There was a “striking increase” in the number of cases of fetal situs inversus at two Chinese obstetric centers after the zero-COVID policies were lifted in the country, researchers reported.
From January through July of this year, the incidence of situs inversus — a rare congenital condition in which visceral organs are reversed from their normal positions — was over four times as high as the mean annual incidence from 2014 through 2022 at the two centers, which were not in the same region, reported Shan Bian, PhD, of Tongji University in Shanghai, and colleagues.
Overall, 56 cases of fetal situs inversus — 52 cases of situs inversus totalis and 4 cases of partial situs inversus — were identified during the first 7 months of 2023, with incidence peaking in April, they noted in correspondence published in the New England Journal of Medicine.
Cases were diagnosed via routine ultrasonography at a gestational age of about 20 to 24 weeks, with no change having been made in diagnostic protocol or physician training.
“Although vertical transmission of SARS-CoV-2 is debated, fetal infection early in gestation could hypothetically affect visceral lateralization; alternatively, SARS-CoV-2-mediated maternal inflammatory responses might indirectly affect left-right organizer function and impair visceral lateralization,” Bian and co-authors wrote.
A surge in COVID infections after zero-COVID policies were lifted in China began in early December 2022, peaking around December 20 and ending in early February 2023, they noted. The surge is estimated to have affected 82% of the population there.
“While these initial observations are, of course, interesting, it is important to note that this is merely an observation, not a firm association or causation,” Katherine Kohari, MD, a maternal-fetal medicine specialist at Yale Medicine in New Haven, Connecticut, told MedPage Today in an email.
“There may be other reasons for the increase in the incidence seen in the population,” she said. “Additionally, there were no increased rates of situs inversus during other time periods during which there were presumably high rates of COVID-19 infection, namely in 2020. We also do not know if the patients whose fetuses were diagnosed with situs inversus also had COVID-19 infection in pregnancy.”
“Therefore, the association would need to be further explored in a peer-reviewed research publication with more detail regarding the pregnancy exposures in each of the diagnosed cases as compared to health controls,” she added. “Even then, causation would be challenging to prove.”
Bethany Stetson, MD, a maternal-fetal medicine specialist at Northwestern University Feinberg School of Medicine in Chicago, echoed this sentiment, noting, “I think this is definitely very early stage. We don’t have a lot of the information that we would like.”
At the same time, any time there is an increase in a birth defect, “it warrants further investigation,” she told MedPage Today, adding that it “never hurts to bring this up for other centers.”
Stetson also said it was a significant jump to say this specific observation is directly related to lifting zero-COVID policies.
Both Stetson and Kohari pointed to well-known viral links to a range of fetal abnormalities, but not to situs inversus, though they said that the latter is not beyond the realm of possibility.
“I am not aware of any viruses associated with the development of situs inversus in the fetus,” Kohari said. “There are other viral infections that are known to cause abnormalities of fetal development, so it is plausible that the COVID-19 virus could also cause fetal abnormalities, but there is [significant research] that still needs to be done to further explore this association.”
As for prognosis, Stetson said that many people with situs inversus indeed have a normal life expectancy. However, there is always a concern and a need to look for any other findings that can also be present, such as congenital heart defects, she added.
Kohari noted that, “generally, if a true mirror image exists, then most people with this diagnosis do very well. Sometimes this diagnosis is made incidentally. However, there are variations of this arrangement that may be more associated with functional and anatomic problems.”
The study authors also stressed that no conclusions could be made regarding causality. At the same time, they said that their observations “suggest a possible relationship between SARS-CoV-2 infection and fetal situs inversus that warrants further study.”
“Further analysis is necessary to verify that genetic abnormalities in primary ciliary dyskinesia-related genes that may not have been detected during prenatal genetic screening did not contribute to the incidence of these cases and to assess the potential contribution of environmental factors,” they wrote. “It is notable that situs inversus diagnoses remained extremely rare despite the increase in incidence at our centers after the SARS-CoV-2 surge.”
Research was supported by grants from the National Key R&D Program of China, the National Nature Science Foundation of China, the Shanghai Municipal Science and Technology Major Project, and the Shanghai Jiao Tong University STAR Grant.
The authors reported no conflicts of interest.
Neither Kohari nor Stetson reported any conflicts of interest.
New England Journal of Medicine
Source Reference: Wang Y, et al “Association of SARS-CoV-2 infection during early weeks of gestation with situs inversus” N Engl J Med 2023; DOI: 10.1056/NEJMc2309215.