From Conception to Early Childhood: Managing pain, fever, and neurodevelopmental risk. Time to apply some common sense? Time for NAC?

 

Donald Trump recently reignited debate about Tylenol (paracetamol/acetaminophen) in pregnancy. His comments drew attention to research linking prenatal use to higher rates of autism and ADHD.

A large review of 46 studies, including work from Harvard, found consistent associations between paracetamol in pregnancy and neurodevelopmental risks. The FDA now advises caution: use the lowest dose for the shortest time.

 

Tylenol in pregnancy linked to higher autism risk, Harvard scientists report

Researchers reviewing 46 studies found evidence linking prenatal acetaminophen (Tylenol) exposure with higher risks of autism and ADHD. The FDA has since urged caution, echoing scientists’ advice that the drug be used only at the lowest effective dose and shortest duration. While important for managing fever and pain in pregnancy, prolonged use may pose risks to fetal development. Experts stress careful medical oversight and further investigation.

 Why the concern?

• Paracetamol depletes glutathione (GSH), the body’s main antioxidant.
• This raises oxidative stress in both mother and fetus.
• The fetus has weak antioxidant defences, so damage may occur during critical brain development.

But here is the dilemma: the fever, pain, or inflammation that drives a mother to take paracetamol is itself risky. We have long known from maternal immune activation models that fever and cytokine surges in pregnancy can disturb fetal brain development and cause autism or schizophrenia. There is also evidence linking maternal immune activation to ADHD in the offspring.

So, what is the solution? Pair paracetamol with NAC.

Why NAC?

• NAC (N-acetylcysteine) is a precursor to glutathione.
• It’s used worldwide in emergency rooms to save lives after paracetamol/ acetaminophen overdose.
• In pregnancy, NAC has been shown to reduce miscarriage risk by 50%,

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss

• Increased pregnancy continuation: Women receiving NAC and folic acid were 2.9 times more likely to continue their pregnancies beyond 20 weeks compared to those receiving folic acid alone
• Higher take-home baby rate: The NAC group had a 1.98 times higher rate of delivering a live baby.
• These findings suggest that NAC, an antioxidant, may help mitigate oxidative stress, a factor implicated in pregnancy loss.

  

A combined Paracetamol/acetaminophen + NAC pill would:

• Prevent liver toxicity,
• Buffer oxidative stress in the fetus,
• Eliminate the overdose suicide risk that haunts current paracetamol use.

So far, no company has produced it. Perhaps the “rotten egg” smell of NAC is a barrier—but solid sustained-release tablets avoid this.

 

Why Paracetamol/acetaminophen use is problematic in under 5s

Paracetamol depletes glutathione (GSH), the body’s primary antioxidant, increasing oxidative stress. A fetus with some genetic predispositions might already be in a state of oxidative stress, as might the mother

Paracetamol is mainly metabolized in the liver. A small fraction is metabolized into NAPQI — a reactive toxic metabolite. Glutathione (GSH) neutralizes NAPQI by forming a harmless conjugate.

If GSH stores are low (or paracetamol is taken in high doses), NAPQI accumulates, causing liver toxicity and GSH is exhausted raising oxidative stress.

Acute oxidative stress can be very damaging to developing brains. The risk after 5 years old fades away, other than in those who have already exhibited a profound metabolic/mitochondrial condition.

Why Oxidative Stress Rises in Pregnancy

Placental development: Early pregnancy is low-oxygen; as blood flow increases, oxygen surges and generates reactive oxygen species (ROS).

High metabolic demand: The mother and placenta require much more energy, leading to increased mitochondrial ROS.

Immune adaptations: Pregnancy involves a shift in maternal immunity, with inflammatory cytokines contributing to oxidative stress.

Fetal growth: Rapid cell division and organ development naturally produce oxidative byproducts, while the fetus’s antioxidant defenses are immature.

Limited antioxidant reserves: Maternal antioxidants (glutathione, vitamins C & E, enzymes) are partly depleted as pregnancy progresses.

 

Compounding Risk Factors

Polycystic Ovary Syndrome (PCOS): Associated with high androgens, insulin resistance, and chronic inflammation. These increase oxidative stress and are linked to higher autism risk in offspring.

