https://orcid.org/0000-0002-7153-868X
Figures
Abstract
Background
Maternal immunization relies on active transplacental transfer of immunoglobulin G. However, very little is known about the efficacy of maternal immunization in the setting of multiple gestation. We aimed to investigate transplacental transfer of maternal antibody in pregnancies with multiple gestation including mono- and dichorionic pregnancies by evaluating anti-Spike antibody transfer at delivery.
Methods
We conducted a cohort study among individuals with singleton or twin pregnancies who received ≥ 2 doses of an mRNA COVID-19 vaccine before delivery. We tested paired maternal and cord blood samples for anti-Spike antibody levels via Roche Elecsys® immunoassays and used linear regression to evaluate associations between pregnancy type and anti-Spike antibody levels. We included as covariates gestational age at birth, timing of last vaccine dose, number of vaccine doses, and small for gestational age birth weight.
Results
Between 2021−2023, we tested paired maternal and cord samples for anti-Spike antibody from 362 singleton pregnancies and 36 twin pregnancies, of which 12 and 24 were monochorionic and dichorionic, respectively. After adjusting for covariates, maternal and cord anti-Spike antibody concentrations were significantly lower in twin pregnancies compared to singleton pregnancies (beta:-0.91, 95% Confidence Interval [CI]: −1.62,-0.19; p = 0.01. beta −1.20, 95% CI: −2.36,-0.04; p = 0.04), however there was no difference in cord:maternal antibody ratios. After adjusting for covariates, there was no difference in maternal and cord antibody concentrations between dichorionic and monochorionic pregnancies, however, cord:maternal antibody ratios remained significantly lower in monochorionic compared to dichorionic pregnancies (beta:-0.49; 95% CI: −0.86,-0.13; p = 0.01).
Conclusions
Twin and singleton infants have similar cord:maternal maternally derived SARS-CoV-2 antibody ratios after maternal COVID-19 vaccine although maternal and cord antibody concentrations are lower in infants from twin pregnancies and specifically antibody transfer is less efficient in monochorionic pregnancies. Further research is needed to investigate impaired transplacental IgG transfer in high-risk pregnancies.
Citation: Stolarczuk JE, Sosa M, Pike M, Baranoff A, Lekander A, Cho H, et al. (2025) Transplacental transfer of maternal SARS-CoV-2 antibodies in dichorionic and monochorionic twin pregnancies. PLoS One 20(9): e0328137. https://doi.org/10.1371/journal.pone.0328137
Editor: Ahmed Mohamed Maged, Kasr Alainy Medical School, Cairo University, EGYPT
Received: May 31, 2024; Accepted: June 26, 2025; Published: September 2, 2025
Copyright: © 2025 Stolarczuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Due to small numbers of unique pregnancies (i.e. pregnancy type, gestational age at delivery) it is impossible to fully de-identify the dataset. Making the data openly available would compromise patient privacy and would breach compliance with the protocol approved by the University of Washington Human Subjects division which delineates that all data must be kept strictly de-identified. Data will be made available on request. Please contact Kirsten Lacombe at kirsten.lacombe@seattlechildrens.org.
