Miralax and antifreeze

Here is the sequence of events that led to this post:

1. A pediatrician had for me, “Is Miralax safe?” Many parents did not want their children using MIralax because it contains antifreeze.
2. An Internet search was performed to better understand where these parents were coming from.
3. Top on the list was a post by HealthLineUpdates.com which, among other things, with claims that Miralax is antifreeze.
4. This post had a photo of a sweet, innocent looking girl reading a book. Further reading of this post by Martin Orefice revealed that it was all an ad for a pro-biotic.
5. Mr Orefice is not only the father of an autistic child but also owner of Aspire Nutrition and was using his his boy was first diagnosed.
6. A momentary bout of righteous indignation was felt. How dare anyone use cute children with non validated claims to sell even a legitimate product! The book reading girl was given sunglasses and a bandana to conceal her identity and the he “elephant in the room” image was created. Inadvertently the image of the little girl turned into a total “bad ass” that in ways describe us all trying to read to the bottom of things because….

There are more elephants in the Miralax room!

1. In a mouse study claiming that Miralax/PEG3350 did not affect anxiety beheavior in mice also showed changes in the microbiome that may be related to autism.
2. Not only is traces of antifreeze, ethylene glycol, in Miralax but it may also be in our water.

These “elephants in the room” 🐘 were discovered researching Mr Orefice’s reasons for not using Miralax.

Reason #1: Potentially Negative (And Permanent) Side Effects That Damage Speech And Behavior – As Well As Spikes In Anxiety And Depression.

Mr Orefice mentioned the FDA quite frequently in his discourse. A search of FDA.gov was performed.

Behavioral Tests

A rodent study in the laboratory of Dr Ross Matz of Nationwide Children’s Hospital tested the hypothesis that two osmotic treatments for pediatric constipation, PEG 3350 and magnesium citrate, could result in changes in the microbiome and result in anxiety behaviors. [2] This paper is summarized in a Pediatrics Nationwide post. Dr. Matz feels comfortable giving Miralax to his family members. The paper is also public access and free to view. [2] Images shown in this post are accessible in the link in reference [2].

An Internet search was performed to provide visuals as to what these rodent “anxiety” and/or depression tests entail.

• Open field exploration Mice were placed in an enclosure and allowed to explore for 300 seconds.
• The light dark test tested the willingness of a mouse to enter a dark and dark compartments of the same enclosure during 300 seconds
• The elevated plus tested the willingness of mice to explore closed arms of a maze.

None of the bacterial relative abundances were significantly correlated with murine anxiety-like behavior according to the authors. [2] Another study compared the microbiome of children with autism and pervasive developmental disorder, not otherwise specified. (PDD NOS) How do the microbiome changes in the mice treated with the high dose of Miralax compare with these children?

Day 14 stool samples

This is when I first realized that I was the little girl trying to read and understand while an elephant stomped around the room. This image that looked like a black and white t.v. screen with poor reception is a highly edited diagram of relative abundance of key bacteria for each mouse in the study. I edited out the ones of lesser importance in order to not go crazy. The darker the pixel, the higher the relative abundance. One obvious change is the cluster of dark gray pixels for Akkermansia on day 14 of the Hi PEG group of mice.

After staring at the supplemental Figure 12 to know which the direction the changes in the text were going, a table was prepared showing changes for male and female mice in the Salman study. [2] The column labeled “genus” sometimes contains phylogenetic families of bacterial. At any rate, the 4th column is checked if this family/genus is increased in children with autism (AD) or pervasive developmental disorder (PDD) The gender difference in the response of the mouse microbiome to Miralax is truly remarkable.

genus	♀	♂	[3]	Ave % in PDD NOS, AD, HC, comments [4]
Alistipes	↑		↑	Especially high in PDD NOS
Bacteroides	↑	↑	↑	Bacteriodes species: 9.67, 14.56, 12.66%
Akkermansia	↑	↑	↑	A muniphilia: 0.08, 0.27, 0.10% degrades mucin
4 Ruminococcaceae	↑		↑	Highest in PDD NOS and HC
5 Ruminoclostridium	↑		NR	sex difference in valproic model of autism PMID
Bilophila		↑	NR
Parasutterella		↑	↑	P. excrementihominis 0.15, 0.10, 0.09%,
Parabacteroides		↑	NR
Anaerofustis		↑	NR	Nothing in PubMed either
Lachnoclostridium		↑	NR
Eubacterium nodatum		↑	↑	Fusobacterium species: 0.45, 0.29, 0.79%
1 Lachnospiraceae		↑	↑	Lachnospira pectinoschiza: 0.09, 0.14, 0.20%

Even though these mice did not demonstrate any signs of depression or anxiety according to some apparently well established tests, one has to wonder about the microbiome changes and other cognitive functions. One word of caution: The scientific literature on Akkermansia muciniphila is far greater than what is presented in this post. 🐘 Miralax tends to increase both Akkermansia and Bacteroides, although temporarily on day 14 later normalizing, both of which are associated with autism, thus would not be surprising to see temporary behavioral issues around day 14 in some individuals. Not to be distracted by this “elephant” roaming about the room, let us move onto Mr Orefice’s reason #2 to avoid Miralax.