Gestational Diabetes: Maternal hyperglycemia and insulin resistance increase ROS, damage the placenta, and expose the fetus to oxidative and metabolic stress.

Other amplifiers: Obesity, infection, fever, or poor nutrition further elevate oxidative stress.

 

How Oxidative Stress Affects the Fetus

Neurodevelopmental disruption: ROS can damage neural stem cells, impair migration, and disturb synapse formation.

Epigenetic reprogramming: Oxidative stress alters DNA methylation and gene expression, shaping long-term brain function.

Immune activation: Inflammatory cytokines cross the placenta and disturb fetal brain development.

Mitochondrial dysfunction: ROS damage fetal mitochondria, reducing energy for developing neurons.

Neurotransmitter imbalance: Antioxidant depletion disrupts glutamate/GABA balance and monoamine systems.

 

Consequences for the Unborn Child

Most pregnancies manage oxidative stress without harm, thanks to maternal–fetal antioxidant defences.

When oxidative stress overwhelms these defences—especially in mothers with PCOS, GDM, or infections—the risk of complications rises:

Preterm birth, growth restriction, or preeclampsia

Higher vulnerability to neurodevelopmental disorders, including autism spectrum disorder (ASD) and ADHD.

Genetic predispositions in antioxidant or mitochondrial pathways may make some fetuses especially sensitive to these oxidative challenges.

Pregnancy naturally involves a controlled increase in oxidative stress, but when combined with maternal conditions like PCOS, gestational diabetes, or acute infections, the oxidative burden can exceed protective capacity. This imbalance may impair placental function and fetal brain development, increasing the risk of adverse outcomes, including autism. 

 

Pregnancy: Choosing safer options for pain and fever

• Paracetamol → Remains the best option if pain relief is absolutely needed, but should be paired with NAC.
• NSAIDs (ibuprofen, mefenamic acid) → Unsafe in later pregnancy due to fetal kidney damage and premature closure of the ductus arteriosus. Premature closure of the ductus arteriosus is a serious condition that occurs when the fetal blood vessel connecting the pulmonary artery to the aorta closes before birth. Do not use NSAIDs!
• NAC supplementation → Low-cost, safe, and evidence-backed for reducing oxidative stress.

 

Infancy and Early Childhood

• Paracetamol
• Licensed from birth.
• Effective for pain and fever, but still depletes glutathione.
• In at-risk infants (metabolic or mitochondrial issues), consider pairing with NAC.
• NSAIDs (ibuprofen, Ponstan)
• Suitable from 3–6 months (depending on guidelines).
• Do not deplete glutathione, making them safer for oxidative stress.
• Hydration matters to protect kidneys.

 

Vaccinations, Fever, and Oxidative Stress

Vaccines work by briefly activating the immune system. This triggers a short burst of oxidative stress—far smaller than that caused by actual infections.

• Healthy children clear this easily.
• At-risk children (mitochondrial disease, metabolic errors, weak antioxidant systems) may struggle, leading to fatigue, regression-like symptoms, or metabolic instability.

Medication choices around vaccines

• NSAIDs → Good for post-vaccine fever. Avoid routine pre-dosing to prevent dampening immunity, unless the child is in the at-risk group.
• Paracetamol → Pre-vaccine dosing can reduce antibody production and reduce GSH. Post vaccine should be paired with NAC.
• Montelukast → Anti-inflammatory, theoretically helpful in at-risk children, but not tested in trials, but is used at metabolic/mitochondrial clinics treating children.
• NAC → Biologically plausible support for antioxidant status, though not studied formally in this setting.

Mainstream pediatrics avoids routine prophylactic anti-inflammatories, but some specialists (e.g., Dr. Kelley, Johns Hopkins) do use them selectively in fragile children. Using paracetamol without NAC is a bad idea.

