Should Parents be Concerned About Miralax?

Last week we received a number of questions about a statement released by a group of parents of children with disparate neuropsychological issues.  The parents claimed that their children’s symptoms began after they began taking the over the counter laxative Miralax (polyethylene glycol 3350) and that the medication was at fault.  Miralax is approved only for use in those age 17 or above, and the parents have expressed concern that they were instructed to give their children the laxative not approved for use in their age group.

This was cause for concern for many parents, especially those whose children have dealt with constipation.  To answer our reader questions we reached out to François Lavallée, a pharmacist in the province of Quebec, Canada and who is also the father of two young children. Matthew Hartings, a professor of chemistry at American University in Washington, DC (and a dad as well), helped out with some of the chemistry.

We have received a number of questions from concerned parents about this story. Thank you for taking the time out of your schedule to speak with me.

I can see why parents would be concerned. I’m a parent myself and nobody wants to put their kids at unnecessary risk. I don’t doubt that the children of the parents coming forward have neuropsychological issues. When you are the parent to a child with neuropsychological issues, depending on the severity, it is very hard both physically and emotionally. I think what they are doing is noble because they want to prevent other children from experiencing something similar, but I’m not sure that the chemical component in Miralax, polyethylene glycol (PEG) 3350, is what has caused the symptoms they are describing.

Right now the symptoms that are being disclosed publicly by the parents are a little vague and aren’t consistent with each other. Some describe, the development of aggression and paranoia, others describe motor issues such as ticks. Usually when symptoms are caused by something children are exposed to there’s an identifiable pattern. It would be so simple if it were the case here, we could just ban that substance and be done with it.

In reality, considering the diverse symptoms reported at this time there is probably more than one cause. What makes it more difficult is that in some cases the individuals are now adults and are claiming the exposure as toddlers caused their symptoms. It is incredibly difficult to pinpoint a cause ten or fifteen years after the onset of symptoms. There may have genetic predispositions to some of these issues or the symptoms may have been acquired through another exposure through food, air, water, or other drugs.

I think parents need to exercise caution when they read things like this online. These articles often lead to really shocking information that’s completely out of context. The important context is usually at the bottom, but they know that most people don’t read articles all the way through. These websites prey on parents’ fears for clicks, and can cause them to panic when they don’t have to.

I think part of what makes this so shocking is the claim that the same chemical that’s in anti-freeze is also in a laxative that parents have been giving their children. Can you tell me a little more about PEG 3350 and antifreeze?

First, it’s important to know that this is not the same chemical that’s in antifreeze, but it is easy to confuse the two. Their names sound very similar.  A number of the articles have confused the two chemicals which is why I really think parents need to exercise caution when reading things like this online.

Ethylene glycol is the chemical that is in antifreeze, it is highly toxic and we see kids sometimes ingest it accidentally if it’s in the garage or not properly secured because it has a sweet taste to it. Polyethylene glycol or PEG starts with “poly”, a prefix meaning “many” or “multiple”. In this case, it means many ethylene glycol molecules linked together, which makes it a different chemical, with different properties.  As you can see here, the two chemicals have the same basic ingredient, simply repeated “n” times in the case of PEG:

Ethylene glycol: C₂H₄O + H₂O → HO–CH₂CH₂–OH

Polyethylene glycol: HOCH₂CH₂OH + n(CH₂CH₂O) → HO(CH₂CH₂O)_n+1H

Even though it is the same basic molecule as ethylene glycol repeated many times, PEG molecules have very different properties, depending on how many are linked together. The number 3350 refers to the weight of the molecule, which is an indication of its size, in this case, it’s a large molecule. PEG can be as small as 400 and as large as 15,000, but 3350 is a large molecule. The larger a molecule, the less likely it is to be absorbed by the body.

The weight of the molecule is very important.  PEG 3350 behaves differently than PEG 400 does, and differently than Ethylene glycol does. What is applicable to one molecule may not apply to another. PEG 3350 is a very stable molecule, which means that it doesn’t change its state (or break down) easily.

Is it possible through some mechanism, that Polyethylene glycol is responsible for the development of the neuropsychological issues in children?

I would be very shocked if the symptoms were caused by PEG 3350. Because of PEG 3350s size, our body isn’t able to absorb it. Given these properties, it is highly unlikely that it causes these neurological symptoms.  I did a review of the literature before we spoke and there’s nothing that supports PEG 3350 with lasting side effects or that explains how it could potentially cause it. Most reported side effects are linked to its laxative properties: abdominal discomfort, cramps, bloating, diarrhea.

The hypothesis put forward by some is that if improperly stored PEG 3350 breaks down into ethylene glycol and that this degradation combined with prolonged exposure in chronically constipated children causes the symptoms being reported. I am skeptical of this hypothesis due to the stability of PEG 3350. As I mentioned before PEG 3350 is very stable, so it would take a lot for it to break down due to improper storage.

