The burden,pathogenesis,clinical outcomes,and treatment of common respiratory virus infections during pregnancy

Abstract

Respiratory illnesses due to respiratory virus infections disproportionately impact pregnant individuals and their infants, leading to significant morbidity and mortality globally. Data describing the incidence and impact of these infections in pregnancy is sparse and more common for influenza and now severe acute respiratory syndrome coronavirus 2 with less data available on other respiratory virus infections in pregnancy. This lack of data is a result of limited prospective surveillance and issues surrounding the calculations of seroprevalence, as well as disproportionately low funding for reproductive health research. In this review article, we aimed to summarize available data on respiratory virus infections in pregnancy and identify gaps in the published literature.

Plain language summary

Respiratory virus infections, like flu and COVID-19, cause serious illness and death in pregnant people and their babies, worldwide. However, there’s not much data on how common these infections are or their full impact during pregnancy, especially for viruses other than flu and COVID-19. This is due to limited ongoing studies, challenges in measuring past infections, and underfunding of reproductive health research. This article reviews what we know about these infections in pregnancy and points out where more research is needed.

Keywords

pregnancy neonate respiratory virus infection

Introduction

Respiratory illnesses disproportionately impact pregnant individuals and their infants, which can lead to adverse health events throughout the mother’s and child’s life.^1,2 Pregnant people undergo substantial physiologic and immunologic changes over the course of their pregnancy increasing their risk for respiratory virus infections.^1,3 More specifically, when individuals become pregnant their immune system adapts to provide a tolerogenic environment for non-host fetal antigens.^4,5 Although respiratory virus infections commonly occur in pregnant persons, data describing the incidence and impact of these infections is sparse and more common for influenza and now severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with less data available on other respiratory virus infections in pregnancy.^6
–8 This lack of data is a result of limited prospective surveillance and issues surrounding the calculations of seroprevalence, as well as disproportionately low funding for reproductive health research.² One cross-sectional study performed in 2018, consisting of 155 pregnant women, found that the most common respiratory infections detected during pregnancy were rhinovirus (27%), seasonal coronaviruses (17%), and respiratory syncytial virus (RSV) (10%).⁹ More recently SARS-CoV-2, the pathogen which causes COVID-19, has been shown to be a common cause of respiratory tract infections during pregnancy. A study conducted in 2021, consisting of 138 pregnant individuals, estimated the cumulative incidence of SARS-CoV-2 infection to be 10.1% in the first trimester alone.¹⁰ The risk of severe symptoms and complications associated with respiratory virus infection during pregnancy drastically increases throughout pregnancy, with the greatest risk presenting in the third trimester.^1,2 It has been estimated that pneumonia resulting from viral infection is diagnosed in 1.5 of every 1000 pregnancies and is associated with increased maternal morbidity and mortality.^11,12 We aimed to summarize available data on common respiratory virus infections in pregnancy, including influenza, RSV, SARS-CoV-2, parainfluenza, human metapneumovirus, parvovirus B19 (fifth disease), rhinovirus, and bocavirus to identify and address gaps in the published literature (Table 1).

Table 1.

Overview of three principal viruses that commonly infect pregnant individuals and newborns.

Virus	Virus classification	Mechanism of infection	Potential outcomes in pregnant individuals	Potential fetal outcomes	Treatments	Maternal vaccination strategies
Influenza	Negative-sense single-stranded RNA	Droplet, aerosol, fomite	Mild to severe acute respiratory illness, death	Preterm birth, low birth weight, fetal demise	Home/over-the-counter interventions and antiviral medication (Oseltamivir)	Seasonal influenza vaccine at the beginning of influenza season, regardless of gestation
RSV	Negative-sense single-stranded RNA	Droplet, fomite, direct contact	Mild to severe acute respiratory illness	Preterm birth, low birth weight	Home/over-the-counter interventions and supportive care	RSV vaccine between 32 and 36 weeks gestation
SARS-CoV-2	Positive-sense single-stranded RNA	Droplet, aerosol, fomite, direct contact	Mild to severe acute respiratory illness, death	Preterm birth, low birth weight, fetal demise	Home/over-the-counter interventions and antiviral medication (Paxlovid)	Seasonal coronavirus vaccine at any gestation

RSV: respiratory syncytial virus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

During pregnancy, the immune system plays two major roles: to adapt to multiple pregnancy stages to ensure a successful pregnancy and to protect the pregnant individual from pathogens.⁵ Upon exposure to a respiratory virus, the immune system induces humoral and cellular responses to prevent or clear the infection. Importantly, the production of protective antibodies occurs. These antibodies work by preventing future virions from entering cells and replicating to establish an infection.⁵ In addition to responding to pathogens, the maternal immune system must dynamically and robustly respond to the four stages of pregnancy to have a successful delivery of a viable fetus.⁵ First, the immune system provides a pro-inflammatory response during the implantation and placentation stages.¹³ To establish a viable placenta for a successful pregnancy, trophoblast cells invade and attach to the surface epithelium of the receptive maternal decidua, which involves the active breakdown and reconstruction of the decidua. Thus, during implantation and early placentation, the immune system responds by releasing pro-inflammatory cytokines, growth factors, chemokines, proteins, and tumor necrosis factors, which also occur when the immune system responds to tissue injury and repair.⁵ While the development of the placenta modulates much of this response, it is also a target for viral infections.¹⁴ It is still unclear how the placenta is directly impacted by infection, but we do know that it has a unique capacity to prevent further replication of viruses and subsequent transmission of infections to the fetus.¹⁴ Next, the immune system provides an anti-inflammatory response utilizing macrophages, decidual natural killer cells, and regulatory T cells during the fetal growth stage.⁵ Pro-inflammatory responses during this stage of the pregnancy, such as those induced by infection, have been shown to result in preterm birth.^15,16 Lastly, the immune system provides a second pro-inflammatory response, which is necessary for the initiation of parturition. The switch to this pro-inflammatory response involves a nuclear factor signaling pathway, which is responsible for initiating and continuing the progress of labor and delivery. Contraction of the uterus, delivery of the infant, and detachment of the placenta are initiated when the myometrium is saturated with immune cells.⁵ Therefore, the immune system not only protects pregnant persons from pathogens but also plays a role in establishing the pregnancy, growing the fetus, and delivery of the fetus.