 

Metabolic Decompensation: The Hidden Risk

Some children with mitochondrial or metabolic disorders cannot handle stress from fever or illness. This can trigger:

• Energy failure (low ATP)
• Accumulation of toxic metabolites (lactate, ammonia)
• Seizures or regression

In developing brains, these crises can leave permanent autism-like features and/or intellectual disability. These symptoms are secondary to brain injury. Prevention is key:

• Hydration, glucose support
• Early fever control
• Antioxidant support (NAC, vitamins C & E)

 

Key Takeaways

• Pregnancy: If pain relief is needed, paracetamol + NAC is safer than paracetamol alone. Avoid NSAIDs.
• Infancy: Paracetamol is widely used, but NSAIDs are safer from 3 months onward when oxidative stress is a concern.
• Vaccination: Vaccines prevent far greater oxidative stress from infections. At-risk children may benefit from antioxidant or anti-inflammatory support, but this should be individualized.
• Metabolic decompensation: Recognize and prevent crises in vulnerable children—this reduces risk of secondary neurodevelopmental injury.

 

Conclusion

Paracetamol has been trusted for decades, but its link with oxidative stress and neurodevelopmental risk is becoming harder to ignore. A Paracetamol + NAC pill makes both medical and common sense—safer for mothers, safer for children, and suicide-proof.

Until then, thoughtful use of NAC, NSAIDs, and tailored fever management could make a real difference in protecting brain development from conception through early childhood.

 

My original draft post was rather long, so here is the “optional” part 2, for any avid readers out there!

 

 

Part 2: Vaccines, Oxidative Stress, and Children at Risk

Why some kids may react differently — and what parents and clinicians can do

Vaccines are one of the greatest public health achievements, protecting children from infections that would otherwise cause significant illness, hospitalization, or death. But for children with mitochondrial disorders, metabolic diseases, or weak antioxidant systems, even routine vaccination can temporarily stress the body.

How Vaccines Trigger Oxidative Stress

• Vaccination works by activating the immune system, prompting cytokine release, mild inflammation, and reactive oxygen species (ROS) production.
• In healthy children, this burst is short-lived. Antioxidant defences like glutathione, superoxide dismutase, and dietary vitamins C & E neutralize ROS quickly.
• In children with mitochondrial or metabolic vulnerabilities, baseline ROS is already elevated, and antioxidant defences may be limited. A small extra load from vaccination can feel disproportionately stressful.

 

Why Some Children React Differently

Mitochondrial Disorders

• Mitochondria produce ATP and ROS. Dysfunction means higher baseline oxidative stress and lower energy reserves.
• A vaccine-induced oxidative spike can linger longer, leading to fatigue, metabolic stress, or regression-like symptoms.

Metabolic Disorders

• Children with amino acid, fatty acid, or urea cycle defects have limited antioxidant capacity.
• ROS accumulation may overwhelm defences, causing secondary mitochondrial stress or toxic metabolite build-up.

Genetic Variants

• Some children carry variants that reduce glutathione production or antioxidant enzyme activity (e.g., GSTM1/GSTT1 deletions, MTHFR variants, impaired SOD/catalase).
• Even minor oxidative challenges can temporarily disturb synapse formation, neurotransmitter balance, and myelination in the developing brain.

 

Medications Around Vaccination

NSAIDs

• Symptom-driven use for fever or pain post-vaccine is generally safe.
• Routine prophylactic use is usually avoided because it can reduce antibody responses, but specialists consider this is likely minimal

Paracetamol

• Pre-vaccine dosing can modestly blunt antibody formation in some vaccines and is unwise because it reduces GSH just before it will be needed most.
• Post-vaccine, symptom-driven use is often considered safe, but is unwise due to the ruction in GSH when needed most
• High-risk children should always avoid paracetamol unless paired with NAC to protect glutathione and limit oxidative stress.

NAC (N-acetylcysteine)

• Biologically plausible support for antioxidant status in at-risk children.
• Safely used during pregnancy and by babies
• Not yet studied in formal vaccine trials, but safe and used in clinical settings for other oxidative stress conditions.

Montelukast

• Anti-inflammatory, may reduce oxidative stress, but not proven for vaccine prophylaxis.
• Used by children at vaccination time when already prescribed it for asthma/allergic disease.

