Blood Is Hard to Draw While Pregnant

Science 's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Yalda Afshar hears the worries every day from her patients: Will COVID-19 hit me harder because I'm pregnant? If I'm infected, will the virus damage my baby? Afshar, a high-risk obstetrician at Ronald Reagan University of California (UC), Los Angeles, Medical Center, understands the women's concerns better than most: Her first child is due in October.

Data on pregnancy and COVID-19 are woefully incomplete. But they offer some reassurance: Fetal infections later in pregnancy appear to be rare, and experts are cautiously optimistic that the coronavirus won't warp early fetal development (see sidebar). But emerging data suggest some substance to the other worry of Afshar's patients: Pregnancy does appear to make women's bodies more vulnerable to severe COVID-19, the disease caused by SARS-CoV-2. That's partly because of pregnant women's uniquely adjusted immune systems, and partly because the coronavirus' points of attack—the lungs and the cardiovascular system—are already stressed in pregnancy.

The prescription for caregivers is simple, says David Baud, an expert on emerging infectious diseases and pregnancy at Lausanne University Hospital: "Protect your pregnant patients. The first ones who need the masks are pregnant women. The first to avoid social contact should be pregnant women."

The best U.S. data available so far were published by the Centers for Disease Control and Prevention (CDC) late in June. Among 91,412 women of reproductive age with coronavirus infections, the 8207 who were pregnant were 50% more likely to end up in intensive care units (ICUs) than their nonpregnant peers. Pregnant women were also 70% more likely to need ventilators, although they were no more likely to die.

CDC's data only offer a partial view, however. Pregnancy status was only available for 28% of the 326,000 U.S. women of reproductive age whose coronavirus infections had been reported to CDC by early June.

A second paper, published by the Public Health Agency of Sweden last month in Acta Obstetricia et Gynecologica Scandinavica, used a more complete data set. Using data for all of Sweden during 4 weeks in March and April, researchers calculated infected pregnant women's rate of ICU admission compared with that of infected, nonpregnant women of reproductive age. The study was small: Only 13 coronavirus-infected pregnant women and 40 nonpregnant infected women were admitted to Swedish ICUs in that time frame. But, Baud says, "From my point of view, it is the most robust data."

The results were sobering: The researchers found that pregnant or immediately postpartum women with COVID-19 were nearly six times as likely to land in ICUs as their nonpregnant, COVID-19–infected peers.

It's well known that pregnancy boosts the risk of serious disease from respiratory viral infections. During the H1N1 flu epidemic of 2009, pregnant women accounted for 5% of U.S. deaths, although they constituted about 1% of the population. One study found pregnant women with severe acute respiratory syndrome (SARS), which is caused by a virus that's a close cousin of SARS-CoV-2, were significantly more likely to be admitted to the ICU and to die than nonpregnant peers.

Viral infections can be more severe in pregnant women in part because "the entire immune system is geared toward making sure not to create any antifetal immune response," says Akiko Iwasaki, an immunologist at the Yale School of Medicine. "The mother has to compromise her own immune defense in order to preserve the baby's health."

At the same time, the immune system is far from inactive in pregnancy, and "the really significant immune response to the infection certainly has the potential to cause complications," says Carolyn Coyne, a virologist at the University of Pittsburgh.

These intense brown stains, made by antibodies to the new coronavirus, show it has invaded the placenta of an infant born with COVID19.

Vivanti et al., Nature Communications (2020) 11, 3572 CC-BY

In addition, SARS-CoV-2 strikes the lungs and the cardiovascular system, which in pregnancy are already strained. "As the uterus grows there is less and less room for the lungs. That's why pregnant women often feel short of breath. And that affects your pulmonary function," says Denise Jamieson, chair of obstetrics and gynecology at Emory University School of Medicine.

To supply the fetus, pregnant women also need extra oxygen and blood to ferry it: up to 50% more by late pregnancy. This may multiply the stress that COVID-19 has been shown to put on the cardiovascular system. "The heart is already working for two," Baud says. "And if you are a virus known to induce vessel change, inflammation, this will increase the workload of the heart even more."

Malavika Prabhu, a maternal and fetal medicine specialist at Weill Cornell Medicine, adds that later in pregnancy, "with so much blood going around and the organs more metabolically active, all that extra fluid can go in places it shouldn't go—including filling your lungs with fluid."

Finally, pregnant women's blood has an increased tendency to clot, thought to be due to their need to quickly staunch bleeding after delivering a baby. But the coronavirus itself can have a similar effect. "COVID is thought to increase your likelihood of clotting, and then pregnancy further increases your likelihood of clotting," Jamieson says.

Elevated dangers to the mother don't end with delivery, according to work by Prabhu and colleagues in the journal BJOG last month. They followed all 675 pregnant women admitted for delivery at three New York hospitals during 4 weeks in late March and April. After giving birth, nine of 70 infected women, or about 13%, had at least one of three complications that doctors watch for after delivery: fever, low blood oxygen, and hospital readmission. Among 605 noninfected women, 27, or 4.5%, had one of these problems. "Many diseases are unmasked in the postpartum period. We learned that COVID-19 is one of those," Prabhu says. She noted that 79% of the pregnant women who tested positive when admitted were asymptomatic.

