Piecing the autism jigsaw together

In Research

Follow this topic

Bookmark

Record learning outcomes

The number of people with diagnosed autism has risen markedly since the 1990s. Yet, based on community case-finding studies, autism’s prevalence has remained stable for the last 70-80 years. More inclusive diagnostic criteria, greater awareness and better access to services probably account for the increase in cases.¹

Autism seems to arise from the interplay between genetic and environmental factors, although many details remain enigmatic.² Nevertheless, researchers are putting the pathogenic picture together – and a new study in Molecular Psychiatry may be an important piece in the autism jigsaw.³

Enter SBIM

Cholesterol, despite the lipid’s cardiovascular bad press, is critical during intrauterine development. Initially, mothers supply sterols (chemicals related to cholesterol). After about 19-20 weeks’ gestation, foetuses start synthesising sterols.³

Disrupted sterol biosynthesis can cause developmental and intellectual disabilities. For instance, the enzyme 7-dehydrocholesterol reductase catalyses the final step in cholesterol synthesis. Genetic mutations resulting in low enzyme levels cause an orphan disease called the Smith-Lemli-Opitz syndrome (SLOS). Three-quarters of SLOS patients live with autism spectrum disorder (ASD).³

The new study investigated the relationship between fifteen sterol biosynthesis inhibiting medications (SBIM) prescribed to mothers during pregnancy and ASD in their 6,135,213 children.³ Overall, 11% of pregnant mothers were prescribed at least one SBIM and 3.8% of the children were diagnosed with ASD.³

Statins inhibit hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the first enzyme in the pathway that synthesises cholesterol. So the study assessed the relationship between ASD and atorvastatin, pravastatin, rosuvastatin and simvastatin.

Increased risk

The other drugs assessed have side-effects that inhibit later stages in the cholesterol synthesis pathway: aripiprazole, bupropion, buspirone, cariprazine, fluoxetine, haloperidol, metoprolol, nebivolol, propranolol, sertraline and trazodone.³

Exposure to at least one SBIM during pregnancy was associated with a 47% increased ASD risk after adjusting for potential confounders. Each additional SBIM co-prescription increased ASD risk by 33%. Four or more SBIMs prescribed simultaneously more than doubled ASD risk (hazard ratio [HR] 2.33).³

Cariprazine (HR 2.59) and aripiprazole (HR 2.18) were associated with the highest risk, more than doubling the likelihood of ASD. Atorvastatin (HR 1.71), pravastatin (HR 1.95), rosuvastatin (HR 1.36) and simvastatin (HR 1.64) increased ASD risk by 36-95%. Bupropion, buspirone, fluoxetine, haloperidol, metoprolol, nebivolol, propranolol, sertraline and trazodone were associated with a 35-86% increased likelihood of ASD.³

The differences in ASD risk may reflect mechanisms of action, half-life and metabolism, drug-drug interactions, ability to cross the blood-brain barrier and the degree to which a drug inhibits sterol synthesis.

Underestimate?

In the US, ASD is typically diagnosed at about 4 years of age. So the 18-72-month-old offspring in the study may not have an established ASD diagnosis. Furthermore, ASD diagnoses are often documented in medical records other than the database used in the study. “As a result, our data might underestimate the potential impact of maternal SBIM use on developing ASD in the offspring,” the authors remark.³

The study could not assess interactions between the medications and variants of the genes that modulate sterol synthesis or the impact of environmental (e.g. insecticides, air pollution, heavy metals, pesticides), socioeconomic and nutritional factors (especially low vitamin D levels).

The study was also unable to define a “safe” SBIM dose for the foetal brain.³

Patient advice

So what should pharmacists tell patients? Firstly, cholesterol turnover in the adult brain takes years. In other words, the authors comment, “these effects are likely negligible for already-formed structures in adults”. Secondly, pregnant women should not stop or alter treatment without medical supervision. After all, SBIMs may be essential, even life-preserving, treatments. Rather, the researchers call for a re-evaluation of prescribing practices and the development of safer alternatives for use during pregnancy.³

“Our findings do not suggest that these medications are unsafe for adults,” concludes author Dr Karoly Mirnics, dean and director of the Munroe-Meyer Institute, University of Nebraska Medical Center. “But they raise important questions about their use during pregnancy, a period when even small biochemical disruptions may have outsized effects on foetal brain development.”