Meta-analysis shows association between autism in children and cardiometabolic diseases

A study conducted by the Centers for Disease Control and Prevention (CDC) from 2009 to 2017 determined that approximately 1 in 44 children ages 3-17 are diagnosed with some form of autism spectrum disorder (ASD). Research also has established that children with ASD have an increased risk of obesity, and obesity has been linked to increased risks for cardiometabolic disorders such as diabetes and dyslipidemia (high level of cholesterol or fat in the blood).

However, the question of whether or not there is an association between autism, cardiometabolic disorders and obesity remains largely unanswered.

To help provide an insight into the possible ASD-cardiometabolic diseases link, Chanaka N. Kahathuduwa, M.D., Ph.D., and a collaborative team from Texas Tech University Health Sciences Center (TTUHSC) and Texas Tech University (TTU) conducted a systematic review and meta-analysis using the PubMed, Scopus, Web of Science, ProQuest, Embase and Ovid databases.

Their study, "Association Between Autism Spectrum Disorders and Cardiometabolic Diseases: A Systematic Review and Meta-analysis," was published in January by JAMA Pediatrics.

For Kahathuduwa, the seeds for the study were planted shortly after he received his Ph.D. in nutritional sciences with a focus on the neuroscience of obesity. Working as a research assistant professor under Mastergeorge, a nationally renowned ASD expert, he was invited by Naima Moustaid-Moussa, Ph.D., director of TTU's Obesity Research Cluster (now the Obesity Research Institute),to present a seminar discussing the neuroscience of obesity and autism.

"When I searched the literature to prepare my presentation, I realized that the evidence on the association between obesity and autism was quite ambiguous," Kahathuduwa recalled. "A solid meta-analysis was needed to address this gap."

That initial meta-analysis led Kahathuduwa to investigate further. He explored how neuroimaging may provide insight into relationships between ASD and obesity, the association between ASD and patients who are underweight and the just-published study on autism and cardiometabolic risks. The studies accelerated after Dhanasekara, who focused on obesity and metabolic health to earn her Ph.D. in nutritional sciences, joined the collaboration.

In their latest meta-analysis, Kahathuduwa, Dhanasekara and their collaborators evaluated 34 studies that included 276,173 participants who were diagnosed with ASD and 7,733,306 who were not. The results indicated that ASD was associated with greater risks of developing diabetes overall, including both type 1 and type 2 diabetes.



The meta-analysis also determined that autism is associated with increased risks of dyslipidemia and heart disease, though there was no significant increased risk of hypertension and stroke associated with autism. However, meta-regression analyses revealed that children with autism were at a greater associated risk of developing diabetes and hypertension when compared with adults.

Kahathuduwa said the overall results demonstrate the associated increased risk of cardiometabolic diseases in ASD patients, which should prompt clinicians to more closely monitor these patients for potential contributors, including signs of cardiometabolic disease and their complications.

"We have established the associations between autism and obesity, as well as autism and cardiometabolic disease, including diabetes and dyslipidemia," Kahathuduwa said. "We don't have data to support a conclusion that autism is causing these metabolic derangements, but since we know that a child with autism is more likely to develop these metabolic complications and derangements down the road, I believe physicians should evaluate children with autism more vigilantly and maybe start screening them earlier than the usual."

Kahathuduwa also believes the study shows that physicians should think twice before prescribing medications such as olanzapine that are well known to have metabolic adverse effects to children with autism.

"Our findings should also be an eye opener for patients with autism and parents of kids with autism to simply be mindful about the higher risk of developing obesity and metabolic complications," Kahathuduwa added. "Then they can talk with their physicians about strategies to prevent obesity and metabolic disease."

Kahathuduwa said the next logical step for the collaborative team would be to generate evidence that either supports or rejects causality with regard to the observed associations.

"We have done some work with the ABIDE (Autism Brain Imaging Data Exchange) dataset regarding how neuroimaging shows the correlation between autism and obesity, but there is more work to be done," Kahathuduwa said. "None of these studies would have been possible without the help of the wonderful mentors, collaborators and students at both TTUHSC and TTU who contributed in numerous ways, and who will continue their important efforts to move these studies forward."

