The 2015 Pediatric Research That Should Change Practice

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Original article written by Alan Greene, MD and Laurie Scudder, DNP, PNP for Medscape Pediatrics on February 11, 2016. Click here to read the original article.

Editor’s Note:
Keeping up with the relentless body of literature in specialty journals is a daunting task for pediatric primary care providers. Nevertheless, keep up they must; much of this new research affects day-to-day practice and, crucially, early detection and management of numerous conditions that first present in the primary care setting. Medscape spoke with Alan Greene, MD, a Medscape advisor, adjunct professor of pediatrics at Stanford University School of Medicine, and founder and CEO of DrGreene.com, about his picks of the most interesting and important studies in 2015 and their implications for practice.

Medscape: A number of studies in the last 12 months have added yet more urgency to the concerns regarding the dangers of child obesity. A paper[1] relying on data from recent National Health and Nutrition Examination Surveys (NHANES) found that less than 1% of US children had an ideal healthy diet score. Type 2 diabetes rates are rising, and another paper[2] found that long-term complications and mortality were worse in these children than their counterparts with type 1 diabetes. New data show that sweetened beverages, including milk products, are a major contributor to obesity.[3] Yet another study, this one conducted in Iran, found that breastfeeding is protective well into childhood.[4] Despite our growing recognition of factors that contribute to obesity, a solution is still elusive and difficult. What are your key take-away messages from the last years’ worth of research, and how do you suggest making it practical and implementable in the primary care setting?

Dr Greene: The study examining NHANES data[1] is striking in that it was looking for a measurable index of cardiovascular (CV) health in kids so that we could see where we are and where we’re going in the future as lifestyle and interventions change. By and large, the researchers found that the overwhelming majority of babies enter the world with pristine CV systems, with hearts and blood vessels that are supple, powerful, and beautiful. However, by the time they are adolescents, under our watch as pediatricians, the great majority of children have already developed significant CV risk factors.

This is a fairly recent phenomenon. When I started in pediatrics, it was very unusual to see a child with elevated blood pressure. Today, there are millions of children in the United States with elevated blood pressure. It used to be unusual to see kids with elevated serum cholesterol or triglycerides or with a waist size of 36 or 40 inches. It was unusual to see kids with elevated glucose unless they had type 1 diabetes.

Today, two thirds of American middle school and high school students already have at least one of those conditions that used to wait until middle age. These data add urgency to the obesity epidemic we currently see. It’s a metabolic ticking time bomb.

The study examining children with young-onset diabetes[2] was equally eye-popping. Traditionally, many of us breathe a sigh of relief when we hear that diabetes is type 2 as opposed to type 1. We know the severity of type 1 diabetes in kids. But this study found that type 2 diabetes in childhood and adolescence actually has more morbidity and greater mortality than type 1, the opposite of that traditional wisdom. We should be even more concerned with kids when they develop type 2 diabetes.

This finding was shocking to me, and I pay close attention to this literature. It lends, again, more urgency to the situation. One little side note from this study is about sweetened beverages as a contributor not just to obesity but to type 2 diabetes. We are already aware of the link between obesity and sugary drinks, sugary sodas, juices, and juice-like beverages. But this study found a strong association with chocolate milk and sweetened milk and type 2 diabetes.

Given this new urgency regarding the risks of diseases comorbid with obesity, what do we do? There are a few things. This is a dominant medical issue of our time, and it belongs as part of every well child visit, something that we’re measuring and tracking over time and helping families to learn key messages with every visit. In early childhood, especially in the first couple of years of life, feeding early and often the flavors and textures that you want kids to learn to love can have a profound trajectory on what kids learn to like and is the key to building good food habits from the start. We need to encourage family meals from the beginning, tell parents to not give up on vegetables, introduce a lot of variety, and serve something green at every lunch and every dinner.

