• A UCLA study has found that "morning sickness" symptoms, including nausea, vomiting and aversions to certain foods and smells, are linked to the body's natural, but complex, immune response during pregnancy.
• In the early stages of pregnancy, a unique mix of inflammatory responses alongside behavioral mechanisms that researchers believe are adaptive, like nausea, achieves a delicate balance, allowing the mother to tolerate and nourish the half-foreign fetus while also avoiding potentially harmful foods.
• The study could have workplace implications for pregnant women, helping to widen recognition that these symptoms are healthy and normal, both reducing stigma and paving the way for common-sense workplace accommodations.

UCLA researchers have uncovered a link between "morning sickness" symptoms and the body's natural, but complex, inflammatory response to biological and bodily changes during pregnancy.

According to the National Institutes of Health, up to 80% of early-stage pregnant mothers experience some nausea, vomiting and aversions to certain foods and smells. While uncomfortable, these symptoms are not typically a sign that anything is wrong with the health of the mother or the developing fetus, but rather an indication of a delicate balance unique to pregnant women.

"During pregnancy, a mother's immune system faces a tricky challenge: it has to protect both her and the fetus from infection, but without accidentally attacking the fetus, whose genetic identity is half-foreign because it is half derived from the father. Normally, the immune system attacks anything that seems foreign, so in pregnancy, it has to carefully adjust to keep the fetus safe while still defending against infection," said UCLA anthropology professor Molly Fox.

Fox is the corresponding author of the study "Of scents and cytokines: How olfactory and food aversions relate to nausea and immunomodulation in early pregnancy," recently published in the journal Evolution, Medicine and Public Health.

The researchers believe that this delicate balance, which protects mother and fetus, is achieved by a unique mix of inflammatory responses. They function to prevent the mother's body from rejecting the fetus, alongside adaptive behavioral mechanisms, like nausea, that encourage the mother to avoid foods that are potentially harmful, especially in the first and second trimesters when the fetus is most vulnerable.

"Nausea, vomiting or aversions to foods or smells are not indications that something is going wrong for the mother or the fetus. It's likely an indication that everything is moving along normally, and a reflection of the body's healthy and helpful immune response," said UCLA anthropology professor and paper co-author Daniel Fessler.

Methodology and findings

For the study, the UCLA-led team of anthropologists and epidemiologists collected and analyzed blood samples to measure immune system molecules called cytokines. Cytokines are proteins that send signals to help the body launch a quick defense against sickness and regulate inflammation. Participants also filled out questionnaires that asked about morning sickness-related symptoms and food and smell aversions during the early stages of pregnancy. The participants were 58 Latina women in Southern California who were followed beginning in early pregnancy through the postpartum.

Sixty-four percent of study participants experienced odor or food aversions, primarily to tobacco smoke and meat. Sixty-seven percent reported nausea and 66% experienced vomiting.

The study team measured cytokines that promote inflammation (pro-inflammatory) as well as cytokines that suppress inflammation (anti-inflammatory). They found that women who experienced an aversion to tobacco smoke showed a noticeable shift toward a more inflammatory response. Food aversions, nausea and vomiting were also associated with a more pro-inflammatory immune balance.

Natural selection?

The correlation is consistent with researchers' theory that these symptoms may be part of an evolutionary adaptation that helps pregnant mothers' bodies minimize exposure to harmful substances, though the study's authors caution that the evidence is not definitive and more research is needed.

They emphasized that the study allowed the team to look at both human biological and behavioral responses during pregnancy.

"In many mammals, the fetal compartment has barriers separating it from the mother's blood supply, where her immune cells are. But in humans, we have a unique setup -- fetal cells are bathed in maternal blood. Humans have the most invasive of all placentas, burrowing deep into maternal tissue. So humans need unique strategies to prevent the mother's immune system from attacking the fetus," said Fox.

These immunological changes may induce nausea, which in turn encourages food avoidance that might act as an additional layer of protection, according to the researchers

"Nowadays, you will see labels on packages of ground beef or soft cheese that warn pregnant women to be cautious about these products because of the risks of foodborne illness during pregnancy. Aversions to certain odors and foods, and nausea and even vomiting, appear to be evolution's way of achieving that same objective," said Fessler.

Practical implications

The researchers, including first author Dayoon Kwon, who just completed her Ph.D. in epidemiology at UCLA (and is now a postdoctoral fellow at Stanford), said that the study could help bolster recognition that nausea and vomiting are normal symptoms with biological underpinnings associated with healthy pregnancies. The study's results could help in paving the way for common-sense workplace accommodations, such as more efficient deployment of health care benefits and other helpful resources to reduce stigma, excessive absences and lost productivity.

They also encourage other researchers to continue to look into the questions raised by the study, to not only explore the evolutionary questions, but to work toward providing clinicians with non- or low-invasive measures of prognoses.

Funding for this study was provided by the National Institute of Health.

The research appeared September 12 in the journal Blood.

Multiple myeloma (MM) is an incurable cancer of plasma, a type of white blood cell that normally makes antibodies to fight infection. MM cells build up in the bone marrow, crowding out healthy blood-forming cells, and produce large amounts of abnormal antibodies. This buildup can weaken the immune system, damage the kidneys and other organs, and cause painful bone disease. MM accounts for nearly 10 percent of all blood cancer diagnoses, and while there are targeted treatments to manage the disease, incidences of symptom relapse and drug-resistant multiple myeloma are increasing.

Although it's unclear what causes multiple myeloma, researchers have observed that MM is often associated with the suppression of ferroptosis, a natural process of cell death associated with excess iron accumulation. Ferroptosis causes oxidative damage to the lipids in the cellular membrane, triggering the cell to break apart. But when that process is suppressed, cell death doesn't occur.

"Cancer cells live like there is no tomorrow," said Mikhail Nikiforov, professor of pathology and biomedical engineering at Duke. "They accumulate iron at levels that would normally be toxic and tear cells apart, but that wasn't what we observed. Instead, these cancer cells adapted to resist the type of cell death triggered by iron overload, and the mechanisms behind this suppression were largely unknown."

But Nikiforov and a team of collaborators across Duke have finally answered this long-standing question by identifying kinase STK17B as a key enzyme responsible for suppressing ferroptosis in MM cells. Typically involved in cell death and T-cell activation, the researchers observed that STK17B was also critical at maintaining the balance of iron in the cell by regulating pro- and anti-ferroptotic proteins.

"Elevated levels of STK17B are associated with poor overall survival in MM patients," said Nikiforov. "STK17B expression is also especially pronounced in relapsed cases of the disease, underscoring its role in therapy resistance."

Using a compound developed by Timothy Willson, the Harold Kohn Distinguished Professor in Open Science Drug Discovery at the UNC Eshelman School of Pharmacy, the team was able to inhibit STK17B's control over iron buildup in the cell, reactivating ferroptosis. They also observed that inhibiting STK17B made cancer cells more sensitive to conventional MM therapies.

As a proof of concept, Nikiforov's team administered an oral version of the inhibitor to MM mouse models. They observed that the compound both induced ferroptosis by increasing the iron uptake of cancer cells and significantly reduced tumor growth in the mouse models.

"These findings establish that STK17B is a critical safeguard protecting MM cells from the toxic consequences of their iron independence," said Nikiforov. "Inhibiting this kinase holds much promise as a therapeutic strategy."

Beyond plans to explore how to improve the formulation, the team has also filed a provisional patent based on their findings with the goal of eventually commercializing the therapy. They also hope to study how the formula could be used to regulate drug resistance in other cancers.

"Many other types of cancer cells are also resistant to ferroptosis," said Nikiforov. "We're curious to see how this inhibitor could improve therapies for other tumors outside of multiple myeloma."

This work was supported by the National Institutes of Health, the National Cancer Institute grants NCI R01CA264984 (M.A.N), NCI R21CA267275 and 17R21CA280499 (Y. K.), NHLBI R01HL168492 (E.A.L.), NCI P30CA014236 (Duke Cancer Institute), and support from the Paula and Rodger Riney Foundation (L.H.B.). The Structural Genomics Consortium (SGC) is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada, through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Under-taking [EUbOPEN grant 875510], Janssen, Merck KGaA (also known as EMD in Canada and the US), Pfizer, and Takeda. Funding for this project was provided in part by the NIH Illuminating the Druggable Genome grant 1U24DK116204-01.