The evidence that Covid-19 vaccines are safe and effective in pregnancy is growing

But Covid-19 vaccine rollout to the pregnant population has been inconsistent around the globe.

For months, the US and many national medical groups — including the American College of Obstetrics and Gynecology, the Society for Maternal-Fetal Medicine, and the Academy of Breastfeeding Medicine — say the vaccine should be offered to this group, in large part because there’s strong evidence that pregnancy elevates the risk for severe Covid-19 and death. (Given this data, the American Society for Reproductive Medicine goes so far as to say the vaccine is “recommended” for those who are pregnant or considering pregnancy.)

“If a pregnant patient gets infected during pregnancy, her risk of intensive care admission is around 5 percent,” says David Baud, chief of obstetrics at Le Centre hospitalier universitaire vaudois in Switzerland, where he studies infections during pregnancy. “I do not know of any disease that put a 30-year-old woman at such high risk to be admitted to the ICU.” Furthermore, if the infection happens late in pregnancy, it increases the risk of preterm birth and the baby needing intensive care.

Israel went as far as adding pregnant women to its vaccine priority list in January. But other countries, such as the UK and Germany, and the World Health Organization are still saying most people who are pregnant should wait.

Why the disagreement? The clinical trials of the new Covid-19 vaccines explicitly excluded pregnant people, and we don’t yet have enough follow-up data from individuals who have opted to get the shots to say for sure they are safe for everyone during pregnancy.

Add to this muddled landscape the persistent misinformation swirling around the Covid-19 vaccines and pregnancy and fertility, and it is little wonder some people are still confused or worried. And most organizations still stop short of advising all pregnant people to definitely get the vaccine.

Thankfully, these information gaps are starting to fill in. Numerous studies are underway following the outcomes of pregnant and breastfeeding people and their offspring after immunization. And a handful of them are now starting to report early, reassuring results.

In the meantime, however, a growing number of people have had to come to their own decision, with the optional help of their care provider, with some uncertainty. And no one needs an extra thing to stress about during a pandemic pregnancy.

So more information about the coronavirus vaccines in pregnancy can’t come soon enough.

4 reasons the coronavirus vaccine should be okay to get while pregnant — but why not everyone is recommending it yet

One of the big reasons why, despite Covid-19’s known risks in pregnancy, not everyone has unequivocally recommended the vaccines that currently have emergency approval in the US for pregnant people is that the way they work is fairly new. But we do have some key pieces of information already:

1) These vaccines don’t contain live coronavirus. The only types of vaccines that are contraindicated in pregnancy contain live virus that has been weakened, such as the chickenpox vaccine. (Even fewer immunizations, such as the smallpox vaccine, are not recommended during lactation.) While these vaccines don’t pose a risk to most people, there is a small, theoretical chance they could cross the placenta and infect the fetus.

The Pfizer/BioNTech and Moderna vaccines, on the other hand, contain just a fragment of genetic material, called messenger RNA, that can tell human cells to build a tiny part of the virus’s outer shell, which the immune system learns to recognize and fight off. The Johnson & Johnson vaccine uses a different method, known as a viral vector (the same platform as the already-used Zika and Ebola vaccines), to get the body to build part of the virus’s shell.

In either case, there is no way the vaccine can cause a Covid-19 infection.

2) The main coronavirus vaccines are very fragile. Once the mRNA enters the body, it likely only reaches local arm muscle cells before the body breaks it down. This means it is unlikely to enter the bloodstream, and even less likely to make it as far as the placenta. Even if it does get that far, “one of the placenta’s main functions is to be an immune barrier to the fetus,” which adds another layer of protection, says Gaw. And although it contains genetic material, it doesn’t enter our cells’ nuclei, meaning that it can’t cause any mutations to our cells — or those of a developing fetus. This mRNA is so fragile, vaccine developers had to wrap it in nanolipids (which are also presumed to be safe for pregnancy) just to keep it intact long enough to reach muscle cells in the arm.

Experts also expect it is unlikely for the mRNA to make its way intact into breast milk. Preliminary research from Gaw and her team, which is in the process of being peer-reviewed, found no trace of the vaccine itself in breast milk samples from hours and days post-vaccination. And even if a small amount of it were to be transferred to a feeding baby, researchers say it (and any lipid nanoparticles) would get broken down by the baby’s stomach acids.

3) Animal studies look promising. Before any shots were given to pregnant humans, vaccine companies gathered safety data in other pregnant mammals. None of these developmental and reproductive toxicity (DART) studies from Pfizer/BioNTech, Moderna, or Johnson & Johnson suggest any safety concerns for use during pregnancy.

Rats, of course, are not humans, and DART study results do not always translate identically into humans. “Some results are similar to humans, and some are very different,“ Gaw says. Nevertheless, they are a good starting point — when combined with strong safety data in the clinical trials and public vaccinations so far.

