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Inflammation-related proteins and brain injury in preterm infants
Breastfeeding and epilepsy —Alan H. Jobe, MD, PhD
Periconceptional febrile illnesses and congenital heart defects —Sarah S. Long, MD
Inflammation-related proteins and brain injury in preterm infants —Alan H. Jobe, MD, PhD
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A
ll will agree that breastfeeding is the optimal source of nutrition for the healthy term infant. The adverse associations with not breastfeeding have been extensively discussed. In this issue of The Journal, a new association is identified: a dose response effect of breastfeeding for a decreased risk of epilepsy. This study from the Danish National Birth Cohort includes large numbers of children from a population with a high rate of breastfeeding. The correlation between breastfeeding and decreased epilepsy is striking, but the explanation for the association is presently unknown. The authors propose the biologically plausible benefits of the nutritional value of human milk on brain growth and development as a likely explanation. However, the reasons for mothers to not breastfeed are not known in this cohort, and associated illness in the mothers or children may contribute to the findings. This epidemiologic study certainly is hypothesis-generating. Article page 924<
T
hrough a large population-based case control study, Oster et al add precision to the evidence of effects of maternal illness on the likelihood of congenital heart defects (CHD) in offspring. The specificity of the events considered (ie, ‘‘fever of 101 F or higher’’ or ‘‘influenza [flu]’’ in the periconceptional period from 3 months prior to conception until 3 months of gestation) and outcomes found (ie, statistically significantly increased odds ratio for right-sided obstructive lesions, as well as atrioventricular septal defects in cases with Down syndrome, but no association with CHD in aggregate) are impressive. Investigators also found that use of antipyretics tended to decrease these associations. An important limitation of the study is that the specific antipyretic agents used were not analyzed. Effects of use of antipyretics in pregnancy are controversial; some studies suggest increased odds of congenital defects with exposure to certain agents. It is noteworthy that the time period of this study preceded widespread use of non-steroidal anti-inflammatory agents. The authors provide an excellent review of previous studies that sought relationship of maternal illnesses with CHD, with discussion of their study methodology and findings in context. There is food for thought regarding pathophysiology, further impetus for implementation of universal annual influenza vaccination policy, and reason to consider treating febrile illness in the periconceptional period with antipyretic therapy, such as acetaminophen. Article page 990<
A
number of years ago, it was believed that brain and lung injury in preterm infants would be directly linked to selective pro-inflammatory cytokines or other inflammatory proteins. This belief was based on solid neurodevelopmental science and lung biology, demonstrating that potent injuries resulted from pro-inflammatory exposures in model systems. All that is needed to sort out the clinical predictors would be analytic techniques for multiple inflammatory mediators and large cohorts of well-characterized preterm infants. There have now been a number of reports measuring multiple pro-inflammatory mediators at selected times after preterm birth in large cohorts, suggesting that a search for a clean inflammatory signal (eg, a cytokine, a pattern of cytokines) may be fruitless. In The Journal, Paananen et al (J Pediatr 2009;154:39-43), reported some significant time dependent trends for the association of cytokines with BPD, as did Ambalavanan et al (Pediatrics 2009;123:1132-41). Leviton et al now report that of 25 proteins measured in blood, VEGF-R1, serum amyloid A, MIP-IB, and IL-8 increased the risk of ventriculomegaly at selected times after birth in a population of 728 infants born before 28 weeks gestation. My take on these reports is that they are far more negative (no helpful associations) than positive. There is no question that preterm birth is associated with inflammation (eg, chorioamnionitis, postnatal sepsis, necrotizing enterocolitis, bronchopulmonary displasia) or that preterm infants have increased risks of poor neurodevelopmental outcomes. However, these large data sets are demonstrating elevated pro-inflammatory profiles of the entire population, perhaps masking the specificity anticipated for these measurements. Vol. 158, No. 6