In addition, in pregnant individuals, a mechanism known as transplacental antibody transfer occurs where antibodies, specifically immunoglobulin G (IgG), from previous exposures and infections, are actively transferred from the mother to fetus across syncytiotrophoblast cells of chorionic villi in the placenta.¹⁷ Other Igs including IgM and IgA are not transferred. The transfer of maternal IgG across the syncytiotrophoblast involves binding to neonatal Fc receptors (FcRn), which is highly dependent on pH. IgG is first endocytosed from the maternal side into the syncytiotrophoblast. The endosomes provide an acidic environment that facilitates the binding of IgG to FcRn. The FcRn–IgG complex is then transcytosed to the fetal side of the syncytiotrophoblast, where IgG dissociates from FcRn due to the return to physiologic pH.¹⁷ The maternally derived IgG obtained via transplacental transfer and present in infants at birth have been shown to be protective against respiratory virus infections and is a primary source of passive immunity in the neonate.^18
–20 The range of time of protection is dependent on the quantity of IgG transferred to the infant and the rate at which the antibodies wane.²¹ For example, one study investigating the transplacental transfer of Influenza (H1N1) binding antibodies found that within 2 months of birth, antibodies waned to below the accepted protective threshold.²² In contrast, studies used to determine the optimal timing of RSV maternal immunization found that maternally derived RSV antibodies waned to a non-protective level in infants between 6 and 24 months after birth.²³ Factors that have been shown to decrease the amount of maternally derived IgG include birth gestation, birth weight, maternal vaccination timing, hypergammaglobulinemia, antibody glycosylation state, IgG subclass, neonatal FcRn efficiency, and antigenic characteristics.^17,24
–28 Protective thresholds are highly variable across different viruses due to the use of different laboratory assays and individual-level exposure patterns. Therefore, more research must be done to get a better understanding of how protective thresholds compare across viruses.

Pregnant persons are at a higher risk for severe signs, symptoms, and complications from respiratory virus infections, with the leading cause of complications due to subsequent pneumonia-inducing respiratory failure.²⁹ These viruses increase the risk of bacterial pneumonias from damage to the respiratory epithelium.³⁰ In addition, physiologic changes during pregnancy, such as decreased total lung volume due to the growing fundus, increase risks associated with respiratory virus infections.³¹ Respiratory virus infection during pregnancy also increases the risk of adverse pregnancy and neonatal outcomes. These include maternal death, pregnancy loss, preterm delivery, and infants born with low birthweight, in addition to other adverse events such as fetal demise.^1,32
–34 Preterm and low birthweight can have lasting impacts on infants throughout their lifetime and potentially increase the risk of comorbidities in adulthood.^1,35 In addition, maternal fever can have a detrimental impact on the growing fetus, and sustained high maternal core temperatures have been associated with an increased risk of developing neural tube defects, congenital heart defects, and oral clefts.³⁶ RSV and SARS-CoV-2 infections during pregnancy can potentially cause vertical transmission, although this is a rare occurrence, and many have speculated on the nature in which the observed vertical transmission cases have been investigated and documented.^37
–39 Therefore, there is an increased focus on preventing respiratory virus infections during pregnancy to mitigate morbidity and mortality of the pregnant person as well as stillbirth and other adverse pregnancy and neonatal outcomes that could potentially have long-lasting effects in infants.

Estimates of influenza virus infection rates in pregnant individuals vary due to differences in antigenic properties and influenza vaccine mismatch across seasons (Figure 1). A systematic review estimated the incidence of influenza infections in pregnant persons to be within the range of 483 and 1097/10,000 pregnancies.⁴⁰ The risk of influenza infection and associated morbidity can be exacerbated if an individual is pregnant during the peak of influenza virus circulation or has other comorbidities.^1,41 One study estimated that over nine influenza seasons, 33% of reproductive-aged women hospitalized for complications due to influenza infection were pregnant.⁴²

Figure 1.

Respiratory viruses detected at Seattle Children’s Hospital, 2020–2024.

