JM Perrin, TL Cheng. NEJM 2025; 393: 1869-1872. “Truly Prioritizing Child Health — The Missed Opportunities of the MAHA Commission”

This commentary welcomes the attention to child health which was a focus of the MAHA commission. This review provides perspectives on the stated policy aims and on what else is needed.

An excerpt:

The [MAHA] commission has highlighted four specific areas of concern: poor diet, environmental chemicals, lack of physical activity and chronic stress, and overmedicalization. The strategy outlined in the MAHA Commission’s recent report, however, misses real opportunities to address the chronic disease epidemic and “whole-person health”…

The MAHA Commission’s view of the state of U.S. child health ignores leading contributors to rising childhood morbidity and mortality: firearm injuries (the leading cause of death among U.S. children), drug overdoses, and motor vehicle injuries. Most striking is the commission report’s silence regarding the association of poverty with poor child health… which contributes to higher rates of asthma, obesity, and mental health conditions...

The first MAHA priority, children’s diets, has long been a concern of the U.S. child health community, particularly the intake of sugar-sweetened beverages, excessive portion sizes, and food additives. But pediatricians and researchers also know that food insecurity, food-industry marketing practices, and limited access to healthy foods are prime drivers of childhood obesity rates. Nutritious meals require money…

The MAHA strategy recommends marginal changes to the diets of U.S. children, such as reducing the use of food dyes and reducing consumption of ultraprocessed foods, even as the government is increasingly limiting public food assistance.

The commission’s focus on environmental chemicals is appropriate, given that exposures to potentially toxic chemicals in foods, household supplies, cleaning agents, farm supplies, and elsewhere have grown dramatically. The MAHA strategy provides little relief, however: a few research projects and no regulatory change…The MAHA report stops short of recommending the research and regulatory reform necessary for identifying, restricting, and mitigating harmful exposures.

Concerns about physical activity and stress are also justified. Many studies have documented alarming declines in physical activity, examined the causes and effects, and found associations with mental health and well-being… Strengthening early-childhood, school-based, and community-based physical activity programs, as well as social media strategies for promoting lifestyle changes, could improve health and reduce stress among young people, but the MAHA Commission mainly orders schools and communities to increase physical activity.

Finally, the commission has raised concerns about medications, especially stimulants and psychotropic agents…In response, the MAHA Commission primarily proposes studying prescribing patterns and “solutions that can be scaled up to improve mental health.” It does not address more fundamental ways of changing medication use…

Despite its attention to children’s health, the MAHA Commission’s lengthy list of aspirations and recommended changes is unlikely to make a real impact. Instead, next steps should include implementing policies, programs, and research supported by the strong evidence base that clinicians and investigators have built painstakingly for many years.

My take: The policies pursued by the current administration like limiting food dyes do not target the big drivers of poor health outcomes in children.

The authors of this commentary also “chaired the National Academies of Sciences, Engineering, and Medicine (NASEM) study described in “Launching Lifelong Health by Improving Health Care for Children, Youth, and Families”¹ [which] provides clear, evidence-based lessons that could help in achieving MAHA objectives.”

Reference: National Academies of Sciences, Engineering, and Medicine. Launching lifelong health by improving health care for children, youth, and families. Washington, DC: National Academies Press, 2024 (https://nap.nationalacademies.org/catalog/27835/launching-lifelong-health-by-improving-health-care-for-children-youth-and-families).

Related blog posts:

• “How to Make America Healthy: the Real Problems — and Best Fixes”
• Longevity Gap Present Even in Wealthy Americans
• Ten Americas: Examining Health Disparities and Life Expectancy
• “Proposed Medicaid Cuts Could Lead to Thousands of Preventable Deaths Annually” & Personal Message
• How Putting America First is Undermining Health Outcomes Here and Globally
• No Exaggeration: Too Many Children Are Dying in the U.S.
• Firearms: #1 Cause of Pediatric Deaths & Households with Guns =More Deaths

Recently Dr. Squires gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

• Bilirubin is derived from the breakdown of red blood cells.
• Each red blood cell contains approximately 250-300 million molecules of hemoglobin. Each molecule of hemoglobin can transport four oxygen molecule; thus a single RBC can carry one billion oxygen molecules

• Unconjugated bilirubin binds to albumin and is taken into cell by OAT1B1 membrane transporter. Conjugation occurs in the endoplasmic reticulum.

