Pregnancy is a natural suppressor of the immune system, increasing gestating women’s susceptibility to infectious diseases, especially those that affect cardiopulmonary functions.

Influenza viruses like H1N1, SARS and MERS having been known to cause severe complications during pregnancy, with SARS and MERS having registered a 25 percent and 18 percent fatality rate among pregnant women, respectively.

One U.K. rapid review of 21 studies showed SARS and MERS were more deadly than COVID-19. Another study found that SARS-CoV-2 infection in pregnancy is not associated with adverse pregnancy outcomes. As compared to influenza, however, COVID-19 outcomes were worse.

Those findings, however, had been called premature since at the time of the study, no pregnant patients with COVID-19 had yet died. But on April 15, an otherwise healthy mother delivered a child successfully, but later died from COVID-19 complications. And by November, an analysis of approximately 400,000 women aged 15–44 years with symptomatic COVID-19, intensive care unit admission, invasive ventilation, extracorporeal membrane oxygenation, and death were more likely in pregnant women than in nonpregnant women. A study in November confirmed this, after finding women with severe or critical COVID-19 had increased composite morbidity, compared to non-pregnant matched controls. By March 2021, it was clear: in global maternal and fetal outcomes have worsened during the pandemic, with an increase in maternal deaths, stillbirth, ruptured ectopic pregnancies, and maternal depression. Some outcomes show considerable disparity between high-resource and low-resource settings. Indeed, neonates who were perinatally exposed to SARS-CoV-2 can sustain adverse health outcomes both directly, as evidenced by higher test result positivity rates when born to socially vulnerable mothers, and indirectly, given the sequelae of preterm birth.  (An April 2021 multinational cohort study confirmed these findings, concluding that for pregnant women, COVID-19 was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications than for women without COVID-19.)

Pregnant women may be hospitalized at a greater frequency (31.5 percent) than non-pregnant women of reproductive age (5.8 percent). To be noted, pregnant women who are Latino or Black might be even more affected, as may be women of older age and those with underlying medical conditions. Curiously a March 2021 study found that for women who gave birth in New York City during the COVID-19 pandemic, no evidence was found for increased racial/ethnic disparities in pre-term births among women who tested positive or tested negative for SARS-CoV-2. This, however, does not indicate equality and rather, confirms systemic inequality. Black infants were – before and during the pandemic – more like to be born preterm and twice as likely to be born very preterm than their white counterparts.

Pregnant women who become COVID‐19‐positive are usually either asymptomatic or mild‐to‐moderately symptomatic, similar to non‐pregnant women. (But while the overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to non-infected women, but symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.) Pneumonia is one of the most common outcomes in pregnant women with COVID‐19. Additionally, among 598 hospitalized pregnant women with COVID-19, severe illness occurred among symptomatic pregnant women, including intensive care unit admissions (16 percent), mechanical ventilation (8 percent), and death (1 percent). Pregnancy losses occurred for 2 percent of pregnancies completed during COVID-19-associated hospitalizations and were experienced by both symptomatic and asymptomatic women. In pregnancies complicated by COVID-19 infection, the rate of perinatal death was about four percent, mainly related to prematurity.

Previously, a study in two New York hospitals of 43 pregnant COVID-19 patients found similar rates of serious illness in pregnant and nonpregnant adults. Yet another study, conducted in the state of Washington, found that the COVID-19 hospitalization and case fatality rate in pregnant patients was significantly higher than in similarly aged adults. Indeed, a May 2021 study found that COVID-19 was associated with increased risk for: acute respiratory distress syndrome, death, sepsis, mechanical ventilation, shock, intensive care unit admission, acute renal failure, thromboembolic disease, adverse cardiac event/outcome and preterm labor with preterm delivery. In contrast, a May study conducted found no differences in the overall risk of preterm, stillbirth, or other perinatal outcomes during the first six months of the COVID-19 pandemic.

