ABOVE: Influenza infections cause negative outcomes during pregnancy. © iStock, Prostock-Studio

Viral infections cause negative outcomes in pregnant patients and their offspring.1,2 To explain this trend, some scientists point to studies showing suppressive immune responses during pregnancy.3,4 “There’s absolutely some evidence for this, but it’s never fully been that simple,” said Sabra Klein, a viral immunologist at Johns Hopkins University who studies the influence of hormonal changes on the immune response.

In a recent study, Klein and her group showed that influenza infection led to reduced levels of the pregnancy-maintaining hormone progesterone (P4). This caused more severe illnesses in pregnant mice than nonpregnant animals and restricted growth in the newborn animals that continued into adulthood. The findings, published in mBio, offer researchers better insights into the mechanisms behind infection risk during pregnancy and potential avenues for treatments.5

“Very little research is ongoing in this area,” said Kristina Adams Waldorf, a reproductive immunologist at the University of Washington who was not affiliated with the study. According to her, the study is a good start to investigating the link between influenza A infections and negative pregnancy outcomes.

To study the correlation between pregnancy and viral infection outcomes, Klein and her team infected female mice at ten days into their gestation with the H1N1 strain of influenza virus. They used genetically dissimilar mice to better replicate the genetic heterogeneity of human pregnancies.

During influenza infection in mice, both pregnant and nonpregnant animals showed viral clearance, but pregnant mice become sicker as indicated by lower body temperatures and greater weight loss. Additionally, pups born to infected mothers were smaller at birth and reached growth and behavior milestones later than animals born to noninfected mothers. “This got us really thinking that it can't just be that pregnant females can't control the virus because of the dampening of antiviral immunity. There's got to be something else going on,” Klein said. “That's when we started to really explore the placenta.”

The team compared the morphologies of placentas from virally infected mice to those from noninfected animals. They showed that viral infection damaged the placenta and reduced the presence of a placental cell type, trophoblasts. Infection also decreased the levels of cytokines produced by these cells, even though viruses weren’t detected in this tissue. Placentas from infected mice contained proinflammatory cytokines and increased populations of macrophages compared to those from noninfected mice.

Normally, gestational hormones such as P4 suppress inflammatory immune activity in the placenta. The team found reduced P4 levels in the placentas from infected mice compared to noninfected mice. “We were really excited, but we didn’t understand how a flu virus in the lungs was causing suppression of progesterone,” Klein said.

To explore this, the team investigated a P4 regulating hormone, prostaglandin F2α (PGF2α). They found increased PGF2α in the lungs, blood, and ovaries of infected, pregnant mice compared to the samples from noninfected, pregnant mice. PGF2α is synthesized by cyclooxygenase-1 (COX-1). They showed that pregnant, infected mice had increased amounts of COX-1 in their lungs compared to their noninfected counterparts. The team confirmed that the elevated COX-1 in the lungs increased PGF2α in the ovaries by treating infected pregnant mice with a pharmacological inhibitor of COX-1. PGF2α levels dropped, and the circulating P4 levels increased.

Finally, the team investigated whether the reduced level of P4 during viral infection contributed to the reduced growth in pups born to infected mothers. They treated pregnant mice with an injectable form of synthetic P4 after infecting them with influenza. Compared to infected, nontreated, pregnant mice, animals that received the synthetic P4 maintained their body temperatures and weight better. Additionally, the pups born to P4-treated mice were larger at birth and met growth and developmental milestones similar to mice born to noninfected mothers.

Klein said that this study provides insights into how respiratory viral infections cause negative maternal and fetal outcomes and how these could be prevented. “What our data suggested is that it isn't about a lack of control of the virus. It's about the placental inflammation,” she said.

Adams Waldorf found the findings interesting but would like to see data on how P4 affects the antiviral response in the lung. “This study also opens up the possibility of using synthetic progestins to treat pregnant women who are infected with viruses,” Adams Waldorf said. “However, we do need to be careful that we are not worsening the impact of viral infection on other organs like the lungs.”

Reference

  1. Frivold C, et al. Acute respiratory infections among individuals seeking outpatient care in the states of Washington and Michigan by pregnancy status, 2011-2016. Influenza other Respir Viruses. 2023;17(12):e132230
  2. Creischer PS, Klein SL. Pathogenesis of viral infections during pregnancy. Clin Microbiol Rev. 2024;0:e00073-23
  3. Ernerudh J, et al. Regulatory T helper cells in pregnancy and their roles in systemic versus local immune tolerance. Am J Reprod Immunol. 2011;66(s1):31-43
  4. Szekeres-Bartho J, et al. The suppressive effect of progesterone on lymphocyte cytotoxicity: Unique progesterone sensitivity of pregnancy lymphocytes. J Reprod Immunol. 1985;7(2):121-128
  5. Creisher PS, et al. Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice. mBio. 2024;15(2): e03065-23