4) We haven’t seen adverse events in pregnant people who have gotten it so far. For the Covid-19 vaccine trials, those of “childbearing potential” were screened for pregnancy before each shot, and those with positive tests were removed from the studies. However, a handful of people (12 who got the vaccine in Pfizer/BioNTech’s study and six who got the vaccine in Moderna’s study) ended up having been pregnant at the time of vaccination — and companies haven’t reported any negative outcomes from these individuals.

A newer and much larger data set is emerging from the Centers for Disease Control and Prevention, which is following pregnant people who sign up for its tracking platform V-safe after being vaccinated — and allowing them to sign up for a more targeted pregnancy-specific vaccine registry.

At the beginning of March, the CDC reported data from more than 1,800 pregnant people in the registry who had received Covid-19 vaccines. Among these individuals, there was not a statistically significant increase in adverse pregnancy or birth outcomes. Nor have they found any significant differences in side effects from the vaccine (such as fatigue or fever).

“From a scientific perspective, there’s no specific reason to think that pregnant individuals would have more adverse reactions to the vaccine or that there would be a risk to the fetus with the vaccine, while we know that there is risk with the Covid infection,” says Alisa Kachikis, an assistant professor of obstetrics and gynecology at the University of Washington.

A January study published in JAMA Internal Medicine, for example, analyzed the outcomes of more than 406,000 people who gave birth in hospitals between April and November 2020 and found that a significantly higher rate of those with Covid-19 had major complications. “The higher rates of preterm birth, preeclampsia, thrombotic [blood clotting] events, and death in women giving birth with Covid-19 highlight the need for strategies to minimize risk,” noted the authors.

So why are some, such as the WHO and the UK, still saying most pregnant people should not get the coronavirus vaccine yet? They are waiting for more data.

There are also, of course, other types of coronavirus vaccines in the works, such as protein-based vaccines (which is the basis for Novavax’s shots). This model of shot has been used for years — including for pertussis and hepatitis B — “and we are very comfortable with [their] safety profile,” Gaw says. Viral vector vaccines (which is how the Johnson & Johnson and AstraZeneca/Oxford shots work) have also been used safely in pregnancy, such as for the Ebola and Zika vaccines, although there is less historical data on these.

So, says Kachikis, if what’s hanging people up about getting a Covid-19 vaccine in pregnancy is mostly the novelty of the mRNA vaccines, having other types to choose from — as long as they’re just as effective — could be a good option.

What studies are happening, and what will they help us learn about the Covid-19 vaccine in pregnancy?

The CDC continues to monitor for any adverse outcomes and side effects through its V-safe program — and related pregnancy registry (which will check in with participants in each trimester, after delivery, and when the baby is 3 months old).

Pfizer/BioNTech started giving vaccine doses in their pregnancy-focused, placebo-controlled clinical trial this February. They are first running a smaller safety study of just 350 healthy pregnant participants before scaling up to give the vaccine to a total of about 4,000 people who are at between 24 and 34 weeks gestation. (This study design, however, will still leave some questions about the safety and efficacy of the vaccine, especially earlier in pregnancy.)

Moderna has created a registry that people can sign up for after receiving their vaccine while pregnant. For its part, Johnson & Johnson plans to conduct trials of its vaccine in pregnant participants later (likely after it studies the vaccine in children).

In the meantime, other researchers are racing to collect and study data from the natural experiment that started in December, when many pregnant people began electing to get vaccines as they became eligible because of their high-risk work in hospitals or long-term care centers.

At the University of Washington, Kachikis is leading a study to also follow vaccination in people who are pregnant. Thousands of people from around the US and the world who have received the vaccine while pregnant have already signed up for the registry, she says. (People who are pregnant or lactating but have not yet gotten vaccinated can also sign up, as can people who are considering becoming pregnant within the next two years.) This research will help them track any adverse outcomes, as well as gather additional data, such as whether any vaccinated individuals (or their newborns) later get Covid-19.

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An additional large-scale clinical trial, which has not started enrolling participants, aims to track 5,000 women and their offspring over the course of 21 months. Other smaller studies are in the works as well, such as one at Duke University.

At UCSF, Gaw and her team are in the midst of separate observational studies. They will more closely follow a smaller group of participants — 100 or so of whom are pregnant and roughly 50 of whom are lactating — “to determine whether the Covid vaccines are equally effective in pregnant and lactating women, how long antibody responses last, and whether immunity is transferred to the baby,” Gaw explains.

Other vaccines are routinely given in pregnancy, such as pertussis, in large part to provide protective antibodies to the fetus and protect the newborn until they are old enough to get the vaccine themselves.

Covid-19 antibodies have been shown to transfer across the placenta in women who were positive for the virus at delivery. The new AJOG study found that even higher levels of antibodies were present in the umbilical cord after Covid-19 vaccination than after natural infection. “The research shows really promising results,” Kachikis says.

If these antibodies prove to be protective, it could be especially helpful, as newborns and infants will likely be among the last to have an authorized vaccine — and have the highest rates for complications and death from the virus among children. “There is still a lot of data that needs to be assessed, but for individuals who are thinking of ways that the vaccine may benefit their newborn, this is really encouraging,” Kachikis says.