Furthermore, several of the reports utilize blood, not plasma, for the measurements, which may reflect cellular, not bioactive, levels of the mediators. Although the hypothesis that pro-inflammation before and after preterm delivery promotes bronchopulmonary displasia and neuro-injury is probably correct, the search for a signature (biomarker) in blood or plasma has been expensive and not very productive. Article page 897<
What constitutes ‘‘normal’’ 25(OH)D? —Thomas R. Welch, MD
The PDA–of mice and not man —Alan H. Jobe, MD, PhD
June 2011
O
ver the past decade, we have learned that calciferol has a number of very important biologic functions beyond its skeletal effects. This was nicely reviewed in a recent Medical Progress report by Russell Chesney (J Pediatr 2011;156:698-703). This understanding has resulted in a number of studies examining the frequency of calciferol deficiency in various groups. A problem of these studies, however, has been defining ‘‘sufficiency’’ of this analyte. Studies that have used measures of bone turnover or parathyroid hormone as evidence of sufficiency may not reflect the levels that are ‘‘normal’’ for calciferol’s non-skeletal effects. In the current issue of The Journal, Zhou et al measured 25(OH)D levels in a population of obese adolescents, and used statistical methods to identify the cutpoints at which increasing levels had no further relationship with the outcome measure being examined. Systolic blood pressure and triglycerides had these levels at 27 and 18 ng/ ml, respectively. This work is clearly preliminary, and we can expect to see many more similar studies in the coming years. It is becoming increasingly evident, however, that in terms of the myriad of non-skeletal effects of calciferol, our current definitions of ‘‘normal’’ may need to be adjusted, depending upon the particular function of the analyte being considered. Article page 930<
T
he mantra for the National Institutes of Health is to promote translational research that will improve outcomes in humans. And not all animal model research translates very well. Shah et al have carefully and elegantly defined the mechanisms and mediators that promote ductal patency and closure over many years in animal models and preterm infants. The use of indomethacin or ibuprofen to close the ductus arteriosis or prostaglandin infusions to keep the ductus open are superb examples of the application of physiology to human disease. In mice, platelets are required to maintain ductal closure following birth. In this issue of The Journal, Shah et al report that, in contrast to mice, there is no correlation between platelet counts and ductal closure with indomethacin in preterm infants. So be it. Article page 919<
A3
Periconceptional febrile illnesses and congenital heart defects —Sarah S. Long, MD
Inflammation-related proteins and brain injury in preterm infants —Alan H. Jobe, MD, PhD
A2
A
ll will agree that breastfeeding is the optimal source of nutrition for the healthy term infant. The adverse associations with not breastfeeding have been extensively discussed. In this issue of The Journal, a new association is identified: a dose response effect of breastfeeding for a decreased risk of epilepsy. This study from the Danish National Birth Cohort includes large numbers of children from a population with a high rate of breastfeeding. The correlation between breastfeeding and decreased epilepsy is striking, but the explanation for the association is presently unknown. The authors propose the biologically plausible benefits of the nutritional value of human milk on brain growth and development as a likely explanation. However, the reasons for mothers to not breastfeed are not known in this cohort, and associated illness in the mothers or children may contribute to the findings. This epidemiologic study certainly is hypothesis-generating. Article page 924<
T
hrough a large population-based case control study, Oster et al add precision to the evidence of effects of maternal illness on the likelihood of congenital heart defects (CHD) in offspring. The specificity of the events considered (ie, ‘‘fever of 101 F or higher’’ or ‘‘influenza [flu]’’ in the periconceptional period from 3 months prior to conception until 3 months of gestation) and outcomes found (ie, statistically significantly increased odds ratio for right-sided obstructive lesions, as well as atrioventricular septal defects in cases with Down syndrome, but no association with CHD in aggregate) are impressive. Investigators also found that use of antipyretics tended to decrease these associations. An important limitation of the study is that the specific antipyretic agents used were not analyzed. Effects of use of antipyretics in pregnancy are controversial; some studies suggest increased odds of congenital defects with exposure to certain agents. It is noteworthy that the time period of this study preceded widespread use of non-steroidal anti-inflammatory agents. The authors provide an excellent review of previous studies that sought relationship of maternal illnesses with CHD, with discussion of their study methodology and findings in context. There is food for thought regarding pathophysiology, further impetus for implementation of universal annual influenza vaccination policy, and reason to consider treating febrile illness in the periconceptional period with antipyretic therapy, such as acetaminophen. Article page 990<