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New stem cell model for research into a life-threatening malformation of the newborn lung

Congenital diaphragmatic hernia (CDH) is a common condition, affecting one in every 2,500 births. Up to 30% of affected babies die from it. The main problem is underdeveloped lungs. The condition also involves a hole in the diaphragm, which pediatric surgeons surgically correct in the first week of life. Until now, there has been little medical knowledge about how CDH develops or about what exactly goes wrong during embryonic development.


Dr. Richard Wagner, a pediatric surgeon and scientist at Leipzig University Hospital, teamed up with researchers from Massachusetts General Hospital in Boston to establish a new patient-specific cell model at Harvard Medical School. Using their model, the researchers investigated possible ways of treating this condition. The work is published in the American Journal of Respiratory and Critical Care Medicine.

Babies with CDH are placed on a ventilator immediately after birth. "We were able to isolate stem cells from the fluid that is sucked out of the children's lungs and otherwise disposed of, and grow them in the laboratory," explains Dr. Wagner, first author of the study.

While working as a postdoctoral researcher in the U.S., the doctor from Leipzig examined the stem cells in the laboratory together with the American researchers, designing cell models of the airways of the tiny patients. This gave them access for the first time to "living" human lung tissue from patients with CDH. They then compared the stem cells from healthy and underdeveloped lungs.

When the researchers looked at the molecular properties of the stem cells, they found that they had been altered due to inflammation. However, drug therapy in the cell model was able to restore functionality. "We also tested this process in animal models and showed that the treatment contributed to better lung development there, too. With the same drug therapy, we were therefore able to achieve positive effects both in human cells in the Petri dish and in the living organism in the established animal model," explains Dr. Wagner.

The treatment was performed with the steroid dexamethasone. This drug is already used in clinical practice to induce lung maturity in the fetus when there is a risk of premature birth during pregnancy.

"What is most appealing is the fact that we already know that this drug is not harmful in pregnancy. If we were to collect more data in laboratory research, it would be possible to investigate later in clinical trials whether there are advantages to administering the drug during pregnancy in order to slow down the possible inflammation in the organism and help the lungs grow," says Dr. Wagner. He added that the aim in the future is to be able to intervene with a drug directly after the diagnosis of a diaphragmatic hernia, which happens at around the 20th week of pregnancy.

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Whether born naturally or via cesarean section, babies receive essential microbes from their mothers, says study

This is an illustration of a mother and infant and the microbes that are transmitted from mother to infant. Credit: Mari-Lee Odendaal....

Do cesarean-born babies miss out on essential microbes? New evidence suggests that the answer may be "no." Researchers report on March 8 in the journal Cell Host & Microbe that mothers are able to transfer microbes to their babies via alternative, compensatory routes. While cesarean-born babies do receive less of their mother's gut microbiome during birth, they make up for this by drinking their mother's microbes in breastmilk

Most microbiome research has focused on the gut, but we also house beneficial microbial communities in other parts of our bodies, such as in our respiratory tracts and on our skin. This study helps clarify how babies, who are generally considered sterile before birth, get essential microbes for their various microbiomes.

"We wanted to have a better idea of how the infant microbiome develops in different parts of their bodies and how it's influenced by factors such as birth mode, antibiotic use, and lack of breastfeeding," says senior author Wouter de Steenhuijsen Piters, a physician and data scientist at the University Medical Center Utrecht in the Netherlands.

To understand how the microbiome develops during the first month of life, the team recruited and repeatedly sampled 120 Dutch mothers and soon-to-be-born babies. From the babies, they collected skin, nose, saliva, and gut microbiome samples two hours after they were born and when they were one day old, one week old, two weeks old, and one month old.

The team also collected six different types of microbiome samples from the mothers—skin, breastmilk, nose, throat, fecal, and vaginal—to determine which of these sources were "seeding" the babies' various microbiomes. Then, they analyzed these results in the context of several factors that are thought to impact microbiome transfer, including mode of delivery, antibiotic use, and breastfeeding.

"We saw that many niches of the mother are important for the transmission of microbes, and if some of these pathways are blocked for one reason or another—in this case, we saw that happening with the cesarean section—then these microbes can still reach the infant through other paths," says de Steenhuijsen Piters.

Regardless of birth route, the researchers found that approximately 58.5% of a baby's microbiome is derived from its mother. However, different maternal microbial communities contributed to different infant microbiomes. Cesarean-born babies received fewer microbes from their mother's vaginal and fecal microbiomes, but—seemingly in compensation—acquired more microbes from breastmilk.

