key: cord-0906798-htbzrb5s
authors: Poon, L. C.; Leung, B. W.; Ma, T.; Yu, F. N. Y.; Kong, C. W.; Lo, T. K.; So, P. L.; Leung, W. C.; Shu, W.; Cheung, K. W.; Moungmaithong, S.; Wang, C. C.
title: Relationship between viral load, infection‐to‐delivery interval and mother‐to‐child transfer of anti‐SARS‐CoV‐2 antibodies
date: 2021-06-02
journal: Ultrasound Obstet Gynecol
DOI: 10.1002/uog.23639
sha: fb682875c4e83852995228c487f53ff188f6ed25
doc_id: 906798
cord_uid: htbzrb5s

OBJECTIVE: To investigate the association of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) viral load and infection‐to‐delivery interval with maternal and cord serum concentrations of anti‐SARS‐CoV‐2 immunoglobulin G (IgG) antibodies and transplacental transfer ratio in pregnant women with active or recovered SARS‐CoV‐2 infection. METHODS: This was a prospective case series of consecutive pregnant women with laboratory‐confirmed SARS‐CoV‐2 infection between 27 March 2020 and 24 January 2021. We collected information regarding deep throat saliva or nasopharyngeal swab (NPS) reverse transcription polymerase chain reaction (RT‐PCR) test results, serial cycle threshold (Ct) values at and after diagnosis, demographic, clinical and outcome data, and neonatal NPS RT‐PCR results. Qualitative and quantitative analysis of IgG and immunoglobulin M (IgM) antibodies against SARS‐CoV‐2 was performed in maternal and cord blood serum samples obtained at delivery. Correlation of maternal Ct values, infection‐to‐delivery interval, infection duration and viral load area under the curve (AUC) with gestational age (GA) at diagnosis, maternal and cord serum IgG concentrations and transplacental transfer ratio of IgG were evaluated using Pearson's correlation. RESULTS: Twenty pregnant women who consented to participate and who had delivered their babies by 31 January 2021 were included in the study, comprising 14 who had recovered from coronavirus disease 2019 (COVID‐19) and six with active infection at delivery. The median GA at clinical manifestation was 32.7 (range, 11.9–39.4) weeks. The median infection‐to‐delivery interval and infection duration were 41.5 (range, 2–187) days and 10.0 (range, 1–48) days, respectively. The median GA at delivery was 39.1 (range, 32.4–40.7) weeks and the median seroconversion interval was 14 (range, 1–19) days. Of 13 neonates born to seropositive mothers with recovered infection at delivery, 12 tested positive for anti‐SARS‐CoV‐2 IgG. All neonatal NPS samples were negative for SARS‐CoV‐2 and all cord sera tested negative for IgM. The median transplacental transfer ratio of IgG was 1.3 (interquartile range, 0.9–1.6). There was a negative correlation between infection‐to‐delivery interval and anti‐SARS‐CoV‐2 IgG concentrations in maternal (r = –0.6693, P = 0.0087) and cord (r = –0.6554, P = 0.0068) serum and a positive correlation between IgG concentration in maternal serum and viral load AUC (r = 0.5109, P = 0.0310). A negative correlation was observed between transfer ratio and viral load AUC (r = –0.4757, P = 0.0409). CONCLUSIONS: In pregnant women who have recovered from COVID‐19, anti‐SARS‐CoV‐2 IgG concentrations at delivery increased with increasing viral load during infection and decreased with increasing infection‐to‐delivery interval. The median transplacental transfer ratio of IgG was 1.3 and it decreased with increasing viral load during infection. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Results Twenty pregnant women who consented to participate and who had delivered their babies by 31 January 2021 were included in the study, comprising 14 who had recovered from coronavirus disease 2019 and six with active infection at delivery. The median GA at clinical manifestation was 32.7 (range, 11.9-39. 4 

Newborn protection from infection is dependent primarily on the neonatal innate immune response and transplacentally acquired antibodies from the mother. Understanding the dynamics of maternal antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and subsequent transplacental antibody transfer could help inform neonatal management as well as maternal vaccination strategies. There are limited data with regard to the immune status of babies born to mothers who have recovered from coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the association of SARS-CoV-2 viral load and infection-to-delivery interval with maternal and cord serum anti-SARS-CoV-2 immunoglobulin G (IgG) antibody levels and transplacental transfer ratio in pregnant women with active or recovered SARS-CoV-2 infection.

This was a prospective case series of consecutive pregnant women with laboratory-confirmed SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) testing of deep throat saliva (DTS) or nasopharyngeal swab (NPS), between 27 March 2020 and 24 January 2021, who gave written informed consent to participate in the study. Women who tested positive for SARS-CoV-2 at any gestational age and continued the pregnancy beyond 24 weeks' gestation were included. As per hospital clinical protocols, SARS-CoV-2 infection was assessed using the cycle threshold (Ct) values obtained from the RT-PCR assay of the DTS or NPS samples. The Ct value represents the number of amplification cycles required for the target gene to reach a detectable level. A higher viral load in the sample can be detected in fewer amplification cycles and thus is indicated by a lower Ct value. Ct value ≥ 35 was defined as a negative result. Approval for the study was obtained from the Joint Chinese University of Hong Kong -New Territories East Cluster Clinical Research Ethics Committee (CREC reference number: 2020.210). The study was registered with ClinicalTrials.gov (identifier: NCT04465474).

Demographic, clinical and outcome data, DTS or NPS RT-PCR results, serial Ct values at and after diagnosis, and neonatal NPS RT-PCR results were collected from the medical records of the patients. In all women, a blood sample was obtained at the time of delivery and cord blood was collected immediately after delivery.