Once kids have really set their initial tastes, by around age 2 or 3 years, one of the most effective ways to get them to like better food is to have them involved in the process, to have family meals at home where everybody is eating some of the same food. In particular, get kids involved in meal prep, go to the farmer’s market to select the foods, and, for families that have the option, get kids involved in growing real food. Cooking classes are one of the most fun things that parents can do with children to get them involved in preparing food they will enjoy and that their bodies will also enjoy.

Medscape: Those are recommendations that are easily implemented and understood by families and provide good advice for clinicians practicing in more resourced areas. But what about those kids who live in stressed, urban environments? Are there practical suggestions for those families that we are missing?

Dr Greene: Smartphones are very prevalent in less advantaged communities. One of the key nutritional barriers these families face, families that reside in food deserts where healthy food is difficult to access, is finding interesting and tasty foods among what is available and learning which foods are the healthiest.

One free Smartphone app that I like is Fooducate. The app allows you to scan any barcode, gives you a letter grade (A, B, or C) for how healthy that food is, and suggests others in the same category that might be healthier. The app ranks foods on both flavor and nutrition and can help lead consumers in a positive direction.

Medscape: This sounds like the kind of thing children would find fun to do at a store.

Dr Greene: Exactly. It’s a great way to eliminate food battles at a grocery store. Parents can tell children they can pick anything that’s a B or better.

Sodium: The Underreported Food Concern for Children

Medscape: Another report,[5] also based on data from NHANES, concluded that US school-aged children, on average, consume sodium in excess of recommended levels regardless of age, sex, race/ethnicity, income, or weight status. Unlike the attention paid to sweetened beverages, sodium doesn’t get as much press. What is the current state of evidence regarding hazards of excessive sodium intake in children?

Dr Greene: Sodium often doesn’t get enough attention. To provide some context, in the early 1970s, Finland had the highest rate of hypertension and one of the highest levels of CV disease, heart attacks, and stroke of any country on the planet. As a country, they decided to take that on and implemented a number of population-wide public health measures, and they were able to get their average national blood pressure down to normal. One of the big ones was that they decreased the average sodium intake by over 25% to reach recommended levels. It had a profound national impact. Very seldom do you see such a major public health advance.

The Centers for Disease Control and Prevention estimates that if we could reach the recommended sodium intake level of 2300 mg/person/day in the United States—perhaps even a generous recommended level—that we would save between 280,000 and 500,000 lives over the next 10 years, not to mention the improved health, brain health, and physical activity that could be had. It’s a big issue. This study published in the MMWR looked at sodium intake among school-aged kids and found that the average daily sodium consumption in children was 3279 mg/day, almost 1000 mg/day above the recommended level of 2300 mg/day. Consumption is even higher among high school students. Most of the sodium intake comes from 10 food categories together: pizza; breads and rolls; cold cuts; savory snacks; sandwiches; cheese; chicken patties, tenders, or nuggets; pasta mix dishes; Mexican mix dishes, and soups.

Becoming more aware of sources of sodium in the average child’s diet and looking for options that are made flavorful can have a profound impact. Sodium, especially in processed foods, is often hidden. People are aware that there is sodium in their fast food French fries. They may not be aware that the milkshake may have more sodium than the French fries.

Sleep: Kids Are Just Not Getting Enough

Medscape: The importance of sufficient sleep as a major contributor to both physical and psychosocial well-being is increasingly recognized. In late 2014, the American Academy of Pediatrics Adolescent Sleep Working Group issued a policy statement[6] urging schools to consider delaying start time in order to allow middle and high school students to achieve sufficient sleep. Dealing with sleep and sleep-related problems, however, can be daunting, particularly in a primary care setting with limited time. Can you summarize the latest research examining brief interventions that can be deployed in the primary care setting to promote healthy sleep?

Dr Greene: I do think that one of the roles of pediatricians is advocacy. The literature would suggest that delaying school start timesto at least 8:30 in the morning would improve health in a variety of ways, including reductions in obesity, hypertension, and attention-deficit/hyperactivity disorder. It would improve mood, decrease depression and suicidal thoughts or actions, and decrease car accidents in teen drivers.

