Is COVID-19 more severe in pregnancy?
Respiratory viruses are known to increase the risk of illness and death in both mothers and fetuses in pregnancy. This has been indicated to be the case with the earlier viruses such as influenza, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS) coronaviruses. A new study by researchers at the University of Maryland, USA, indicates that pregnant women are more likely to develop severe disease following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The team has released their findings as a preprint on the medRxiv* server, while the article undergoes peer review. SARS-CoV-2 is the agent that caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has so far totaled 179.6 million confirmed cases and over 3.89 million deaths. Background  Earlier research has produced contradictory findings for and against the increased propensity for severe COVID-19 in pregnancy. The current study aimed to examine this aspect once again, using indicators of severity such as oxygen supplementation, invasive mechanical ventilation, hospitalization, intensive care unit admission, and death. Pregnancy is characterized by profound changes in the functioning of the body, as well as the immune system. Among these are oxygen consumption, which increases by 15% to 20%, reduced functional residual capacity, a higher excretion of bicarbonate from the kidneys to overcome the respiratory alkalosis. The result is that the pregnant body has lower physiological reserves to maintain homeostasis. Immunomodulatory effects, such as reduced cell-mediated immunity, lower numbers of natural killer and helper T cells, and increased activity of T helper 17/regulatory T cells, can result in a dampened immune response. This may be one reason for increased morbidity and mortality in pregnancy with COVID-19. Others may be pandemic-specific, relating to the reduced availability of prenatal care or frequency of routine visits or the use of too-low flow rates of supplemental oxygen in pregnancy. Thirdly, COVID-19 affects more pregnant women of non-white ethnicities, who are more likely to develop severe illness already. The multi-center study included females aged 18-45 years, all of whom were pregnant and confirmed to have SARS-CoV-2 infection by laboratory testing, matched with controls who were not pregnant when they acquired the infection. COVID-19 severity was determined by the National Institute of Allergy and Infectious Disease (NIAID) eight-point ordinal severity score, from 0 for asymptomatic patients to 7 for fatal outcomes. Any score of three or more indicated severe disease, including patients who required at least oxygen supplementation or non-invasive ventilation. Among the approximately 190 pregnant patients and 1,000 non-pregnant patients, the former had a lower mean age, at 28 years, vs. 34 years in the latter. They were also less likely to have underlying illnesses, which were observed in a quarter of the first cohort but over a third of the second. The pregnant COVID-19 cohort was composed of a higher proportion of Hispanic women (50%) and Black women (31%), with less than a quarter being White women. Conversely, the non-pregnant cohort comprised about 54% Black women, 16% Hispanic women and 15% white women. The proportion of women with moderate to severe COVID-19 was higher in the pregnant group, at almost 20%. Over a quarter of this group required hospitalization, 9% in the intensive care unit, with 5% each receiving medication to maintain adequate blood pressure levels and invasive mechanical ventilation. The findings showed that significantly more pregnant women with COVID-19 had moderate to severe illness, at 25% vs. 16% in controls. Almost the same difference was present with respect to hospitalization. Differences between cases and controls in intensive care unit (ICU) admission, treatment with vasoactive substances and the need for invasive mechanical ventilation were present but below the level of significance. This could be because of the small size of the sample. Deaths were equal in both groups. On laboratory tests, leukocytes were higher in pregnant COVID-19 patients, as were D-dimer levels. The latter is a sign of pregnancy, say some researchers, pointing to its marked elevation even in normal pregnancies. Hemoglobin, ferritin and creatinine levels were lower in this group of patients, and almost two in three had positive findings on chest X-rays compared to just above one-third of non-pregnant COVID-19 patients. Lymphopenia and thrombocytopenia were not observed. The risk of severe COVID-19 was increased independently by the presence of underlying illnesses, advancing age, Hispanic race, higher body mass index, lung disease and diabetes. However, pregnancy was also found to increase the risk, irrespective of other factors. Thus, pregnant women had twice the odds of severe disease compared to non-pregnant women, especially Hispanic women, who had approximately three times higher odds. The risk increases further with each additional year of age and each unit increase in body mass index. Chronic lung disease and diabetes are also associated with over four times the odds of severe COVID-19. Approximately 41% of pregnancies were complicated, especially by hypertensive disorders of pregnancy, seen in about a fifth of patients. The median term of pregnancy at delivery was 32 weeks. About a tenth of babies were born premature, while over one in ten mothers had gestational diabetes. Early miscarriages occurred in 2%, and late losses in almost the same number, but no neonatal deaths were reported in this small group. As expected from the report of the U.S.s Centers for Disease Prevention and Control (CDC), pregnant women appeared to be at higher risk of severe COVID-19. The underlying changes in physiologic function and immune response could be partly responsible. Hypertensive disorders of pregnancy were also highly prevalent in pregnant COVID-19 patients, but the question of causality remains undetermined. Another alternative idea is that the same patients who developed severe COVID-19 are also more likely to develop hypertension in pregnancy. This is suggested by the fact that both groups show a higher cytokine profile and also because genetic variability in the angiotensin-converting enzyme 2 (ACE2) affects individual susceptibilities to the virus. Irrespective of pregnancy, older and heavier Hispanic women are at increased risk of severe COVID-19, especially if they already have chronic lung disease. We recommend close surveillance of symptomatic pregnant women with COVID-19, especially in the presence of other risk factors such as Hispanic ethnicity and chronic lung disease, say the researchers. This population may also deserve priority in vaccination and treatment. It is also unfortunate that the ethical and technical implications of treating two lives in a pregnant woman make it difficult to include them in early drug and vaccine trials, despite their unique needs. This increases the risk of adverse outcomes in this group. Ways and means should be debated to enable that pregnancy is not an automatic bar to such trials. *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.