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Miralax Safety

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Periodically questions about the safety of Miralax arise. Recently, several colleagues have received some questions about the use of Miralax due to information on the internet. You may want to familiarize yourself with this link due to the misinformation which is provided:

http://www.gutsense.org/gutsense/the-role-of-miralax-laxative-in-autism-dementia-alzheimer.html

Some of the misleading statements:

  • Miralax has never been tested for safety in children
  • Miralax makes one cancer-prone by leaving the colon unprotected
  • Miralax may result in severe malnutrition ..leading to Autism
  • Miralax can cause memory loss and neurologic side effects

It is true that there is not enough adequate long-term data on the use of Miralax, though there are studies showing its effectiveness/safety (see below).  However, according to the FDA, there are no neuropsychiatric warnings needed for Miralax:

As with all medications, one has to weigh the risks and the benefits.  Clearly, the risk and consequences of untreated defecation problems can be severe in some children and may have terrible adverse effects on daily living.  The known safety profile of Miralax is very good and its usage has been recommended by the American Gastroenterological Association (AGA) and by the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) in position statements on the treatment of constipation:

An article from NY Times on this subject:

Related Blog Posts:

Related references:

-Aliment Pharmacol Ther 2011; 33: 33-40.  Comparison of golytely vs miralax.
-Gastro & Hep 2008; 4: 489.  Safety/effectiveness of PEG3350 as sole agent for cleanout in 245 adults.  Used 204 gram in 32 oz of water.
-Pediatrics 2006; 118: 528.  Data on safety and effectiveness in 79 children (39 c PEG, 40 c MOM).  PEG outperformed MOM.  compliance for PEG was 95%, after 12 months, 62% improved c PEG and 33% recovered (did not need med anymore).
-JPGN 2004; 39: 536. n=75.  good experience with infants & toddlers; 85% short-term/91% long-term success.
-JPGN 2004; 39: 106.  Miralax cleanout: 4 glasses of Miralax, clears , two doses of senna or bisacodyl, & 1 saline enema.
-J Pediatr 2004; 144: 358.  4 day cleanout with Miralax, 1.5g/kg/day; last day with clears.  No enemas given.
-Arch Pediatr Adolesc Med 2003 Pashankar DS et al; n=83. Rx avg 8.7mo. insignificant adverse effects. no loss of efficacy
-Clin Pediatr 2002; Gremse DA. Lactulose & Miralax equivalent , but Miralax preferred
-JPGN 2004; 39: 197.  Published use in infants, n=28
-JPGN 2003; 37: 329 (9A) use of Miralax to 2mo or older, n=23.
-J Pediatr 2002; 141: 410-14.  PEG 3350 at doses of 1-1.5g/kg/d for 3 days relieved an impaction in 95%.
-JPGN 2002; 34: 372-377. n=28 pts + 21 pts c MOM control.  61% vs  67% doing well at 12 month f/u.
-OnlineJournal of Digestive Health 1999; 1.  Miralax results in good long-term success without salt absorption.
-J Pediatr 2001; 139: 428-32.  Mean effective dose was 0.84 g/kg/day (range 0.3-1.4 g/k/d) n=24 (for 8 weeks) 18mo to 11 years.
-JPGN 2001; 32: 514. Safety of miralax & references.

Where is the Journal Editor?

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A recent article is titled “Determination of Bone Age in Pediatric Patients with Crohn’s Disease Should Become Part of Routine Care” (Inflamm Bowel Dis 2013; 19: 61-65). (Thanks to Ben Gold for suggesting this reference.)

Does the study merit the authors’ conclusion that ‘determination of bone age (BA) should become the standard of care in pediatric Crohn’s disease (CD) patients, allowing clinically meaningful interpretation of growth…leading to improved treatment recommendations?’

No.  This small study (n=49, 84% Caucasian) simply showed that a lot of pediatric CD patients have a delayed bone age.  This is not a novel finding.

Specifically, the mean BA Z score was -1.40 ± 1.5 in this population and 41% had a BA Z score of < -2.0.  This cross-sectional study was conducted between 2007-2009.  Patients were consecutively approached for enrollment during this time period.

Clinical factors associated with delayed bone age included Caucasian race, Tanner stage 1-3, history of steroid exposure, colonic disease location, azathioprine/6-mercaptopurine usage, and female sex.  Interestingly, these variables are not entirely consistent with prior studies in which male sex was associated with delayed bone age.

The reason why the conclusion is a far-reach is that there is no data in the study showing how bone age influences any clinical decision-making in these patients.  There is no information on cost-effectiveness of their proposed “standard of care.”  There is no longitudinal data to suggest that the delayed BA or the recognition of a delayed BA  resulted in a different outcome.