 

Managing Vaccination in At-Risk Children

1.     Ensure good hydration, feeding, and metabolic stability before vaccination.

2.     Monitor closely for post-vaccine fever, fatigue, or regression-like symptoms.

3.     Have supportive measures ready:

o    NAC or other antioxidant support

o    Symptom-driven NSAIDs

o    Avoid paracetamol unless paired with NAC

o    Quick access to a specialist if metabolic stress occurs

 

Takeaways for Parents and Clinicians

• Vaccines do cause a small, transient oxidative stress, but it is far less than the oxidative burden from infections.
• Children with mitochondrial or metabolic vulnerabilities may need extra care before and after vaccination.
• NAC, hydration, symptom-driven NSAIDs, and careful monitoring can reduce risk without compromising immunity.
• Always coordinate with a metabolic or mitochondrial specialist when planning vaccination for high-risk children.

By understanding oxidative stress, supporting antioxidant defences, and tailoring care, parents and clinicians can protect both immunity and neurodevelopment.

Since most parents, in reality, do not have access a mitochondrial specialist it pays to do your homework in advance. All the needed resources are in plain view.

You do wonder why nobody makes a combined Paracetamol/acetaminophen + NAC pill.

Such a pill is perfect for pregnant women.

Nobody would be able to commit suicide with this pill. This pill blocks the harmful effect on the liver that ultimately can lead to death.

NAC does smell of rotten eggs. One argument against such a pill is that it would stink and pregnant women are often feeling nausea. If the pill is solid (like NAC Sustain) there is no smell of rotten eggs. So you certainly can have a combined pill.

Personally, I would ban all liquid formulations of Paracetamol, other than for babies under 3 months. Many countries have long used exclusively Ibuprofen or Ponstan for children. Once a child is 5 years old the potential for paracetamol to do neurodevelopmental harm should have faded.

You can give babies NAC, it is sold in a liquid form for this purpose. NAC acts as a mucolytic, meaning it thins mucus in the airways.

How common is Metabolic Decompensation as a cause of severe autism? We know it exists, but I think we will never know how common it is. Hannah Poling is the best-known example. Evidence of an inconvenient truth.

 

Immune modulatory treatments for autism spectrum disorder

Need a wizard, or your local doctor?

I was intrigued to come across a recent paper on immune modulatory treatments for autism by a couple of doctors from Massachusetts General Hospital for Children.  The lead author has interests in:

·      Autism spectrum disorders

·      Psychopharmacology

·      Developmental Disabilities

·      Williams syndrome

·      Angelman syndrome

·      Down syndrome

Apparently, he is an internationally-recognized expert in the neurobiology and neuropsychopharmacology of childhood-onset neuropsychiatric disorders including autistic disorder.  Sounds promising, hopefully we will learn something new.

The paper is actually a review of existing drugs, with immunomodulatory properties, that have already been suggested to be repurposed for autism. The abstract was not very insightful, so I have highlighted the final conclusions and listed the drugs, by category, that they thought should be investigated further.

All the drugs have already been covered in this blog and have already been researched in autism.

One important point raised in the conclusion relates to when the drugs are used.  Autism is a progressive condition early in life and there are so-called “critical periods” when the developing brain is highly vulnerable.

For example, Pentoxifylline has been found to be most effective in very young children.  This does not mean do not give it to a teenager with autism, it just means the sooner you treat autism the better the result will be.  This is entirely logical.

Some very clever drugs clearly do not work if given too late, for example Rapamycin analogs used in people with TSC-type autism.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Importantly, each of these developmental abnormalities that are caused by enhanced mTOR pathway has a specific window of opportunity to respond to rapamycin. Namely, dyslamination must be corrected during neurogenesis, and postnatal rapamycin treatment will not correct the cortical malformation. Similarly, exuberant branching of basal dendrites is rectifiable only during the first 2 weeks postnatally while an increase in spine density responds to rapamycin treatment thereafter.  

Back to today’s paper.

Immune modulatory treatments for autism spectrum disorder

The identification of immune dysregulation in at least a subtype ASD has led to the hypothesis that immune modulatory treatments may be effective in treating the core and associated symptoms of ASD. In this article, we discussed how currently FDA-approved medications for ASD have immune modulatory properties.

“Risperidone also inhibited the expression of inflammatory signaling proteins, myelin basic protein isoform 3 (MBP1) and mitogen-activated kinase 1 (MAPK1), in a rat model of MIA. Similarly, aripiprazole has been demonstrated to inhibit expression of IL-6 and TNF-α in cultured primary human peripheral blood mononuclear cells from healthy adult donors.”

