A new Danish study published on the preprint server medRxiv* in June 2020 shows that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in early pregnancy does not carry an increased risk of fetal harm.
The Potential Risk of COVID-19 in Early Pregnancy
Pregnancy is considered a period of immunosuppression when viral infections are capable of causing severe outcomes for the mother and fetus. Respiratory viruses are particularly associated with a high risk of severe pneumonia. The reason for this higher susceptibility in pregnancy is thought to a pro-inflammatory state.
While earlier coronavirus epidemics such as the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks took a heavy toll on pregnant women, the current pandemic has not been studied in detail concerning its effect on pregnancy. It is known that maternal-to-fetal transmission can occur in Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes Simplex, all collectively known as the TORCH agents, as well as the Zika virus, in the first trimester of pregnancy, causing severe damage to the developing fetal tissues.
SARS-CoV-2 infection at the early stages of pregnancy could be potentially much more serious than at later stages. However, information on the effect of SARS-CoV-2 in pregnancy is limited because minimal serological testing has been carried out in this population segment so far.
Assessing Pregnancy Loss Against COVID-19
The current study is the first to analyze SARS-CoV-2 infection in the context of first-trimester pregnancy. The researchers used serological testing to look at women who had been infected early in pregnancy, with respect to the effect on the fetus using measures like nuchal translucency scan and pregnancy loss.
The study was based on a cohort of pregnant women in Denmark who had had a double test carried out between February 17, 2020, and April 23, 2020, and women who had lost a pregnancy before the time for double testing had arrived, from April 14 to May 21, 2020. For the former, blood from the double test specimen was used, while for the latter category, a blood test was carried out. Baseline demographic and medical data were taken from medical files.
All participants answered a short questionnaire about COVID-19 symptoms in pregnancy, smoking, body mass index, flu shots in 2019-2020, and other coexisting illnesses.
A short questionnaire concerning symptoms of COVID-19 during the pregnancy, smoking habits, body mass index (BMI), influenza vaccination in 2019/2020, and comorbidity was completed by all participating women.
Each maternal blood sample was tested for Immunoglobulin G (IgG) and Immunoglobulin M (IgM) antibodies against SARS-CoV-2. There were about 1,020 women who completed double testing, and 36 women who lost an early pregnancy before the second test could be performed. These are referred to as Cohort 1 and Cohort 2, respectively.
IgM and IgG antibody values ≤8 AU/mL were defined as negative results, according to the test kit recommendations. Values ≥12 AU/mL were defined as positive results. Values >8.0 and <12.0 AU/mL were considered to be in the gray zone.
Antibodies Unrelated to Miscarriage Risk
Overall, SARS-CoV-2 antibodies were found in 2.9% of women in Cohort 1, with 14 (1.4%) having IgM or IgG antibodies and 16 (1.6%) being in the gray zone. All Cohort 2 women were antibody-negative.
The next step was to look for a link between SARS-CoV-2 antibody titers and the results of the first-trimester scan assessing the nuchal translucency thickness, and the double test. This part of the study excluded fetuses with a chromosomal anomaly.
The researchers found that there was no significant difference between women who had antibodies to the virus and those who were negative, with respect to nuchal translucency thickness and double marker test values, after adjusting for maternal age and gestational age. Gray zone vs. negative antibody titers also showed the same lack of differentiation for these markers of fetal abnormality.
There were 54 early pregnancy losses in all, with 36 occurring before double testing, 15 between the double test and nuchal translucency scan, and three diagnosed at the time of the scan.
Of the 30 positive tests, only two women had a pregnancy loss, while 27 women with positive or gray zone titers had ongoing pregnancies. Among Cohort 1, COVID-19 symptoms were reported more significantly by women with gray zone than with negative titers, with the odds being almost fivefold for the former. However, this was not seen when comparing women who had positive with those who had negative antibody titers.
These results suggest that serologic testing in pregnancy helps identify past infections as well as to designate high-risk groups. However, the current study indicates that first-trimester COVID-19 infection does not increase the risk of severe infection. This corroborates the findings from studies on pregnant women in the third trimester, from Wuhan.
Limitations and Possible Implications
The limitations of the study include the normal median BMI, with almost none of the women being smokers. This could lead to lower generalizability of the findings to women who smoke or are overweight and are therefore more likely to have lifestyle diseases. These are known factors for more severe COVID-19 infection, and the study does not address the risk for more adverse fetal outcomes with more severe disease.
The low seroprevalence in Denmark, at about 1.1%, as of May 23, 2020, might be due to the general mobility restrictions and other measures implemented by the Danish government early in the course of the epidemic. Moreover, pregnant women were likely even more careful to avoid acquiring the virus, even before official government instructions to self-isolate.
The study concludes, “We did not find a higher median nuchal translucency thickness at the first-trimester scan among women with positive SARS-CoV-2 IgM or IgG antibodies than among women without SARS-CoV-2 antibodies. Women with SARS-CoV-2 antibodies were not overrepresented among women with pregnancy loss before the double test.”
To understand the impact of COVID-19 later on in pregnancy, more serologic studies will be necessary to develop better guidelines for clinical practice, as well as to restrict the social interactions of pregnant women in the COVID-19 era.
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