COVID-19 during pregnancy can cause placental inflammation and impaired immunity

A new study conducted by a team of researchers at Johns Hopkins University, USA, has observed how pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show stunted antiviral immune responses. The team also observed signs of inflammation in the placenta. These findings could inform therapeutic approaches to coronavirus disease 2019 (COVID-19) in pregnant women. The study has been made available as a preprint on the medRxiv* server.

The general impression is that COVID-19 in pregnancy is mostly asymptomatic or mild, even though typically pregnant women and their babies are at higher risk for severe complications from infections. This is known to be due to the significant alterations in immunological and endocrine functions in pregnancy.

Study: Dysregulated immunity in SARS-CoV-2 infected pregnant women. Image Caption: SUKJAI PHOTO / Shutterstock
Study: Dysregulated immunity in SARS-CoV-2 infected pregnant women. Image Caption: SUKJAI PHOTO / Shutterstock

The U.S. Center for Disease Control (CDC) has reported that among women aged 15-49 years who were hospitalized with COVID-19 from March 1 to August 22, 2020, a quarter of them were pregnant. Moreover, the report went on to say that these women were much more at risk of requiring mechanical ventilation than other women. Preterm birth is also more common in this subset of pregnant women.

The immune function in pregnancy changes remarkably. During viral infection, the secretion of the proinflammatory cytokines IL-1β and IL-6 occurs at the infected site and at the placenta. These can cross into the fluid surrounding the baby, and may hinder normal development. Thus, the fact of COVID-19, irrespective of its severity and clinical features, can itself harm the fetus in the short and long term.

However, the immune response is basically a protective one, and can lead to the transplacental transfer of anti-SARS-CoV-2 antibodies via the Fc receptor (Fc-Rn), to the neonate, preventing infection.

The researchers looked into the immunological responses in pregnancy using samples of maternal blood, cord blood, and placental tissue from pregnant women with or without COVID-19 (22 and 11, respectively). They measured IgG antibodies to the spike and receptor-binding domain (RBD) as well as neutralizing antibodies (NAbs), proinflammatory cytokine messenger RNA (mRNA) and placental cytokine and Fc-Rn levels. They also measured these parameters in 17 non-pregnant women with COVID-19.

They found that overall, the median age of SARS-CoV-2 infected pregnant women was lower, at 27 – with 32 being the median for non-infected pregnant women. The former were predominantly non-white, about half being Hispanic or Latina, and almost a quarter Black. Other characteristics were comparable.

In comparison with non-pregnant infected women, too, pregnant women were younger, their median age being 27 years (versus 34 in the other group). The non-pregnant women were around 50% White compared to less than 15% in the pregnant group, and only 6% were Hispanic or Latina compared to 50% of the pregnant group.

Cytokine profile in an infected pregnancy

The presence of inflammation in pregnancy is deleterious to fetal and neonatal development, in many cases. The researchers found that IL1β mRNA was expressed more highly in asymptomatic infected pregnant mothers than in symptomatic, and within 14 days of a positive real-time polymerase chain reaction reverse transcription (RT-PCR) test. However, IL6 expression showed no change.

Antibody titers in pregnancy versus nonpregnant women

The researchers measured antibodies at a median of 34 days from infection in both pregnant and non-pregnant women. The median lag from the confirmed test in pregnant women was around 19 days, and in non-pregnant women it was double that period.

Both showed similar IgG to the full-length spike, and similar Nab titers, but anti-RBD IgG was lower in the first group. The only antibody that was lower in pregnancy was the anti-RBD IgG in symptomatic infected women. Nab titers were undetectable (<1:20 dilution) in almost half of pregnant women, versus around 10% of non-pregnant women, despite the fact that NAb titers were comparable with or without COVID-19.

Anti-RBD titers in pregnancy and in non-pregnant women alike were always higher than NAbs. With undetectable NAbs, therefore, the anti-RBD IgG titers were lower than if they were above 1:20, and showed no significant variation with time since a positive RT-PCR or time from symptom onset.

The researchers say, “These data suggest that, independent of time, pregnancy may reduce the quality of antiviral antibodies against SARS-CoV-2.”

Antibody transfer in COVID-19

The study also found that the titers of anti-S and anti-RBD were comparable in the mother’s blood and cord blood, but NAbs were higher in the former, while Fc-Rn concentrations remained unaltered. Since this is a marker of transplacental transfer, this shows that IgG transfer remained unchanged with SARS-CoV-2 infection in pregnancy, symptomatic or not.

As a control experiment, the titers of anti-tetanus IgG were also measured in maternal and cord blood. This showed that antibody transfer remained unimpaired by pregnancy in general, but NAb transfer to SARS-CoV-2 may be reduced.

What are the implications?

Recent studies show that COVID-19 in pregnancy may have different clinical features. For instance, these women may be less likely to have a fever and a cough. Again, they may be more likely to be hospitalized or to be admitted to the intensive care unit (ICU), and to require invasive mechanical ventilation, compared to nonpregnant women. However, they are at no increased risk of death, and mortality may actually be lower in this group.

Earlier research has also shown that in pregnancy, neutrophils and D-dimer levels are higher, but that lymphocytes, the ratio of CD4 to CD8 T cells and IgG titers are lower than in nonpregnant women with this infection. The current study also indicates a higher inflammatory response but impaired adaptive immune response during pregnancy. These findings can impact current standards of care for pregnant women with COVID-19.

The selective increase in IL-1β but not IL6 in mild or moderate COVID-19 in pregnancy, as seen in severe males and nonpregnant women, and on the fetal aspect of the placenta, indicates the inflammatory response to the virus. Inflammation in pregnancy is known to be linked to neurodevelopmental abnormalities, such as autism spectrum disorder and schizophrenia. This is known to be mediated by inflammatory cytokines like maternal IL-1β, which cross the placenta. Thus, blockading the receptor for IL-1 in fetal mice has a protective effect against brain injury by weakening the extent of microglial activation and protecting against inflammatory injury to the fetal brain cortex, which could have long-term neurobehavioral effects.

Secondly, the study shows lower IgG antibodies against the RBD in pregnant women and higher odds of undetectable NAb titers coupled with low anti-RBD titers. This indicates impaired antiviral immunity, which was not apparently associated with symptom severity or worse outcomes. However, the researchers say, “It is possible that the reduced antibody titers could increase the potential for reinfection following pregnancy.”

This study showed the presence of IL-1β mRNA in the placenta and in the mother’s blood. Further study will be required to demonstrate the presence of the protein itself in the mother and the newborn following COVID-19 in pregnancy. Newborn testing for the virus and follow-up for developmental milestones may be necessary to identify the harm caused by SARS-CoV-2 infection and its resulting inflammation, singly or in combination.

The study concludes, “Understanding the impact of SARS-CoV-2 infection during pregnancy on the maternal immune system, and how these changes alter maternal and fetal susceptibility to disease is crucial for the development of vaccines and other therapeutics for COVID-19. The safety, immunogenicity, and efficacy of SARS-CoV-2 vaccines in pregnant women must be considered.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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