"Microbiome transfer and development are so important that evolution has ensured that those microbes are transferred one or another way from mother to child," says first author Debby Bogaert, a physician scientist at the University of Edinburgh. "Breastfeeding becomes even more important for children born by cesarean section who do not receive gut and vaginal microbes from their mom."

"It's a smart system, and it makes sense from an evolutionary perspective that these types of pathways are redundant to ensure that the child can begin life with the appropriate 'starter kit,'" says de Steenhuijsen Piters.

Now, the team want to know more about non-maternal influences on infant microbiome development. "We could see that the maternal microbiome explains almost 60% of the infant's total microbiome, but there's still 40% that we don't know about," says de Steenhuijsen Piters. "It would be interesting to stratify that unknown fraction to see where all the microbes come from; whether fathers contribute, for example, or siblings, or the environment."

Ultimately, the researchers want to understand how microbiome development in infants relates to long-term health. "Next, we want to explore whether this early life process, influenced by mom, is affecting not only short-term infection risk in the first year of life but also longer-term health in terms of things like allergies and asthma," says Bogaert. "In the future, we might be able to utilize this knowledge to help prevent, diagnose, or treat health problems."

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Researchers find rate of fatal opioid poisonings among children more than doubled over 13-year span

     Researchers from Children's Hospital of Philadelphia (CHOP) have found that opioids were responsible for more than half of all fatal poisonings in children ages 5 and younger between 2005 and 2018, more than double the proportion of fatal poisonings caused by opioids in 2005. Additionally, over-the-counter drugs still contribute to fatal poisonings in this age group despite increased regulation. The findings, published today in the journal Pediatrics, underscore the need for improved intervention to prevent further fatal poisonings.

More than half of all reported poisonings affect children ages 5 and younger and have the highest rate of emergency department visits for unintentional drug-related poisonings. While child-resistant packaging for many medicines and hazardous products has substantially decreased the number of unintentional fatal poisonings in young children, the escalating opioid epidemic in the United States has contributed to recent child poisoning deaths.

Studying fatal poisonings in young children on a broad scale in the U.S. has been challenging for researchers. Every state conducts child death reviews, which investigate how and why these deaths happen and what steps can be taken to prevent them. Child death reviews are conducted by teams that often take a multidisciplinary approach when reviewing pediatric fatalities. The National Center for Fatality Review and Prevention provides resources for these child death reviews and maintains a reporting system that collects data from these committees.

"By comprehensively assessing fatal poisonings among children at a national level, we were able to better understand the scale of this tragic and preventable public health issue," said first study author Christopher Gaw, MD, a Pediatric Emergency Medicine Fellow with the Poison Control Center and the Center for Injury Research and Prevention at CHOP. "We were also able to specifically characterize the proportion of poisoning deaths that could be attributed to opioids each year."

The study team used data from 40 states participating in the National Fatality Review-Case Reporting System on deaths attributed to poisonings among children 5 years and younger between 2005 and 2018. During that period, 731 poisoning-related fatalities were reported by child death reviews.

The researchers found that more than two-fifths of these poisoning deaths occurred among children 1 year old or younger, and more than 65% of these fatalities occurred at home. Nearly one-third of children who died by poisoning were supervised by someone other than a biological parent. Opioids were the most common substance contributing to death, followed by over-the-counter medications for pain, colds and allergies. In 2005, opioids contributed to 24.1% of deaths, but this proportion increased to 52.2% by 2018.

The authors noted that while initiatives focused on reducing opioid prescribing resulted in a transient reduction in these deaths in the early 2010s, in the past decade, new opioid sources—including heroin and synthetic opioids such as fentanyl—have reversed prior public health gains. Additionally, while medication safety initiatives like unit dose packaging have shown promise in reducing these unintended exposures, the approach does not address all prescription opioids or illicit opioids.

"It's clear from these findings that preventing fatal pediatric poisonings requires a multifaceted approach involving caregiver education and community-level interventions," said senior study author Daniel J. Corwin, MD, MSCE, an attending physician and Associate Director of Research in the Division of Emergency Medicine at CHOP. "One such intervention is improving the availability of naloxone for the public, which can rapidly reverse opioid overdose and is safe and effective for use in children."

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New study uncovers key culprit behind pediatric brain cancer metastasis

New research pinpoints a key cause of metastasis from an aggressive form of brain cancer in children and provides a potential new therapy for treating these tumors in the future.