Funding: This project was supported by a National Institute of Allergy and Infectious Diseases (NIAID) grant (grant no. K23 AI153390; received by AK), a Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant (grant no. 2 K12HD001264 Women’s Reproductive Health Research (WRHR) Award; received by AK) and the Thrasher Research Fund (AK). The Research Electronic Data Capture (REDCap) program received support by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR002319. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests: The authors do not have conflicts of interests to disclose related to this publication. Outside of this work, A.K. was an unpaid consultant for Pfizer and GlaxoSmithKline and was co-investigator on a study funded by Merck. A.K. is co-investigator on studies funded by Pfizer. J.A.E. receives grant support to her institution from Merck, GlaxoSmithKline, AstraZeneca, and Pfizer and is a consultant for Abbvie, AstraZeneca, GlaxoSmithKline, Merck, Moderna, Sanofi Pasteur and Meissa Vaccines, Inc. A.L.G. reports central contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen and Hologic and research support from Gilead, outside of the described work. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
The immunization of pregnant persons against infections offers dual benefit to both pregnant individuals and their fetuses and neonates. Maternal immunization describes the administration of vaccinations during pregnancy to boost maternal antibody concentrations and enhance active maternal-fetal transfer of vaccine-specific maternal Immunoglobulin G (IgG) [1,2]. Maternal IgG binds to neonatal fragment crystallizable receptors (FcRn) on the syncytiotrophoblast of chorionic villi [3]. The maternal IgG is released into fetal capillaries and helps provide immune protection for neonates and infants in the first months of life. Vaccination in both uncomplicated and complicated pregnancies is a key strategy to prevent or mitigate severe illness from infectious disease, particularly respiratory tract infections, in pregnant persons and their infants [4]. For example, administration of COVID-19 vaccines before or during pregnancy has been shown to protect pregnant individuals and their infants against severe infection and hospitalization from SARS-CoV-2 [5–7]. However, there is little research on the efficiency of transplacental transfer of SARS-CoV-2-specific antibodies in twin pregnancies.
Multiple factors may affect transplacental antibody transfer including gestational age of the pregnancy, total IgG antibody, IgG antibody subclass, properties of the antigen, maternal co-morbidities and placental factors [2]. Physiologic adaptations of pregnancy are often magnified in twin compared to singleton pregnancies, which may impact placental function and maternal vaccination [8]. For example, it is plausible that the further amplified increases in maternal blood volume and hemodilution in a twin pregnancy may result in lower maternal IgG concentration after vaccination, or impaired transplacental IgG transfer. In addition, infants from twin pregnancies are particularly at risk for prematurity and low birth weight compared to infants from singleton pregnancies [9–11]. These risks are further increased in monochorionic compared to dichorionic twin pregnancies [12–14]. Due to a vulnerable immune system and small airways, prematurity places infants at increased risk of infection by respiratory pathogens such as SARS-CoV-2; thus, infants rely on transplacental transfer of maternally derived IgG prior to birth as a key protection mechanism during the first few months of life [4].
Few studies have assessed transplacental antibody transfer in twin pregnancies compared to singleton pregnancies. One study of 50 twin pregnancies found that the mean maternal IgG level was higher in the umbilical cord than the maternal serum; and the cord IgG levels were in range for singletons of the same gestational age [15]. Stach et al. showed that umbilical cord total IgG concentrations were higher in dichorionic compared to monochorionic twin pregnancies [16]. However, the impact of twin pregnancy compared to singleton pregnancy and of chorionicity within twin pregnancies on transplacental transfer of SARS-CoV-2 IgG has not been studied. Our study seeks to understand how multiple gestation and chorionicity impacts transplacental maternal IgG transfer by investigating COVID-19 vaccines and SARS-CoV-2 anti-Spike (S) antibody transfer in monochorionic and dichorionic twin and singleton pregnancies.
Materials and methods
Participants
We recruited participants and acquired informed written consent for an ongoing prospective cohort study on maternal immunizations at the University of Washington (UW). Maternal blood samples were collected within 72 hours of delivery and cord blood samples at delivery. We included samples from participants with a singleton and monochorionic or dichorionic twin pregnancies. All subjects received two or more doses of an mRNA based COVID-19 vaccine prior to delivery, had no known significant fetal genetic condition or structural anomaly, and paired maternal and cord blood samples as well as complete SARS-CoV-2-specific antibody data were available. Samples were excluded if participant received less than two doses of a COVID-19 vaccine prior to delivery, received a non-mRNA-based vaccine, had a triplet pregnancy or had incomplete SARS-CoV-2-specific antibody data. Ethics approval for the study was received by the UW Human Subjects Division.
