged rupture of membranes, maternal fever, prolonged second stage of labor, failed vacuum delivery, and tight nuchal cord. Although newborns with NAIS and HIE both experienced higher rates, when compared with controls, of sentinel events (uterine rupture, placental abruption, cord prolapse, and maternal collapse), abnormal fetal tracing patterns, thick meconium, and shoulder dystocia, these findings were significantly more common in HIE. The findings of this study point to our pressing need to understand better the pathophysiology underlying those intrapartum events common to NAIS and stroke. More research is needed to clarify the roles of infection and other triggers of thromboinflammatory responses in the placenta and fetus that might lead to adverse intrapartum events and poor neonatal outcomes. Article page 62<
T
he Barker hypothesis focuses on the role of fetal factors and growth on subsequent life course outcomes, such as the development of obesity, diabetes, and cardiovascular disease. As the hypothesis has been further developed into a developmental origin of disease concept, the impact of postnatal growth and other factors has become apparent. In this issue of The Journal, Perng et al evaluated the impact of birth size and early weight gain on obesity and cardiometabolic health in midchildhood. They found that gain in body mass index after 1 year appears to work independent of size at birth, whereas the influence of weight gain during the first year of life may differ depending on size at birth. This creates a more complicated set of relationships but also may help to clarify how we may identify groups at higher risk of developing obesity in the future. Article page 122< 3