As each of the FDA-authorized COVID-19 vaccines became available, the Centers for Disease Control and Prevention consistently asserted that they should not be withheld from people who are pregnant and want the vaccine. But since all the clinical trials excluded people who were pregnant, no safety data was available for those who had to make that choice.
Now, since tens of thousands of people have chosen to get vaccinated while pregnant, the largest retrospective study yet provides strong evidence of the mRNA vaccines’ safety during pregnancy. The findings come soon after research confirmed the seriousness of COVID-19 during pregnancy, including an increased risk of preterm birth and stillbirth. Two other studies have also shown that vaccinated mothers pass more protective SARS-CoV-2 antibodies on to their newborns than mothers who had COVID-19 while pregnant.
The safety study, published April 21 in the New England Journal of Medicine, relied on multiple vaccine surveillance systems from December to February to assess the safety of the Pfizer/BioNTech and Moderna vaccines in more than 35,000 pregnant women. The study found no increased risks during pregnancy or birth complications or identifiable risks to the fetus among those who received the vaccine. When CDC Director Rochelle Walensky highlighted the findings at an April 23 briefing, she seemed to suggest the agency was updating their official recommendations for this population.
“As such, CDC recommends that pregnant people receive the COVID-19 vaccine,” Walensky said. “We know that this is a deeply personal decision, and I encourage people to talk to their doctors or primary care providers to determine what is best for them and for their baby.”
Protecting mothers is the priority with COVID-19 vaccination because of the risk the disease poses in pregnancy. An April 22 study in JAMA Pediatrics found a greater risk of preterm birth, preeclampsia (a dangerous high blood pressure condition in pregnancy), admission to the ICU, and death in pregnant women with COVID-19 compared to pregnant women without an infection. Both mothers and newborns were more likely to have severe complications of any kind in pregnancies with COVID-19. Even asymptomatic women had a higher risk of preeclampsia and maternal complications. Similarly, a recent meta-analysis of studies involving more than 430,000 pregnant people found that COVID-19 during pregnancy doubled the risk of stillbirth as well as raised the risk of preeclampsia and preterm birth.
Walensky’s comments initially caused confusion when it was widely reported after the briefing that the CDC was changing its guidance to recommend COVID-19 vaccination in pregnant people. CDC vaccine recommendations come from the Advisory Committee on Immunization Practices (ACIP), which had not announced any changes to guidance for mRNA vaccines during pregnancy, and guidelines on the CDC website have not changed.
The CDC did not respond to a request for comment by press time, but CBS News reported that the agency had partly clarified Walenksy’s statement, specifying that Walensky “was conveying that CDC recommends pregnant people be offered the vaccine.”
“The CDC is trying to balance allowing pregnant women, because they’re at risk, to have access to the vaccine,” Carol Baker, a professor of pediatrics at UTHealth in Houston, says. “The CDC is trying to give wiggle room for the whole conversation about risk-benefit.”
The new study offers the best news yet for those considering the vaccine while pregnant, says Linda Eckert, a professor of obstetrics and gynecology at the University of Washington School of Medicine in Seattle.
“I’m very happy to see this data coming in and that the safety data so far are reassuring,” Eckert says. “We haven’t seen any increased risk of adverse pregnancy outcomes in women who are immunized with the COVID vaccine compared to those who are not.”
Baby receives protective antibodies
A subset of nearly 4,000 participants in the study enrolled in the v-safe pregnancy registry—designed to track adverse events in vaccine recipients after their shots—including 29 percent in their first trimester, 44 percent in their second trimester, and 25 percent in their third trimester. Among the 827 in this group who completed their pregnancy, 86 percent had a live birth. Nearly all of the 14 percent who had a pregnancy loss (92 percent) were in their first trimester. That is consistent with numbers during non-pandemic times, according to the study, when 10 to 26 percent of all first-trimester pregnancies result in miscarriage.
Rates of preterm birth (9 percent), infants underweight for their week of delivery (3 percent), and birth defects (2 percent) in the vaccinated cohort were in the same range as those seen in pre-pandemic pregnancy research.
The most common side effects women experienced were pain at the injection site, fatigue, headache, and muscle aches. Less than one percent of participants had a fever of at least 100°F after the first dose and less than 8 percent had one after the second dose. Overall, pregnant women experienced more arm pain but less systemic reactions than similarly aged women who were not pregnant.
A week after that study’s publication, a pair of studies in Obstetrics & Gynecology found that infants receive substantially more antibodies against SARS-CoV-2 from mothers who received an mRNA vaccine during pregnancy than from mothers who had a COVID-19 infection during pregnancy. This research reaffirms findings in March that found a stronger immune response from mRNA vaccines than from COVID-19 in pregnant women and detected maternal antibodies in breastmilk and in newborns’ umbilical cord blood, which indicates the infants’ antibody levels.
“That there’s good transplacental antibody transfer is not surprising,” Ruth Karron, a professor of international health and director of the Center for Immunization Research at Johns Hopkins Bloomberg School of Public Health, says. “It’s consistent with what we see with other pathogens, and it’s a potential additional benefit of the immunization of pregnant women.”
