Prenatal Fentanyl Exposure Suspected in Novel Syndrome

A possible link between a novel cholesterol metabolism disorder and prenatal fentanyl exposure is under investigation.

The hypothesis is that prenatal fentanyl exposure possibly interferes with cholesterol metabolism, leading to findings resembling Smith-Lemli-Opitz syndrome (SLOS) in 10 infants. However, Erica Fernandes, DO, a clinical geneticist at Nemours Children’s Health in Wilmington, Delaware, and study co-authors cautioned that causality has yet to be determined in their report, which was published in Genetics in Medicine Open.

Infants included in the report were born after a pregnancy complicated by multiple drug exposures, including nonprescription fentanyl, Fernandes and colleagues noted.

The babies all shared distinctive features, such as short stature, microcephaly, shortened nasal tip, micrognathia, cleft palate, single palmar crease and adducted thumb, toe syndactyly, genital anomalies, rocker-bottom feet, and dysgenesis of the corpus callosum.

Due to clinical suspicion for SLOS, biochemical testing was performed. Among the infants, elevated 7-dehydrocholesterol (7-DHC) or 8-dehydrocholesterol (8-DHC) was present shortly after delivery. However, genetic testing was nondiagnostic, and 7-DHC and 8-DHC levels subsequently normalized.

“The elevated 7- and 8-DHC levels are consistent with a disturbance of the cholesterol metabolism pathway prenatally, caused by an extrinsic factor rather than an inborn error of metabolism, allowing for normalization of the metabolic studies in later childhood,” Fernandes and colleagues wrote. “The overlap of findings in the novel syndrome with those seen in patients of SLOS supports prenatal cholesterol metabolism abnormalities as the potential cause.”

Certain psychotropic drugs have been shown to affect cholesterol metabolism by inhibiting DHCR7, the enzyme catalyzing the final step in the process, the researchers noted. They hypothesized that prenatal exposure to fentanyl, as a Sigma-1 ligand, similar to cholesterol and many cholesterol precursors, “may affect cholesterol synthesis by inhibition of DHCR7 in the developing fetus, giving rise to physical findings resembling SLOS.”

An alternative hypothesis is that fentanyl “replaces cholesterol in the smoothened receptor’s cholesterol binding pocket, thereby impairing GLI transcription factors activation,” they added.

“We have our babies from our study [who] have the very striking facial features that look very much like SLOS, and then we also have patients, who we did not include in the paper, who have many features, but not all,” Fernandes told MedPage Today. This is “something that we are taking a much, much closer look at, hopefully being able to delineate more.”

Fernandes and colleagues reiterated the early stage of their small report, and the need for additional studies before drawing any definitive conclusions. They noted the lack of laboratory studies on fentanyl effects on cholesterol metabolism and fetal development as well as the absence of an animal model recapitulating the phenotype.

Furthermore, because of difficult social and legal implications, it was not possible to accurately quantify the timing and amount of prenatal fentanyl exposure in this report, they added.

“Although fentanyl’s effect on cholesterol metabolism has not been directly tested, based on indirect evidence it is biologically plausible that it affects cholesterol metabolism in the developing fetus,” the authors maintained. The next steps for this group includes work on determining whether fentanyl itself or contaminants in fentanyl, among other possibilities, may be disrupting the cholesterol pathway, Fernandes said.

However, a specialist in obstetrics and gynecology and in addiction medicine urged caution regarding these findings.

“In terms of development, I would say that, generally speaking, we overstate the potential risks or harms of in utero chemical exposure, and grossly minimize the importance of the caregiving environment,” Mishka Terplan, MD, MPH, medical director at Friends Research Institute in Baltimore, told MedPage Today.

He further cautioned against the potential for stigma and assumptions that may be harmful to a pregnant individual, her family, or her future.

Terplan stressed that treatment is effective for individuals who have an opioid-use disorder (OUD) during pregnancy regardless of what the primary opioid is (i.e. prescription opioids, heroin, or fentanyl). “We know that treatment works, that methadone and buprenorphine are the safest and most effective medications for the both the mother and the fetus and the newborn, and that the treatment of chronic conditions, including addiction in pregnancy, improves birth outcomes.”

However, there remain significant barriers to treatment, he said.

A recent study found that of the estimated 2.5 million U.S. adults with OUD in the past year, only 22% received medications to treat it in 2021.

Cost, stigma, and limited availability in pharmacies are among known obstacles to medications for OUD.

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