The work described here firmly establishes the critical requirement for cholesterol biosynthesis during brain development and indicates that exposure to SBIMs during pregnancy may have neurodevelopmental effects. The concern that medication used during pregnancy could predispose to adverse outcomes for the baby is not new (112), and medication package inserts developed by pharmaceutical companies clearly state the risks of medications if taken during pregnancy. Unfortunately, although the package inserts are easily accessible for physicians and patients, the relevant data are often buried in the large amount of information in them. Notably, in 2015, the FDA retired the A, B, C, D, and X risk pregnancy categories, which had been used since 1979 (113). The categories were replaced with narrative sections and subsections to allow for more nuance and data transparency. However, these narrative sections may cause more confusion, especially for patients with low health literacy and for physicians attempting to balance the time burden of their clinical duties with interpreting the often complex and sometimes conflicting study results listed in the inserts.

Importantly, the data from our recent study (23) suggest only one of likely several important associations with ASD and do not conflict with the extensively documented, strong genetic component of ASD (114–116). Not all pregnancies prescribed SBIMs resulted in a child with ASD, and it is not yet clear which factors may exacerbate the sterol-inhibiting effects (or side effects) of these medications. The variables that could interact with SBIM use are nearly endless, including the sterol biosynthesis gene variants of the mother and developing baby, comorbidities, polypharmacy, environmental influences, socioeconomical circumstances, and nutritional factors. Furthermore, the dose, duration, and timing of SBIM administration are likely to also be critical determinants of ASD risk.

Notably, one potential risk factor is widely overlooked. There is extremely limited data on the effects of paternal SBIM use in the context of reproductive health. Cholesterol is essential for male fertility as a precursor to testosterone and a structural component of sperm membranes (117). Sperm divide extremely fast, and animal model studies show a negative effect of aripiprazole on male fertility, sperm motility, and sperm quality (118, 119). Similarly, atorvastatin treatment has been shown to alter semen parameters in healthy males, including the total number of spermatozoa, vitality, total motility, and kinetics (120). The effect of paternal SBIM use on fetal development is thus far untested. However, given that paternal alcohol consumption before conception can disrupt offspring’s brain, skull, and face development (121), investigating the impact of environmental factors including paternal SBIM use on neurodevelopmental outcomes should become a priority (122).

It is also important to acknowledge that in addition to its neurodevelopmental roles, cholesterol is also critical for adult brain function. As in the developing brain, cholesterol is critical in the adult brain for structural integrity and to enable efficient synaptic transmission. Dysregulated cholesterol homeostasis may contribute to the development of neurodegenerative diseases, including Alzheimer’s disease (123, 124). How interventions including SBIMs may interact with this biology is another area of intense interest in the field (125).

Finally, the combined findings above raise a critical question: Are we only seeing the proverbial tip of the iceberg? Can prenatal SBIM exposure lead to other developmental challenges, such as dysmorphologies, obsessive-compulsive disorder, learning difficulties, or anxiety later in childhood or as an adult? Does fetal sterol biosynthesis inhibition permanently rewire the developing brain, with functional/behavioral outcomes that may only reveal themselves years after the initial insult? We propose that the strongest inhibition of sterol biosynthesis might result in earlier and more clinically apparent changes (e.g., dysmorphologies), while more moderate inhibition may have primarily microanatomical and behavioral consequences (Figure 2). This complex framework deserves further investigation.

Proposed neurodevelopmental pathophysiology and consequences of developmental sterol inhibition. SBIMs utilized during pregnancy can interact with the normal developmental trajectory of the fetal brain and body. The magnitude of the sterol inhibition depends on many factors highlighted in the circle. We propose that the strongest sterol inhibition would result in SLOS-like dysmorphologies, while a more moderate inhibition would result in functional consequences with a delayed manifestation of functional connectivity changes that could persist through a lifetime. ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder.

In summary, developmental cholesterol biosynthesis is fundamental for CNS maturation. The spatiotemporal regulation of sterol synthesis, enzyme expression, and intercellular lipid transport ensures adequate cholesterol supply for membrane biogenesis and signaling throughout neurodevelopment. Prenatal disruption of this finely tuned system — whether by medications or genetic, metabolic, or environmental factors — can have lasting consequences for brain structure and function. Prescription of SBIMs to pregnant women increased considerably over the period of our study, from 4.6% in 2014 to 16.8% in 2023 (23). Given the potential risks of the sterol biosynthesis–inhibiting effects, the increased utilization of SBIMs, likely reflecting increased provider comfort with prescribing these medications during pregnancy, is a cause for concern (126, 127).