SARS-CoV-2 in First Trimester Pregnancy

A Cohort Study

N. la Cour Freiesleben; P. Egerup; K.V.R. Hviid; E.R. Severinsen; A.M. Kolte; D. Westergaard; L. Fich Olsen; L. Prætorius; A. Zedeler; A.-M.H. Christiansen; J.R. Nielsen; D. Bang; S. Berntsen; J. Ollé-López; A. Ingham; J. Bello-Rodríguez; D.M. Storm; J. Ethelberg-Findsen; E.R. Hoffmann; C. Wilken-Jensen; F.S. Jørgensen; H. Westh; H.L. Jørgensen; H.S. Nielsen

Disclosures

Hum Reprod. 2021;36(1):40-47. 

In This Article

Abstract and Introduction

Abstract

Study Question: Does maternal infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss?

Summary Answer: Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significantly increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester.

What is Known Already: Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies.

Study Design, Size, Duration: Cohort study of 1019 women with a double test taken between 17 February and 23 April 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between 14 April and 21 May 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark.

Participants/Materials, Setting, Methods: Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving ~12% of pregnant women and births in Denmark. All participants in the study provided written informed consent.

Main Results and the Role of Chance: Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 16) versus negative (n = 966) (P = 0.62). There was no significantly increased risk of pregnancy loss for women with antibodies (n = 1) (OR 3.4, 0.08–24.3 95% CI, P = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies.

Limitations, Reasons for Caution: These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection.

Wider Implication of the Findings: Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significantly increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning COVID-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow-up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection.

Study Funding/Competing Interest(S): Prof. H.S.N. and colleagues received a grant from the Danish Ministry of Research and Education for research of COVID-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. A.I., J.O.-L., J.B.-R., D.M.S., J.E.-F. and E.R.H. received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). A.I. received a Novo Scholarship. J.O.-L. is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). D.W. is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). A.M.K. is funded by a grant from the Rigshospitalet's research fund. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). A.M.K. has received speaker's fee from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest.

Trial Registration Number: N/A

Introduction

The first case of Coronavirus disease 2019 (COVID-19) was reported in Wuhan, China, in December 2019 and within a few months, it developed into a worldwide pandemic (Johns Hopkins University of Medicine, 2020). COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of 11 October 2020, more than 37.1 million people worldwide were infected resulting in 1 070 355 deaths (WHO, 2020).

Pregnant women are more vulnerable to viral infections and therefore represent a potential risk group for severe outcomes in relation to viral infections (Silasi et al., 2015). Especially, they have an increased risk of severe pneumonia following infections with respiratory pathogens (Liu et al., 2020). The increased susceptibility during first trimester pregnancy may be due to a pro-inflammatory state (Liu et al., 2020).

For pregnant women, previous coronavirus epidemics such as middle east respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes (Schwartz and Graham, 2020). Only a few documented cases of SARS in pregnant women have been reported. A case study from Hong Kong of seven first trimester cases showed a pregnancy loss rate of 57% in women infected with SARS (Wong et al., 2004). Only 11 confirmed cases with MERS infection during pregnancy have been documented worldwide showing a maternal and infant fatality rate of 27% (Assiri et al., 2016; Schwartz and Graham, 2020).

Vertical maternal-fetal transmission with serious fetal consequences may occur in relation to maternal infection with TORCH agents (Toxoplasma, Other, Rubella, Cytomegalovirus, Herpes) and Zika virus (Silasi et al., 2015; Alvarado and Schwartz, 2017; Schwartz, 2020). As the fetal organs develop during the first trimester of pregnancy, maternal infections at this stage may be more severe compared to later gestational ages (Silasi et al., 2015; Alvarado and Schwartz, 2017). Parvovirus B19 infection in first trimester pregnancy, even in asymptomatic women, has in case reports been associated with an increased nuchal translucency thickness (edema) (Smulian et al., 1998; Markenson et al., 2000; Grubman et al., 2019) and may be harmful for the fetus. However, Sebire et al. (1997) found that increased fetal nuchal translucency in the first trimester was not associated with infection with toxoplasmosis, rubella virus, cytomegalovirus, herpes virus or parvovirus B19. Vertical transmission in relation to SARS and MERS has not yet been documented (Schwartz, 2020) and needs to be investigated.

Evidence concerning COVID-19 in pregnancy is still limited and serological testing for SARS-CoV-2 antibodies has only been reported in few studies of pregnant women in the third trimester of pregnancy (Flannery et al., 2020; Zeng et al., 2020) and measured in one study of 138 pregnant women attending for first trimester screening (Cosma et al., 2020). One study from Wuhan, China, reported very good maternal, fetal and neonatal outcomes of seven pregnant women infected in late pregnancy and stresses that the effect of SARS-CoV-2 in earlier stages of pregnancy is unknown (Yu et al., 2020). A cohort study in the UK with 427 pregnant women admitted to hospital with PCR confirmed SARS-CoV-2 infection asks for serological studies of COVID-19 in first trimester pregnancies (Knight et al., 2020). Thus, there is a general paucity of data on which to base public health policies for pregnant women and risks associated with SARS-CoV-2 infection.

In this study, we used unselected serological testing in more than 1000 women to identify if SARS-CoV-2 infection in early pregnancy has an impact on the nuchal translucency thickness and pregnancy loss.

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