We then described emerging treatments for ASD which have been repurposed from nonpsychiatric fields of medicine including metabolic disease, infectious disease, gastroenterology, neurology, and regenerative medicine, all with immune modulatory potential. Although immune modulatory treatments are not currently the standard of care for ASD, remain experimental, and require further research to demonstrate clear safety, tolerability, and efficacy, the early positive results described above warrant further research in the context of IRB-approved clinical trials. Future research is needed to determine whether immune modulatory treatments will affect underlying pathophysiological processes affecting both the behavioral symptoms and the common immune-mediated medical co-morbidities of ASD. Identification of neuroimaging or inflammatory biomarkers that respond to immune modulatory treatment and correlate with treatment response would further support the hypothesis of an immune-mediated subtype of ASD and aid in measuring response to immune modulatory treatments. In addition, it will be important to determine if particular immune modulating treatments are best tolerated and most effective when administered at specific developmental time points across the lifespan of individuals with ASD.

Here are the drugs they listed:-

1.     Metabolic disease

Spironolactone

Pioglitazone

Pentoxifylline

Spironolactone is a cheap potassium sparing diuretic. It has secondary effects that include reducing the level of male hormones and some inflammatory cytokines.

Pioglitazone is drug for type 2 diabetes that improves insulin sensitivity.  It reduces certain inflammatory cytokines making it both an autism therapy and indeed a suggested Covid-19 therapy.

Pentoxifylline is a non-selective phosphodiesterase (PDE) inhibitor, used to treat muscle pain.  PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.  Roflumilast and Ibudilast are PDE4 inhibitors that also may improve some autism.  The limiting side effect can be nausea/vomiting, which can happen with non-selective PDE4 inhibitors.

I did try Spironolactone once; it did not seem to have any effect.  It is a good match for bumetanide because it increases potassium levels.

I do think that Pioglitazone has a helpful effect and there will be another post on that.

PDE inhibitors are used by readers of this blog. Maja is a fan of Pentoxifylline, without any side effects. Roflumilast at a low dose is supposed to raise IQ, but still makes some people want to vomit. The Japanese drug Ibudilast works for some, but nausea is listed as a possible side effect.

2.     Infectious disease

Minocycline

Vancomycin

Suramin

Minocycline is an antibiotic that crosses in to the brain.  It is known to stabilize activated microglia, the brain’s immune cells.  It is also known that tetracycline antibiotics are immunomodulatory.

Vancomycin is an antibiotic used to treat bacterial infections, if taken orally it does not go beyond the gut.  It will reduce the level of certain harmful bacteria including Clostridium difficile.

Suramin is an anti-parasite drug that Dr Naviaux is repurposing for autism, based on his theory of cell danger response.

  

3.     Neurology

Valproic acid

Valproic acid is an anti-epileptic drug.  It also has immunomodulatory and HDAC effects, these effects can both cause autism when taken by a pregnant mother and also improve autism in some people.

Valproic acid can have side effects. Low dose valproic acid seems to work for some people. 

4.     Gastroenterology

Fecal microbiota transplant (FMT)

FMT is currently used to treat recurrent Clostridium difficile infection and may also be of benefit for other GI conditions including IBD, obesity, metabolic syndrome, and functional GI disorders.

Altered gut bacteria (dysbiosis) is a feature of some autism which then impairs brain function.  Reversing the dysbiosis with FMT improves brain function.  

5.     Oncology

Lenalidomide

Romidepsin

  

Lenalidomide is an expensive anti-cancer drug that also has immunomodulatory effects.

Romidepsin is a potent HDAC inhibitor, making it a useful cancer therapy.  HDAC inhibitors are potential autism drugs, but only if given early enough not to miss the critical periods of brain development. 

6.     Pulmonology

N-acetylcysteine

Many people with autism respond well to NAC. You do need a lot of it, because it has a short half-life.

7.     Nutritional medicine and dietary supplements

Omega-3 fatty acids

Vitamin D

Flavonoids

Nutritional supplements can get very expensive.  In hot climates, like Egypt, some dark skinned people cover up and then lack vitamin D.  A lack of vitamin D will make autism worse.