Where this change has been implemented, that is exactly what has been found. This is an intervention that works, but many school districts are reluctant to adopt this change for a variety of practical reasons. It’s a great issue, and pediatricians should get involved by speaking, writing or calling their local school board, and letting their community know that we as a profession are behind this. The Academy of Pediatrics is behind it, but we as local pediatricians must also say clearly that we are behind it.

As far as things to do in the office, one of my favorites is to try to support the circadian rhythm, so named because it’s “circa dian.” It’s about a day. For most of us, it would be about a 25-hour rhythm where not only do we have sleepiness and arousal that rise and fall, but we also have fluctuations in blood pressure, body temperature, and many hormones. It is a profound rhythm that we share with other living beings that is reset daily by certain cues from the environment. We are seasonal creatures. If we were in a cave and had none of these external cues, our circadian rhythm would eventually get completely off from other people in the external world. But for us, that rhythm is reset by something called zeitgebers.

Zeitgebers are our friends. The more they are in line with each other and the more they are consistent, then the better, longer, and deeper sleep we have. The most profound zeitgeber is probably light. We are very light-sensitive creatures. When we look back before the invention of the electric light bulb, kids tended to sleep like a baby—all night long, soundly, profoundly without waking up, even if there was a loud noise. Today sleeping like a baby often means waking up crying every couple of hours. Sleep for teenagers is often something that’s disrupted as well. Childhood sleep is not as peaceful as it used to be.

One thing that we can do is try to keep the environment as dim as possible between sunset and sunrise. That can have a profound impact on sleep. When you’re camping, you tend to get very drowsy a couple of hours after sunset. That’s difficult in our modern, urban, digital life, but the more we can at least remove the wavelengths of light that trigger melatonin suppression, the easier it is to sleep.

That means paying attention to screens. There are now apps for a variety of different computer and smartphone screens that will pull out the blue wavelength of light, about 475 nm. You can get light bulbs that pull out that wavelength of light in the evening or wear blue-blocker sunglasses to get rid of it. There is a pigment in the retina, melanopsin, that responds to a 475-nm signal and suppresses melatonin or disorganizes it for the rest of the night. Eliminating that sunset to sunrise is a rather simple thing that can help people get drowsy earlier. Part of that means not viewing screens in the last hour or so before bed at least.

Another strong zeitgeber is temperature. For most of the history of humanity, we have experienced our evenings and nights as much cooler than daytime; but with central air and central heating, we have compressed our temperature window in a very narrow range. Creating a cooler nighttime environment, 7 degrees cooler or more, helps with falling and staying asleep.

 

Iron Status in Infants: Does It Matter?

Medscape: Delaying cord clamping after birth for approximately 3 minutes has been demonstrated to result in improved iron stores in infants up to 4 months of age.[7] A follow-up paper[8] published earlier this year examined the effects of those increased iron stores on neurodevelopment and concluded that the practice benefits fine motor and social skills in early childhood, particularly among boys. This finding is in contrast to a systematic review[9] that concluded that while there may be some evidence demonstrating that routine iron supplementation in children 6-24 months of age may improve hematologic values, evidence of an improvement in clinical outcomes, including developmental outcomes, is lacking. How should pediatric providers be monitoring—and potentially addressing—iron insufficiency in young children?

Dr Greene: The systematic review[9] article earlier this year did suggest that there is not conclusive evidence that testing for iron deficiency anemia by checking hemoglobin and hematocrit and then supplementing with iron does anything to improve developmental outcomes. You can change the hematologic indices, but we may or may not be able to change the cognitive deficits and behavior problems that we do see with iron deficiency.