• Three main causes of indirect hyperbilirubinemia: defective bilirubin uptake, defective bilirubin conjugation, and hemolysis. In older patients, medications are another reason for indirect hyperbilirubinemia
• Evaluation for hemolysis can include CBC, LDH, Haptoglobin, and retic count
• Breastmilk jaundice (aka Lucey-Driscoll syndrome) is a different entity than “suboptimal intake jaundice” (aka breastfeeding jaundice). Suboptimal intake jaundice occurs in the fist week of life. Due to less intake, there are increased delays in meconium passage and increased reabsorption of bilirubin. Breastmilk jaundice which is much less common can result in very elevated indirect bilirubin levels.

• With Gilbert, the molecular defect affects the promoter region of the UGT1A1 gene. Defects here are less critical than with Crigler-Najjar. For Gilbert’s, it is like there are fewer exits to reduce bilirubin. Whereas with severe forms of Crigler-Najjar, it is like all of the exits are blocked

• Especially in the newborn period, very elevated unconjugated hyperbilirubinemia can result in kernicterus/severe neurologic sequelae. This can occur at older ages as well. The risk is related to the bilirubin to albumin ratio
• For Crigler-Najjar, phototherapy is less effective with age and is associated with a reduction in the ratio of body surface area to plasma volume

Conclusions:

Related blog posts:

• Genetic Diseases and Newborn Unconjugated Hyperbilirubinemia
• Year-in-Review for Pediatric Hepatology (2024) How Gilbert’s may be beneficial –>hopeful news for the mildly jaundiced children that we see. Science (M Leslie, 6/8/23): Can ‘toxic’ bilirubin treat a variety of illnesses
• Can Ceftriaxone Be Given (Safely) to Infants with Unconjugated Hyperbilirubinemia?
• Gene Therapy for Crigler-Najjar
• Unbound Bilirubin and Prematurity
• Understanding Breast Milk Jaundice

Recently Dr. Squires gave our group a terrific lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

Key points:

• 2023 AASLD Practice Guidance is very helpful and Dr. Squires considers its advice akin to a ‘North Star’

• There are several etiologies for the sclerosing cholangitis phenotype – including primary disorders and secondary causes.

• Pancolitis is most common presentation of IBD with PSC, often with rectal sparing and backwash ileitis

• PSC often has subclinical inflammation and poor growth. PUCAI scores typically underestimate IBD activity

• Diagnosis can be challenging – but often “I know it when I see it”

• MMP-7 is still being studied as a biomarker. Thus far, it appears a little better than GGT and Alk phos as a marker for biliary injury
• ERCP should be avoided as part of diagnostic workup but is important for therapeutic intervention

Deneau et al (Hepatology 2017; 66: 518) study wit 781 children has a wealth of information on natural history. In children, 38% developed portal HTN and 25% developed biliary complications over 10 years. However, once these complications developed, the need for transplantation develops more quickly. Median survival with native liver after the development of portal HTN was 2.8 yrs and it was 3.5 yrs after development of biliary strictures

• Cholangiocarcinoma is rare in pediatrics ~1%
• ASC (overlap of AIH and PSC) is fairly common in children and often a manifestation of early PSC. Many evolve to PSC without overlap features. Dr. Squires counsels families that most patients will need multiple biopsies to help determine need for ongoing immunosuppression

• In patients with IBD, some liver test abnormalities and autoimmune features may be transient. Some watchful waiting may be beneficial prior to extensive evaluation
• Multiple factors can predispose to PSC, including EBV infection which is associated with OR 12. Genetics, environment, immune dysregulation, toxic bile acids, microbiome, leaky gut/inflammation are additional factors
• SCOPE is very useful prognostic tool

• Ursodeoxycholic acid (UDCA) is a first line therapy. However, if no response to treatment, it is likely not beneficial

• Oral vancomycin has not been proven to improve liver outcomes in PSC thus far (not recommended by AASLD 2023 Practice Guidance). However, further studies are ongoing and it has been associated with improvement in IBD activity