Starting around the second trimester and then ramping up in the third is “a mechanism for shoveling antibodies from the maternal side to the fetal side of the placenta,” Karron says. That’s true for most of a subset of the mother’s antibodies known as IgG, but antibodies against proteins—such as the coronavirus spike protein—transfer especially efficiently, Baker adds.
There is strong evidence that SARS-CoV-2 maternal antibodies, induced by vaccines, transfer to the fetus. This antibody transfer is also true for the pertussis (Tdap) and annual influenza vaccines, both of which are recommended during pregnancy. The goal of pertussis vaccination, recommended between weeks 27 and 36 of pregnancy, is to protect infants in their first few months against whooping cough, whereas the flu shot is intended to protect the mother as well as the baby, Karron says.
Vaccine trials in pregnant participants “paradigm-changing”
COVID-19’s threat during pregnancy is what led vaccine manufacturers to begin trials in pregnant women, says Sandra Hurtado, an obstetrician/gynecologist with McGovern Medical School at UTHealth in Houston, and the principal investigator for the Pfizer/BioNTech clinical trial site there.
Pfizer is recruiting people between 24 and 34 weeks of pregnancy for the international phase two and three placebo-controlled trial that will enroll 351 participants for phase two and 3,660 participants for phase three. The trial focuses on safety and testing antibody levels in participants, in their newborns at birth, and in the infants at six months old. Johnson & Johnson has plans for a trial in pregnant women, but Moderna has not announced plans.
The Pfizer/BioNTech trial includes 83 locations in the U.S., but the trial only started in February. Since the vaccine has been available to pregnant people for several weeks or longer, recruitment is a challenge.
“The women who want the vaccine are going to go ahead and get vaccinated, and the women who don’t want the vaccine are waiting to be vaccinated later or won’t be vaccinated at all, so it’s difficult to enroll patients,” Hurtado says.
Since the trial is focused more on safety than on effectiveness, and since restricting people from getting a vaccine in a pandemic would be unethical, participants will be unblinded one month after delivery and offered the vaccine if they received the placebo, she says.
Experts, including Karron, have called for trials in pregnant women for months, but testing vaccines during pregnancy has always been contentious, says Baker. Until the 2009-2010 H1N1 influenza pandemic, when the danger of H1N1 to pregnant women and their need for immunization became clear, such trials were almost unheard of.
“There was a real interest at that time to make sure in any future pandemic we would enroll pregnant women in those studies,” says Kevin Ault, professor of obstetrics and gynecology at the University of Kansas Medical Center. “The problem we had this time is it wasn’t clear for the first six to eight months while those studies were being designed that pregnant women were at increased risk [from COVID-19].”
That data emerged in fall, when the trials were well underway. “Had we known that right off the bat, we might have designed things differently,” Ault says.
The fact that trials are occurring even now is “paradigm-changing,” Baker says. “I’m very personally and professionally pleased that the concept of immunizing pregnant women to protect themselves and their young infants from vaccine preventable disease has leapt forward by great bounds,” she says. “I think this will change the way we go forward.”
Questions remain regarding J&J vaccine
Despite the safety data now available for mRNA vaccines, the equivalent data isn’t yet available for the Johnson & Johnson vaccine. Experts are split on what that means since the discovery that the vaccine can, in extremely rare cases, cause blood clots. Unlike the mRNA vaccines, which consist of mRNA encapsulated within a lipid droplet, the J&J vaccine uses a deactivated adenovirus as a vector to carry DNA into the body. Scientists suspect the adenovirus vector may be what triggers the rare blood clot reaction in some people.
Eckert noted that the clots associated with the J&J vaccine differ from the type of clots that people have a higher risk of developing during pregnancy. That said, the risk is only about 7 clots per million doses in women aged 18-49, per a CDC clinical update. Eckert doesn’t explicitly advise against the J&J vaccine and says some of her patients prefer the single shot.
Ault wants to see more data before recommending one vaccine over another. Karron, however, has argued that women under 50 should preferentially receive mRNA vaccines because we lack data on clot risk from the J&J vaccine during pregnancy. Baker agrees, noting that some healthy women without risk factors nevertheless develop clots during pregnancy.
“It’s rare, but I would avoid vaccines that have even a rare complication of thrombi [blood clots] of any kind just because pregnancy is a thrombus-risk time,” Baker says. She also thinks waiting to get vaccinated until late in the second trimester or early in the third is ideal because it’s at the beginning of viability, when all fetal organs are fully formed. It is also when the greatest antibody transfer from mother to the fetus occurs. Further, the third trimester is when the most severe COVID-19 complications are likely in pregnant people, Karron adds.
Ault and Eckert do not make any recommendations about getting the vaccine during a particular trimester. When they bring up the vaccine to patients, they ask what the patient thinks about the vaccines and whether they can answer any questions or offer information to the patient. Both have seen the full spectrum of hesitancy to enthusiasm about the vaccines and have lately seen vaccine confidence rising. Eckert says she shares with patients her opinion that the benefits outweigh the risks and her concerns about the dangers of COVID-19 during pregnancy but doesn’t pressure patients.
“I stop short of saying you should absolutely get it,” Eckert says, “but I come very close.”