An earlier review of 21 articles confirmed there were no differences in clinical characteristics of pregnant and non-pregnant women with COVID-19. The exception was for pregnant women with pre-existing comorbidities, high maternal age, and high body mass index, who were at higher risk for severe covid-19. SARS-CoV-2 test positivity was also associated with a higher prevalence of preeclampsia and lower prevalence of induction of labor. Implementation of COVID-19 mitigation measures, however, was associated with a substantial reduction in the incidence of preterm births.

Additionally, a review of 538 pregnant COVID-19 patients showed that even though maternal mortality and vertical transmission rates were less than one percent (including among newborns rooming-in and direct breastfeeding from mothers with acute COVID-19), preterm birth and cesarean delivery rates were high for women with COVID-19. There are, however, recommended breastfeeding guidelines for mothers with COVID-19. (It has been reported, however, that despite guidelines, 17.9 percent of hospitals reported that in-person lactation support had decreased.)

A July study confirmed these findings, stating pregnant women (especially Latin-American women who are obese) tend to deliver via cesarean section and have higher rates of premature delivery, due to fetal distress. A review conducted in Brazil, specifically, found that for COVID-19 patients, premature births, maternal death, intrauterine fetal death or neonatal death, cases of intrauterine fetal distress, miscarriage, decreased fetal movements, and severe neonatal asphyxia were the most frequent. In developing countries with limited access to care, the increase in stillbirths born to mothers with COVID-19 might include reduced intrapartum care and delay in transport, particularly as neonatal mortality has increased, despite fewer admissions (suggesting less overcrowding and reduced health-care worker to patient ratio). 

And an August study confirmed that vertical transmission of SARS-CoV-2 has occurred only in a small minority of cases of maternal COVID-19 infection in the third trimester, with rates of infection are being similar to that of other pathogens that cause congenital infections. (One study contests this, stating the cause of pre-term delivery - fetal exposure to maternal inflammation or cytokine storm - may be what causes complications for neonates.) However, because SARS-CoV-2 has been detected in the amniotic fluid, cord blood and placentas of infected women, there exists a theoretical risk of infection during pregnancy or delivery. Pathological examinations, for example, have found SARS-CoV-2 is in the outermost layer of placental villi, suggesting that but for the presence of a placental barrier, there could be potential intrauterine transmission of SARS-CoV-2. One study found that placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. However, placenta from COVID-patients has also shown inflammatory, thrombotic, and vascular changes that have been found in other inflammatory conditions, suggesting the inflammatory nature of SARS‐CoV‐2 infection could cause adverse obstetric and neonatal effects.

Outcomes after maternal SARS-CoV-2 infection have not been well-described. In a prospective U.S. registry of 263 infants born to mothers testing positive or negative for COVID-19, status was not associated with birth weight, difficulty breathing, apnea or upper or lower respiratory infection through 8 weeks of age. A Scandinavian study showed that there was no difference in either head circumference, abdominal circumference, femur length and estimated fetal weight z‐scores between pregnancies complicated and those not complicated by SARS‐CoV‐2 infection both at the second and third trimester scan. By April 2021, another study in Scandinavia found that maternal SARS-CoV-2 infection in pregnancy was significantly associated with small increases in the absolute risk of respiratory disorders and some other neonatal morbidities.

A review of 49 studies (of 666 neonates and 655 women) found that neonatal COVID-19 infection is uncommon (newborns are very rarely infected and if infected, only show mild symptoms), with the rate of infection no greater whether the baby is born vaginally, breastfed or allowed contact with the mother, indicating caesarean sections, strict isolation and formula feeding are not necessarily needed to prevent transmission from mother to child. For those same reasons, a prospective cohort study in the U.K. also supported international guidance to avoid separation of mother and baby. One study found that of 116 positive mothers delivering neonates, 100 percent did not test positive for COVID-19. Another study found that among 91 tested neonates, 8.8 percent were positive for nucleic acids or SARS-CoV-2 antibodies, and 26.7 percent were symptomatic. And another study found that while rare, transplacental transmission of SARS-CoV-2 is possible (particularly at the end of gestation) and that neonatal manifestations, including the incidence of being asymptomatic, are similar to those in adults. So, while the risk is still small, all symptomatic neonates born to infected mothers should receive tests for SARS-CoV-2 to initiate appropriate treatment and quarantine.

