Background: Hirschsprung disease is a congenital neurocristopathy that affects 1 in 5000 newborns. The disease involves fetal gut aganglionosis due to the defective migration and differentiation of neural crest cells in the intestines. The condition is associated with intractable constipation, megacolon ileus and the need for colectomy in childhood. While it was previously known that gestational exposures such as maternal vitamin A deficiency, ibuprofen intake, and BP-3 sunscreen use had implications on the development of Hirschsprung, we found that these variables share effects common to the RET proto-oncogene pathway. Methods: An initial systematic review was done on the NIH library, PubMed and Scorpus databases to evaluate existing literature on maternal gestational exposures tied to Hirschsprung disease. Search queries involved keywords “Hirschsprung disease”, “maternal exposure” and “developmental pathway”. Inclusion criteria for accepted studies were: peer reviewed status, sample size greater than twenty, human models, discussion of developmental mechanisms, and published within the past twenty years. Based on these studies, we categorized the maternal exposure variables and further reviewed the specific biologic pathways impacted. From this list of pathways, the mechanism common between the highest number of categories was selected for this report. Results: This study explores how maternal exposures to vitamin A deficiency, BP-3, and ibuprofen increase the risk of Hirschsprung disease by affecting the RET proto-oncogene, which is essential for neural crest cell migration and implicated in at least 20% of all Hirschsprung cases. Retinoic acid, the active form of vitamin A, upregulates RET transcription. As a result, low vitamin A levels can downregulate RET and impair neural crest cell migration. Benzophenone-3 (BP-3), a sunscreen ingredient, reduces RET levels by disrupting fetal enteric neuron development and neural crest cell migration via the SLIT2/ROBO1-miR-218-RET/PLAG1 pathway. While ibuprofen does not directly affect RET, it may affect RET signaling by increasing acetylcholinesterase (AchE) activity, as suggested by studies showing co-expression of RET and choline acetyltransferase in enteric ganglia. Conclusion: Our study found that vitamin A deficiency, BP-3, and ibuprofen increase the risk of Hirschsprung disease via different pathways, with the RET proto-oncogene being the most commonly implicated gene. Vitamin A deficiency and BP-3 exposure both affect the RET signaling pathway, while ibuprofen appears to indirectly increase risk through a separate mechanism. These findings highlight the need to monitor and mitigate maternal exposures to reduce Hirschsprung disease risk and suggest the RET proto-oncogene as a potential target for treatment and prevention.