My conclusion:

Many pediatric patients with CD have delayed BA and some may benefit from a BA determination.  I think extrapolating a much broader conclusion from this study is not warranted.

Vitamin D deficiency and metabolism in pediatric Crohn’s disease

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As noted in previous blog posts (see links below), vitamin D has received a great deal of attention with a number of chronic diseases.  In this latest study from CHOP, the incidence and mechanisms of vitamin D deficiency in pediatric Crohn’s disease are explored (Inflamm Bowel Dis 2013; 19: 45-33).

At diagnosis (2002-2005), Crohn’s disease (CD) participants (n=78) had their serum vitamin D assays and parathyroid hormone (PTH) levels checked.  Then, these values were sequentially followed at 6 months, 12 months, and a median of 43 months later (n=52). The average age of the CD patients was 12.7 years.

Key findings:

  • 42% of CD participants were 25-OH D deficient (<20 ng/mL) with an odds ratio of 2.1 compared with controls.
  • Among patients with 25-OH D <30 ng/mL, CD patients had a lower PTH than controls.
  • At final visit, 3% remained 25-OH D deficient and PTH levels corrected.
  • Risk factors, besides CD, for vitamin D deficiency: black race (OR 10.4), visit in winter (OR 2.4), age 12 to <15 (OR 2.7), age >15 (OR 3.2).  Greater disease activity was associated with lower vitamin D levels at baseline.

Implications of this study:

  1. Vitamin D deficiency normally causes secondary hyperparathyroidism.  With newly-diagnosed CD, there was a relative hypoparathyroidism that resolved with therapy.  “It is conceivable that proinflammatory cytokines associated with CD …prevent an appropriate PTH response.”
  2. The authors state that ‘vitamin D deficiency likely contributes to the pathogenesis of CD through effects on T and B lymphocyte, macrophage, and dendritic cell regulation.”  Correcting vitamin D deficiency may improve CD treatment response in addition to potential improvements in bone health.

Related posts:

Limiting Cow’s Milk for EoE

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A small retrospective study suggests that eliminating cow’s milk, without other interventions, can be effective in the treatment of Eosinophilic Esophagitis (EoE) (JPGN 2012; 55: 711-16).

Out of 161 children with EoE, 17 patients were identified who excluded only cow’s milk from their diet.  Remission was noted in 65%.  Complete histologic remission (≤1 eosinophil/hpf) was noted in 7 patients (41%) and 4 (24%) had “significant remission” (defined as peak eosinophil count of 2-15/hpf).

This study, conducted in Chicago, took place between 2006-2011.  The majority of the patients treated at this institution are treated with dietary elimination: 61% with empiric elimination diet, 8% empiric elimination diet with topical steroids, and 7% with elemental diet.

The authors suggested that younger children may be more likely to benefit from this approach but cautioned against drawing firm conclusions due to the small ‘scope’ of this retrospective study.

 Related posts:

T-cell therapy for Crohn’s disease

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Data from the Crohn’s and Treg Cells Study (CATS1) are very preliminary but indicate that administration of antigen-specific T-regulatory cells (Tregs) to refractory Crohn’s disease (CD) patients could be effective (Gastroenterol 2012; 143: 1207-17).  Tregs are specialized subpopulations of T-cells.

In this study, the investigators, performed a 12-week open-label multicenter single injections study of 20 patients with refractory CD.  After withdrawing blood from patients, mononuclear cells were isolated and cultured.  Subsequently, T cells were cloned.  A specific subset with high IL-10/IL-13 production and low IL-4 production were selected.

Key findings:

  • 8 of 20 (40%) patients had a CDAI reponse at 5 and 8 weeks.  This was associated with a reduction in serum CRP and a trend of decreasing fecal calprotectin.
  • Remission was noted in 3 patients at week 5 and in 2 patients at week 8.
  • Overall, regardless of dose used, the safety profile was “in line” with severe active refractory CD.  Gastrointestinal adverse events were common.  7 patients had CD flares. One patient died due to suicide.

To understand this study more fully, an accompanying editorial is in the same issue (pages 1135-38).  A more complete discussion of the function of Treg cells is given, included their physiologic role of patrolling the gut lamina propia for antigens ‘derived from food and commensal flora.’  Circulating Treg cells may be deficient in IBD patients and thus contribute to the pathogenesis.

While injecting Treg cells may become a useful therapy, other ways of boosting Treg cells may be enhanced as an alternative.  Currently, granulocyte colony-stimulating factor (GCSF), anti-TNFα agents, and IL-2 all have the potential to enhance Treg cell function.  This supports the editorial’s conclusion that ‘Treg cells are rapidly moving from the bench to the bedside.’

Given the experimentation with stem cell therapy and bone marrow transplantation for CD, Treg cells show promise of a much more targeted effect on the immune system.