Related blog posts:

• ESPGHAN Guidelines for PSC in Children (2025)
• AASLD 2023 Practice Guidance for Primary Sclerosing Cholangitis and Cholangiocarcinoma
• Liver Transplantation for PSC: Long-term Outcomes and Complications
• Development of Primary Sclerosing Cholangitis in Pediatric Patients with Inflammatory Bowel Disease
• PSC in IBD
• How Primary Sclerosing Cholangitis Alters Outcomes in Inflammatory Bowel Disease | gutsandgrowth
• Cholangiocarcinoma Risk in Pediatric PSC-IBD Plus one
• Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC | gutsandgrowth
• Online Aspen Webinar (Part 3) -Primary Sclerosing Cholangitis
• Big Study of Primary Sclerosing Cholangitis -Pediatrics 2017
• Active Colitis More Likely in Children in Clinical Remission Who Have PSC and IBD
• Easy Advice for Pediatric Hepatologists: PSC Guidelines from AGA  Best practice advice 6: “Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20.”
• Liver Problems with Inflammatory Bowel Disease

In response to this morning’s post, 5 Rights and H pylori Treatment, one reader commented: “How often does the susceptibility test come back without a result? Unable to grow out pathogen?”

From the study senior author, Dr. Bonilla: “We ultimately partnered with a specialty lab, Mayo Laboratories, for our H pylori susceptibility testing.  Another important point is establishing clear communication with the lab. We now integrate results directly into EPIC so physicians see when a culture is positive and susceptibilities are pending. Final susceptibility reports often take 5–7 business days. In my experience, when we take the time to explain this to families, they are comfortable waiting in order to receive the most effective antibiotics. In the meantime, patients can start a PPI if needed for symptomatic relief.

At present, our culture growth rate is approximately 90%. For the remaining 10% without susceptibility results, we are working to implement a reflex molecular pathway using PCR for detection and, when positive, next-generation sequencing for susceptibilities on FFPE samples. We are also exploring the use of stool samples for the same molecular testing. Our goal is to ensure that all patients receive targeted, effective therapy even when culture is unsuccessful. Broader adoption of molecular techniques will be an important part of the future of pediatric H. pylori care. We are actively generating data to support clinical usefulness, expand access, and hopefully facilitate insurance coverage.”

Related blog post: How To Achieve Helicobacter Pylori Cure Rates of >95% (lists labs that run susceptibility testing)

A de Geus et al. Lancet Child Adolesc Health 2025 https://doi.org/10.1016/S2352-4642(25)00219-6. Open Access! Efficacy and safety of pharmacological therapies for functional constipation in children: a systematic review and meta-analysis

Thanks to Ben Gold for sharing this reference

Methods: In this systematic review and meta-analysis, the authors identified “4595 articles, of which 59 randomised controlled trials were included, representing 7045 participants with functional constipation. Interventions included polyethylene glycol (n=36 studies), lactulose (n=18), magnesium oxide or magnesium hydroxide (n=7), picosulfate (n=1), liquid paraffin (n=4), prucalopride (n=1), lubiprostone (n=2), linaclotide (n=3), plecanatide (n=1), enemas (n=2), and domperidone (n=1).”

Key findings:

• Meta-analyses for treatment success showed that polyethylene glycol was probably more effective than placebo (RR 1·74, moderate certainty of evidence) and may be more effective than lactulose (1·35], low certainty of evidence)
• Linaclotide probably leads to higher defecation frequency than placebo
• Prucalopride is probably not more effective than placebo
• “Most other therapies provided evidence that was of very low certainty, due to methodological limitations and insufficient information to assess the risk of bias, precluding any evidence-based conclusions”

The discussion reviews the problems with trial design, problems with underpowered studies, and “pervasive issues with heterogeneity.  The use of concomitant therapeutics or permitted interventions and the disease severity of the patient populations varied greatly from study to study.”

My take: This study outlines what is needed to improve future research for pediatric constipation. For now, there is little certainty regarding the effectiveness of most constipation medications.