I do understand that in 2008 trace amounts of ethylene glycol (15 µg/ml) were found in eight bottles of Miralax. This is a very small amount and is essentially harmless to an adult. But the question is, is that amount enough to cause problems in a child, especially if the child is exposed daily and over a long period of time (for example years). This is not something that I know the answer to as ethylene glycol toxicity is usually seen in the hospital, so I asked Matthew Hartings, a professor of chemistry at American University in Washington, DC.

Matthew confirmed what I thought, which is that the dose found in the bottles is not enough to be toxic to a child in a single dose. Matthew calculates that for a child to consume a toxic dose of ethylene glycol at the doses found in the bottles, they would need to consume 1L of the powdered product. The product isn’t available for retail consumer purchases in packages that large. He also says that ethylene glycol does not bioaccumulate so it’s unlikely that prolonged exposure to ethylene glycol could cause problems through that mechanism.

Matthew and I both agree that the ethylene glycol should not be in the bottles period and it’s not a good thing and it’s unacceptable that the manufacturer couldn’t account for how it got there.  It’s never a good thing when something that shouldn’t be in a product winds up in it, even if the dose isn’t enough to cause harm.

So what exactly does PEG 3350 do, and why is it in laxatives?

It’s an osmotic laxative, which means that it attracts water. Our intestines are very good at absorbing water, which is part of their jobs, but when a child (or an adult) becomes constipated their stools become very hard with very little water in them, and it makes them difficult and sometimes painful to pass. PEG 3350 holds water in the intestines which allow the stool to soften, which makes it easier to pass normally. It is a passive laxative, which means that it doesn’t cause the intestines to contract or actively push stool through. This is why it has been used so much for children. It is important to note that the main reason why it can express an osmotic force to retain water in the intestines is that it isn’t absorbed by the body. It goes right through, from one end to the other.

Part of the concern seems to be that a medication that is only indicated for adults has been used for children, why has it been recommended off-label for use in children?

We knew that it is safe as a one-time use to empty a child’s bowels before a procedure. As we know it is safe in a large dose at one time, some doctors and pharmacists started to extrapolate that knowledge and say, maybe it is safe in a small dose over a longer period of time.

At the beginning of my career, I didn’t see PEG 3350 used very much in children in part because the product was new to the market. At first I started seeing individual clinics using it and then [a large area pediatric hospital] started using it, shortly after it became much more common.

This isn’t to say that PEG 3350 hasn’t been studied in children. It has been studied extensively and has shown to be safe and more effective than a placebo. But it hasn’t gone through the same level of trials that we require before approving a drug for adults. I know in the United States the Food and Drug Administration (FDA) is funding a study of the long-term safety of the use of PEG 3350 in children with chronic constipation, at the Children’s Hospital of Philadelphia (CHOP), but I don’t know what prompted the study. I see it as a good thing that can help confirm safety in longer-term use. The more studies we have, the more confident we can be in a product’s safety.

I think a lot of parents are wondering why doctors are recommending medication for children that isn’t approved for children.

As you know, it’s very difficult to get approval to test drugs on children. It’s pretty obvious why. Would you allow someone to test a drug on your child? You don’t know what the drug will do to your child. No one would sign their child up for that. It’s not ethical, so we don’t test drugs on children in large trials. Unfortunately what this means is that we sort of test things in the real world. We take that little bit of information that we have in one area and we extrapolate it and then we report on what we find until we have enough data to have something similar to a clinical trial, then there’s usually a reclassification.

Additionally, and this is unfortunate to say, there isn’t a lot of money in pediatric drugs for large pharmaceutical companies. Kids are only kids for a little while, so it doesn’t offer a good return on investment for them. Another deterrent for companies to invest and develop drugs for kids is that they don’t like to be sued, so they will usually go for the safest patients to treat: Adults with functioning kidneys and liver. Kids, the elderly, pregnant women, people with kidney or liver disease, are all populations that are less researched, so treatment is trickier.

As companies hate to get sued, they will put on their labels only what they studied and they know it is safe. That is common sense. But when a label says “Use for no more than 7 days without a doctor’s advice”, it doesn’t mean the product is poison if used for 8 days. It means if you need to use it for longer, you might have a more serious issue and should be examined by a doctor. Once you’ve been examined and it has been confirmed that everything is in order, under the doctor’s advice, you can use the product for longer, as long as there is a proper follow-up.

What are some things that parents can do to manage constipation at home if they don’t want to use an over the counter laxative like Miralax?

The most important thing is that parents talk to their doctor or pharmacist first if they have concerns about chronic constipation in their children. They best know your child’s medical history and are most familiar with the various treatment options.

With that said, there are some first-line defense options that parents can try at home if they have a concern about acute constipation. These are things like prune or pear juice, or simply adding more of these fruits into their child’s diet, which I know can be difficult if their child is a picky eater. They can also ensure their child gets plenty of water and plenty of exercise, as those both really help with constipation.

Originally Posted at TheScientificParent.org