Additional references:

  • -Blood 2010; 116:6123-32.  Autologus stem cell transplantation in patients with refractory CD.
  • -Gut 2008; 57: 211-17.  Autologus stem cell transplantation for refractory CD.
  • -Gut 2010; 59: 1662-69.  Mesenchymal stromal cell treatment for luminal Crohn’s.

Green beans for short gut syndrome

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A recent article indicates that the addition of green beans may improve diarrhea and reduce dependence on parenteral nutrition (Adding Dietary Green Beans to Formula Resolves the Diarrhea …) (ICAN. DOI: 10.1177/1941406412469403). Thanks to Kipp Ellsworth for pointing out this reference on his twitter feed.

This small retrospective study of 18 infants examined the addition of green beans to the diet of infants with short bowel syndrome (SBS) (1 jar of stage 2 baby food green beans to every 8 ounces of 30 cal formula).  The average gestational age of the patients was 32 weeks (range 23-39 weeks) and the average birth weight was 1938 gram.  Nine patients had NEC, four had gastroschisis, two had Christmas tree defect, and three had other reasons for either SBS or intestinal failure.  The IF group (n=10) was defined as being dependent on parenteral nutrition to meet nutritional needs; the SBS group (n=8), who were more severely affected, was defined as the malabsorptive state that follows a massive resection.

Products that were used:

  • Gerber Natural Select: 3 gm of fiber per 4 ounce
  • Beach-Nut Homestyle: 2 gm of fiber per 4 ounce
  • HyVee Mother Choice: 2 gm of fiber per 4 ounce
  • These products average 32% soluble and 68% insoluble fiber

While the authors note that they use only amino-acid based formulas currently, at the time of the study, 61% were receiving Peptamen Junior.

It is not clear in the manuscript exactly at what age green beans are introduced. However, a previous case study suggested addition of green beans at ~4 months or >44 weeks postconception.  This prior case study indicated that adding stage 2 green beans changed the caloric density of 30 cal formula to 22 cal/ounce (Nutrition in Clinical Practice 2005; 20: 674-77).  In addition, this adds 2 gm/kg/day of fiber.

Results from current study:

  • 9 of 10 IF patients were able to discontinue parenteral nutrition
  • 2 of 8 SBS patients were able to discontinue parenteral nutrition
  • All infants had improvements in stool consistency, typically within 24 hours of dietary change.

While the authors acknowledge the limitations of the study, they hypothesize that the reason for improvement is due to the fiber content of green beans.   Fermentation of dietary fiber produces short chain fatty acids (SCFAs) which in turn have a trophic effect on the mucosa and enhance nutrient absorption.

Studies have shown that adults with IF or SBS have improved stool consistency with the addition of fiber.  However, the authors note that there have been no studies documenting the effectiveness of dietary fiber in the pediatric SBS/IF population.

Whether green beans would outperform other sources of fiber like pectin, guar gum, bananas or benefiber is not clear.

Additional references/links:

Feeling the urge and stopping the shame

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So many parents misinterpret withholding behavior in children.  Many indicate that their child is trying to go but cannot and others indicate that their child does not feel an urge to defecate.  Now more insight into this common issue has emerged (JPGN 2013; 56: 19-22).

The authors reviewed their experience with colonic manometry (n=410).  150 patients were identifed as having functional constipation.  Among this group, 56 patients volunteered that they had no urge to defecate.

Yet, during colonic manometry, when the first high-amplitude propagating colonic contraction (HAPC) occurred, this was associated with retentive posturing, grimacing or denial of sensation.  When the HAPC occurred, the examiner would explain that it was causing pain that would improve if the child defecated.  Ultimately, “every patient acknowledged an urge to defecate and successfully defecated.”

One other interesting part of this publication is the discussion of psychological aspects.  Do you remember Erikson’s stages (Erik Erikson – Wikipedia, the free encyclopedia)?  The authors note, “if toilet training is not achieved or the process involves negative experiences including being shamed into the process, shame and doubt will persist.  Shame, according to Erikson, is an infantile emotion and leads to secretive behavior.  Therefore, children who failed toilet learning may deny sensations of the urge to defecate…all the while having shame and embarrassment.”

These psychological issues are important in the propagation of constipation. The authors note that, even in children with rectal distention due to chronic constipation which could result in decreased sensation, studies have shown rectal compliance was not associated with treatment failure.  Therefore, constipation and soiling are not simply due to a mechanical issue of not knowing when to go.

Related posts:

Colic Microbiome

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A new study identifies a potential microbiome signature that is associated with colic (Pediatrics 2013; 131: e550-58). Thanks to Mike Hart for this reference.