A
number of years ago, it was believed that brain and lung injury in preterm infants would be directly linked to selective pro-inflammatory cytokines or other inflammatory proteins. This belief was based on solid neurodevelopmental science and lung biology, demonstrating that potent injuries resulted from pro-inflammatory exposures in model systems. All that is needed to sort out the clinical predictors would be analytic techniques for multiple inflammatory mediators and large cohorts of well-characterized preterm infants. There have now been a number of reports measuring multiple pro-inflammatory mediators at selected times after preterm birth in large cohorts, suggesting that a search for a clean inflammatory signal (eg, a cytokine, a pattern of cytokines) may be fruitless. In The Journal, Paananen et al (J Pediatr 2009;154:39-43), reported some significant time dependent trends for the association of cytokines with BPD, as did Ambalavanan et al (Pediatrics 2009;123:1132-41). Leviton et al now report that of 25 proteins measured in blood, VEGF-R1, serum amyloid A, MIP-IB, and IL-8 increased the risk of ventriculomegaly at selected times after birth in a population of 728 infants born before 28 weeks gestation. My take on these reports is that they are far more negative (no helpful associations) than positive. There is no question that preterm birth is associated with inflammation (eg, chorioamnionitis, postnatal sepsis, necrotizing enterocolitis, bronchopulmonary displasia) or that preterm infants have increased risks of poor neurodevelopmental outcomes. However, these large data sets are demonstrating elevated pro-inflammatory profiles of the entire population, perhaps masking the specificity anticipated for these measurements. Vol. 158, No. 6
Furthermore, several of the reports utilize blood, not plasma, for the measurements, which may reflect cellular, not bioactive, levels of the mediators. Although the hypothesis that pro-inflammation before and after preterm delivery promotes bronchopulmonary displasia and neuro-injury is probably correct, the search for a signature (biomarker) in blood or plasma has been expensive and not very productive. Article page 897<
What constitutes ‘‘normal’’ 25(OH)D? —Thomas R. Welch, MD
The PDA–of mice and not man —Alan H. Jobe, MD, PhD
June 2011
O
ver the past decade, we have learned that calciferol has a number of very important biologic functions beyond its skeletal effects. This was nicely reviewed in a recent Medical Progress report by Russell Chesney (J Pediatr 2011;156:698-703). This understanding has resulted in a number of studies examining the frequency of calciferol deficiency in various groups. A problem of these studies, however, has been defining ‘‘sufficiency’’ of this analyte. Studies that have used measures of bone turnover or parathyroid hormone as evidence of sufficiency may not reflect the levels that are ‘‘normal’’ for calciferol’s non-skeletal effects. In the current issue of The Journal, Zhou et al measured 25(OH)D levels in a population of obese adolescents, and used statistical methods to identify the cutpoints at which increasing levels had no further relationship with the outcome measure being examined. Systolic blood pressure and triglycerides had these levels at 27 and 18 ng/ ml, respectively. This work is clearly preliminary, and we can expect to see many more similar studies in the coming years. It is becoming increasingly evident, however, that in terms of the myriad of non-skeletal effects of calciferol, our current definitions of ‘‘normal’’ may need to be adjusted, depending upon the particular function of the analyte being considered. Article page 930<
T
he mantra for the National Institutes of Health is to promote translational research that will improve outcomes in humans. And not all animal model research translates very well. Shah et al have carefully and elegantly defined the mechanisms and mediators that promote ductal patency and closure over many years in animal models and preterm infants. The use of indomethacin or ibuprofen to close the ductus arteriosis or prostaglandin infusions to keep the ductus open are superb examples of the application of physiology to human disease. In mice, platelets are required to maintain ductal closure following birth. In this issue of The Journal, Shah et al report that, in contrast to mice, there is no correlation between platelet counts and ductal closure with indomethacin in preterm infants. So be it. Article page 919<
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