There is currently no evidence showing COVID-19 can be transmitted through breastmilk. (In one study, after two samples where spiked with replication-competent SARS-CoV-2 DNA, viral RNA or culturable virus were not detected). In another, 76 percent of the milk samples collected from women with COVID-19 contained SARS-CoV-2-specific IgA, and 80 percent had SARS-CoV-2-specific IgG. In addition, 62 percent of the milk samples were able to neutralize SARS-CoV-2 infectivity in vitro, whereas milk samples collected prior to the COVID-19 pandemic were unable to do so. This indicates that mother-to-infant transmission of the virus via milk is unlikely. There are, however, recommendations to prevent respiratory transmission from mother to child, including having uninfected caregivers bottle feed babies.

In another study, newborns of SARS-CoV-2–positive mothers born in Israel during a three-month period all tested negative for the virus post-delivery. A total 74.5 percent of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40 percent of the households, there were additional SARS-CoV-2–positive residents. A total of 85 percent of the newborns were breastfed post-discharge. Results for all 60 percent of the newborns retested for SARS-CoV-2 post discharge were negative.

Even though the risk of intrauterine transmission has not been established, adverse effects on the fetus (related to prenatal infection ) may still be experienced due to COVID-19. Effectively, one study of found that six percent of its volunteers had detectable IgG and/or IgM antibodies at delivery, with 87 percent of infants having detectable IgG antibodies at birth, with high anti-spike IgG levels in sera and saliva. (To other studies found significant secretion of SARS-CoV-2 specific IgA and IgG in human milk and plasma after SARS-CoV-2 vaccination). The transplacental transfer during pregnancy ratio was more than 1.0, and there was a positive correlation between maternal and infant antibody titers. Indeed, one study found a robust maternal neutralizing and anti-receptor-binding domain IgG response after SARS-CoV-2 infection, even if there was a lower-than-expected efficiency of transplacental antibody transfer and a significant reduction in neutralization between maternal blood and cord blood. Furthermore, SARS-CoV-2 antibody levels in pregnant mothers were correlated with presence of maternal symptoms and passive immunity in neonates. Indeed, one study found that maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than two months before delivery and that maternally-derived passive immunity may protect infants up to six months of life.

Because gestating women are often excluded from clinical trials – for safety reasons – drugs used for treating COVID-19 patients are often not advised for treating pregnant COVID-19 ones. Still, practical implications of some drugs have been examined, with pregnant patients in mind, to help mitigate the effects of COVID-19 on this population. Meantime, a paper called for testing standards for pregnant women be reconsidered – stating the only way to prioritize the interests of pregnant women is to enable them to make autonomous, informed decisions about participating in trials.

A letter to the editor of Pediatric Research echoed that call, and also asked researchers and review boards to be transparent about why they exclude pregnant women and children from their trials.) Another letter called for the creation of systems designed to help model profiles of transmission, diagnosis, treatment, and prevention in pregnant women, to better understand the outcome of COVID-19 on both mothers and their infants, with outcomes covering those with and without infections, as both will bear the burdens of altered health services, psychosocial stress, and economic downturn. And finally, another letter calls for vaccine testing in pregnant women to close the gaps in knowledge that prevent the public health community from understanding the effects on this population.

As vaccines began rolling out, it was found that the available mRNA vaccines generated robust humoral immunity in pregnant and lactating women, without obvious safety signals more so than natural infection (mRNA COVID-19 vaccines in pregnant women lead to maternal antibody production as early as five days after the first vaccination dose, and passive immunity to the neonate as early as 16 days after the first vaccination dose.) The American College of Obstetricians and Gyncologists called for pregnant women, especially women who are at increased risk of COVID hospitalization, admission to the ICU, intubation or mechanical ventilation, or death, be vaccinated. (This would put many in the first phases of vaccination groups). Another called for vaccinating women who are pregnant, especially in the cases where benefits are expected to outweigh risks, as most vaccines – including the SARS-CoV-2 vaccines – are allowed during pregnancy (the exception being MMR).

