key: cord-0823403-ga61ya38
authors: Kubiak, Jeffrey M.; Murphy, Elisabeth A.; Yee, Jim; Cagino, Kristen; Friedlander, Rachel L.; Glynn, Shannon M.; Matthews, Kathy C.; Jurkiewicz, Magdalena; Sukhu, Ashley C.; Zhao, Zhen; Prabhu, Malavika; Riley, Laura; Yang, Yawei J.
title: SARS-CoV-2 serology levels in pregnant women and their neonates.
date: 2021-01-23
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2021.01.016
sha: 47eab390a85afb4abdc005c82724a13255b04df7
doc_id: 823403
cord_uid: ga61ya38

Background Pregnant women and their neonates represent two vulnerable populations highly susceptible to viral infections with an interdependent immune system. The immune response of pregnant women to SARS-CoV-2 and the interplay of how the maternal immune response affects neonatal passive immunity have not been systematically studied. Objectives We characterized the serologic response in pregnant women and studied how this serologic response correlates with maternal clinical presentation and with the rate and level of passive immunity from mothers to neonates. Study Design Between March 22-May 31, 2020, women giving birth who tested positive for semi-quantitative IgM or IgG detection in a New York City Hospital were included in the study. Retrospective chart review of the cases that met inclusion criteria was conducted for presence of COVID19 symptoms and use of oxygen support. Serology levels between the symptomatic and asymptomatic patients were compared with Welch’s two sample t-test. Further chart review of the same patient cohort was conducted in order to identify dates of self-reported onset of COVID-19 symptoms, and the timing of the peak of IgM and IgG antibody levels after symptoms onset were visualized using local polynomial regression smoothing (LOESS) on log2-scaled serological values. To study the neonatal serology response, cord blood samples of neonates born to a subset of all serology positive pregnant women were tested for serology. Maternal antibody levels of serology-positive vs. serology-negative neonates were compared with the Welch’s two sample t-test. The relationship between quantitative maternal and quantitative neonatal serologic data was studied using Pearson correlation and linear regression. Multiple linear regression analysis was conducted using maternal symptoms, maternal serology levels, and maternal use of oxygen support to determine predictors of neonatal IgG levels. Results Eighty-eight serology positive pregnant women were included in this study. Antibody levels are higher in symptomatic pregnant women compared to asymptomatic pregnant women. Serology studies in 34 women with symptom onset data reveal that maternal IgM and IgG levels peak around 15 and 30 days post COVID-19 symptoms onset, respectively. Furthermore, studies of fifty neonates born to a subset of serology positive women show that passive immunity in the form of IgG is conferred upon 78% of all neonates. Presence of passive immunity is dependent on maternal antibody levels, and levels of neonatal IgG correlate with maternal IgG levels. Maternal IgG levels and maternal use of oxygen support were predictive of neonatal IgG levels. Conclusions We demonstrate that maternal serologies correlate with symptomatic maternal infection, and higher levels of maternal antibodies are associated with passive immunity. Maternal IgG levels and maternal use of oxygen support, a marker of disease severity, predict neonatal IgG levels. These data will further guide the screening for this unique linked population of mothers and their babies, and can aid in developing maternal vaccination strategies.

As the novel SARS-CoV-2 virus spread rapidly through New York City in March 93 2020 -at that time the global epicenter of the disease -the obstetric unit within a New 94

York City hospital implemented universal testing of all women admitted to labor and 95 delivery to screen this uniquely vulnerable patient population. During this peak of the 96 pandemic, 10-15% of all women admitted to New York City area labor and delivery units 97 tested positive for SARS-CoV-2 by RT-PCR testing. 1,2 An updated report from the CDC 98 in October 2020 found that pregnant women with symptomatic COVID-19 infection were 99 at increased risk of ICU admission, invasive ventilation, extracorporeal membrane 100 oxygenation, and death. 3 Further prospective and retrospective studies have shown that 101 pregnant women infected with SARS-CoV-2 are at increased risk of other morbidities as 102

well, including higher rates of cesarean delivery, increased post-partum complications 103 (including fever, hypoxia, and hospital readmissions post-discharge), as well as 104 placental pathology including fetal vascular malperfusion; however it should be noted 105 that the risk of preterm birth may still require further study. 4-11 106