Influenza virus is commonly transmitted through exposure to respiratory droplets carrying influenza virions. The immune system responds in multiple ways to neutralize the infection which commonly causes fever, chills, fatigue, malaise, runny nose, and cough.^1,43 This clinical presentation is similar for both influenza A and B, with the most common seasonal infections occurring from Influenza A H3N2 and H1N1.⁴³ Antibodies for influenza have shown to be protective for multiple subtypes and strains; however, the level of cross-protection varies by how genetically similar previous and subsequent exposure viruses are.⁴³ Influenza infection during pregnancy generally requires diagnostic testing to verify infection, and treatment is limited by the timing of clinical presentation. Common recommendations include home and over-the-counter interventions such as rest, increased fluid intake, and fever-reducing medication. In addition, the American College of Obstetricians and Gynecologists (ACOG) recommends starting empiric antiviral treatment within 48 h of symptom onset without waiting for confirmation from respiratory infection test results.⁴⁴ Oseltamivir is the preferred antiviral medication in pregnancy, with a treatment regimen of 75 mg orally twice daily for 5 days. In addition, Individuals who are pregnant with a moderate risk of severe illness and those with a high risk of severe illness should be seen in the ambulatory clinic and emergency department, respectively, for evaluation.^44,45

The most effective method used to prevent influenza infection during pregnancy is maternal immunization. The seasonal influenza vaccine is recommended for all pregnant individuals as soon as it is available during flu season.⁴⁶ A multiyear meta-analysis estimated that the maternal influenza vaccine was associated with a 64% decrease in risk of laboratory-confirmed infection, with variability by year due to differences in antigenic properties and vaccine mismatch by season.⁴⁷ These vaccines protect the pregnant individual by inducing immune responses. The humoral immune response produces antibodies specific to the vaccine antigen, which prevent the binding of the influenza surface proteins and host-cell receptors, ultimately inhibiting infection.^43,48 Not only do these vaccines protect individuals during pregnancy, but they also result in protection in infants after birth. During pregnancy, transplacental transfer of influenza antibodies from mother to fetus takes place.^22,49,50 These antibodies work similarly immunogenically in infants as they do in their mothers, by blocking the binding of the virion and host-cell and inhibiting infection.^43,50 Meta-analyses have estimated a 72% decrease in the risk of influenza infection during the first 6 months of life in infants whose mothers received the seasonal influenza vaccine.⁴⁷

Individuals are repeatedly exposed to and infected with RSV throughout their lifetimes, with most people experiencing their first infection before the age of 3.⁵¹ Transmission of RSV is typically seasonal with the most circulation occurring between January and April in the USA with the highest burden of disease in children <5 years of age (Figure 2).⁵² A meta-analysis including 11 studies between 2010 and 2022 estimated the incidence rate of RSV infections in pregnant individuals was 26 episodes/1000 person-years.⁵³ However, the exact number of infections in pregnant persons is likely underestimated due to a lack of prospective surveillance and asymptomatic case presentation, which is common in reproductive-age individuals.⁵¹ One study tested asymptomatic and symptomatic pregnant individuals in their second and third trimesters and found 10% were infected with RSV.⁹

Figure 2.

Country-specific RSV epidemiology.

Similar to influenza, RSV is most commonly transmitted through exposure to respiratory droplets carrying RSV virions. The immune system responds by inducing humoral and cellular responses, which can present as upper respiratory tract cold-like symptoms with persistent cough and, less commonly, as respiratory distress in adults.³⁰ Individuals can be infected and present without symptoms, increasing the risk of transmission due to normal day-to-day activities, which increases interactions with others.⁵¹ There are two types of RSV (A and B); studies have shown that infection from one strain usually results in the production of cross-reactive antibodies, which provide protection to both strains upon future exposure.⁵⁴ Antibodies are developed against RSV antigens, including surface glycoproteins F and G.⁵⁵ There is a fourfold rise in antibodies after natural infection in adults, which return to baseline concentrations within 2 years.⁵⁶ Higher levels of antibodies are generally thought to correlate with higher resistance to infection, however, there is no defined serologic threshold for protection in children or adults.^57,58

Treatment for RSV in pregnant individuals combines multiple supportive care interventions such as the use of bronchodilators, supplemental oxygen, intravenous fluid, and antipyretics.⁵⁹ Ribavirin, a nucleoside analog, is currently the only Food and Drug Administration (FDA)-approved antiviral therapy for use against RSV for infants and young children, but is not recommended for pregnant persons or their male partners, given teratogenicity seen in animal studies.^60,61 Results of a Ribavirin Pregnancy Registry (NCT00114712) that was established in 2003 to evaluate pregnancy outcomes after Ribavirin exposure showed congenital anomaly rates that exceeded the Metropolitan Atlanta Congenital Defects Program, however, no clear pattern of pathophysiology for teratogenicity was found.⁶¹

In the past, mitigation methods against RSV typically included normal measures against respiratory infections such as hand hygiene and masking. Recently in 2023, the FDA approved a bivalent pre-fusion F protein RSV vaccine, Abrysvo™ (Pfizer Inc., New York, NY, USA), for pregnant persons. This vaccine provides some maternal protection in the mid to late third trimester of pregnancy but is mainly used for infant protection from RSV via transplacental antibody transfer to the fetus. Phase 3 clinical trial results showed that in infants, the vaccine reduced the risk of severe lower respiratory tract disease from RSV infection by 82% within 90 days of birth and 69% within 180 days of birth.⁶² The FDA approved this vaccine to be administered between 32 and 36 weeks gestation, given a numerical imbalance in preterm births in Abrysvo recipients (5.7%) compared to placebo recipients (4.7%), which was only seen in one participating middle-income country.⁶³ In addition, a new RSV monoclonal antibody directed against the same F protein used in the RSV vaccine has been licensed and recommended by the Centers for Disease Control for administration to infants for the prevention of RSV in the first year of life for both healthy and at-risk children, with good effectiveness already demonstrated in the United States.^64,65

SARS-CoV-2 is a pathogen that emerged in the last 5 years, sparking a global COVID-19 pandemic. Since the pandemic, the SARS-CoV-2 virus has become endemic, and in the past 2 years, patterns show that it has seasonally circulated with other respiratory viruses in the USA (Figure 3).⁶⁶ Although there has been an influx of research surrounding this pathogen, we still know very little about the burden this virus has on pregnant individuals and their infants, in part because many infections may be asymptomatic and partially due to the complex nature of the immune response to SARS-CoV-2 infection. One study found that ~10% of individuals who became pregnant just before or during the first wave of the COVID-19 pandemic tested positive for SARS-CoV-2 within their first trimester of pregnancy. A moderate proportion (42%) of these individuals were asymptomatic.¹⁰ One large meta-analysis and another cohort study found that individuals who were diagnosed with SARS-CoV-2 during pregnancy were more likely to be hospitalized, admitted to the intensive care unit, delivered preterm, and required cesarean sections.^67,68 Although infected pregnant persons were more likely to experience severe illness and adverse events, there was a low incidence (1.4%) of SARS-CoV-2 documented in their newborns.⁶⁷

Figure 3.