In a paper, published in Nature Cell Biology, physician-scientists from the University of Pittsburgh and UPMC Children's Hospital of Pittsburgh discovered that medulloblastomas hijack a skill that normal brain cells use during their early development and then manipulate it to help tumors spread.

Brain tumors are the leading cause of cancer death in children. The most common malignant children's brain tumor is medulloblastoma, which form in a region of the brain called the cerebellum, with about 500 new cases diagnosed in the U.S. each year. Medulloblastomas are commonly treated with surgery followed by radiation and chemotherapy, but in up to one-third of children, the tumor will metastasize, or spread out to tissues and organs beyond where the tumor originated. When tumor cells spread, treatments no longer work and the outcomes are grim.

To learn how medulloblastoma cells metastasize, Hu and his team leveraged patient and experimental mouse data. They found that levels of a gene called SMARCD3 were significantly higher in metastatic tumors compared to those that had not spread.

They also showed that SMARCD3 hijacks neurodevelopmental signaling pathways to promote tumor cell spreading. These pathways are used by healthy brain cells during early cerebellar development and are shut off when the cerebellum matures.

Next, the researchers targeted these pathways with a drug called dasatinib, which has been approved to treat leukemia in the clinic. In a mouse model of medullobastoma, dasatinib preferentially killed metastatic tumors with higher levels of SMARCD3, suggesting that the drug causes little or no harm to normal brain cells and could be safe for treating patients with medulloblastoma metastasis.

"We've been thinking of medulloblastoma metastasis from the perspective of neuroscience and understanding how abnormal brain development causes and influences brain tumors," said Hu. "This approach helped us to pinpoint fundamental mechanisms of medulloblastoma metastasis, which will help us develop safe, effective and personalized treatments for children with this devastating brain cancer."

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Detecting anemia earlier in children using a smartphone

Researchers at UCL and University of Ghana have successfully predicted whether children have anemia using only a set of smartphone images.

The study, published in PLOS ONE, brought together researchers and clinicians at UCL Engineering, UCLH and Korle Bu Teaching Hospital, Ghana, to investigate a new non-invasive diagnostic technique using smartphone photographs of the eye and face.

The advance could make anemia screening more widely available for children in Ghana (and other low- and middle-income countries) where there are high rates of the condition due to iron deficiency, as the screening tool is much cheaper than existing options and delivers results in one sitting.

The paper builds on previous successful research undertaken by the same team exploring use of an app—neoSCB—to detect jaundice in newborn babies.

Anemia is a condition causing a reduced concentration of hemoglobin in the blood, which means oxygen is not transported efficiently around the body.

It affects two billion people globally and can have a significant impact on developmental outcomes in children, increasing their susceptibility to infectious diseases and impairing their cognitive development.

The most common cause of anemia globally is iron deficiency, but other conditions such as blood loss, malaria and sickle-cell disease also contribute.

First author, Ph.D. candidate Thomas Wemyss (UCL Medical Physics & Biomedical Engineering) said, "Smartphones are globally popular, but research using smartphone imaging to diagnose diseases shows a general trend of experiencing difficulty when transferring results to different groups of people.

"We are excited to see these promising results in a group which is often underrepresented in research into smartphone diagnostics. An affordable and reliable technique to screen for anemia using a smartphone could drive long-term improvements in quality of life for a large amount of people."

Traditionally, diagnosis of anemia requires blood samples to be taken, which can be costly for patients and health care systems. It can create inequalities related to the expense of traveling to hospital for a blood test. Often families need to make two trips, to have a blood sample taken and then to collect their results, due to samples being transported between the clinic and the laboratory for analysis.

In the 1980s a handheld device, the HemoCue, was developed to provide more immediate results, but this carries significant upfront and ongoing costs, as well as still needing a finger-prick blood sample.

The researchers knew that hemoglobin has a very characteristic color due to the way it absorbs light, so aimed to develop a procedure to take smartphone photographs and use them to predict whether anemia is present.

They analyzed photos taken from 43 children aged under four who were recruited to take part in the study in 2018. The images were of three regions where minimal skin pigmentation occurs in the body (the white of the eye, the lower lip and the lower eyelid).