Some people with mild brain disorders do seem to benefit from some omega-3 therapies.

Flavonoids are very good for general health, but seem to lack potency for treating brain disorders.  Quercetin and luteolin do have some benefits. 

8.     Rheumatology

Celecoxib

Corticosteroids

Intravenous immunoglobulin (IVIG)

Celecoxib is a common NSAID that is particularly well tolerated (it affects COX-2 and only marginally COX-1, hence its reduced GI side effects).

NSAIDS are used by many people with autism.

Steroids do improve some people’s autism, but are unsuitable for long term use.  A short course of steroids reduces Covid-19 deaths – a very cost effective therapy.

IVIG is extremely expensive, but it does provide a benefit in some cases. IVIG is used quite often to treat autism in the US, but rarely elsewhere other than for PANS/PANDAS that might occur with autism.

9.     Regenerative medicine

Stem cell therapy

I was surprised they gave stem cell therapy a mention. I think it is still early days for stem cell therapy.

Conclusion

I have observed the ongoing Covid-19 situation with interest and in particular what use has been made of the scientific literature.

There are all sorts of interesting snippets of data. You do not want to be deficient in Zinc or vitamin D, having high cholesterol will make it easier for the virus to enter your cells.  Potassium levels may plummet and blood becomes sticky, so may form dangerous clots. A long list of drugs may be at least partially effective, meaning they speed up recovery and reduce death rates. Polytherapy, meaning taking multiple drugs, is likely to be the best choice for Covid-19.

Potential side effects of some drugs have been grossly exaggerated, as with drugs repurposed for autism.  Even in published research, people cheat and falsify the data. In the case of hydroxychloroquine, the falsified papers were quickly retracted.

The media twist the facts, to suit their narrative, as with autism.  This happens even with Covid-19. Anti-Trump media (CNN, BBC etc) is automatically anti-hydroxychloroquine, and ignores all the published research and the results achieved in countries that widely use it (small countries like China and India). 

Shutting down entire economies when only 5-10% of the population have been infected and hopefully got some immunity, does not look so smart if you are then going to reopen and let young people loose.  They will inevitably catch the virus and then infect everyone else. Permanent lockdown restrictions, if followed by everyone, until a vaccine which everyone actually agreed to take, makes sense and living with the virus makes sense, but anything in between is not going to work. After 3 months without any broad lockdown, and allowing young people to socialize, most people would have had the virus and then those people choosing to shield could safely reemerge. The death rate with the current optimal, inexpensive treatment, as used in India or South Africa is very low, in people who are not frail to start with. Time to make a choice.  Poor people in poor countries cannot afford to keep going into lockdown, they need to eat.

What hope is there for treating a highly heterogeneous condition like autism, if it is not approached entirely rationally and without preconceptions and preconditions?  In a pandemic we see that science does not drive policy and translating science into therapy is highly variable.  The science is there for those who choose to read it.

I frequently see comments from parents who have seen some of the research showing that autism has an inflammatory/auto-immune component.  They ask why this has not been followed up on in the research.  It has been followed up on.  It just has not been acted upon.

Why has it not been acted on?

This missing stage is called “translation”.  Why don’t doctors translate scientific findings into therapy for their patients?

What is common sense to some, is “experimental” to others. “Experimental” is frowned upon in modern medicine, but innovation requires experimentation.

Many people’s severe autism is unique and experimental polytherapy/polypharmacy is their only hope.

The cookie cutter approach is not going to work for autism. 

Thankfully, for many common diseases the cookie cutter approach works just fine.

Do the authors of today’s paper, Dr McDougle and Dr Thom, actually prescribe to their young patients many of the drugs that they have written about?  I doubt it and therein lies the problem.  

Time for that wizard, perhaps? 

A few years ago I did add the following tag line, under the big Epiphany at the top of the page. 

An Alternative Reality for Classic Autism - Based on Today's Science

You can choose a different Autism reality, if you do not like your current one.  I am glad I did. I didn't even need a wizard.  

There are many immuno-modulatory therapies for autism that the Massachusetts doctor duo did not mention, but it is good that they made a start.