Variables
We collected clinical data by performing chart abstraction from electronic medical records (EMR) and organized data into our database through REDCap (version 13.10.6, 2024) as previously described [17]. In short, we categorized participant race and ethnicity data using the Centers for Disease Control and Prevention’s categories [18]. Participant insurance status was categorized by public, private or Tricare/Military, Federal, or other. We calculated body mass index (BMI) using maternal weight at delivery. We used the American College of Obstetricians & Gynecologists’ (ACOG) criteria to define pregestational diabetes, preeclampsia with and without severe features, chronic hypertension, chronic hypertension with superimposed preeclampsia, and eclampsia [19]. Designated autoimmune diseases/inflammatory disorders included conditions such as systemic lupus erythematous and Crohn’s disease, and rheumatoid arthritis, among others. Patients on long-term corticosteroids, biologics, or other immunosuppressive medications were categorized as receiving immunosuppressing medications. Participants’ number of COVID-19 doses vaccine data was collected through the Washington State Immunization Registry data linked to the EMR. COVID-19 infection status prior to or during pregnancy was determined through provider indication or positive test result. In addition, twin pregnancy chorionicity was determined via ultrasound report in the EMR.
Antibody testing
We tested maternal and cord blood samples for anti-S and anti-Nucleocapsid (N) antibody concentrations using the semi-quantitative Roche Elecsys® immunoassays at the University of Washington Virology Laboratory which has a reported sensitivity of 99.5% and specificity of 99.8% for SARS-CoV-2 anti-N detection [20]. In our analysis, we converted results from the Roche Elecsys® Anti-SARS-CoV-2 S immunoassay to binding antibody units (BAU)/mL and log2-transformed antibody levels. We defined evidence of past SARS-CoV-2 infection to be positive COVID-19 antigen or a PCR test, or positive anti-N serology. Maternal total IgG (mg/dL) was tested in the UW Immunology Clinical Laboratory using an Optilite analyzer with standard reagents.
Analysis
We reported demographic, pregnancy, and neonatal characteristics as absolute numbers with percentages or as medians with interquartile ranges (IQR). We compared characteristics using t-tests, Wilcoxon rank-sum tests, chi-square tests, and Fisher’s exact tests. We analyzed relationships between type of pregnancy (singleton versus twin) as well as chorionicity (monochorionic versus dichorionic) and maternal and cord anti-S antibody levels using Wilcoxon rank sum tests and linear regression analyses. Similar analyses were performed for the ratio of cord to maternal (cord:maternal) anti-S antibody concentrations based on untransformed values, which were tested with t-tests and linear regression. Cord:maternal antibody ratios of >1 are generally considered “efficient” placental antibody transfer in published studies [1], however are distinct and may not correlate to correlates of protection against a specific antigen. Anti-S IgG antibody levels were log2-transformed and reported as geometric mean concentrations (GMC) and 95% confidence intervals (CI). A boxplot of cord:maternal ratios for singleton, monochorionic, and dichorionic pregnancies was created using the median, interquartile range, and range of the ratio in each group to show differences. We selected covariates a priori and based on significant associations with the exposure of twin gestation or chorionicity and outcomes of maternal and cord anti-S antibody concentrations. Covariate associations were tested using chi-square tests, t-tests, and linear regression. For the comparison of singleton versus twin birth, minimally adjusted models included gestational age at delivery and time between last COVID-19 vaccine dose and delivery (in weeks). A fully adjusted model additionally included number of COVID-19 vaccine doses prior to delivery and small for gestational age. For the comparison of monochorionic versus dichorionic, the minimally adjusted linear regression model included time between last COVID-19 vaccine dose and delivery (in weeks). The fully adjusted model additionally included gestational age at delivery and number of vaccine doses before delivery. Linear regression models for cord anti-S antibody levels and cord:maternal antibody ratios allowed for intragroup correlation by specifying clusters of twins, relaxing the requirement that the observations be independent. We performed statistical analyses using Stata version 18.0 (StataCorp, College Station, TX, USA) [21]. We considered a two-sided P-value less than 0.05 as statistically significant, and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline [22].
