Novel Syndrome Associated with Prenatal Fentanyl Exposure

Individuals with prenatal fentanyl exposure may exhibit shared traits, including short stature, microcephaly, distinctive facial features, and congenital anomalies, suggesting the emergence of a new syndrome.

December 2023

Doctors report they are seeing what they believe is a new syndrome in babies who are exposed to fentanyl while in the womb.

Identification of a recurrent pattern of congenital anomalies may result in the delineation of a new syndrome. The definition of syndrome includes shared causality between affected individuals. Exome and genome analysis allows efficient identification of shared genetic variants. New syndrome delineation now often involves screening particular individuals based on their shared genetic variants. In contrast, embryopathies , such as the recently described congenital Zika syndrome and the more common fetal alcohol syndrome (FAS) or fetal alcohol spectrum disorder, do not have single-gene causes.

Here, we report on a cohort of patients, whose physical findings and biochemical abnormalities in the neonatal period suggested a diagnosis of Smith-Lemli-Opitz syndrome (SLOS), a multiple congenital anomaly syndrome caused by biallelic variants of DHCR7 that affect brain metabolism. cholesterol . The individuals did not have pathogenic variants consistent with SLOS and did not share other genetic abnormalities. In contrast, all were born after a pregnancy complicated by exposure to over-the-counter fentanyl , suggesting that fentanyl is a possible shared teratogen .

Summary

A new syndrome was suspected in people who shared short stature, microcephaly, distinctive facial features, and congenital anomalies . We enrolled 6 patients in an institutional review board-approved study and evaluated medical history, findings, facial photographs, and test results in this original cohort. Doctors from outside institutions contributed four additional cases with similar findings, bringing the number of reported cases to 10 and supporting the existence of this new syndrome.

All six people enrolled in the institutional review board-approved study shared microcephaly, short stature, and distinctive facial features . Congenital malformations included cleft palate, talipes equinovarus or rocker foot, and cordee or hypospadias. There were short, wide thumbs, a single palmar crease, and mild syndactyly of 2.3 fingers. Hypoplasia of the corpus callosum was observed in 3 of 5 with appropriate evaluation. His growth and physical findings were suggestive of Smith-Lemli-Opitz syndrome. Biochemical studies shortly after delivery indicated abnormalities in the cholesterol metabolism pathway that subsequently resolved. No shared genomic or genetic cause was identified. All individuals were born after a pregnancy complicated by prenatal exposure to over-the-counter opioids, particularly fentanyl , suggesting that fentanyl is a teratogen .

Prenatal exposure to fentanyl possibly interfered with cholesterol metabolism , leading to findings resembling Smith-Lemli-Opitz syndrome. This new syndrome is clinically recognizable. Four additional cases contributed clinically similar findings, increasing the number of cases to 10 and supporting a new syndrome associated with prenatal fentanyl exposure. Evaluation of the Shepard and Bradford Hill criteria could be consistent with fentanyl as a teratogen, although caution is needed before assigning causality and data replication is necessary.

Novel Syndrome Associated with Prenatal Fentanyl E
Figure : Facial photographs of individuals 1-6 (AF) as used in the GestaltMatcher analysis. Below each image is a side facial view, a photo of a hand and a foot of the respective individual. 

Comments

All of the babies have cleft palates and unusually small heads, and all were born to mothers who said they had used fentanyl and other drugs during pregnancy.

Six babies were first identified at Nemours Children’s Health in Wilmington, Delaware, two in California, one in Massachusetts and one in Rhode Island. Erin Wadman  , a genetic counselor at Nemours, and her colleagues recently reported on the babies in the journal  Genetics in Medicine Open .

The discovery of a possibly novel syndrome occurred in August 2022, when Wadman consulted on the case of a baby who had been born with birth defects.

"I was sitting there at the appointment and I thought this face looked so familiar. This story sounds so familiar. And I was thinking about how this patient reminded me so much of a patient I had seen earlier in the year and then other patients I had seen "Wadman told  NBC News  . "That’s when we thought we might have stumbled upon something really big here."

All 10 babies also had unusually small bodies and tended to have droopy eyelids. Their noses were typically upturned and their lower jaws were often undersized, the researchers said. His feet pointed downward and inward, and two of his middle toes were webbed. The baby boys had genital irregularities. Some had feeding problems and their thumbs were not fully formed.

Wadman and his colleagues first thought of a syndrome called  Smith-Lemli-Opitz , in which genetic mutations affect the way fetuses process cholesterol.

None of the babies were found to have the variant, so doctors began to wonder if fentanyl could be causing similar alterations in cholesterol metabolism during pregnancy.

"Although the effect of fentanyl on cholesterol metabolism has not been tested directly, based on indirect evidence, it is biologically plausible that it affects cholesterol metabolism in the developing fetus," the authors wrote in the new report. Still, Wadman said much more work is needed to confirm the findings. Experts agreed that more research is essential.

The women in the study were "...taking a lot of drugs," Dr. Nora Volkow  , director of the National Institute on Drug Abuse, told  NBC News  . "It’s very difficult to determine whether this is just the effect of fentanyl or is it really the effect of other drugs or other combinations."

"That said, reports like this are very important because they shed light on issues that we need to systematically investigate," Volkow added. The fentanyl-cholesterol theory will also be explored by researchers at the University of Nebraska Medical Center (UNMC),  NBC News reported . Dr. Karoly Mirnics , director of UNMC’s Munroe-Meyer Institute, told  NBC News  that she has dedicated research to studying the impact of a variety of medications on cholesterol metabolism.

Cholesterol is "essential for the entire body, for every cell membrane, for every function," Mirnics explained. "If there is no cholesterol, there is no life . "

Mirnics plans to study the blood of babies identified at Nemours and other locations.

"This is concerning,"  March of Dimes President  Dr. Elizabeth Cherot told NBC News  . "As we see these shared characteristics identified, we may be uncovering a real syndrome."

Dr. Sonja Rasmussen , a medical geneticist at Johns Hopkins School of Medicine in Baltimore, praised the "astute doctors" at Nemours for noticing what could be an important trend.

"That’s how fetal alcohol syndrome was recognized . That’s how isotretinoin [acne medication] was recognized as causing a distinct pattern of birth defects," said Rasmussen, one of the first to describe the defects associated with the virus. Zika while at the US Centers for Disease Control and Prevention.

Final message

A novel syndrome was recognized, including small size for gestational age, distinctive facial features, cleft palate, single palmar crease, genital anomalies, and syndactyly 2,3. When tested in the first weeks after birth, abnormalities of cholesterol metabolism suggested SLOS, but genetic testing did not confirm this diagnosis and subsequent biochemical testing showed resolution of the abnormalities. No common genetic or genomic abnormality was identified, but prenatal fentanyl exposure was shared between pregnancies.

Although the effect of fentanyl on cholesterol metabolism has not been tested directly, indirect evidence suggests that it is biologically plausible that it affects cholesterol metabolism in the developing fetus. Additional cases reported by other physicians support the causal relationship of prenatal fentanyl exposure. Despite the limitations of this case report, including the lack of quantifiable prenatal drug exposure and the lack of laboratory evidence directly demonstrating the effect of fentanyl on cholesterol metabolism and embryological development, recognition of the new syndrome associated with prenatal fentanyl exposure is critically important.

Future studies are needed to determine long-term outcomes, particularly regarding cognitive abilities and general well-being. In light of the current epidemic of fentanyl use, the public health impact of the new syndrome associated with prenatal fentanyl exposure is likely to be significant. Patients with suggestive findings should be asked about prenatal fentanyl exposure.