Jan. 13, 2023

Sylvie Girard, Ph.D., is a reproductive immunologist at Mayo Clinic in Minnesota. Dr. Girard and colleagues from the Universite de Montreal have attempted to understand the role of inflammation in preterm birth (PTB), considered a birth that occurs before 37 weeks of pregnancy. They discovered new genes and inflammatory biological processes abnormally expressed at the maternal-fetal interface.

In Canada, approximately 10% of pregnant women deliver preterm, and about 12% deliver preterm in the U.S. The investigators hope that a better grasp of PTB and inflammation will allow targeted PTB interventions to prevent its long-term complications.

This study is part of Dr. Girard's larger research interest in new compromised maternal-fetal environmental biomarkers in the effort to intercede.

"I'm interested in stressors — infections, underlying maternal conditions and inflammation — which occur during pregnancy, and how they shape fetal and postnatal development," says Dr. Girard. "One developmental aspect we sought to understand better is the role of inflammation in spontaneous PTB. We don't understand why the body decides a baby needs to come out early or what maternal-fetal environmental factor is compromised. Is it from placental, fetal or maternal factors?"

The research team published the study results in a 2022 issue of the American Journal of Obstetrics and Gynecology (AJOG). This work was initiated by Dr. Girard and her team at the Universite de Montreal prior to her move to Mayo Clinic, where she is now continuing the work.

"As PTB can have immediate and long-term impacts, it's imperative the obstetrical community understands the mechanisms behind what's happening to minimize complications and develop new therapeutic strategies," she says.

PTB's etiology is so broad, says Dr. Girard, that the obstetrical field dubbed it a syndrome. Yet, shared factors have begun to emerge.

"What's common in preterm births is inflammation," says Dr. Girard. "Inflammation is needed for a normal pregnancy and delivery. We wanted to pinpoint what normal and abnormal inflammation are so we could target bad inflammation."

Dr. Girard says even in iatrogenic PTB cases, in which the PTB is medically indicated, inflammation is still observed. PTB often is indicated due to improper fetal growth. Obstetricians face a dilemma: leave the baby in the uterus or prompt early delivery with its potential consequences.

"If the baby's too small and hasn't grown in a few weeks, it is sometimes necessary for the baby to come out to receive help to grow," she says.

Dr. Girard hopes to define pregnancies proceeding well versus those not proceeding well and determine why favorable or unfavorable outcomes occur.

PTB versus term delivery study

In the study, the researchers prospectively recruited 79 pregnant women presenting at the hospital; some delivered preterm and others at term. Investigators analyzed the women's blood samples and placentas using techniques such as flow cytometry and inflammatory mediator assessment. They also performed histologic analysis of the placentas and RNA sequencing of the tissue. They conducted transcriptomic analyses and discovered 102 genes differentially expressed in PTB.

Some of the genes detected were previously reported; others were unknown before this. Through gene ontology analysis of targets discovered, the researchers observed significant inflammatory biological processes. These results were associated with a higher number of CD3- cells, especially the monocyte subset, in PTB compared with term births. They also noted fewer CD3+ and CD4+ lymphocytes, particularly the Th17 subset. Women who delivered preterm demonstrated higher fetal membrane, placental and plasma proinflammatory mediator levels compared with those who delivered at term, especially in the amnion.

At first review, iatrogenic and spontaneous preterm births did not demonstrate distinctive proinflammatory factors. However, investigators' deeper, molecular-level analyses found an increased inflammatory profile in spontaneous versus iatrogenic PTBs with more inflammatory lesions. In placentas with inflammatory lesions, the investigators observed enriched proinflammatory pathways.

"This study provides new answers about what's transpiring in the immune system during pregnancy, which will help identify women at high PTB risk," says Dr. Girard. "It also gives us crucial information about novel therapeutic strategies targeting inflammation in PTB."

Study perspectives

Dr. Girard indicates she has studied thousands of placentas so far in her career, a unique field with few researchers dedicated to reproductive immunology in North America.

She says during the study, a research nurse carefully approached pregnant women arriving at the hospital regarding study participation, ensuring that the needs of the patient were addressed prior to any mention of research.

"It's important to collect and analyze this data," says Dr. Girard. "But at the same time, we want these women and their babies to be doing as well as possible in the circumstances. Their pregnancies already put these women in a stressful position. We didn't want to add stress to the situation."

The findings of this study on inflammation in PTB are crucial due to potential consequences for the short- and long-term health of infants born prior to 37 weeks.

"We want infants born preterm to develop as well as possible," says Dr. Girard. "Unfortunately, there are major differences in implication between PTB infants and those born at term. Multiple potential effects may arise from an infant missing the final weeks in utero. PTB especially affects the lungs and brain. An infant may have brain injury or developmental delay with preterm birth, which might be detected only later during development."

The increased inflammation and additional lesions discovered in the placenta of pregnancies with PTB compared with those at term are meaningful for placental status.

"This means the placenta is not functioning well," says Dr. Girard. "Since the placenta delivers nutrition from the mom to the baby, if lesions are present, the transfer might not be optimal. If the placenta is not working properly, it has a tremendous impact on the baby. In some cases, an infant's growth may be sufficient despite this."

Treatment implications

Given the inflammatory results found in the placentas of women who delivered preterm, Dr. Girard hopes to utilize placentas to identify fetuses at high risk and factors that require preterm infant medical attention.

"The challenge is: Which infants born preterm do you treat?" says Dr. Girard. "Everyone?"

Dr. Girard and her team found that although maternal changes occur during pregnancy, the overall number of changes — particularly in the mother's circulation — were not as important as anticipated, surprising the research team.

However, significant maternal-fetal interface changes occur in PTB, especially in the fetal membrane and placenta; thus, this interface is an appropriate PTB target.

Dr. Girard is excited about the increasing value discovered in the study of the placenta. She says looking at placentas is easy and could be a means to identify infants at high risk of developmental abnormalities early after delivery.

She also strongly feels physicians who care for infants as they grow could benefit from receiving key placental information about their patients.

"There's a lot more value in looking at the placenta than we thought," she says.

PTB prevention

Dr. Girard says women who deliver PTB infants tend to question themselves, saying, "What did I do wrong?"

She indicates there is not necessarily any bodily abnormality in the mother or anything the mother did wrong to lead to a PTB.

Further research

While satisfied with the data gained in the study, Dr. Girard says the number of participants included was low. Now, her team studies over 250 placentas, via analysis and categorization into subtypes.

She indicates a finding that PTB babies have less progesterone than those delivered at term has led to further studies into this hormone's role in PTB, particularly in abnormal inflammation. Dr. Girard says studies on the maternal-fetal interface are ongoing at Mayo Clinic.

PTB-related referrals

According to Dr. Girard, physicians should consider referral for patients who were born prematurely or who delivered a preterm baby.

For more information

Couture C, et al. Proinflammatory changes in the maternal circulation, maternal-fetal interface, and placental transcriptome in preterm birth. American Journal of Obstetrics and Gynecology. In press.

Refer a patient to Mayo Clinic.