Pregnancy-associated morbidity and mortality during pandemics: Looking to the past in order to prepare for the future

Abstract

Pregnant women are at high risk of adverse outcomes in the setting of viral-associated outbreaks and pandemics. In this forum, we discuss the impact of past and current pandemics on pregnant women and make recommendations to protect this vulnerable population.

The SARS-CoV-2 pandemic has highlighted the disproportionately harmful effects that infections can have on pregnant women. Studies from even the earliest stages of the pandemic have made it clear that pregnant women are at a significantly higher risk of developing severe COVID-19 that requires hospitalization and/or ventilation compared to non-pregnant women. Similarly, mortality rates of pregnant women in previous influenza pandemics are significantly higher than in non-pregnant women. For example, the 1918 influenza pandemic was associated with an ~25% mortality rate in pregnant women. However, while epidemiologic studies show that pregnant women have an increased risk of adverse outcomes from infections [reviewed in Kumar et al.¹], most studies describing the immune responses to these infections have excluded pregnant and/or lactating mothers. There are many factors that impact clinical outcomes in pregnant women, including physiological and immunological changes specific to pregnancy, stress, maternal vaccination, and access to treatment (Figure 1).

Figure 1. Improving maternal health pandemic response.

Lessons from previous pandemics have yielded strategies and protocols that should be implemented to improve maternal health during a future pandemic.

Pandemics have revealed vital public health lessons regarding protocols to protect from infection, established surveillance and management programs to monitor the spread of infection, and highlighted healthcare inequalities that prevent access to adequate treatments. All of these lessons have the potential to guide and improve responses to protect the general population during future pandemics. These insights also illustrate that prevention and treatment of pregnant women from future pandemics is vital and may require unique measures. The current pandemic has also underscored the need for comprehensive studies that evaluate the epidemiology and treatment of infections, particularly those of pandemic potential, in pregnant women. In this forum, we will detail some of the lessons learned during the current COVID-19 pandemic and address the shortcomings in research surrounding pregnant women to better prepare and protect this vulnerable population from the next pandemic or outbreak. Here, we use the term pregnant women because most studies that seek to investigate the implications of pandemic-causing viruses on pregnant people solely include pregnant individuals that identify as women.

Immune responses to viral infections during pregnancy

The disparate clinical outcomes resulting from viral infections of pregnant women are perhaps not surprising, given the significant immunological adaptations that occur during pregnancy. Pregnancy is a unique immunological state that has adapted to promote tolerance of the semi-allogenic fetus while also providing immune protection from infectious agents. These adaptations cause a range of distinct immunological responses to viral infections. Both previous influenza pandemics and the current SARS-CoV-2 pandemic have shed light on immune responses of pregnant women to viral infections that can be used to guide future research and pandemic preparedness plans.

Immunological and endocrinological changes likely contribute to the increased susceptibility and/or inability to clear infections during pregnancy. Comorbidities during pregnancy including obesity, metabolic diseases, and smoking history, and heart or respiratory diseases worsen these outcomes.² Pregnancy has come to be regarded as a heightened, rather than suppressed, state of immunity, and it is the enhanced capacity of the immune system in pregnancy to respond to viral infections that may be associated with the increased morbidity and mortality. Consistent with this, influenza virus infections in pregnant women elicit an increased chemokine and cytokine response compared to non-pregnant women [reviewed in Oseghale et al.³]. Similarly, influenza A-infected pregnant women exhibit enhanced cellular immune responses, characterized by enhanced expression of antiviral cytokines from T cells and NK cells, in comparison to lymphocytes from non-pregnant women.⁴ These elevated immune responses have been suggested to increase the risk of post-viral sequelae, suggesting that the unique immune state observed in pregnant women is directly linked to their increased risk of morbidity and mortality during viral infections. Moreover, it is important to note that immunological changes differentially occur over the three trimesters of pregnancy; therefore, disease outcomes can vary depending on gestational stage.

Few studies have investigated the immune responses associated with COVID-19 in pregnant women. In the few studies that have been performed, there were relatively small cohorts, which limits the applicability of some of these studies across the population. A recent study compared the responses of peripheral blood mononuclear cell (PBMC) from pregnant women and non-pregnant women to SARS-CoV-2 stimulation.⁵ This study revealed the differential immune responses to SARS-CoV-2 in pregnant and non-pregnant women, including decreased levels of cytokines such as IFN-β and IL-8. Although the mechanism(s) by which the differential responses might impact clinical outcomes is unclear, they may directly contribute to the clinical course in pregnant women with COVID-19.