With new technology, the microbiome’s role in many gastrointestinal conditions is being unraveled.  For colic, there has been concern about that an abnormal microbiome has been contributing to the pathophysiology.  On a personal level, I have had an interest in this subject for quite a while:

In this current study, the authors serially followed the microbiome infants in a prospective longitudinal project.  Nine stool specimens were obtained from each infant. Four were obtained in the first month at day of life 2, 7, 14, and 28 days.  Five were obtained at 3 to 5 months.  All specimens were stored at -20°C until analyzed by the “Human Intestinal Tract Chip (HITChip).” The HITChip microarray was considered satisfactory if 2 independent hybridizations had >95% correlation.  These microarrays “showed a dynamic range of >10,000-fold and >200 independent microarray readouts were used.”

Of 160 healthy term infants, the authors identified colic in 25% who averaged >180 minutes of crying per day over a four-day period.  Then, the authors selected the 12 infants who cried the most and compared them to the 12 infants who cried the least.

Results:

  • In the infants who were highly similar, the “infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.”  Proteobacteria, including Enterobacter aerogenes, Escherichia coli, and Klebsiella pneumoniae, were increased with more than a doubled abundance.  Bifidobacteria and lactobacilli were decreased in colicy infants.
  • At about 3-4 months of age, the colic group had a similar microbiome as the non-colicy group.
  • The authors speculate that proteobacteria might cause inflammation and may displace helpful bacteria.  Certain butyrate-producing bacteria like Butyrivibrio crossotus and Coprococcus estates were more commonly present in the non-colicy group.  The authors note that butyrate reduces the pain sensation in adults.

Bottom-line:

These results could explain why administration of probiotics (and possibly antibiotics) can result in a decrease in colic symptoms.

Related blog entries:

Additional references:

  • -Pediatrics 2010; 126: e526.  Double-blind randomized placebo-controlled trial of Lactobacillus reuteri.
  • -J Pediatr 2009; 155:823. Increased calprotectin in colicy infants. n=36. editorial pg 772.
  • -J Pediatr 2009; 154: 514-20. Colic and reflux. (Orenstein et al), & 475 (editorial -Putnam). PPIs (lansoprazole) do not help colicy Sx in infants c GERD. n=162. Increased resp infections in pts on PPIs. 44% response in Rx & control group.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Pediatrics 2005; 116: e709. Low-allergen maternal diet was helpful.
  • -Arch Pediatr Adol Med 2002; 1183 &1172. lack of sequelae on maternal mental health.
  • -Arch Pediatr Adol Med 2002; 156: 1123-1128. colic 24% of infants, breastfeeding did not help.
  • -Pediatrics 2002; 109: 797-805. carbohydrate malabsorption with breath testing in colicy infants, n=30. 2 hour fasting period.
  • -Arch Dis Child 2001; 84: 138-41. Lack of benefit (vs placebo) of chiropractic manipulation for colic, n=100. 86 completed study. 70% improved vs 60% in placebo.
  • -JPGN 2001; 33:110-111. Lack of assoc c GER
  • -Pediatrics 2000; 106: 1349. Use of hydrolysate decreased crying by 63mins/day
  • -Pediatrics 2001; 108; 878-882. No assoc between colic and markers of atopy/asthma/allergy.

Predictors of colectomy in pediatric UC

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A recent review of children in the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) examined risk factors for proctocolectomy in children with Ulcerative Colitis (UC) (JPGN 2012; 55: 534-40).  Two of the investigators (Stanley Cohen and Ben Gold) are colleagues of mine at GI Care for Kids.

In total, 406 children with UC were reviewed.  The average age at diagnosis was 10.6 years.  The average followup was 6.8 years.  57 (14%) underwent surgery with a median time to surgery of 3.8 years.  Overall risk factors for colectomy included the following:

  • Presenting with weight loss, HR 2.55
  • Presenting with hypoalbuminemia (<3.5 g/dL), HR 6.05
  • First-degree relative with UC, HR 1.81
  • Treatment with cyclosporine, HR 6.11
  • Treatment with tacrolimus, HR 3.66

While this data expands on the knowledge of these factors in children, the findings are not unexpected.  Low albumin levels and poor nutritional status have been identified in other studies as risk factors for UC relapse and for colectomy.

With regard to first-degree relatives, the findings imply that children with a first-degree relative are more likely to have a more severe form of UC.

The use of calcineurin inhibitors, cyclosporine and tacrolimus, are given only in the presence of severe disease.  Thus, while use of these agents is associated with an increased risk of colectomy, it is unlikely that this is a causal relationship.  Interestingly, the use of infliximab was not identified as a risk factor.  However, this retrospective study examined patients between 1999-2003.  Since this timeframe, there has been increased use of infliximab for refractory UC.

Going forward, it is likely that contemporary studies would incorporate PUCAI (pediatric UC activity index) measurements and would have the ability to enroll far greater numbers of patients from database consortiums.

Related blog posts: