As the initial priority groups are being offered a COVID-19 vaccine in the U.S., one population in particular faces a difficult decision: Pregnant people who are health care personnel or essential workers—categories that are eligible for the early phases of the vaccination program—“may choose to be vaccinated,” according to the latest official guidance from the Centers for Disease Control and Prevention. The problem is that there are scant data available on the safety of COVID-19 vaccines in pregnant individuals. They were not included in the clinical trials, as has historically been the case with most vaccines and drugs.
“We’ve put pregnant women between a rock and a hard place,” says Melanie Maykin, a maternal-fetal medicine fellow at the University of Hawaii at Manoa. She belongs to a committee at the Society for Maternal-Fetal Medicine that advocates for equitable care during pregnancy.In a recent study, Maykin and her colleagues noted that an evaluation last spring had found all nine global COVID-19 vaccine trials at the time listed pregnancy as an explicit exclusion criterion.
Epidemiologist David Schwartz, a specialist in global maternal health and obstetric, placental and perinatal pathology, says the tradition of not including those who are pregnant or lactating in vaccine development is partially attributable to the biological changes they undergo. “You’re dealing with a tremendously altered human being,” he says. “The maternal cardiovascular system is different, as well as the hemodynamics, the immunology and the pharmacodynamics.” Also, vaccines and drugs can potentially pass through the placenta, and it is very hard to assess their effects on the fetus. From a legal perspective, there are medical liability issues as well.
Pregnant people are often classified as a “vulnerable population,” Maykin notes, and there is a strong historical reason for this. In the past, women of color and low-income women have, at times, been submitted to clinical trials without proper informed consent. Acts of exploitation included the initial birth control pill tests, which used high doses that were found to have harmful side effects. “However, the solution is not to exclude [pregnant trial participants],” Maykin says, “but rather to intentionally and justly include them, especially women of color and [those who are] low-income, as stakeholders in decisions around drug and vaccine development.”
What We Know So Far about Safety
Despite the reluctance to include pregnant individuals in clinical trials, this population still gets vaccines, and their safety has been closely monitored. “In general, vaccines seem quite safe in pregnant women,” says Sonja Rasmussen, a professor in the departments of pediatrics and epidemiology at the University of Florida. Flu shots that do not involve a weakened live virus and the tetanus, diphtheria and whooping cough vaccine (called Tdap), for example, are not only considered safe but are actively recommended during pregnancy.
The latest review on the safety of the flu shot during pregnancy, conducted by the CDC, analyzed all of the 671 reports related to influenza vaccine and pregnancy in the Vaccine Adverse Event Reporting System (VAERS) from 2010 to 2016. Although conditions such as spontaneous abortion and major birth defects were reported, their prevalence in vaccinated pregnant individuals was similar to what occurs in the general population of pregnant people. This suggested that the flu shot was not associated with pregnancy problems. A recent systematic review focusing on the Tdap vaccine also concluded that, when administered during second and third trimesters, it was not associated with any clinically significant harm to the fetus.
Although these findings are reassuring, a direct extrapolation to COVID-19 vaccines should be avoided. “The challenge is that we don’t have a previous vaccine with the mRNA technology,” says Linda Eckert, a professor of obstetrics and gynecology at the University of Washington. Both of the two vaccines that have been approved in the U.S.—which were developed by Pfizer and BioNTech and Moderna, respectively—use this technology.
One general guiding principle for vaccination during pregnancy is that live-virus vaccines are not recommended because of a hypothetical risk to the fetus, Maykin says. Neither the Pfizer-BioNTech or Moderna vaccine contain a live virus. They work by introducing mRNA, which is a set of instructions for our cells to build a piece of protein found on the surface of SARS-CoV-2, the virus that causes COVID-19. Our immune system then develops a response against that protein, producing antibodies that can fight the actual virus. “When you think of the biologic plausibility that this set of instructions, this mRNA, could cause any harm to the pregnant woman or the fetus, it’s very unlikely because that mRNA gets degraded very quickly after the cell uses it to make the protein,” Maykin says.
Experts also emphasize that the mRNA vaccines cannot alter human DNA. “One of the rumors that we’re hearing is that this vaccine will mix with the fetal DNA, and that’s not true,” Eckert says. The mRNA never enters cells’ nucleus, which houses our DNA, and therefore cannot affect the genetic material of the pregnant individual or fetus.
Animal experiments carried out by Moderna also suggested that its vaccine had no adverse effect on reproduction or on the development of fetuses in female rats. Pregnancy-related animal data for the Pfizer-BioNTech vaccine also seem to point toward similar conclusions, Eckert says, citing a verbal statement made by the Food and Drug Administration in a recent meeting (although that information has not yet been published).
The Johnson & Johnson COVID-19 vaccine, whose phase III results were announced on Friday, is based on a distinct technology. It uses an adenovirus that has been genetically modified to be unable to cause illness as a vector. Like the Pfizer-BioNTech and Moderna vaccines, it was not tested in pregnant individuals.
Other vaccines developed by Johnson & Johnson that use the same adenovirus platform have been administered to a small number of people who happened to get pregnant around the time of the studies. But the data are not robust enough to draw any conclusions about its safety in this population. The company notes, however, that there is “no concerning pattern of [adverse events] in the pregnancies initiated around the time of vaccination.”