Another study found that throughout pregnancy, the neutralizing antibody titer remained stable, while a significant decline in the non-neutralizing antibodies was observed after 16 weeks of gestation, indicating vaccine in pregnancy should be considered in selected women to avoid reinfection. (This was slightly contradicted by another study that found vaccine-specific titers were comparable, but slightly lower, between pregnant and lactating women, compared to non-pregnant controls. Among pregnant women, higher antibody titers and functions were found in those vaccinated with the Moderna vaccine.) COVID-19 vaccination during pregnancy was also not associated with increased pregnancy or delivery complications.

That consideration could be informed by data on accidental pregnancies that occurred during vaccine trials, or outcomes in pregnant people who have opted to take the vaccine. Finally, one study showed that because antibodies from vaccines have been found in breastmilk (and in maternal cord blood) maternal vaccination may lead to SARS-CoV-2 specific immunoglobulins that could serve as protection for infants. Effectively, one study of maternal and cord blood sera from patients who received the BNT162b2 vaccine fond that all were positive for anti S- and anti-RBD-specific IgG. Cord blood antibody concentrations were correlated to maternal levels and to time since vaccination. Another study found that vaccination in pregnancy induces a robust maternal immune response, with transplacental antibody transfer detectable in cord blood as early as 16 days after the first dose, indicating antenatal SARS-CoV-2 vaccination may provide maternal and neonatal protection. (One May study confirmed this, finding mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Another study that took place in Israel found that vaccinated mothers and mothers with previous infection generated and transferred protective IgG antibodies across the placenta. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.)

Vaccine acceptance in pregnant women, however, varies not only by country but by perception of vaccine safety and effectiveness – and in the U.S., is lowest among minority pregnant women, for the same reasons. A study of 16 countries found that given a 90 percent COVID-19 vaccine efficacy, 52 percent of pregnant women indicated an intention to receive the vaccine, compared to the 69.2 of pregnant women who indicated an intention to vaccinate their children. Vaccine acceptance was generally highest in India, the Philippines, and all sampled countries in Latin America. It was lowest in Russia, the United States and Australia, with the strongest predictors of vaccine acceptance being confidence in the vaccine’s safety, worries about COVID-19, the belief in the importance of vaccines in their own country, mask compliance and trust in public health and vaccination in general.

COVID-19 in pregnant women is also not exempt from health equity indicators. A study in New York showed that transmission of the virus in pregnant women is also impacted by socioeconomic factors, with those residing in neighborhoods with high unemployment rates and larger households having been more affected than those residing in neighborhoods with higher median incomes and smaller households. Another study showed that minority pregnant women tended to be less depressed and anxious during the lockdowns. While this is a positive finding, its likely reasons are rooted in systemic inequity. First, they are consistent with an increasing body of research showing minority women living in low socioeconomic status are exposed to high levels of stress on a daily basis and, as such, have developed greater resilience to crisis. Second, the very factors that tend to be stress-causing in low-income households (childcare, limited partner and family support, reduced time flexibility secondary to formal and informal employment obligations) may have been ameliorated by forced lockdowns – even though they illustrate the glaring inequalities faced by lower-income women.

It should be noted that health equity indicators in other countries also show minority pregnant women being adversely affected by COVID-19. In the U.K., a study found that more than 50 percent of all pregnant women admitted to the hospital with COVID-19 are of ethnic minority (even as they only make up 25 percent of all births).

Finally, clinically significant posttraumatic stress, anxiety/depression, and loneliness are highly prevalent in pregnant and postpartum women across 64 countries during the COVID-19 pandemic.

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