The team found that when these were evaluated together to predict blood hemoglobin concentration, they were able to successfully detect all cases of individuals with the most severe classification of anemia, and to detect milder anemia at rates which are likely to be clinically useful.

Principal investigator Dr. Terence Leung (UCL Medical Physics & Biomedical Engineering) said, "Since 2018, we've been working with University of Ghana on affordable ways to improve health care using smartphones. Following our success in screening neonatal jaundice, we are so excited to see that the smartphone imaging technique can also apply to anemia screening in young children and infants."

Senior author Dr. Judith Meek (UCLH) added, "Anemia is a significant problem for infants, especially in low- and middle-income countries, and we hope this sort of technology will lead to earlier detection and treatment in the near future."

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Novel cutpoints for diagnosing cardiac hypertrophy in adolescents and young adults

The three-decade-old international cutpoint for diagnosing children and adolescents with an enlarged heart misclassifies normal heart size as cardiac damage in adolescents, a paper published in the American Journal of Physiology-Heart and Circulatory Physiology concludes. The study was conducted in collaboration between the University of Bristol in the U.K. and the University of Eastern Finland.


An enlarged heart, often described as left ventricular hypertrophy, is a sign of early cardiac damage which has been linked to long-term cardiovascular diseases and death in adults. In children and adolescents, left ventricular hypertrophy is often recognized as a consequence of elevated blood pressure and metabolic disorders.


Echocardiography can be used to assess left ventricular hypertrophy. The most accurate echocardiography measurement is left ventricular mass indexed for muscle mass. This requires a dual energy-X-ray absorptiometry scan of muscle mass which is often not available due to cost. Other indices for left ventricular mass such as height and body surface area are useful although less accurate.

The most widely used cutpoint for diagnosing left ventricular hypertrophy in children and adolescents was established over 30 years ago and the average age of the children participating in that study was about 12 years. The established cutpoint identified left ventricular mass indexed for height greater than 38.6g/m2.7 as left ventricular hypertrophy in a pediatric population. The 38.6g/m2.7 is the 95th percentile value, meaning that 95% of children remain below this value, and it corresponded to 3.4g/kg of left ventricular mass indexed for muscle mass.

Among adults, the established cut point for diagnosing left ventricular hypertrophy is 51g/m2.7. Until now, there have been no large enough studies to define an accurate cutpoint for diagnosing left ventricular hypertrophy during late adolescence and young adulthood. The current pediatric cutpoint is significantly low for mid- and late-adolescents and the adults' cut point is quite high, both leading to the misclassification of adolescents with normal cardiac mass as abnormal.

The current study was conducted among 868 adolescents who were 17 years old and followed up for 7 years until young adulthood at age 24 years. All 868 adolescents had dual-energy X-ray absorptiometry body composition measurements and echocardiography measurements at baseline and follow-up.

The results revealed that during growth from age 17 years to 24 years, muscle mass and left ventricular mass increased significantly in both males and females, although more in males. However, when left ventricular mass was indexed for total body muscle mass, it removed the difference in the cardiac mass between the males and females by young adulthood.

The researchers also observed that estimating left ventricular mass by height2.7 or 3 had the best agreement with left ventricular mass divided by muscle mass. The left ventricular mass indexed for muscle mass 95th percentile cutpoint for males and females was 4.3g/kg and 4.6g/kg respectively at age 17 years. At 24 years of age, the 95th percentile cutpoints were 4.7g/kg and 4.6g/kg for males and females, respectively.

Correspondingly, the 95th percentile cutpoint for left ventricular mass indexed for height reflecting left ventricular hypertrophy in males and females was 49.5g/m2.7and 46.8g/m2.7 respectively at age 17 years. At 24 years of age, the 95th percentile cutpoints were 57.1g/m2.7 and 50.2g/m2.7 for males and females, respectively.

"These new cutpoints for the young population are higher than the pediatric cutpoint and lower than the adult cutpoint, except among 24 year old males. Thus, an extra 10–20g/m2.7 left ventricular mass indexed for height in comparison to the currently used pediatric cutpoint may be normal in adolescents and young adults, depending on sex.

"Therefore, pediatricians, cardiologists, physiologists, researchers, and caregivers are encouraged to familiarize themselves with the new cutpoints in order to accurately stratify adolescents and young adults at risk of an enlarged heart and premature cardiac damage," says Andrew Agbaje, a physician and clinical epidemiologist at the University of Eastern Finland.

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