Experts all say better data are desperately needed to understand and address the risks to pregnant, coronavirus-infected women. Jamieson notes that registries gathering data on pregnant women infected with H1N1 influenza in 2009 and with Zika in 2015 and 2016 were abandoned after those epidemics passed. "We really need investment in a long-term, well-funded surveillance system that captures pregnancy outcomes."

With a colleague at UC San Francisco, Afshar is co–principal investigator of the Pregnancy Coronavirus Outcomes Registry now collecting data from more than 1100 U.S. pregnant women. She hopes it will begin to answer urgent questions such as the impact on mother and fetus of drugs being given to fight COVID-19; how infection influences a mother's immune status; and whether and how anticlotting drugs ought to be used in pregnant women with COVID-19.

"It has been very strange to counsel women and their families, and witness their stress, and not be able to give them evidence-based recommendations," Afshar says. "I lose sleep for every woman I take care of, to make sure I am doing the right thing for her. And it's just the same, I would say, for myself."

Related story

COVID-19 unlikely to cause birth defects, but doctors await wave of fall births

By Meredith Wadman

When a pregnant woman gets sick, her doctors have two patients: the woman and her fetus. While obstetricians work to understand COVID-19's impact on mothers-to-be (see main story), they are also carefully tracking the virus' impact on the fetus, acutely aware that other viruses, including Zika, cytomegalovirus (CMV), and rubella, can cause serious birth defects. Researchers are cautiously optimistic the same will not prove true with the new coronavirus.

A case study published last month demonstrated conclusively that fetuses can be infected late in pregnancy (see photo above). But such infections appear to be "extremely rare," says lead author Daniele De Luca, a critical care neonatologist at Paris Saclay University Hospitals AP-HP. Stanley Plotkin, a physicianscientist who invented the widely used rubella vaccine, notes: "This is not rubella." The 1964 epidemic of that disease led to the births of tens of thousands of damaged babies in the United States.

It's still too soon to be certain that fetuses won't be damaged if they are infected during the sensitive first trimester, when tissues and organs take shape. But Carolyn Coyne, a virologist who studies placental infections at the University of Pittsburgh, is optimistic. "If [the virus] was a devastating pathogen causing fetal malformations early in pregnancy, we would have very clear cases from China," which had the earliest surge of COVID-19 cases. Senior Chinese obstetricians contacted by Science said they had seen no cases of congenital anomalies but warned that numbers were too small to draw firm conclusions.

Plotkin notes rubella and CMV are commonly blood-borne, allowing those viruses to reach the placenta during the first trimester, before it is a fully formed barrier to viral invasion. "Although SARS-CoV-2 virus does occasionally get into the blood, it is not basically a [blood-borne] infection," he says. "That's important."

In one study of nearly 700 pregnant women admitted to three New York hospitals for delivery, 71 babies born to infected moms were uninfected themselves. Another study published this month in eLife suggests the virus is unlikely to easily invade placental cells. Scientists led by Roberto Romero at the National Institute of Child Health and Human Development and Wayne State University found placental cells rarely simultaneously express a pair of molecules that the virus relies on to invade cells: ACE2, a membrane-bound receptor, and TMPRSS-2, an enzyme that activates the virus after it has bound ACE2. By contrast, they found that receptors for Zika and CMV are abundant on placental cells.

Still, a mother's SARS-CoV-2 infection could affect her fetus' growth. Researchers in the New York study also examined placentas from a subset of women and found clots in blood vessels on the fetal side of the placenta in nearly half—14 of 29—of COVID-19–infected mothers. Only 11% of placentas—12 out of 106—from uninfected moms had similar clots. Another study, by researchers at Northwestern University, found significantly more blood vessel injury and clots on the maternal side of the placenta in 15 of 16 infected women than in controls.

Blood clots could limit the oxygen and nutrients delivered to the fetus. These studies suggest the need to closely monitor fetal growth during the second half of a COVID-19–affected pregnancy, says Malavika Prabhu, a maternal and fetal medicine specialist at Weill Cornell Medicine and first author on the New York study.

Meanwhile, she and others await a wave of babies conceived early in the pandemic and due in the fall. "If you have COVID-19 at 8 weeks during embryonic development, what is the outcome for that baby? That's data that needs time to gestate," says Yalda Afshar, a high-risk obstetrician at Ronald Reagan University of California, Los Angeles, Medical Center.

*Correction, 6 August, 11:05 a.m.: This article has been corrected to report that none of 71 newborns born to infected mothers in a study at three New York City hospitals tested positive for coronavirus.

Blood Is Hard to Draw While Pregnant

Source: https://www.science.org/content/article/why-pregnant-women-face-special-risks-covid-19