More nuanced research might also eventually help advise on optimal timing for the Covid-19 vaccine during pregnancy. For example, Gaw notes, “there needs to be sufficient time for the mom to develop a robust antibody response, and then pass [this] to the baby.” After extensive research, the Tdap vaccine is recommended around 27 weeks of gestation so as to provide the best protection for the infant after birth. Without such information for the Covid-19 vaccine, many experts are recommending that those who decide to get the shot treat it like the flu shot — getting it as soon as it’s available to them, regardless of where they are in their pregnancy.

People who are lactating were also excluded from the vaccine trials. So researchers at a number of institutions are now working to study how the vaccine might impact breast milk contents and a nursing child. A study from October 2020 showed that most people who had recovered from Covid-19, as well as those suspected of being infected, passed on antibodies to the virus in their breast milk.

The recently released AJOG paper found a high level of antibodies in breast milk from women who had received the Covid-19 vaccine. Gaw’s team also has new findings, which are currently in peer review, that show a solid dose of Covid-19 antibodies in breast milk samples after vaccination. This, they hope, will provide some protection from the virus for babies.

“It’s all reassuring,” Gaw says. But “all the studies have been small…[so] we can’t 100 percent determine safety until a lot more people have been vaccinated and it’s been reported on.”

Wait, why weren’t pregnant people included in the early research to begin with?

Pregnancy has, for decades, been considered a “vulnerable” condition when it comes to researching new medical treatments and preventions, meaning people who are pregnant have been excluded from general trials in much the same way as have those who are unable to give informed consent, like children and those with severe mental disabilities.

Part of the reason for this might be due to the damaging legacy of thalidomide. This drug was given to pregnant women around the world starting in the 1950s as a way to ease nausea (although it was never approved specifically for use in pregnancy in the US). Soon, thousands of these babies were being born with devastating birth defects. This hammered home for scientists and the public that, when it comes to pregnant women and their fetuses, much more care ought to be taken in giving medications or vaccines.

But this conclusion, many are now saying, has it backward, as the oft-repeated phrase indicates: Protect pregnant people “through research, not from research.” If thalidomide had been carefully and systematically studied for pregnancy, it likely never would have been approved for use (or used unofficially) in this population, preventing the majority of these tragic outcomes.

“It can’t be emphasized enough that pregnant women should be included in vaccine trials from the get-go,” Kachikis says.

Gaw agrees: “We actually cause harm by not including [pregnant people] in early research, as they have to wait longer for good data to be published.”

So when will we have more data about the coronavirus vaccine in pregnancy and lactation?

One big challenge with researching anything to do with pregnancy is that it takes a long time: nine months, plus follow-up time to monitor infant outcomes. And subsequent study during lactation while you’re at it, and maybe preconception research, too.

Consider that it took vaccine makers just 10 months to develop the Covid-19 vaccines and ensure they were safe and effective in adults. But with formal studies in pregnant people just getting underway (and with many having not yet started, and others, like Pfizer’s, currently limited to late pregnancy), it could be late 2021 or beyond until we have comprehensive, robust safety data for all stages of pregnancy. And even later to assess long-term outcomes for babies.

Follow-up to the early work Gaw and colleagues are doing at UCSF will take “at least six to nine months, as we have to wait for a sufficient number of babies to deliver,” Gaw says.

Kachikis and her team at the University of Washington plan to follow the outcomes of people who sign up for their list for about a year, with hopes to continue more long-term follow-up. For example, they plan to test babies months after birth to see how long antibodies from vaccines given during gestation persist — and if these antibodies are equally as effective at fighting off the coronavirus as those found in the vaccinated adults.

But they aren’t waiting that long to start sharing what they learn. “The focus is on getting any data out,” Kachikis says. And “if multiple groups can get some data out, that will be better than having absolutely nothing,” which has been the situation, she notes.

For now, much of the official guidance in the US stresses the need for people to conduct their own analysis of the known increased risks of Covid-19 in pregnancy with the remaining unknowns of the vaccine. And this calculus is not the same for everyone.

“As more evidence is coming out, it’s tilting to more benefit of getting the vaccine,” Gaw says. “But every individual has a different level of risk they’re willing to take” — as well as the amount of risk they might have of contracting the virus or getting extremely sick from it. The bottom line, based on the latest Covid-19 vaccine research in pregnancy, she says, is that “it’s looking more and more like it does work, it does pass antibodies to the baby (although we don’t know yet how protective they are), and there doesn’t look like there’s any harm at this moment.”

Additionally, even those who are reluctant to advocate the vaccine for all pregnant people just yet, such as the WHO, do suggest it should be available to those at high risk of exposure to the virus or underlying health conditions that increase their risk of severe Covid-19.

And some might elect to wait until there is more solid data. So to help move along the plodding process, people who are pregnant and have gotten the vaccine — or are considering it — can contribute to getting more and better guidance sooner by opting in to registries and studies.

Katherine Harmon Courage is a freelance science journalist and author of Cultured and and Octopus! Find her on Twitter at @KHCourage.