Two recently published studies have highlighted the potential impact of SARS-CoV-2 infections during pregnancy. The studies found placental abnormalities and fetal haemorrhages could be associated with COVID during pregnancy. Researchers are now monitoring children exposed to the virus prenatally to investigate whether there are long-lasting neurodevelopmental effects.
Before SARS-CoV-2 emerged in 2020 there had been a significant body of study investigating the effects of viral infections during pregnancy. Due to the immunosuppressive nature of pregnancy, it is well understood that viral infections can be dangerous, increasing the risk of maternal morbidity, stillbirth or preterm birth.
But even infections that present as mild to a pregnant person can have longer-term developmental impacts on their growing fetus. The infamous Zika virus, for example, often presents with either no symptoms or just a mild illness in adults, yet infections during pregnancy can lead to birth defects and neurological disorders in children.
Influenza infections during pregnancy have also been well researched. Several long-term studies looked back at children born during the 1918 flu pandemic and suggested in utero exposure to influenza led to a variety of deleterious effects in adulthood, from increased rates of cardiovascular disease to lower levels of educational attainment.
More recently, modern studies have associated maternal influenza infections with higher rates of autism and schizophrenia. But exactly how a child's neurodevelopment could be affected by viral exposure during gestation is unclear. Some research has suggested fever during pregnancy is the key factor disrupting fetal neurodevelopment, especially during the first trimester. Other studies have pointed to inflammatory molecules triggering changes to fetal brain growth.
Importantly, these long-term effects on neurodevelopment have been detected following mild viral infections during pregnancy. These are infections that generally don't lead to significant medical intervention or have an effect on birth weight or gestation length.
So considering that pre-existing body of evidence, researchers have been closely studying the effects of COVID during pregnancy. And only now, three years after the emergence of this novel coronavirus, are we starting to get insights into how prenatal infections are influencing fetal development.
One new study, led by researchers from King's College London, has looked at over 600 samples of fetal brain tissue, collected from elective pregnancy terminations between 2020 and 2022.
Around 5% of the samples analyzed were found to have cortical haemorrhages, and in all of those samples the researchers also detected the presence of SARS-CoV-2. Katie Long, lead investigator on the study, said it was unusual to find so many haemorrhagic brain tissue samples in a random collection.
"While haemorrhages do occasionally occur in developing brains, it is extremely unusual for there to be this many instances within a 21-month period," said Long. "It is now of the utmost importance that we follow up with children that were prenatally exposed to COVID-19 so that we can establish if there are any long-lasting neurodevelopmental effects.”
Of most concern to the researchers is the observation that the majority of haemorrhages detected were found in fetal brain tissue from the late first and early second trimesters. The researchers note it is unclear whether these abnormalities would have naturally resolved over the course of a healthy pregnancy, but maternal immune activation during this crucial early period of neurodevelopment could plausibly cause long-lasting problems.
"… the majority [of the haemorrhages detected] were between 12 and 14 pcw, a critical window of human fetal brain development when the endothelial tight junctions increase to form the blood brain barrier," the researchers write. "Further investigation is needed to understand if these effects on the cortical tissue are long lasting, or are able to resolve with minimal consequence. It is possible that an immune cell response could have a positive outcome, resulting in some resolution of these haemorrhages. However, maternal immune activation can have many long-lasting effects in neurodevelopment."
Another newly published study, from a team of researchers in Austria, has used MRI to study the effects of SARS-CoV-2 infections on the placenta and fetus. This is the first work to use prenatal MRI to study placental structure and fetal organ in pregnant persons who recovered from COVID infections.
The research conducted MRI investigations on 38 pregnant persons with confirmed SARS-CoV-2 infection. The scans were conducted, on average, around 80 days after each participant's first positive PCR test. Each COVID-positive participant was matched with a non-infected control carrying a child at a similar gestational age.
The findings revealed those participants with SARS-CoV-2 infections showed significantly more placental abnormalities compared to the control cases. These included changes to the shape and thickness of the placenta and vascular lesions.
... this study highlights the need for pregnant women to be vaccinated against COVID-19, thus avoiding complications for both mother and baby.
The study also revealed pre-omicron variants of the virus led to greater placental damage than currently circulating omicron variants. The researchers indicate it is possible this difference is because omicron causes less severe disease compared to prior variants, but it may also be likely increased rates of vaccination have attenuated the impact of the virus.
"This varying occurrence of placental lesions due to different viral variants may be due to the lower pathogenicity of the omicron variant and to the higher vaccination coverage rate as the pandemic progressed," the researchers write. "Our results show that the two unvaccinated pregnant women infected with SARS-CoV-2-Omicron developed globular placentas, but only one of six triple-vaccinated women did."
These two studies, of course, are subject to the same caveats facing lots of these kinds of investigations. They cannot determine causality and shed no light on the long-term implications of any cited abnormality.
It will be years before researchers have any understanding of potential associations between in utero SARS-CoV-2 exposure and neurodevelopmental disorders. A study published in mid-2022 offered some of the first clues, looking at several hundred 12-month-old children born to mothers who faced COVID infections during pregnancy in the very first waves of the pandemic.
Those findings revealed higher rates of developmental disorders relating to motor function or speech and language compared to an unaffected control group. However, because many of these babies were born preterm it is unclear whether the viral infection was directly causing neurodevelopmental problems, or whether COVID was simply triggering premature birth, which itself has been associated with developmental delays.
Other researchers commenting on the 2022 study suggested it was too early to diagnose developmental disorders in children. Dorothy Bishop, a developmental neuropsychologist from the University of Oxford, was particularly critical of the study, suggesting it's implausible children are being effectively diagnosed with developmental disorders at 12 months of age.
"As an expert in children’s speech and language disorders, I find it hard to see how these conditions could be diagnosed in such young children, because even if a child is producing no words at all, that would not be abnormal," Dixon said. "Clearly pregnant women should do their best to avoid COVID, but if they do get it, the odds are high that their infant will not have evident neurodevelopmental problems in the first year of life."
Lucilla Poston, a material and fetal health researcher at King's College London, said it is certainly possible COVID during pregnancy affects the developing fetal brain. And while further study over the coming years will inevitably offer insights into that association, Poston said it is clear vaccination against COVID during pregnancy will be crucial in reducing the severity of infections.
"We know that severe viral infection may influence the fetal brain, but this important study is the first to suggest that this may occur in pregnancies affected by COVID infection," said Poston, commenting on the King's College fetal tissue findings. "Whatever the cause, a direct effect of the virus or an indirect consequence of maternal infection, this study highlights the need for pregnant women to be vaccinated against COVID-19, thus avoiding complications for both mother and baby."
An ongoing study called BIBS (Brain Imaging in Babies Study) is underway at King's College London. It will follow children born to mothers who tested positive to COVID during their pregnancy. Using MRI imaging and behavioral assessments the researchers will look at brain development up to four years of age.
The fetal tissue study was published in the journal Brain, while the placental MRI study was published in The Lancet Regional Health.
Sources: King's College London, Medical University of Vienna