There has been a recent interest in serology testing as a means of detecting 107 exposure to SARS-CoV-2, limiting disease spread, and potentially predicting 108 outcomes. 12-14 Studies have reported that nearly 100% of patients with confirmed system. The interactions between the maternal immune system and fetal placenta result 116 in changes that alter both innate and adaptive host responses to infections. 21 For this 117 reason, current studies on the serologic responses to SARS-CoV-2 may not be 118 applicable to the pregnant population. Studies to date have demonstrated the rate of 119 seropositivity in pregnant women, 22 ,23 but a detailed analysis of the timing and levels of 120 response in these pregnant patients have not been well characterized. 121

Passive transfer of antibodies against SARS-CoV-2 has not been systematically 122 studied beyond the demonstration of neonatal antibodies in a small number of cases, 123

and it is not clear whether these antibodies are protective against disease. 24 There have 124 been reports of transplacental transmission of SARS-CoV-2 as well as symptomatic 125

neonates who tested positive for SARS-CoV-2 born to PCR positive mothers. 25-30 126 However, in these cases, the serologic status of the mother was either negative or not 127

reported. A small case series demonstrated the presence of antibodies in RT-PCR 128 negative asymptomatic neonates born to symptomatic women. 31 However, the rate of 129 transfer of maternal antibodies from mother to neonate and whether even asymptomatic 130 women may transfer antibodies to neonates is not yet established. 32 In this paper, we 131 (serology positive) at a single institution in New York City were included in this study. Neonates born to these mothers were also included in this study and underwent 143 serology testing on cord blood. 144

Patients were tested for IgM and IgG antibodies against SARS-CoV-2 on serum or 146 plasma of peripheral blood (mothers) or on plasma from cord blood (neonates) using a 147 fluorescence-based reporting system which allows for semi-quantitative detection of 148 anti-SARS-CoV-2 antibodies using the clinical testing Pylon 3D platform (ET HealthCare, 149

Palo Alto, CA). This platform utilizes a fluorescence-based reporting system which 150 allows for semi-quantitative detection of anti-SARS-CoV-2 IgG and IgM with a specificity 151 of 99.4% and 98.8% for IgM and IgG, respectively. 8 Antibody levels were expressed as 152 log2(value) + 1. 153

To study the association of symptoms with serologic results, retrospective chart review 155 was conducted in order to identify symptoms at the time of serology testing. Patients 156 with any of the following COVID19 symptoms (self-reported fever, cough, sore throat, categorized as asymptomatic. IgM and IgG values of symptomatic and asymptomatic 161 patients were plotted as continuous variables and are expressed as the median (IQR) 162 with error bars representing 95% confidence. The serology levels between the 163 symptomatic and asymptomatic patients were compared with Welch's two sample t-test. 164 P value of < 0.05 was considered statistically significant. showed that 29/39 (74%) neonates were RT-PCR negative, but 10/39 neonates were 209 not tested due to lack of sample capture. To study the factors that dictate passive 210 immunity of SARS-CoV-2 antibodies, we analyzed the IgG levels of these mothers and 211

neonates. Neonates with SARS-CoV-2 specific IgG were born to mothers with 212 significantly higher IgG levels than neonates without IgG (p=1.7e -11 ) ( Figure 3B infections. [15] [16] [17] 33 Asymptomatic women mount an immune response, albeit weaker than 233 symptomatic women, which is consistent with similar findings in non-pregnant 234 individuals. 9 Passive immunity has been demonstrated in small cohorts or case studies, 235 but our semi-quantitative study on a large mother-baby dyad cohort demonstrates that 236 there is a correlation between maternal antibody levels and the amount of IgG 237 demonstrated in neonatal cord blood. Furthermore, we demonstrate that maternal IgG 238 and maternal oxygen supplementation-a marker of disease severity--predict neonatal 239

