BACKGROUND: Holoprosencephaly is the most common malformation of the forebrain 
(1 in 250 embryos) with severe consequences for fetal and child development. 
This study evaluates nongenetic factors associated with holoprosencephaly risk, 
severity, and gene-environment interactions.
METHODS: For this retrospective case control study, we developed an online 
questionnaire focusing on exposures to common and rare toxins/toxicants before 
and during pregnancy, nutritional factors, maternal health history, and 
demographic factors. Patients with holoprosencephaly were primarily ascertained 
from our ongoing genetic and clinical studies of holoprosencephaly. Controls 
included children with Williams-Beuren syndrome (WBS) ascertained through online 
advertisements in a WBD support group and fliers.
RESULTS: Difference in odds of exposures between cases and controls as well as 
within cases with varying holoprosencephaly severity were studied. Cases 
included children born with holoprosencephaly (n = 92) and the control group 
consisted of children with WBS (n = 56). Pregnancy associated risk associated 
with holoprosencephaly included maternal pregestational diabetes (9.2% of cases 
and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 
1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or 
sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant 
gene-environment interactions were identified including for consumption of 
cheese (p < .05) and espresso drinks (p = .03).
CONCLUSION: The study identifies modifiable risk factors and gene-environment 
interactions that should be considered in future prevention of 
holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm 
these findings.