Related blog posts:

• Position Paper: Pediatric Refractory Constipation Management
• ANMS Virtual Symposia on Constipation
• Pictographic Constipation Action Plan
• New Data on Bisacodyl for Pediatric Constipation
• Safety of Senna-Based Laxatives
• Constipation Action Plan: Better Instructions, Fewer Phone Calls
• Does It Make Sense to Look for Celiac Disease in Children with Functional Constipation?
• You Can Do Anorectal Manometry in Your Sleep, But Should You?
• More than Two Years of Constipation Before Specialty Help
• Is There a Residual Impact of a Tethered Cord on Colonic Motility
• AGA Constipation Guidelines
• Radiographs and Constipation -Bad Practice and Good Study
• Quality Improvement: Fewer Xrays for Constipation
• Long Term Use of Polyethylene Glycol (PEG 3350)
• Is It a ‘Waste’ to Do Colonic Manometry in Kids with Autism?
• Reliability of colonic manometry

F Rahimov et al. NEJM 2025; 393: 1589-1598. Common Diseases in Clinical Cohorts — Not Always What They Seem

This was a two-part study. First the authors examined the frequency of monogenetic rare diseases among patients with primary diagnosis of multiple sclerosis, inflammatory bowel disease (IBD), or atopic dermatitis using the UK Biobank. The UK Biobank is a prospective cohort with >500,000 participants.

In the second part of the study, the authors examined populations with these diseases who had participated in clinical trials. For IBD, the authors utilized five (phase 3) clinical trials includingthe two SERENE trials (SERENE CD, SERENE UC) which examined the use of adalimumab, two risankizumab trials, and one trial of upadacitinib. In total, exome sequencing was performed in 580 with Crohn’s disease and 900 with ulcerative colitis.

This summary of this article focuses on the findings relative to IBD.

Key findings:

• In the UK Biobank a diagnosis of a rare monogenetic disease was identified in 53 of 1850 (2.86%) with multiple sclerosis, 75 of 6681 (1.12%) with a diagnosis of inflammatory bowel disease, and 25 of 998 (2.50%) with a diagnosis of atopic dermatitis
• Among 1480 clinical trial IBD participants with sequencing data, the authors identified 70 (4.73%) who had a molecular diagnosis of a rare disease 
• Patients with rare clinical variants responded poorly to medical treatments. For example, in the SERENE-adalimumab studies, 31 of 33 (94%) did not have clinical or endoscopic remission within a year

Discussion Points:

• “It is estimated that collectively 4 to 6% of the general population are affected by some form of a rare disease.³⁷” In the absence of routine exome sequencing, diagnosing rare diseases has been a lengthy and difficult process 
• “The higher fraction of rare diseases identified in the clinical trials cohort (4.73%) than in the U.K. Biobank cohort (1.12%) may be attributed to the targeted recruitment of patients with moderate-to-severe inflammatory bowel disease“
• TNFRSF13B was the most common pathogenetic variant in both the Biobank group (25 of 75) and the trials cohort (39 of 70). This variant causes common variable immunodeficiency and “is probably misdiagnosed as inflammatory bowel disease or primarily manifests with inflammatory bowel disease–like symptoms.”
• “Rare disease–associated genes may offer insights into potential mechanisms of nonresponse, as we found in this study, and may help in the identification of novel therapeutic targets for inflammatory bowel disease. Conversely, some patients with rare diseases could present opportunities for drug repurposing when they have a serendipitous response to treatments in clinical trials.”

My take:

1. This study shows that misdiagnosis of rare disease as common conditions is not infrequent.
2. If the trial IBD population had enrolled young children, the frequency of rare monogenetic diseases would have been higher and captured a wider variety of disorders.
3. For IBD, use of exome sequencing is widely recommended in those with very early onset disease and is a good idea in those with unusual features and in those who are not responding favorably to treatment.

Related blog posts:

• Immune Dysregulation and Inflammatory Bowel Disease (2023) This blog post summarizes a lecture on the topic of rare diseases presenting as IBD.
• How Very Early Onset-Inflammatory Bowel Disease is Different, Plus One
• VEO-IBD -Useful “Position” Paper is Really a Review
• Patterns and Puzzles with Very Early Onset Inflammatory Bowel Disease