The exact etiology of neonatal small left colon syndrome is not known.

Several theories have been proposed, including neural, humoral, and drug-induced etiologies.

A frequent association of neonatal small left colon syndrome with maternal gestational diabetes mellitus has been reported.

Maternal gestational diabetes mellitus induces neonatal hypoglycemia which affects intestinal motility via activation of the autonomic nervous system and glucagon release.

Glucagon release is known to decrease motility in the left colon.

Neonatal hypoglycemia also stimulates the sympathetic and parasympathetic autonomic nervous system.

Parasympathetic stimulation results in increased motility in its area of distribution, which ends at the splenic flexure, whereas sympathetic stimulation results in diminished motility.

The combined effect of glucagon release with sympathetic and parasympathetic stimulation results in an overall diminution in intestinal motility, with a functional obstruction in the colon beyond the splenic flexure.

In 1974, Davis et al. reported the association of neonatal small left colon syndrome with abnormalities of intestinal neurohistology. Their initial report described increased numbers of immature small ganglion cells in the myenteric plexus (in both the narrowed and dilated parts of the colon) in patients with neonatal small left colon syndrome. They compared the histology from patients with small left colon syndrome with that of control subjects, including infants of diabetic mothers without colon changes, premature infants, and term infants. They concluded that the hypercellularity observed in the specimens from patients with neonatal small left colon syndrome most closely resembled the histology observed in the colons of premature infants.

Neonatal small left colon syndrome could be a form of intestinal neuronal dysplasia with an increase in the number of acetylcholinesterase (AChE)-stained fibers in the mucosa and increased submucosal ganglia or large ganglia. These changes are also observed with prematurity, and because most infants with neonatal small left colon syndrome in these reports were premature, it is difficult to conclude on these findings.

Maternal drugs used during the third trimester can cross the placenta and affect the fetus. This was observed in infants born to mothers using psychotropic drugs with known anticholinergic effects. This as well as the hypermagnesemia (in infants born to eclamptic mothers treated with magnesium sulfate) can also cause hypomotility.

Stress (eclampsia) may mediate the same changes through similar mechanisms.

Most patients with neonatal small left colon syndrome are born at or near term and are of normal birth weight.