COVID-19 new hospital admissions and NAAT percent positivity, by week, in the USA, reported to CDC.

Like other respiratory viruses, SARS-CoV-2 is also commonly transmitted via contact with respiratory droplets expelled by an infected individual. Compared to nonpregnant reproductive-aged individuals, pregnant people are at a significantly higher risk for severe adverse pregnancy and fetal outcomes.⁶⁹ The pathophysiology for more severe outcomes in the pregnant population may be due to physiologic changes in pregnancy, including decreased lung capacity due to the growing fundus, increased heart rate and oxygen consumption, alterations in the immune system, and higher risk for a thromboembolic event.^69
–71 In general, pregnant individuals with SARS-CoV-2 infection are at higher risk for ICU admission, need for invasive ventilation, need for ECMO, or death compared to non-pregnant individuals.⁶⁹ In addition, there is also a higher risk for preeclampsia, need for preterm delivery, and stillbirth.^72,73 SARS-CoV-2 infections can significantly affect the placenta and result in fibrin deposition, and chronic placental insufficiency with outcomes as described above.⁷⁴ Vertical transmission of the SARS-CoV-2 virus resulting in congenital SARS-CoV-2 infection has been demonstrated but is thought to be rare.⁷⁵

Treatment for symptomatic COVID-19 illness in pregnant persons is similar to that of non-pregnant adults.^76,77 Antiviral medications including ritonavir-boosted nirmatrelvir (Paxlovid; Pfizer Inc., New York, NY, USA) and remdesivir have been studied in pregnancy and are considered safe.⁷⁷ Other supportive measures, as well as monoclonal antibodies, if indicated, are also acceptable in pregnancy.⁷⁷

SARS-CoV-2 vaccination is the most efficient way to reduce the risk of excess negative maternal and fetal outcomes associated with infection during pregnancy. Although pregnancy was an excluding factor in the initial COVID-19 vaccine clinical trials, observational studies have provided reassuring data regarding the safety and efficacy of COVID-19 vaccination in pregnancy.^78,79 In fact, multiple studies have shown that the overall rates of adverse perinatal outcomes, such as preterm birth and fetal growth restriction, did not increase after maternal COVID-19 vaccination.^80
–82 Instead, COVID-19 vaccines decrease the risk of adverse maternal and neonatal outcomes seen with SARS-CoV-2 infections in pregnancy.^83
–85 The current recommendations from the World Health Organization, Centers for Disease Control and Prevention, the Society for Maternal-Fetal Medicine, and the ACOG recommend the COVID-19 vaccine for pregnant persons.^86
–88 Four COVID-19 vaccines (1. Pfizer Inc., New York, NY, USA & BioNTech SE, Mainz, Germany; 2. Moderna, Inc., Cambridge, MA, USA; 3. Johnsen and Johnsen Services, Inc., New Brunswick, NJ, USA; 4. University of Oxford, Oxford, UK & AstraZeneca, Cambridge, UK) have published data regarding their use in pregnant persons. This research has shown that pregnant individuals mount a robust maternal antibody response post-vaccination.^28,89 However, studies have found that significant waning in antibodies occurs when vaccinated during the third trimester, but antibodies increase again after a booster dose further into the pregnancy.^28,89 In the USA, COVID-19 vaccination is currently recommended at any time during pregnancy.^87,88 COVID-19 vaccine has also been shown to be beneficial for newborns with maternal immunization, decreasing the risk of hospitalization due to COVID-19 illness in infants in the first 6 months of life.⁹⁰