Clinical Implications: We found that both symptomatic and asymptomatic women 241 mounted a detectable antibody response; however, symptomatic women mounted a 242 higher IgG response. Since asymptomatic non-pregnant patients are more likely to 243 convert to seronegative in the convalescent phase of infection, 19 and since a large 244 cohort of the pregnant women are also asymptomatic, these data hint at a potential 245 faster conversion to seronegative in many pregnant women implying that even women This study strongly suggests that maternal SARS CoV-2 specific IgG is 257 transferred to the neonate particularly when the mother has a high IgG level. This 258 implies that maternal SARS CoV-2 infection stimulates IgG antibody production that 259 readily crosses the placenta, consistent with other maternal infections. These data 260 suggest that if the mother mounts an antibody response secondary to a vaccination 261 against SARS-CoV-2, then those antibodies could also cross the placenta into the 262 neonate, potentially protecting both the mother and her neonate(s) from future infection. 263

It is not known how protective this maternally derived IgG antibody is for the neonate 264 and how long the protection lasts. The majority of our neonate samples utilized cord blood which may risk maternal 297 blood contamination; however, we believe these findings are not due to maternal blood 298 contamination because 1) these samples were utilized for neonatal blood typing without 299 any issues or maternal blood typing confusion, 2) none of the neonates born to IgM 300 positive mothers tested IgM positive as would be expected if contamination did occur, 301 and 3) peripheral blood samples available in some neonates served as confirmation that 302 the presence of IgG was not due to maternal blood contamination (data not shown). 303

The findings on predictors of neonatal serology levels are limited by clinical data 304 capture, and the sample size may obscure other predictors of neonatal serology 305 response. In addition, the data on maternal oxygen supplementation used in the 306 multiple linear regression analysis was limited to a small number of patients, and we 307 suspect that oxygen supplementation in the mothers is a marker of disease severity. 308

Conclusions. These data on the timing of the IgG and IgM response following infection 309 and the duration of the antibody response during pregnancy may help inform the use of 310 a protective vaccine for pregnant women. Our findings suggest that maternal 311 vaccination that stimulates maternal IgG response may confer protection to the neonate. 312

Furthermore, a certain level of maternal IgG may be necessary to transfer sufficient 313 antibody to the neonate. 314

Universal Screening for SARS-CoV-2 316 in Women Admitted for Delivery

Among Patients Admitted for Childbirth in Southern Connecticut

Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection 323 by Pregnancy Status -United States

Pregnancy and postpartum outcomes in 326 a universally tested population for SARS-CoV-2 in New York City: A prospective 327 cohort study

Pregnant women with severe or critical 330 COVID-19 have increased composite morbidity compared to non-pregnant 331 matched controls

Maternal and neonatal outcomes in COVID-334 19 infected pregnancies: A prospective cohort study

Maternal COVID-19 infection

Clinical manifestations, risk factors, and 345 maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: 346 Living systematic review and meta-analysis

Impact of COVID-19 on maternal and 349 neonatal outcomes: a systematic review and meta-analysis

Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -353

Seroprevalence analysis of SARS-CoV-362 2 in pregnant women along the first pandemic outbreak and perinatal outcome

SARS-CoV-2 antibody 365 characterization in emergency department, hospitalized and convalescent 366 patients by two semi-quantitative immunoassays

Antibody responses to SARS-CoV-2 in patients 369 with COVID-19

Temporal profiles of viral load in posterior 371 oropharyngeal saliva samples and serum antibody responses during infection by 372

SARS-CoV-2: an observational cohort study

Immune phenotyping based on neutrophil-to-375

Seroprevalence and presentation of SARS-CoV-2 in pregnancy

SARS-CoV-2 seroprevalence among 389 parturient women in Philadelphia

COVID-19 and pregnancy: A review of 392 clinical characteristics, obstetric outcomes and vertical transmission

SARS-CoV-2 infection

COVID-19 during Pregnancy and Possible Vertical Transmission

IgM (red) values per pregnant woman plotted as a 431 function of elapsed time from first COVID-19 symptoms. All positive serology cutoff is 1 432 (dashed line). Values are shown on log 2 scale. Data is plotted as a LOESS curve for 433 each group

3: Passive immunity and the serology levels in neonates

Neonates were tested for serology in order to understand the rate of passive immunity 436 and the pattern of passive immunity between mother to child. A, Neonates that are 437 serology negative (beige) vs. IgG positive (purple)

Maternal IgG antibody levels grouped by those mothers who gave birth to serology 439 positive neonates (purple, N=39) or the mothers that gave birth to serology negative 440 neonates (beige, N=11). C, IgG levels of mothers vs. IgG levels of neonates. All positive 441 serology cutoff is 1 (dashed line)