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Immune response turned up, not down, by flu during pregnancy, Stanford/Packard study finds

Stanford University Medical Center

Pregnant women have an unusually strong immune response to influenza, an unexpected finding that may explain why they get sicker from the flu than other healthy adults, new research from the Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford has found.

The results were surprising because immune responses are thought to be weakened by pregnancy to prevent the woman's body from rejecting her fetus.

The study, which will be published online Sept. 22 in the Proceedings of the National Academy of Sciences, is the first to examine the reactions of immune cells taken from pregnant women to influenza viruses, including the H1N1 strain that caused the 2009 flu pandemic.

"We were surprised by the overall finding," said Catherine Blish, MD, PhD, assistant professor of infectious diseases and the study's senior author. "We now understand that severe influenza in pregnancy is a hyperinflammatory disease rather than a state of immunodeficiency. This means that treatment of flu in pregnancy might have more to do with modulating the immune response than worrying about viral replication."

In the study, immune cells taken from 21 pregnant women and 29 healthy, nonpregnant women were exposed to different flu viruses in the lab. The immune cells were obtained by collecting blood samples from the women before and seven days after they received flu vaccines. Cells taken from pregnant women six weeks after their babies were delivered were also tested. The researchers studied responses to two flu viruses: pandemic H1N1 and a strain of seasonal influenza, H3N2.

Pregnancy enhanced the immune response to H1N1 of two types of white blood cells: natural killer and T cells. Compared with the same cells from nonpregnant women, H1N1 caused pregnant women's NK and T cells to produce more cytokines and chemokines, molecules that help attract other immune cells to the site of an infection.

"If the chemokine levels are too high, that can bring in too many immune cells," Blish said. "That's a bad thing in a lung where you need air space." Getting the flu during pregnancy, especially pandemic strains such as those that caused the pandemics of 1918, 1957 and 2009, carries a heightened risk for pneumonia and death, she noted.

Both strains of flu also caused NK and T cells to be activated in a greater variety of ways in pregnant than nonpregnant women, the study found.

Today, pregnant women with influenza are usually treated with drugs to slow the replication of the flu virus in their bodies. Although this is a useful treatment, the new findings suggest that it isn't the only good option, the study's authors said.

"If our finding ends up bearing out in future studies, it opens the possibility that we can develop new immune-modulating treatment approaches in the setting of severe influenza, especially in pregnant women," said Alexander Kay, MD, instructor in pediatric infectious diseases and the study's lead author.

The researchers are curious about whether the response of pregnant women's immune cells to other viruses would be similarly heightened, an idea they have yet to test.

"I suspect this is peculiar to influenza for a variety of reasons," Blish said. Having influenza during pregnancy quadruples a woman's risk for delivering her baby prematurely, she said.

"I wonder if this is an inflammatory pathway that is normally activated later in pregnancy to prepare the body for birth, but that flu happens to overlap with the pathway and aberrantly activates it too early," Blish said.

Blish and Kay plan to continue the research by studying pregnant and nonpregnant women who have contracted flu infections in their day-to-day lives.

And they hope that their research will remind women who are pregnant or planning a pregnancy to get their flu shots. "Flu vaccination is very important to avoid this inflammatory response we're seeing," Kay said. "But only 50 percent of pregnant women are currently vaccinated for influenza."

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The study's other Stanford co-authors are graduate student Julia Fukuyama; Natali Aziz, MD, clinical assistant professor of obstetrics and gynecology and director of perinatal infectious diseases at Lucile Packard Children's Hospital Stanford; Cornelia Dekker, MD, professor of pediatric infectious diseases and medical director of the Stanford-LPCH Vaccine Program; Sally Mackey, associate director of the vaccine program; Gary Swan, PhD, consulting professor at the Stanford Prevention Research Center; Mark Davis, PhD, professor of microbiology and immunology; and Susan Holmes, PhD, professor of statistics. Blish, Dekker and Davis are members of Stanford's Child Health Research Institute.

The study was funded by a Doris Duke Foundation Clinical Scientist Development Award, a McCormick Faculty Award, the Child Health Research Institute at Stanford/Stanford Clinical and Translational Science Award (grants UL1TR000093 and T32AI78896-05) and the Human Immunology Project Consortium Infrastructure and Opportunities Fund (grant U19AI090019).

More information about Stanford's Department of Medicine and Department of Pediatrics, which also supported this work, are available at http://medicine.stanford.edu/ and http://pediatrics.stanford.edu.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Lucile Packard Children's Hospital Stanford. For information about all three, please visit http://med.stanford.edu.

Stanford Children's Health, with Lucile Packard Children's Hospital Stanford at its core, is an internationally recognized leader in world-class, nurturing care and extraordinary outcomes in every pediatric and obstetric specialty from the routine to rare, for every child and pregnant woman. Together with our Stanford Medicine physicians, nurses, and staff, we deliver this innovative care and research through partnerships, collaborations, outreach, specialty clinics and primary care practices at more than 100 locations in the U.S. western region. As a non-profit, we are committed to supporting our community - from caring for uninsured or underinsured kids, homeless teens and pregnant moms, to helping re-establish school nurse positions in local schools. Learn more about our full range of preeminent programs and network of care at stanfordchildrens.org, and on our Healthier, Happy Lives blog. Join us on Facebook, Twitter, LinkedIn and YouTube.

Lucile Packard Children's Hospital Stanford is the heart of Stanford Children's Health, and is one of the nation's top hospitals for the care of children and expectant mothers. For a decade, we have received the highest specialty rankings of any Northern California children's hospital, according to U.S. News & World Report's 2014-15 Best Children's Hospitals survey, and are the only hospital in Northern California to receive the national 2013 Leapfrog Group Top Children's Hospital award for quality and patient care safety. Discover more at stanfordchildrens.org.

Print media contact:

Erin Digitale at (650) 724-9175 (digitale@stanford.edu)

Broadcast media contact:

Winter Johnson at (650) 498-7056 (wijohnson@lpch.org)

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