Results
Baseline demographic and medical characteristics
From February 2021 to April 2023, a total of 398 pregnant participants met the inclusion criteria. Of these, 362 were singleton pregnancies and 36 were twin pregnancies, of which 12 and 24 were monochorionic and dichorionic, respectively. Baseline demographic and medical characteristics are presented in Table 1. There was no difference between groups in any of these recorded variables, including race, ethnicity, insurance status, delivery BMI and rates of pregestational diabetes mellitus, pre-eclampsia, autoimmune/inflammatory disorders, or use of immunosuppressing medication. However, singleton pregnancies had higher rates of chronic hypertension than twin pregnancies (p = 0.04). Maternal total IgG concentrations were greater in singleton pregnancies than in twin pregnancies (p = 0.003), with a median of 692 (IQR 577,821) mg/dL and 525 (392,699) mg/dL, respectively. However, no difference in maternal total IgG levels was noted between mono- and dichorionic pregnancies.
Pregnancy outcomes
Pregnancy outcome data is presented in Table 2. Twin pregnancies delivered at an earlier median gestation of 36.0 weeks (IQR 34.1, 36.9) than singleton pregnancies (39.0 weeks, IQR 36.7, 39.9; p < 0.001) with no difference in gestational age at delivery between mono- and dichorionic twins (35.4 weeks, IQR 34.5, 36.4, versus 36.1 weeks, IQR 33.8, 36.9, respectively; p = 0.31). Twin pregnancies had a lower median birth weight (2353 grams, IQR 2034, 2691) than singleton pregnancies (3175 grams, IQR 2648, 3565; p < 0.001) and were more likely to have a neonate admitted to the neonatal intensive care unit (NICU) (twin n = 47, 65.3%; singleton n = 83, 22.9%; p < 0.001).
COVID-19 infection and vaccine history
Prior to delivery, whether prior to pregnancy or during pregnancy, 178, 154, and 66 participants received 2, 3, and 4 + COVID-19 vaccines, respectively. The number of COVID-19 vaccine doses prior to delivery or during pregnancy, median latency time between the last vaccine dose and delivery or gestational age at last vaccine dose were not significantly different among singleton and twin pregnancies (Table 1). No difference in the number of COVID-19 vaccines in pregnancy or median time between last vaccine dose and delivery was seen between mono- and dichorionic twin pregnancies, however individuals with dichorionic pregnancies were more likely to receive the last COVID-19 vaccine dose at an earlier gestational age than monochorionic pregnancies (p = 0.01). There was no difference in people with history of COVID-19 infection or positive anti-N serology between singleton and twin pregnancies or between mono- and dichorionic twin pregnancies (Table 1).
Anti-S antibody analysis
The unadjusted maternal anti-S antibody GMC was 3553 BAU/mL (95% CI 3017, 4185) and the unadjusted cord anti-S antibody GMC was 4083 BAU/mL (95% CI 3499, 4766) (Table 3). There was no difference seen between singleton and twin pregnancies (p = 0.96; p = 0.18) or between mono- and dichorionic twin pregnancies (p = 0.50; p = 0.21) when comparing the maternal and cord anti-S antibodies, respectively. The cord:maternal antibody ratio of singleton pregnancies was higher (1.23, 95% CI 1.17, 1.31) than twin pregnancies (0.87, 95% CI 0.69, 1.08; p < 0.001). Additionally, the cord:maternal antibody ratio of dichorionic pregnancies (1.25, 95% CI 1.14, 1.36) was higher than monochorionic pregnancies (0.42, 95% CI 0.24, 0.73; p < 0.001; Fig 1). We compared cord:maternal antibody ratio between singleton and dichorionic or monochorionic twin pregnancies. While there were no significant differences between transfer ratios in dichorionic twin pregnancies compared to singleton pregnancies (p = 0.35), cord:maternal antibody ratio of monochorionic pregnancies was lower than singleton pregnancies (p < 0.001).
Abbreviation: anti-S = anti-Spike antibody.