That review is still somewhat controversial. These researchers were not able to detect a difference in development with screening and subsequent iron supplementation. The US Preventive Services Task Force also now thinks that there is insufficient evidence to recommend routine iron screening.[10] Of note, the issue of iron supplementation was called into question this year with publication of a very interesting paper[7] suggesting a powerful impact from an easier intervention. That is something I would call optimal cord clamping. It’s often called delayed cord clamping in the literature, but I favor the term “optimal.” I don’t think it’s delayed.

The story here is that at the moment a baby is born, about a third of their blood is still circulating in the placenta and umbilical cord. For most of human history, people would watch the cord pulse and pump blood into the baby, largely eliminating iron deficiency anemia. With that blood, the cord would also pump in oxygen, oxygen-carrying capacity in the red blood cells, white blood cells, antibodies, stem cells—a whole host of good things.

But in the early 20th century, the medical community decided to clamp the cord immediately after birth so that we could examine the child. In doing that, we separated ourselves from our history as a species. It’s not just us. There is not one known mammalian species that actively cuts the cord prior to it stopping pulsing.

The idea of waiting an extra maybe 90 seconds to 3 minutes after the baby is born is now supported by published studies looking at the neurodevelopment in kids that had this extra bolus of iron at birth as humans typically had in the past; researchers found improved fine motor and social skills years later, particularly in boys.[11] That’s a zero-cost and easy way to help kids start off with a better iron store.

The American Academy of Pediatrics recommends that exclusively breastfed kids be supplemented with iron.[12] I think that’s a reasonable thing to do, but it kind of raises the question of why? Breast milk is presumably the perfect food, the ideal food for human babies. Why would it not have enough iron? There are two important nutrients that kids seem to need that are not present in breast milk. One of those is vitamin D, and that makes sense because historically we got very little vitamin D from breast milk and a lot of it from the sun. Now that children spend most of their childhood indoors, they need another source.

The second nutrient is iron. Is that because the kids weren’t getting iron supplements or iron-fortified cereals throughout history? I think the reason is that kids historically got a big bolus of iron from a different direction, and restoring that would be a simple way to help improve iron status throughout childhood.

Medscape: You note that the rationale behind earlier cord clamping was to allow examination of the child. Were concerns about maternal-fetal transfusion another reason for implementation of immediate clamping?

Dr Greene: There wasn’t a concern at the time about jaundice or maternal-fetal transfusion. The change happened around 1913. One of the big reasons was a concern about maternal hemorrhage. The thought was that immediate clamping would be safe for the baby and safer for the mom in terms of hemorrhage.

It turns out that earlier clamping did nothing to reduce hemorrhage. And while it did allow quick examination and resuscitation of the child if necessary, you don’t need to clamp the cord to examine and resuscitate a child. The extra blood and oxygen that the infant is getting during that golden minute is exactly what we’d want to be giving them anyway.

 

What About the Microbiome?

Medscape: The microbiome continues to be a fascinating area of research with better recognition that microbiota are ecologically engineered by mothers and breastmilk. Can you review what we’ve learned in the last year, particularly in regard to the influence of breast milk on both fetal and postnatal development?

Dr Greene: There are a number of risk factors that we know influence the odds that a child will end up developing allergies. Examples are type of delivery (caesarean vs vaginal), exposure to smoking in the household, pets or no pets, birth order of the child, urban vs rural residence, and breast-fed vs formula-fed.

The thing that is striking is that all of those seemingly separate risk factors each have a profound influence on the developing microbiome in the baby. The microbiome may be the common pathway in the development of allergic disease, atopic disease, and eczema.

It is surprising to learn that there are more than 200 ingredients in breast milk that are not digestible and do not directly nourish the baby. Why are they there? Well, it turns out that they cultivate a particular microbiome and nourish the bacteria colonizing the infant’s gut.

There are a growing number of studies that provide evidence of a long shadow from the microbiome that colonizes a child. In particular, some of these studies are looking at the relationship between the type of bacteria with which a child is colonized, short-term symptoms like cough, and long-term symptoms like childhood obesity.