Pregnant individuals are at increased risk of respiratory virus infection. Although much of the available research has been conducted on Influenza, RSV, and SARS-CoV-2, there is some research present regarding other respiratory viruses during pregnancy, such as parainfluenza, metapneumovirus, parvovirus B19 (Fifth Disease), and bocavirus. A study investigated the prevalence of symptomatic respiratory viruses during pregnancy in 2556 women between 2014 and 2017 and identified 17 cases of parainfluenza and four cases of human metapneumovirus.⁹¹ Although parainfluenza normally produces symptomatic illness in young children, there have been documented cases of adverse fetal outcomes, including fetal ventriculomegaly and hydrocephalus.^92,93 Another study was conducted to determine the incidence of human metapneumovirus among pregnant individuals and found that 17.2% tested positive.^93,94 In addition, a study performed in Nepal investigating birth outcomes associated with human metapneumovirus infection during pregnancy found that human metapneumovirus infection during pregnancy was associated with an increased risk of having a small for gestational age newborn, but no increased risk of premature birth or significant differences in birth weight.^93,95 Parvovirus B19 has been estimated to infect 1%–5% of pregnant women but can infect between 3% and 20% during epidemics.^96
–98 In most cases, infection with B19 has no impact on pregnancy outcomes.⁹⁶ However, as gestation continues, the likelihood of fetal anemia, non-immune hydrops, and mortality due to maternal infection increases.⁹⁶ Rhinovirus is a common pathogen that infects pregnant persons and causes symptomatic respiratory illness, with one study estimating that 27% of their cohort was infected at some point during pregnancy.⁹ One study conducted in Nepal, consisting of 3693 pregnant individuals, found that pregnant persons infected with rhinovirus during pregnancy were more likely to deliver low birthweight babies.⁹⁹ Although rhinovirus seems to pose little risk of severe maternal and fetal outcomes, one study did find that infants born to mothers with documented rhinovirus infections during pregnancy were more likely to experience wheezing at 12 months old.¹⁰⁰ Although active bocavirus infection is rarely detected in healthy adults due to prior long-lasting immunity from infections in early life, there have been a small number of bocavirus infections documented in pregnant individuals.¹⁰¹ Because bocavirus is rarely detected in adults, the clinical implications for pregnant persons and their infants are still unclear. However, there have been case studies in which fetal demise has been documented in pregnant women with bocavirus infections. In addition, bocavirus has been detected in human placental tissues from aborted pregnancies.¹⁰² There is little information available on the pathogenesis of these viruses in pregnant persons, and no vaccines or clinical treatments are available for pregnant individuals.

Conclusion

In this work, we have summarized the burden, pathogenesis, clinical outcomes, and treatment of influenza, RSV, SARS-CoV-2, parainfluenza, human metapneumovirus, parvovirus B19 (fifth disease), rhinovirus, and bocavirus during pregnancy. Our study is not without limits, as it only relies on previously published findings, which can be inconsistent or inaccurate. However, we feel confident in our assessment of the existing literature and feel that we have accurately summarized the available information. As interest in respiratory viruses increases, due to the COVID-19 pandemic and the development of new vaccines, significant knowledge gaps on the impact of respiratory virus infections and vaccines in pregnancy are becoming more apparent.¹⁰³ More research is necessary to properly understand the nuances of respiratory virus infections during pregnancy to better protect these individuals from these potentially dangerous pathogens. Unfortunately, research studies that comprise pregnant individuals and their infants are disproportionately underfunded compared to other high-risk groups. However, the studies that have been conducted have allowed researchers to develop safe and effective respiratory virus vaccines, as is the case with the RSV and Influenza vaccines. These promising developments highlight the need for more resources to be devoted to maternal and reproductive health research. Future discoveries can help us better prevent respiratory virus infections and aid in the application of new treatment methods.

Footnotes

Author contributions

Kalee E. Rumfelt: conceptualization; resources; writing-original draft; writing—review and editing; visualization. Janet A. Englund: conceptualization; resources; writing—review and editing. Alisa Kachikis: conceptualization; resources; writing—review and editing; supervision; project administration; funding administration.

ORCID iDs

Kalee E. Rumfelt

Alisa Kachikis

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by an NIAID K23 AI153390 grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors do not have competing interests to disclose related to this publication. Outside of this work, A.K. was an unpaid consultant for Pfizer and GlaxoSmithKline and is a co-investigator on studies funded by Merck and Pfizer. J.A.E. also receives grant support to her institution from Merck, GlaxoSmithKline, AstraZeneca, and Pfizer, and is a consultant for AbbVie, Ark Biopharma, AstraZeneca, GlaxoSmithKline, Moderna, Pfizer, Sanofi Pasteur, and Meissa Vaccines, Inc. outside of the described work.

References

Azziz-Baumgartner

Grohskopf

Patel

Realizing the potential of maternal influenza vaccination. JAMA 2021; 325(22): 2257–2259.

Englund

Chu

HY.

Respiratory virus infection during pregnancy: does it matter?. J Infect Dis 2018; 218(4): 512–515.

Auriti

De Rose

Santisi

, et al. Pregnancy and viral infections: mechanisms of fetal damage, diagnosis and prevention of neonatal adverse outcomes from cytomegalovirus to SARS-CoV-2 and Zika virus. Biochim Biophys Acta Mol Basis Dis 2021; 1867(10): 166198.

Takeda

Hisano

Komano

, et al. Influenza vaccination during pregnancy and its usefulness to mothers and their young infants. J Infect Chemother 2015; 21(4): 238–246.

Mor

Aldo

Alvero

AB.

The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017; 17(8): 469–482.

Shi

McAllister

O’Brien

, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390(10098): 946–958.

Paget

Spreeuwenberg

Charu

, et al. Global mortality associated with seasonal influenza epidemics: new burden estimates and predictors from the GLaMOR Project. J Glob Health 2019; 9(2): 020421.

UNICEF UNCF. COVID-19 confirmed cases and deaths, https://data.unicef.org/resources/covid-19-confirmed-cases-and-deaths-dashboard/ (accessed 24 April 2025).

Hause

Avadhanula

Maccato

, et al. A Cross-sectional surveillance study of the frequency and etiology of acute respiratory illness among pregnant women. J Infect Dis 2018; 218(4): 528–535.

10.

Cosma

Borella

Carosso

, et al. The “scar” of a pandemic: cumulative incidence of COVID-19 during the first trimester of pregnancy. J Med Virol 2021; 93(1): 537–540.

11.

Chen

Liu

Goraya

, et al. Host immune response to influenza A virus infection. Front Immunol 2018; 9: 320.

12.

Goodrum

LA.

Pneumonia in pregnancy. Semin Perinatol 1997; 21(4): 276–283.

13.