To test for the association between singleton and twin pregnancies and maternal and cord anti-S antibody levels we ran linear regression analysis and, in our fully adjusted model, we controlled for time between last vaccine dose and delivery, gestational age at delivery, fetal growth restriction and number of vaccine doses prior to delivery (Table 4). Both maternal and cord antibody concentrations were significantly lower in twin pregnancies compared to singleton pregnancies (b: −0.91, 95% CI −1.62, −0.19; p = 0.01; b:-1.20, 95% CI −2.36, −0.04; p = 0.04, respectively) although there was no difference in cord:maternal antibody ratios.
We ran a second adjusted linear regression analysis to test the association between chorionicity in twin pregnancies and maternal and cord anti-S antibody levels (Table 5). In this model we adjusted for timing of the last COVID-19 dose prior to delivery, gestational age at delivery and number of vaccine doses, and no difference was found for maternal or cord anti-S antibodies. However, cord:maternal antibody ratios were significantly lower in monochorionic pregnancies compared to dichorionic pregnancies (β: −0.49; 95% CI: −0.86, −0.13; p = 0.01).
Discussion
Our study shows a significant difference in transplacental transfer of anti-S antibody between monochorionic and dichorionic or singleton pregnancies. Paired cord:maternal anti-S antibody ratios in dichorionic pregnancies resemble anti-S antibody ratios in singleton pregnancies, demonstrating efficient transplacental antibody transfer in both singleton and dichorionic pregnancies, similar to other published studies on SARS-CoV-2-specific antibody transfer ratios [23]. However, given significantly lower transplacental antibody transfer ratios in monochorionic pregnancies, an additional COVID-19 vaccine dose during pregnancy may help boost anti-S antibodies in order to optimize IgG levels available for transfer.
Our study focused on maternal antibody transfer post-COVID-19 vaccination in multiple gestation pregnancies and found that twins (both mono- and dichorionic pregnancies combined) has lower maternal and cord anti-S antibody levels compared to singleton pregnancies after covariate adjustment. Additionally, our data revealed significantly lower cord:maternal anti-Spike IgG ratios in mono- versus dichorionic twin pregnancies (p < 0.001). These findings are consistent with a prior study from 2014 investigating total IgG concentrations in mono- and dichorionic pregnancies by Stach et al. where monochorionic twins had lower total IgG transfer ratios than dichorionic twin infants [16]. However, in a further study from the same group specifically focused on umbilical cord serum concentrations and transfer ratios of IgG antibody directed against group B streptococcus, LPS from Klebsiella species and pseudomonas species, chorionicity was not associated with differences in IgG transfer ratios [24]. Lower cord:maternal antibody ratios can be potentially explained by multiple factors including gestational age at delivery (although we adjusted for this), and concentrations of FcRn receptors which increase in the 3rd trimester. In addition, the nature of the antigen and specific antibody characteristics may affect antibody transfer [25–27]. Another proposed explanation is that transplacental transfer of IgG in monochorionic pregnancies are distributed between two fetuses via placental vascular anastomosis, leading to lower levels of IgG than if antibodies were distributed amongst two placentas [16,28]. While lower antibody ratios signify lower antibody transfer to the fetus relative to maternal antibody concentrations, they do not necessarily correlate with immune protection from a pathogen or correlates of protection which are often not known. Further research, specifically into placental factors involved in chorionicity and transplacental antibody transfer in twin pregnancies, may shed more light on our findings.
Current clinical guidelines for COVID-19 vaccine in pregnancy recommend at least one dose of an updated COVID-19 vaccine prior to delivery [29]. Optimization of maternal antibody levels prior to delivery appears to be advantageous for individuals with vaccine-mediated or hybrid immunity [30]. A growing proportion of the population has become infected with SARS-CoV-2, and the primary COVID-19 vaccine series is no longer available. Twin infants from both monochorionic as well as dichorionic pregnancies benefit from anti-S antibody transfer in potential protection against SARS-CoV-2 infection. In monochorionic pregnancies, an additional COVID-19 vaccine dose during pregnancy may help boost maternal anti-S antibodies in order to optimize transplacental antibody transfer to the fetuses. More studies are needed to elucidate whether additional vaccine boosters given to individuals with monochorionic pregnancies would boost anti-S antibody transfer to the significantly higher levels seen in singleton and dichorionic pregnancies.