One of the things that we have learned is that, in addition to the gut microbiome that is most familiar to us, there is also a genital microbiome. There is a skin microbiome, varying skin microbiomes, an oral microbiome, and the nasal microbiome.

Recently we’ve learned that the placenta, which we used to think was sterile, has its own microbiome. The developing baby is influenced by a community of bacteria as well. It turns out that the placental microbiome that people thought would be similar to mom’s vaginal microbiome is not, nor is it similar to the gut microbiome. It is actually closest to the oral microbiome for reasons we haven’t really learned yet.

Just prior to birth, the infant gut is sterile. However, the gut is colonized early on, and that early colonization depends on two things. First, it depends on what bacteria the baby is exposed to early on. For a caesarean -section baby, the first bacteria may be mom’s skin bacteria. For a vaginally delivered infant, that exposure may be vaginal and gut bacteria. Maternal stool is often involved in delivery, and that may be a nonaccidental part of the system.

The second factor that affects early infant gut colonization is the food that is nourishing the bacteria. Breast milk contains a certain set of bacteria linked to mom’s gut. Formula contains other, often more inflammatory types of bacteria.

Most of us are aware of the alteration in the gut microbiome associated with antibiotics, but as you know, there are many other factors out there that will disrupt the microbiome. Sometimes those disruptions are inevitable. We’re going to have to alter that gut microbiota, so what are the implications? Is that something that should factor into a decision whether or not to treat a child with an antimicrobial? Where does that leave us with probiotics? Is that something that should be initiated or not? Do we have the answers to those questions yet?

There are a number of studies showing hints of long-term problems with antibiotics. We know that in livestock, antibiotics have been used as growth promoters to help fatten up cattle more quickly. There are some suggestions that antibiotics could also produce obesity in kids.

Disruptions in microbiota may also be associated with autoimmune problems. One recent study this year found an association between antibiotic use and development of arthritis in kids.[13] We just have glimpses of what those connections may be and don’t know the full picture. But we do know that as many as 50%, maybe more, of the antibiotics that are given to children for respiratory conditions are not helpful.[14,15] It makes all the sense in the world to reserve antibiotics for when they are most useful and most necessary.

Clearly antibiotics have been one of the greatest discoveries and inventions in the history of humanity, but reserving them for situations where they’re most necessary only makes them more powerful and can help eliminate some of the unintended consequences we don’t even understand yet.

On the probiotic side, there’s also a lot we don’t know. There have been some studies going back more than 100 years showing that yogurt, for instance, led to improved health and longevity. There have been a number of placebo-controlled, double-blinded studies recently showing specific outcomes from specific strains in probacteria, improvement in things like the length of diarrhea, illness, symptoms of abdominal discomfort, eczema, and likelihood of getting respiratory infections including the flu.

But each of those also is a relatively tiny glimpse into the potential benefits of supporting and cultivating a diverse ecosystem within the gut. Probiotics may be helpful. It’s hard to say at this point which ones would be the best or how much. One thing that we can say is that eating a healthy diet is likely to select for bacteria that thrive on the healthy diet and would be a reinforcing virtuous circle. It would help you crave those foods more and help get the most benefit out of those foods.

Is Looking at Glycemic Index Valid?

Medscape: Are there any other recent studies that you would like to discuss?

Dr Greene: I think one very interesting 2015 study, published in November, looked at the glycemic index.[16] The idea behind the glycemic index is to measure the effect of a particular food or type of food on the subsequent blood glucose curve. Foods with a high glycemic index tend to raise blood sugar a lot. Low glycemic index foods have a much more muted effect on blood glucose. Glycemic index provides one way to look at why a food might be healthier or less healthy. You can find tables listing the glycemic index for a wide variety of foods.