Health disparities among pregnant women

As we prepare for future pandemics, we must first address the underlying health disparities that can exacerbate disease outcomes. Pandemics have negative effects on maternal health, but the severity of these outcomes can depend on underlying social and economic status. Pregnant women of color have disproportionately higher rates of COVID-19 and related mortality that can be attributed to socioeconomic, structural, and environmental conditions of health.⁶ The long-standing disparities that exist within disadvantaged communities prevent individuals in these communities from accessing proper treatments, and this is exacerbated during pandemics. These disparities are evident across the world, including the United States, which has the highest rates of maternal mortality of any developed country. In the U.S., Hispanic and Black pregnant women had SARS-CoV-2 seropositivity rates of 19.3% and 14.0%, respectively, compared to Asian and white women who had rates of 3.2% and 2.7%.⁷ It is clear from these studies and others that COVID-19 disproportionately affects select populations. Even as we continue to develop better treatments for pregnant women, there will remain unnecessary morbidity and mortality if implicit biases and inequalities in healthcare are not resolved. Implementing effective strategies to improve healthcare disparities will aid in decreasing the excess morbidity and mortality observed in these communities, particularly during pregnancy. For example, these strategies include restructuring the current health care infrastructure, establishing required implicit bias training programs for medical providers, and promoting diverse environments within health care settings.

We must also consider both the inability to pay and access treatment as a potential hurdle for seeking care among disadvantaged communities. There is an estimated 8%–39% increase in maternal deaths per month due to COVID-19 related resulting from inability to access prenatal care.⁸ In some cases, women must travel substantial distances to access maternity care, especially in rural areas globally. During a pandemic, this travel thus introduces new exposure risks for pregnant women, further compounding their already vulnerable states. Increasing clinics and other medical care facilities in rural areas reduces travel distance and will positively impact pregnant women’s ability to receive care while reducing their exposure to infectious diseases. Additionally, limited educational resources and knowledge surrounding efficient treatment and protection protocols can impact overall pandemic outcomes, which can unnecessarily harm pregnant women. Prenatal resources to educate about transmission and treatment should be uniformly implemented to prevent and protect pregnant women. By making the necessary resources attainable during pandemics (e.g., patient education and treatments), we will protect all communities from the detrimental effects of pandemics and other respiratory infection outbreaks.

Maternal immunization strategies

Given the significant risks associated with disease outbreaks in pregnant women, prioritizing this group for vaccination is critical to prepare for future pandemics. Vaccination during pregnancy also provides protection for the fetus via passive immunity that occurs due to transplacental antibody transport. Although the benefits of vaccination are clear, guidance has been inconsistent throughout the distribution of the COVID-19 mRNA vaccine with respect to pregnant women. Vaccine hesitancy in pregnant women has also been compounded by the lack of early data regarding vaccine safety and efficacy during pregnancy. The lack of early data regarding vaccine efficacy and safety in pregnant and lactating patients was primarily due to their exclusion during the development of the COVID-19 vaccine. As the pandemic has progressed, studies including pregnant women in COVID-19 vaccine trials were published; however, these data came over a year after the COVID-19 vaccine became available to the broader population.⁹ Ultimately, the lag of information serves as a deterrent for pregnant women when considering vaccination and clear guidelines and safety information should be communicated as early as possible during future pandemics.

There have been previous successes with vaccinations during pregnancy that have protected against morbidity and mortality. However, the optimal gestational timing of vaccination remains unclear, as does the question of whether there are differential responses to vaccination in pregnant and non-pregnant women. Influenza vaccines elicit similar responses in pregnant and non-pregnant women.¹⁰ However, the immunological responses to maternal immunization are ill defined, and efforts to better define these responses across gestation is critical to develop efficient vaccine strategies during pregnancy.

Efficacy and safety trials of vaccines often do not consider pregnant women, because pregnancy is an exclusion criterion in many of these clinical trials. By adjusting clinical trial criterion to allow the inclusion of pregnant women, we will not only allow these patients to make informed decisions regarding vaccination but also combat vaccine hesitancy. Additionally, given that some pathogens pose higher threats to pregnant women than others, minimal vaccine side effects may outweigh the detrimental effects of the pathogen. To ensure we are prepared for the next pandemic, it is crucial that pregnant individuals are considered in the development of treatments and vaccines.

There is also a need to increase vaccine availability. A decrease in COVID-19 vaccination rates in developing countries is largely due to lack of access. To achieve global immunity, vaccines must be produced at scale, priced affordably, distributed globally, and dispersed to all local communities.¹¹ Strategies must be established to increase manufacturing capacity of vaccines. Additionally, many countries that have limited access to vaccines do not have the resources to safely distribute vaccines, owing to a deficit of ultra-cold chains and programs that disperse vaccines to low-income communities. Implementing vaccination programs at schools, workplaces, and community landmarks may increase vaccine uptake. These vaccination programs should also prioritize education strategies, with educational resources made more widely available. Also, prioritizing vaccination in women who are preparing to conceive but are not yet pregnant may also enhance protection during pregnancy.