Mor

Cardenas

Abrahams

, et al. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 2011; 1221(1): 80–87.

14.

Silasi

Cardenas

Kwon

, et al. Viral infections during pregnancy. Am J Reprod Immunol 2015; 73(3): 199–213.

15.

Romero

Espinoza

Gonçalves

, et al. The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25(1): 21–39.

16.

Elovitz

Mrinalini

Animal models of preterm birth. Trends Endocrinol Metab 2004; 15(10): 479–487.

17.

Wilcox

Holder

Jones

CE.

Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy. Front Immunol 2017; 8: 1294.

18.

Halasa

Olson

Staat

, et al. Maternal vaccination and risk of hospitalization for Covid-19 among infants. N Engl J Med 2022; 387(2): 109–119.

19.

Sahni

Olson

Halasa

, et al. Maternal vaccine effectiveness against influenza-associated hospitalizations and emergency department visits in infants. JAMA Pediatr 2024; 178(2): 176–184.

20.

Kampmann

Madhi

Munjal

, et al. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med 2023; 388(16): 1451–1464.

21.

Malek

Sager

Kuhn

, et al. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol 1996; 36(5): 248–255.

22.

Wang

Chen

, et al. Transplacental transfer efficiency of maternal antibodies against influenza A(H1N1)pdm09 virus and dynamics of naturally acquired antibodies in Chinese children: a longitudinal, paired mother-neonate cohort study. Lancet Microbe 2023; 4(11): e893–e902.

23.

Anderson

Dormitzer

Nokes

, et al. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine 2013; 31(Suppl 2): B209–B215.

24.

Kachikis

Eckert

Englund

Who’s the target: mother or baby?. Viral Immunol 2018; 31(2): 184–194.

25.

van den Berg

Westerbeek

EAM

Smits

, et al. Lower transplacental antibody transport for measles, mumps, rubella and varicella zoster in very preterm infants. PLoS One 2014; 9(4): e94714.

26.

Okoko

Wesumperuma

Fern

, et al. The transplacental transfer of IgG subclasses: influence of prematurity and low birthweight in the Gambian population. Ann Trop Paediatr 2002; 22(4): 325–332.

27.

Jennewein

Goldfarb

Dolatshahi

, et al. Fc glycan-mediated regulation of placental antibody transfer. Cell 2019; 178(1): 202–215.e14.

28.

Kachikis

Pike

Eckert

, et al. Timing of maternal COVID-19 vaccine and antibody concentrations in infants born preterm. JAMA Netw Open 2024; 7(1): e2352387.

29.

Goodnight

Soper

DE.

Pneumonia in pregnancy. Crit Care Med 2005; 33(Suppl 10): S390–S397.

30.

Nam

Ison

MG.

Respiratory syncytial virus infection in adults. BMJ 2019; 366: l5021.

31.

Jain

Sami-Zakhari

. Pulmonary complications of obstetric and gynecologic conditions. Pulm Complications of Non-Pulmonary Pediatric Disorders 2017; 24: 139–61.

32.

Meijer

van Noortwijk

AGA

Bruinse

, et al. Influenza virus infection in pregnancy: a review. Acta Obstet Gynecol Scand 2015; 94(8): 797–819.

33.

Delahoy

Whitaker

O’Halloran

, et al. Characteristics and maternal and birth outcomes of hospitalized pregnant women with laboratory-confirmed COVID-19—COVID-NET, 13 states, March 1–August 22, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(38): 1347–1354.

34.

Moza

Duica

Antoniadis

, et al. Outcome of newborns with confirmed or possible SARS-CoV-2 vertical infection—a scoping review. Diagnostics 2023; 13(2): 245.

35.

Frey

Klebanoff

MA.

The epidemiology, etiology, and costs of preterm birth. Semin Fetal Neonatal Med 2016; 21(2): 68–73.

36.

Dreier

Andersen

AMN

Berg-Beckhoff

Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics 2014; 133(3): e674–e688.

37.

Manti

Cuppari

Lanzafame

, et al. Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress. Pediatr Pulmonol 2017; 52(10): E81–E84.

38.

Lucot-Royer

Nallet

Vouga

, et al. Analysis of the transplacental transmission of SARS CoV-2 virus and antibody transfer according to the gestational age at maternal infection. Sci Rep 2024; 14(1): 3458.

39.

Simões

Silva

Leal

CRV

. Is SARS-CoV-2 vertically transmitted? Front Pediatr 2020; 8: 276.

40.

Katz

Gessner

Johnson

, et al. Incidence of influenza virus infection among pregnant women: a systematic review. BMC Pregnancy Childbirth 2017; 17(1): 155.

41.

Darling

Federspiel

Wein

, et al. Morbidity of late-season influenza during pregnancy. Am J Obstet Gynecol MFM 2022; 4(1): 100487.

42.

Holstein

Dawood

O’Halloran

, et al. Characteristics and outcomes of hospitalized pregnant women with influenza, 2010 to 2019: a repeated cross-sectional study. Ann Intern Med 2022; 175(2): 149–158.

43.

Hilleman

MR.

Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002; 20(25–26): 3068–3087.

44.

Influenza in pregnancy: prevention and treatment: ACOG committee statement no. 7. Obstet Gynecol 2024; 143(2): e24–e30.

45.

Beigi

Venkataramanan

Caritis

SN.

Oseltamivir for influenza in pregnancy. Semin Perinatol 2014; 38(8): 503–507.

46.

Centers for Disease Control (CDC). Summary: prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2023–24, https://stacks.cdc.gov/view/cdc/137358 (accessed 24 April 2025).