Analysis of serum antibodies against SARS-CoV-2 was performed using two serological assays. Qualitative detection of the anti-SARS-CoV-2 antibodies (IgG and immunoglobulin M (IgM)) directed against the nucleocapsid protein (N-protein) of the virus was carried out using the Elecsys ® Anti-SARS-CoV-2 assay (Roche Diagnostics, Rotkreutz, Switzerland) on a Cobas ® e411 analyzer (Roche Diagnostics). The result was expressed as negative for anti-SARS-CoV-2 antibodies when the cut-off index (COI) was < 1.0 and positive for anti-SARS-CoV-2 antibodies when COI was ≥ 1.0. Quantitative measurement of the IgG and IgM antibodies against the SARS-CoV-2 spike protein (S1) was performed using enzyme linked immunosorbent assays (ELISA) (ImmunoDiagnostics Limited, Hong Kong). All tests were performed in duplicate according to the manufacturer's instructions. Results were interpreted as negative when the optical density (OD) was < 0.2 and as positive when OD was ≥ 0.2. For samples with a positive result, anti-S1 concentrations (ng/mL) were further calculated.

Continuous variables were expressed as median with interquartile range (IQR) and/or range. Categorical variables were summarized as counts and percentages. Infection duration was determined from the time of manifestation of symptoms or a positive RT-PCR test until a negative RT-PCR test or delivery. Viral load during the infection period was calculated by 2ˆ Ct values and presented as log 10 copies/mL. We also calculated the viral load area under the curve (AUC), which indicates the total amount of virus shed over the duration of the infection, i.e. the infectiousness and severity of the infection. Transplacental transfer ratio of IgG was calculated as cord serum IgG concentration divided by maternal serum IgG concentration. The correlation of maternal Ct values, infection-to-delivery interval, infection duration and viral load AUC with the gestational age (GA) at diagnosis, maternal and cord serum IgG concentrations and transfer ratio were evaluated using Pearson's correlation. The statistical software SPSS for Windows version 26 (SPSS Inc., Chicago, IL, USA) was used for data analysis.

Of 33 pregnancies with confirmed SARS-CoV-2 infection, 25 (75.8%) agreed to participate in the study. Of these, two women withdrew from the study because they returned to their home country for delivery, one had a spontaneous miscarriage, one underwent termination of pregnancy for social reasons and one was undelivered at the time of reporting. Therefore, 20 women who delivered their babies by 31 January 2021 were included in the analysis, comprising 14 who had recovered from COVID-19 and six with active infection at delivery. ng/mL). The median transplacental transfer ratio of IgG was 1.3 (IQR, 0.9-1.6). All neonatal NPS samples were negative for SARS-CoV-2. All cord serum samples tested negative for anti-SARS-CoV-2 IgM. The cord serum and maternal serum IgG concentrations at delivery were positively correlated (r = 9301, P < 0.0001) (Figure 2 ). There was a negative correlation between infection-to-delivery interval and anti-SARS-CoV-2 IgG concentrations in maternal (r = -0.6693, P = 0.0087) and cord (r = -0.6554, P = 0.0068) serum (Figure 3b) . A positive correlation was observed between IgG concentrations in maternal serum and viral load AUC (r = 0.5109, P = 0.0310) (Figure 3d ). In addition, a significant negative correlation was noted between transplacental transfer ratio and viral load AUC (r = -0.4757, P = 0.0409) (Figure 4d ).

Our findings demonstrate that, in pregnant women who have recovered from COVID-19, the higher the viral load during infection and the shorter the infection-to-delivery interval, the higher is the anti-SARS-CoV-2 IgG concentration in maternal serum at delivery. The median transplacental transfer ratio of anti-SARS-CoV-2 IgG was 1.3 and it decreased with increasing viral load AUC.

Similar to most pathogens, maternal infection with SARS-CoV-2 leads to higher concentration of IgG in umbilical cord serum than in maternal blood [1] [2] [3] 4 . In contrast to the findings of Flannery et al. who demonstrated, based on 72 mother/newborn dyads who were seropositive at delivery, that the transfer ratio of anti-SARS-CoV-2 IgG correlated positively with the interval between onset of infection and delivery 5 , we did not find a significant change in transplacental transfer ratio with increasing infection-to-delivery interval. Our study additionally evaluated the effect of viral load on transplacental IgG transfer and showed that, even though a high viral load leads to higher concentrations of anti-SARS-CoV-2 IgG antibodies in mothers, it affects negatively the transplacental transfer of IgG to the fetuses. The transplacental transfer of IgG in pregnancies with SARS-CoV-2 infection is related to trophoblast Fc glycosylation and FCGR3A expression 4 . Our findings raise the question regarding the potential impact of vaccine-induced immune response on mother-to-baby transfer of anti-SARS-CoV-2 IgG. There is an urgent need to generate clinical data on the efficacy and safety of the different available COVID-19 vaccines in pregnant women, as well as to determine the vaccine technology and timing of vaccination which can deliver the maximum potential benefits to pregnant women and their babies.

We thank Lijia Chen, Tracy C. Y. Ma, Maggie Mak, Ching Man Mak, Angela S. T. Tai, Christy Kwok, Hung San Lam, Lisa L. S. Chan, Yat Wah Kwan, Ngai Man Chan and Yu Ming Fu who were involved in study coordination, all participants and their attending obstetricians, nurses, midwives, and laboratory technicians at all participating hospitals for facilitating the performance of this study.

L.C. Poon has received speaker fees and consultancy payments from Roche Diagnostics and Ferring Pharmaceuticals. In addition, she has received in-kind contributions from Roche Diagnostics, PerkinElmer, Thermo Fisher Scientific and GE Healthcare. The other authors report no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Reagents for the qualitative detection of anti-SARS-CoV-2 antibodies were provided free of charge by Roche Diagnostics.

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