In this study, the researchers measured about 50,000 different meals in 800 subjects and found something that in retrospect should have been obvious but was very surprising to me. The authors concluded that, to a large degree, individual foods do not have their own glycemic index. Rather, the glucose response to a particular food depends on the person. For instance, tomato is considered to be a very low glycemic index food, and yet for one subject in the study, tomatoes specifically prompted high blood glucose levels.

Data from a continuous blood glucose monitor worn by another individual demonstrated a glucose level that shot up to 260 mg/dL after a meal that included brown rice, which is reasonable from a glycemic index perspective. Different foods do, in fact, affect different people differently. We’re at the beginning of being able to figure out what that all means. It is probably a combination of an individual’s genetics and microbiome. Different foods really affect us differently, and the same great diet isn’t good for everyone.

References

  1. Ning H, Labarthe DR, Shay CM, et al. Status of cardiovascular health in US children up to 11 years of age: the National Health and Nutrition Examination Surveys 2003-2010. Circ Cardiovasc Qual Outcomes. 2015;8:164-171. Abstract
  2. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes. Diabetes Care. 2013;36:3863-3869. Abstract
  3. O’Connor L, Imamura F, Lentjes MA, Khaw KT, Wareham NJ, Forouhi NG. Prospective associations and population impact of sweet beverage intake and type 2 diabetes, and effects of substitutions with alternative beverages. Diabetologia. 2015;58:1474-1483. Abstract
  4. Yan J, Liu L, Zhu Y, Huang G, Wang PP. The association between breastfeeding and childhood obesity: a meta-analysis. BMC Public Health. 2014;14:1267.
  5. Cogswell ME, Yuan K, Gunn JP, et al. Vital signs: sodium intake among U.S. school-aged children – 2009-2010. MMWR Morb Mortal Wkly Rep. 2014;63:789-797. Abstract
  6. AAP Adolescent Sleep Working Group, Committee on Adolescence, and Council on School Health. School start times for adolescents. Pediatrics. 2014;134:642-649. http://pediatrics.aappublications.org/content/134/3/642 Accessed July 20, 2015.
  7. Andersson O, Hellström-Westas L, Andersson D, Domellöf M. Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial. BMJ. 2011;343:d7157.http://www.bmj.com/content/343/bmj.d7157 Accessed July 20, 2015.
  8. Andersson O, Lindquist B, Lindgren M, Stjernqvist K, Domellöf M, Hellström-Westas L. Effect of delayed cord clamping on neurodevelopment at 4 years of age: a randomized clinical trial. JAMA Pediatr. 2015;169:631-638.
  9. McDonagh MS, Blazina I, Dana T, Cantor A, Bougatsos C. Screening and routine supplementation for iron deficiency anemia: a systematic review. Pediatrics. 2015;135:723-733. Abstract
  10. US Preventive Services Task Force. Iron deficiency anemia in young children: screening.http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/iron-deficiency-anemia-in-young-children-screening Accessed January 4, 2016.
  11. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2013;7:CD004074.http://www.cochrane.org/CD004074/PREG_effect-timing-umbilical-cord-clamping-term-infants-mother-and-baby-outcomesAccessed January 4, 2016.
  12. Baker RD, Greer FR; American Academy of Pediatrics, Committee on Nutrition. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics. 2010;126:1040-1050. Abstract
  13. Horton DB, Scott FI, Haynes K, et al. Antibiotic exposure and juvenile idiopathic arthritis: a case-control study. Pediatrics. 2015;136:e333-e343. Abstract
  14. Centre for Clinical Practice at NICE (UK). Respiratory Tract Infections – Antibiotic Prescribing. NICE Clinical Guidelines, No. 69. July 2008. http://www.ncbi.nlm.nih.gov/books/NBK53632/ Accessed January 4, 2016.
  15. Kronman MP, Zhou C, Mangione-Smith R. Bacterial prevalence and antimicrobial prescribing trends for acute respiratory tract infections. Pediatrics. 2014;134:e956-e965. Abstract
  16. Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015;163:1079-1094.Abstract

 

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