47.

Quach

THT

Mallis

Cordero

JF.

Influenza vaccine efficacy and effectiveness in pregnant women: systematic review and meta-analysis. Matern Child Health J 2020; 24(2): 229–240.

48.

Fiore

Bridges

Cox

NJ.

Seasonal influenza vaccines. Curr Top Microbiol Immunol 2009; 333: 43–82.

49.

Albrecht

Pagenkemper

Wiessner

, et al. Infant immunity against viral infections is advanced by the placenta-dependent vertical transfer of maternal antibodies. Vaccine 2022; 40(11): 1563–1571.

50.

Zhong

Haltalli

Holder

, et al. The impact of timing of maternal influenza immunization on infant antibody levels at birth. Clin Exp Immunol 2019; 195(2): 139–152.

51.

Reicherz

Abu-Raya

, et al. Waning immunity against respiratory syncytial virus during the coronavirus disease 2019 pandemic. J Infect Dis 2022; 226(12): 2064–2068.

52.

Obando-Pacheco

Justicia-Grande

Rivero-Calle

, et al. Respiratory syncytial virus seasonality: a global overview. J Infect Dis 2018; 217(9): 1356–1364.

53.

Kenmoe

Chu

Dawood

, et al. Burden of respiratory syncytial virus-associated acute respiratory infections during pregnancy. J Infect Dis 2024; 229(Suppl 1): S51–S60.

54.

Anderson

Hierholzer

Tsou

, et al. Antigenic characterization of respiratory syncytial virus strains with monoclonal antibodies. J Infect Dis 1985; 151(4): 626–633.

55.

Collins

Melero

JA.

Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res 2011; 162(1–2): 80–99.

56.

Falsey

Singh

Walsh

EE.

Serum antibody decay in adults following natural respiratory syncytial virus infection. J Med Virol 2006; 78(11): 1493–1497.

57.

Hall

Walsh

Long

, et al. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis 1991; 163(4): 693–698.

58.

Walsh

Falsey

AR.

Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults. J Infect Dis 2004; 190(2): 373–378.

59.

Broadbent

Groves

Shields

, et al. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses 2015; 9(4): 169–178.

60.

American Academy of Pediatrics Committee on infectious diseases: use of ribavirin in the treatment of respiratory syncytial virus infection. Pediatrics 1993; 92(3): 501–504.

61.

Sinclair

Jones

Miller

, et al. Final results from the ribavirin pregnancy registry, 2004–2020. Birth Defects Res 2022; 114(20): 1376–1391.

62.

Federal Drug Administration. FDA approves first vaccine for pregnant individuals to prevent RSV in infants, https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-pregnant-individuals-prevent-rsv-infants (accessed 24 April 2025).

63.

The American College of Obstetricians and Gynecologists (ACOG). Maternal respiratory syncytial virus vaccination, https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/09/maternal-respiratory-syncytial-virus-vaccination (accessed 24 April 2025).

64.

Balbi

Nirsevimab: a review. Pediatr Allergy Immunol Pulmonol 2024; 37(1): 3–6.

65.

Moline

Tannis

Toepfer

, et al. Early estimate of nirsevimab effectiveness for prevention of respiratory syncytial virus-associated hospitalization among infants entering their first respiratory syncytial virus season—New Vaccine Surveillance Network, October 2023–February 2024. MMWR Morb Mortal Wkly Rep 2024; 73(9): 209–214.

66.

Centers for Disease Control (CDC). Trends in United States COVID-19 hospitalizations, deaths, emergency department (ED) visits, and test positivity by geographic area, https://covid.cdc.gov/covid-data-tracker/#trends_weeklyhospitaladmissions_testpositivity_00 (accessed 24 April 2025).

67.

Khalil

Kalafat

Benlioglu

, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinicalMedicine 2020; 25: 100446.

68.

McClymont

Albert

Alton

, et al. Association of SARS-CoV-2 infection during pregnancy with maternal and perinatal outcomes. JAMA 2022; 327(20): 1983–1991.

69.

Zambrano

Ellington

Strid

, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(44): 1641–1647.

70.

Vlachodimitropoulou Koumoutsea

Vivanti

Shehata

, et al. COVID-19 and acute coagulopathy in pregnancy. J Thromb Haemost 2020; 18(7): 1648–1652.

71.

Ramsey

Ramin

KD.

Pneumonia in pregnancy. Obstet Gynecol Clin North Am 2001; 28(3): 553–569.

72.

Papageorghiou

Deruelle

Gunier

, et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol 2021; 225(3): 289.e1–289.e17.

73.

Mullins

Perry

Banerjee

, et al. Pregnancy and neonatal outcomes of COVID-19: the PAN-COVID study. Eur J Obstet Gynecol Reprod Biol 2022; 276: 161–167.

74.

Verma

Carter

Mysorekar

IU.

SARS-CoV2 and pregnancy: an invisible enemy?

Am J Reprod Immunol 2020; 84(5): e13308.

75.

Garcia-Ruiz

Sulleiro

Serrano

, et al. Congenital infection of SARS-CoV-2 in live-born neonates: a population-based descriptive study. Clin Microbiol Infect 2021; 27(10): 1521.e1–1521.e5.

76.

National Institutes of Health (NIH). Anti-SARS-CoV-2 monoclonal antibodies, https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ (accessed 31 December 2024).

77.

Society for Maternal Fetal Medicine. COVID-19 outpatient treatment for pregnant patients, https://assets.noviams.com/novi-file-uploads/smfm/Clinical_Guidance/COVID_Resources/COVID_treatment_table_6-21-22__final_.pdf (accessed 24 April 2025).