As attention towards maternal immunization strategies grows, it is important to evaluate transplacental IgG transfer in the setting of high-risk pregnancy conditions such as monochorionic multiple pregnancies including investigations of the placenta and FcRn receptors. In addition, transplacental transfer relies on multiple factors including specific characteristics of the pathogen-specific antibody and the placenta. In the case of prior SARS-CoV-2 infection, studies have shown alterations to the placenta as well as potential augmentation of antibody transfer after COVID-19 infection [31,32]. Further studies into characteristics contributing to high-risk pregnancies may help optimize maternal immunization specifically for infants particularly at risk for infectious morbidity.
Strengths and limitations
Our analysis encompasses a prospective cohort from an institution with large numbers of both low- and high-risk pregnancies, with relatively broad inclusion criteria, enabling us to increase generalizability of our results. Our methods to evaluate efficient transplacental transfer with cord:maternal anti-Spike antibody ratios at a threshold > 1 has been previously proposed in published literature [33]. We collected paired maternal and cord blood for all subjects with minimal missing variables which allowed for comprehensive assessment of pertinent outcomes related to maternal vaccination. In addition, the ability to link to the Washington State Vaccination Registry allowed abstraction of accurate vaccine data for our participants and is a strength of the study. Finally, the evaluation of COVID-19 vaccines and anti-S antibodies in multiple gestations with sub-analysis by chorionicity is a clinically important topic given the increased risk in these pregnancies for preterm delivery and low birth weight.
Although our study is unique in reporting on anti-S concentrations in pregnancies and multiple pregnancies stratified by chorionicity, we were limited by sample size, which comes with a few implications for the data. First, we found a significant difference between cord:maternal ratios, but not in maternal or cord antibody concentrations. With the small sample sizes, our ability to detect differences in maternal and cord concentrations may be limited. Second, fully-adjusted models may be overfitted and therefore, uncertainty remains around the results. Third, there may be additional confounders, measured and unmeasured, that we were not able to investigate due to the small sample size or unavailability of data. We do not report results from neutralizing assays, although previously published studies have shown good correlation with anti-S antibody levels and neutralizing function [34]. In terms of anti-S testing, the upper limit of Roche Elecsys® Anti-SARS-CoV-2 S immunoassay is 25,720 BAU/mL. Of our participants 64 (16.1%) of maternal samples and 70 (16.1%) of cord samples reached this level. It also tests predominantly for IgG but may pick up small quantities of IgM and IgA [35]. While these immunoassay characteristics do not affect maternal and cord antibody concentration analyses, there may be limitations for interpretation of cord:maternal antibody ratios.
Conclusions
The results of the study suggest that chorionicity in twin pregnancies and not multiple gestation itself affects the transfer of maternal anti-S IgG transfer in pregnancy. Although pregnancies included in our study displayed significant transplacental antibody transfer following vaccination with two or more doses of an mRNA COVID-19 vaccine regardless of number of fetuses or placentas, monochorionic twin pregnancies showed reduced antibody transfer ratios compared to dichorionic twin pregnancies and singleton pregnancies. Maternal immunization with the COVID-19 vaccine in twin pregnancies and particularly in monochorionic pregnancies to augment maternal IgG antibody concentrations and thus cord antibody concentrations may be beneficial for improving infant immune protection against COVID-19.
Acknowledgments
We would like to thank the participating individuals who contributed their samples and time to this study. We are also grateful for the clinical care providers and specifically the registered nurses on the UW Medicine Center Montlake’s Labor and Delivery and Mother-Baby units and Northwest’s Childbirth Center who made this research possible.
Portions of these data were presented at the annual ID Week conference in Boston, MA on October 12, 2023 and at the 6th International Neonatal and Maternal Immunization Symposium (INMIS) in San Jose, Costa Rica, on March 13th, 2024.
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