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

Materials and Methods

All pregnant women in Denmark are offered a combined first trimester risk assessment (performed at gestational age 11–14 weeks) as part of the public antenatal and obstetric health care service, free of charge. More than 90% of the women accept (The Danish Fetal Medicine Database, 2018). The risk assessment includes a double test (blood sample for pregnancy-associated plasma protein A (PAPP-A) and free beta hCG (β-hCG)) and a nuchal translucency measurement with ultrasonography. PAPP-A and free β-hCG values are converted to MoM values (Multiples of the Median). One MoM corresponds to the median value at the specific gestational age for a normal material of patients. The excess serum from the double test is stored at −80°C at the hospital.

Participants

The Department of Obstetrics and Gynecology at Copenhagen University Hospital Hvidovre is the largest obstetric department in Denm serving ~12% of pregnant women and births in Denmark. The geographical admission area of the hospital is Copenhagen South and West. All pregnant women, who had a double test performed at Hvidovre Hospital from 17 February 2020 to 23 April 2020 were invited to participate in the study. The women were contacted electronically with written information about the study. If they agreed to participate an informed consent form was signed and the women were included in the study (Cohort 1). We included women who consented up until 28 May 2020.

From 14 April to 21 May 2020, women referred with a pregnancy loss before the time of the double test were also invited to participate. If a woman with a pregnancy loss wanted to participate, a blood sample was drawn, and baseline characteristics were collected by cross-referencing medical files (Cohort 2).

A questionnaire concerning symptoms of COVID-19 during the pregnancy, smoking habits, BMI, influenza vaccination in 2019/2020 and comorbidity was completed by all participating women.

Antibody Analysis

The stored excess serum from the double tests and the blood samples from women with pregnancy loss, 30 μl serum from each sample, were analyzed for antibodies (IgM and IgG) against SARS-CoV-2 as an indicator of previous SARS-CoV-2 infection (Infantino et al., 2020b). Antibodies may be present from Day 4 following the first symptoms (Xiang et al., 2020) and the median seroconversion time is Day 12 for IgM and Day 14 for IgG (Zhao et al., 2020).

Samples were analyzed using YHLO's iFlash 1800 and SARS-CoV-2 IgM/IgG kits (Chemiluminescence immunoassay; YHLO Biotechnology, Shenzhen, China). IgM antibody values <8.0 AU/ml were considered a negative test result and values ≥8.0 AU/ml were considered a positive result. IgG antibody levels <10.0 AU/ml were considered a negative test result and IgG values ≥10.0 AU/ml were considered a positive result. If IgM and IgG or IgG-only was positive, the patient was classified with previous SARS-CoV-2 infection. Patients with IgM-only antibodies were considered to be negative for infection unless there was a positive IgG follow-up sample. According to a recent study the sensitivity (95% CI) was 42.0% (34.4–50.0%) for IgM and 94.0% (89.0–96.8%) for IgG and the specificity was 99.7% (98.8–99.9%) for IgM and 99.3% (98.3–99.7%) for IgG (Harritshøj et al., 2020).

Statistical Analysis

Data and figures were analyzed and produced using R, an open-source statistical software (the R foundation, www.r-project.org). Comparisons of nuchal translucency thickness, free β-hCG and PAPP-A between women with and without SARS-CoV-2 antibodies were performed using the Wilcoxon Rank-Sum test. Multivariable modeling of the effect of COVID-19 infection in first trimester pregnancy on nuchal translucency thickness was performed using an ordinal regression model, taking maternal age and gestational age into account. Differences in reported COVID-19 symptom frequency were analyzed using Fishers exact test. A P-value of <0.05 was considered statistically significant.

Ethical Approval

The study was approved by Knowledge Centre for Data Protection Compliance, the Capital Region of Denmark (P-2020-255) and by the Scientific Ethics Committee of the Capital Region of Denmark (journal number H-20022647). All participants in the study provided written informed consent.

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