Platforms to study treatments during pregnancy

Current regulations exclude pregnant women from clinical trials, primarily due to ethical concerns that experimental drugs or treatments could result in teratogenic effects or induce pregnancy complications such as pre-term delivery. Harmful effects on the pregnant woman should also be considered and could include complications such as alterations in uterine function or immunological changes that induce loss of tolerance. It is critical to consider the teratogenic potential of all therapeutics that could be used in pregnancy and to develop systems to better model this phenomenon. Moreover, given the complex developmental changes that occur throughout gestation, modeling the impact of possible therapeutics across gestation should be prioritized.

While experimental models of pregnancy exist, many of these models are inadequate and inaccurately assess potential dangers to the mother and fetus. One platform that has emerged as a possible valuable in vitro model of therapeutic impacts in pregnancy is organoids, which recapitulate aspects of the cellular complexity of the human placenta. Of note, organoids derived from placental tissue can be used to investigate the implications of treatments on fetal- and maternal-derived tissues, such as the fetal membranes and placenta, or maternal tissues, including the uterus.^12,13 In addition to modeling the maternal-fetal interface, organoid-based platforms can also be applied to the study of possible teratogenicity. For example, cerebral organoids developed from iPSCs model the developing fetal brain in the first trimester and can thus be applied to studies of possible impacts of therapeutics on brain development. These cerebral organoids proved useful during the ZIKV outbreak and were used to define mechanisms by which the virus induced microcephaly. Organoids simultaneously retain the benefits of in vitro systems while continuing to capture genetic and clinical variability across humans. In the clinic, pregnant women present with comorbidities or pre-existing conditions, such as hypertension, diabetes, or cardiovascular disease, which may contribute to treatment efficacy or safety. Pregnant women with these conditions may thus have higher risks of developing more severe clinical outcomes. Due to the derivation of organoids from primary human tissue, organoids may have the capacity to retain phenotypes associated with these disorders and provide insights into potential complications prior to the implementation of treatments. Thus, these models will be critical for researchers when evaluating treatments suitable for pregnant women in vitro. However, these in vitro models are unable to recapitulate immunological responses during pregnancy, which remains a major hurdle to studies assessing differential immunity during pregnancy.

Pandemic preparedness

Over previous pandemics we have learned lessons that will aid in our efforts to be prepared for the inevitable future infectious threats. To prepare for future pandemics, we must survey our previous responses and identify any weaknesses that should be addressed. These weaknesses include the disproportionate impact of pandemics on vulnerable populations including pregnant women. Despite epidemiological evidence associating viral infections with adverse pregnancy outcomes including pre-term birth, this population has been historically overlooked when preparing for pandemics and addressing major health outbreaks. Conclusive studies must be conducted to establish clear regulations and guidelines for prevention and treatment during pregnancy. These studies should include evaluating infection outcomes during all stages of pregnancy, particularly given that complications have emerged during previous pandemics dependent on gestational stage.

At the beginning of the SARS-CoV-2 pandemic, there were very few treatments and management strategies that were approved for pregnant women; thus the focus was shifted to prevention strategies.¹⁴ Precautions such as limiting close contact with others, maintaining proper hand hygiene, disinfecting commonly used surfaces, and using a face mask have been recommended for pregnant women to limit exposure to infectious diseases that could cause future outbreaks. Ensuring that pregnant women do not become infected will contribute to the goal of protecting pregnant women during a pandemic. Prevention is the most effective strategy to decrease the impact of infectious diseases during pregnancy, particularly given the dearth of treatment options during pregnancy.

The management of COVID-19 disease has been similar between pregnant and non-pregnant women. The differences in treatment are mainly in diagnostic imaging due to the concern for fetal health. Many of the therapeutic treatments that are withheld from COVID-19-positive pregnant women are based on concerns for the fetus, but there have been no supporting studies that determine a significant threat to the development of the fetus.¹⁵ Management of infection should be based on the stage of pregnancy, comorbidities, and other conditions that can affect the outcome of the pregnancy. Therapies for COVID-19 infection in pregnant women should be continuously studied and developed based on current studies to guide future treatments during the pandemic.

Public health surveillance during infectious disease outbreaks includes reporting and monitoring cases, implementing preventative strategies, and interpreting data. Implementing clear surveillance protocols aids researchers and health protection agencies in determining necessary steps that should be taken to protect the health of the public. Specific guidelines for public health surveillance of pregnant women should be developed to monitor closely the impact of infectious disease outbreaks in this population, particularly in the early stages of such outbreaks. These guidelines should include educational resources that can be widely accessible to all communities. The widespread efforts of educating all populations will positively influence the ways that individuals know how to prevent, manage, and treat themselves during a pandemic. Furthermore, using surveillance strategies we can more accurately assess and predict the needs of all communities to influence the resources that should be given to individuals.

Pregnant women are at high risk of adverse outcomes in the setting of viral-associated outbreaks and pandemics. Future research that focuses on the physiological adaptations and immunological response throughout human pregnancy will define the mechanisms of increased disease severity observed in pregnant women.