Animal studies done with an adenovirus vaccine against Ebola showed no maternal or fetal toxicity in female rabbits vaccinated during or immediately before pregnancy, according to Johnson & Johnson.
How COVID-19 Is Affecting Pregnant People
The absolute risk for developing severe COVID-19 during pregnancy is low. But compared with nonpregnant individuals, those who contract COVID-19 while pregnant are at increased risk of intensive care unit admission, invasive ventilation and death, according to U.S. data.
Additionally, several cases of SARS-CoV-2 infection have been reported in newborns. A recent systematic review analyzed 176 published cases, and in about 70 percent, the babies were probably infected after birth. In the other 30 percent, the virus is believed to have been transmitted by the pregnant individual, either during delivery or through the placenta. The latter scenario seems to be very rare, but cases have been documented.
Schwartz and his colleagues proposed a set of diagnostic criteria to determine which newborns were most likely to have been infected through the placenta before delivery. Together with a team of researchers from five countries, Schwartz identified a cohort of six live-born babies, as well as five cases of stillborn ones, who demonstrably acquired the infection when they were still in the womb. By analyzing these cases, the team identified two unusual placental abnormalities that seemed to occur in all the patients.
Though initial data from China in early 2020 seemed to suggest that the new coronavirus was not particularly harmful to pregnant people or their offspring, this perception changed as the disease spread and cases of severe pneumonia in pregnant people—as well as deaths among such individuals—were reported. “We realized that not only is this potentially life-threatening for a small percentage of pregnant women, but it seems to also be affecting the newborns,” Schwartz says.
One of the first documented cases of SARS-CoV-2 infecting the placenta was registered at Yale New Haven Hospital in March 2020. Infectious disease specialist Shelli Farhadian, who is an assistant professor at the Yale School of Medicine, and her colleagues reported the case of a woman in the second trimester of pregnancy who was admitted to a hospital with COVID-19 symptoms. She developed severe preeclampsia and lost the fetus. After getting the patient’s permission to check, the researchers found evidence of the virus in her placenta.
“She was one of the first cases, and we didn’t know how common this would end up being,” Farhadian says. Since then she and her team have systematically studied the placentas of COVID-19-positive patients admitted to the hospital at the time of delivery. In a new paper currently under review, they state that it is very rare to find evidence of SARS-CoV-2 infection of the placenta in full-term pregnancies. But people infected earlier in pregnancy have not been systematically studied, Farhadian notes.
Pregnancy’s Unique Immunologic State
For many years, it was believed that pregnancy was a state of immunologic weakness. The fact that pregnant individuals died more from diseases such as influenza was attributed to this state. More recently, it became clear that immunologic changes in pregnancy were much more complex than that. “They were not dying because they were immunosuppressed,” says Gil Mor, scientific director of the C. S. Mott Center for Human Growth and Development at Wayne State University. “They were dying because their immune system was so strong and activated that they produced a massive inflammation that killed them.”
Mor, who is an expert in the immunology of pregnancy, says there are several mechanisms to maintain the delicate balance between too much and too little inflammation during that state. If this balance is not maintained for any reason, the risk of severe COVID-19 symptoms rises.
The University of Florida’s Rasmussen notes that it is still not clear if the increased risk to severe disease during pregnancy is related to an altered immune system or to other changes typical of the state, such as occasional breathing difficulty.
Weighing Risks and Benefits
The American College of Obstetricians and Gynecologists (ACOG) recently published a practice advisory recommending that COVID-19 vaccines should be available for pregnant or lactating individuals who are part of the priority groups defined by the CDC’s Advisory Committee on Immunization Practices (ACIP). “What the ACOG really advocates for is for women to be able to make the decision for themselves and their fetus—that they have information so they can look at their particular circumstances and risks,” says Eckert, who is ACOG’s liaison on ACIP and helped develop the organization’s practice advisory.
“At this point, we are recommending that women talk with their health care providers and weigh the risks and the benefits,” Rasmussen says. For example, she adds, those who can work from home and avoid exposure may consider postponing vaccinations until after giving birth if their physician finds that appropriate. Frontline health care workers who are pregnant might consider getting the vaccine as soon as possible, however. Another variable to consider is the presence of other risk factors for COVID-19, such as cardiovascular or respiratory problems, which could weigh in favor of getting the vaccine promptly.
It is also unclear when it is best to be vaccinated during pregnancy. One known possible side effect of the authorized COVID-19 vaccines is fever, which is important to avoid during pregnancy—especially in the first trimester, when fever is associated with an increased risk of birth defects—Rasmussen says. Pregnant individuals vaccinated from the second trimester onward could potentially extend the protection to their developing child. In that stage, Mor says, the recipient is able to transfer antibodies through the placenta.
With so many variables and unknowns, experts acknowledge that this is a tough decision. “That’s why I think it’s important to have a trusted and reliable source of information, like your doctor, who is really staying abreast of the data and can help guide the decision-making,” Maykin says. “Understandably, women might be hesitant.”
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