78.

Kachikis

Englund

Singleton

, et al. Short-term reactions among pregnant and lactating individuals in the first wave of the COVID-19 vaccine rollout. JAMA Netw Open 2021; 4(8): e2121310.

79.

Shimabukuro

Kim

Myers

, et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N Engl J Med 2021; 384(24): 2273–2282.

80.

Carbone

Trinchillo

Di Girolamo

, et al. COVID-19 vaccine and pregnancy outcomes: a systematic review and meta-analysis. Int J Gynaecol Obstet 2022; 159(3): 651–661.

81.

Lipkind

Vazquez-Benitez

DeSilva

, et al. Receipt of COVID-19 vaccine during pregnancy and preterm or small-for-gestational-age at birth—Eight Integrated Health Care Organizations, United States, December 15, 2020–July 22, 2021. MMWR Morb Mortal Wkly Rep 2022; 71(1): 26–30.

82.

Magnus

Örtqvist

Dahlqwist

, et al. Association of SARS-CoV-2 vaccination during pregnancy with pregnancy outcomes. JAMA 2022; 327(15): 1469–1477.

83.

Stock

Carruthers

Calvert

, et al. SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland. Nat Med 2022; 28(3): 504–512.

84.

Villar

Ariff

Gunier

, et al. Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID multinational cohort study. JAMA Pediatr 2021; 175(8): 817–826.

85.

Barros

Gunier

Rego

, et al. Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study. Am J Obstet Gynecol 2024; 231(4): e1–e16.

86.

Centers for Disease Control (CDC). COVID-19 vaccines while pregnant or breastfeeding, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html#:~:text=CDC%20and%20professional%20medical%20organizations,at%20any%20point%20in%20pregnancy (accessed 24 April 2025).

87.

The American College of Obstetricians and Gynecologists (ACOG). COVID-19 vaccines and pregnancy: conversation guide, https://www.acog.org/covid-19/covid-19-vaccines-and-pregnancy-conversation-guide-for-clinicians (accessed 24 April 2025).

88.

Society for Maternal Fetal Medicine. COVID-19 vaccination in pregnancy, https://assets.noviams.com/novi-file-uploads/smfm/Clinical_Guidance/COVID_Resources/SMFM_COVID_Vaccine_2023.pdf (accessed 24 April 2025).

89.

Yang

Murphy

Singh

, et al. Association of Gestational Age at Coronavirus Disease 2019 (COVID-19) vaccination, history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and a vaccine booster dose with maternal and umbilical cord antibody levels at delivery. Obstet Gynecol 2022; 139(3): 373–380.

90.

Halasa

Olson

Staat

, et al. Effectiveness of maternal vaccination with mRNA COVID-19 vaccine during pregnancy against COVID-19-associated hospitalization in infants aged <6 months—17 states, July 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022; 71(7): 264–270.

91.

Azziz-Baumgartner

Veguilla

Calvo

, et al. Incidence of influenza and other respiratory viruses among pregnant women: a multi-country, multiyear cohort. Int J Gynaecol Obstet 2022; 158(2): 359–367.

92.

Seidman

Nass

Mendelson

, et al. Prenatal ultrasonographic diagnosis of fetal hydrocephalus due to infection with parainfluenza virus type 3. Ultrasound Obstet Gynecol 1996; 7(1): 52–54.

93.

Schwartz

Dhaliwal

. Infections in pregnancy with Covid-19 and other respiratory RNA virus diseases are rarely, if ever, transmitted to the fetus: experiences with coronaviruses, HPIV, hMPV RSV, and influenza. Arch Pathol Lab Med 2020; 144(8): 920–928.

94.

Murphy

Powell

Wark

PAB

, et al. A prospective study of respiratory viral infection in pregnant women with and without asthma. Chest 2013; 144(2): 420–427.

95.

Lenahan

Englund

Katz

, et al. Human metapneumovirus and other respiratory viral infections during pregnancy and birth, Nepal. Emerg Infect Dis 2017; 23(8): 1341–1349.

96.

Gigi

Anumba

DOC

. Parvovirus b19 infection in pregnancy—a review. Eur J Obstet Gynecol Reprod Biol 2021; 264: 358–362.

97.

Crane

and Society of Obstetricians and Gynaecologists of Canada. Parvovirus B19 infection in pregnancy. J Obstet Gynaecol Can 2002; 24(9): 727–743; quiz 744–746.

98.

Tolfvenstam

Broliden

Parvovirus B19 infection. Semin Fetal Neonatal Med 2009; 14(4): 218–221.

99.

Philpott

Englund

Katz

, et al. Febrile rhinovirus illness during pregnancy is associated with low birth weight in Nepal. Open Forum Infect Dis 2017; 4(2): ofx073.

100.

Murphy

Mattes

Powell

, et al. Respiratory viral infections in pregnant women with asthma are associated with wheezing in the first 12 months of life. Pediatr Allergy Immunol 2014; 25(2): 151–158.

101.

Al Bishawi

Ben Abid

Ibrahim

. Bocavirus infection in a young pregnant woman: a case report and literature review. Am J Case Rep 2021; 22: e928099.

102.

Hansen

Brockmann

Schildgen

, et al. Human bocavirus is detected in human placenta and aborted tissues. Influenza Other Respir Viruses 2019; 13(1): 106–109.

103.

Marchant

Sadarangani

Garand

, et al. Maternal immunisation: collaborating with mother nature. Lancet Infect Dis 2017; 17(7): e197–e208.