Reason #2 – Miralax And Antifreeze Are Like 1^st Cousins

Another group from Nationwide Children’s Hospital shared some of Mr Orefice’s concerns. Blood samples were drawn from 9 children who were being treated for constipation with Miralax/PEG 3350 (6-12 years old) before and every 30 minutes for 3 hours after receiving 17 g of PEG 3350.  PEG 3350, tap water, and blood samples from 18 age- and sex-matched controls also were analyzed. [4] Liberty has been taken to embellish 1 of the Williams study with structures from PubChem. The PubChem convention is to draw oxygen red to illustrate that they carry a partial negative charge.

Potential PEG degradation product DEG was actually higher in the controls than the Miralax kids. A time course was also performed because maybe the baseline values were lower in the Miralax kids because their bodies were geared up to eliminating the degradation products.

Some of the issues could be the water supply used to mix the Miralax at the outpatient or in the tap water.

Reducing the ethylene glycol 🐘 to a 🐇

🐘 PubChem has a database of ethylene glycol toxicology studies for many species of test animals. It takes about 4.7 grams per kilogram (oral dose) of the stuff to kill 50% of the rats tested. Neurological symptoms are seen at around 1g ethylene glycol per kg of the rat. An 11 lb (5 kg) dog could die if he lapped up 24 g (less than 24 mL) of antifreeze. This is less than 1/10^th of a can of soda.

🐎 If we do the math, about 1.4 μg ethylene glycol (EG) per mL comes out to be 332 μg per 237 mL dose. If the ethylene glycol concentration in tap water is really about 0.08 μg per mL [4], anyone could imbibe 80 μg in a liter of water. For non-scientists, there are 1000 μg in one gram.

🐇 A 70 pound (31 kg) child would have to drink 30 g of ethylene glycol to start seeing neurological symptoms and 4-5x as much to die. Let’s take the math slowly: 332 μg ethylene glycol in one dose of Miralax comes out o be about 0.3 g ethylene glycol. Our 70 pound child would have to drink 100 doses of Miralax at once to reach the ethylene glycol amounts for neurological symptoms.

The real 🐘 in the room is that Mr Orefice is misleading consumers into forgetting that “dose defines the poison” so that he may sell his probiotics.

We will need to ignore this issue for now so we can move on to Mr Orefice’s reason #3.

Reason #3 – MiraLax Doesn’t Even Recommend It.

Mr Orefice made a big deal of MiraLax not recommending their product for children under 16 years of age. Perhaps the company already knows that there are treatment effects when given to children under two years of age with constipation and fecal impaction. [5] This study was published in the Journal of Pediatric Gastroenterology and Nutrition. In the UK Movicol (PEG3350) plus electrolytes is licensed for chronic constipation in children 2 –11 years of age and fecal impaction (FI) in children 5 years or older . [5] . This study documented treatment effects (TE) of PEG3350 + E in children less than two years old between September 2003 and July 2019. [5] During this time period 13,235 children were treated for constipation indication and 40 for fecal impaction. “No safety signals of concern were identified for PEG 3350+E in the treatment of constipation in children under 2 years of age.” [5]

Whether or not these “treatment effects” are simply the result of “electrolyte disturbances” it is clear why the manufacturers of PEG 3350 do not want parents giving their product to young children without the supervision of a healthcare professional. 🐘 That (11+22) 33 out of 13,235 children <2yo, which is about 1 in 400, had seizure or LOC which is enough to warrant caution.

Conclusions

1. 🐘 Miralax may cause temporary changes in the microbiome in mice [2] that are consistent with microbiome changes seen in autistic children. [3]
2. 🐇 Miralax does contain small amounts of ethylene glycol, aka antifreeze, but in amounts way below toxic levels associated with morbidity and mortality of companion animals. {4]
3. 🐘 Miralax can cause neurological symptoms in children under two years of age. These symptoms may or may not be due to electrolyte imbalances. Miralax has a good track record for older children. [5]

If Mr. Orefice has a concern over the low levels of ethylene glycol in Miralax, he should have similar concern for anyone that chooses to drink public water. We trust that Mr Orefice makes available his certificates of analysis that his probiotic is free of chemical and biological contaminants. We await Mr. Orefice’s independent placebo controlled studies regarding the probiotic that he is fear marketing.

References

1. potential-signals-serious-risksnew-safety-information-identified-adverse-event https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/october-december-2011-potential-signals-serious-risksnew-safety-information-identified-adverse-event Accessed 07 October 2022.
2. Salman SS, Williams KC, Marte-Ortiz P, Rumpf W, Mashburn-Warren L, Lauber CL, Bailey MT, Maltz RM. Polyethylene Glycol 3350 Changes Stool Consistency and the Microbiome but not Behavior of CD1 Mice. J Pediatr Gastroenterol Nutr. 2021 Oct 1;73(4):499-506. Free paper
3. De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013 Oct 9;8(10):e76993. PMC free article
4. Williams KC, Rogers LK, Hill I, Barnard J, Di Lorenzo C. PEG 3350 Administration Is Not Associated with Sustained Elevation of Glycol Levels. J Pediatr. 2018 Apr;195:148-153.e1. free article
5. Roy D, Akriche F, Amlani B, Shakir S. Utilisation and Safety of Polyethylene Glycol 3350 With Electrolytes in Children Under 2 Years: A Retrospective Cohort. J Pediatr Gastroenterol Nutr. 2021 May 1;72(5):683-689. PMC free article