Why Opioid Use Disorder (OUD) May Contribute to Preterm Birth

Opioid use during pregnancy—whether of highly addictive drugs like fentanyl or controlled opioids like buprenorphine—doubles the risk of preterm birth. A new Yale study reveals that inflammation may be the culprit.

The United States has seen a dramatic rise in opioid use. In 2022, 82,000 people died from opioid overdose—a 10-fold increase since 1999. For the first time, a team of researchers has investigated the direct impact of opioids on pregnancy. The results were published February 1 in the Journal of Reproductive Immunology.

The researchers found that the use of buprenorphine, a type of opioid that helps reduce withdrawal symptoms and cravings in opioid use disorder, was associated with increased inflammation and weakened fetal membranes—the tissue that surrounds and protects a developing fetus. They also identified biological mechanisms underlying these associations. In future studies, they hope to continue this work on other opioids—both those for treating OUD like methadone and unregulated opioids like fentanyl.

The work was a collaboration between the laboratories of Vikki Abrahams, PhD, professor of obstetrics, gynecology & reproductive sciences at Yale School of Medicine; Kimberly Yonkers, MD, professor and Katz Family Chair in Psychiatry at the University of Massachusetts Chan Medical School and professor adjunct of psychiatry at Yale School of Medicine; and Ryan Logan, PhD, professor of psychiatry and neurobiology at the University of Massachusetts Chan Medical School.

“This is giving us new insights into why women who take opioids during pregnancy are at such high risk for preterm birth,” Abrahams says.

The fetal membrane is the tissue that makes up the amniotic sac. When this membrane ruptures, an individual’s “water breaks” and labor begins. Preterm birth can happen when the fetal membrane breaks too soon, and it’s a leading cause of neonatal morbidity and mortality globally.

In their new study, the researchers wanted to study whether and how buprenorphine impacted this fetal membrane tissue. Inflammation can degrade and break the fetal membrane. They selected buprenorphine because it is a commonly used opioid for the treatment of OUD. So first, the researchers investigated if the drug could cause inflammation in the fetal membrane tissue.

The team collected fetal membranes from women who had donated their placentas and associated fetal membranes to the Yale University Reproductive Sciences Biobank. They cultured small pieces of the donated tissue and exposed them to either buprenorphine or a control. Then, they analyzed the samples for levels of inflammatory cytokines and chemokines—molecules linked to preterm birth.

“We found that buprenorphine significantly elevated all of the cytokines and chemokines that we measured,” Abrahams says. Their analysis also revealed the elevation of molecules associated with fetal membrane weakening.

Next, the researchers investigated the mechanisms underlying the upregulation of these molecules. They identified three types of cell surface receptors through which buprenorphine appeared to be triggering inflammation and membrane-weakening: the μ-opioid receptor, Toll-like Receptor 4 (TLR4), and the NLRP3 inflammasome. Blocking those receptors reduced the harmful effects buprenorphine had on fetal membranes, the researchers found.

The μ-opioid receptors are a class of receptors known to bind buprenorphine and other opioids. Thus, its identification as one the mediators was unsurprising, says Abrahams.

TLR4 is known to detect bacteria. But the receptor can also become triggered in the absence of bacterial infections—by molecules released from injured tissue, for example, or environmental pollutants—and induce inflammation. “Buprenorphine is essentially triggering sterile inflammation through this innate immune receptor that classically recognizes infections,” Abrahams says.

The NLRP3 inflammasome is a protein complex that mediates the production of a highly potent pro-inflammatory cytokine called interleukin-1 beta. Interleukin 1 beta is a major driver of uterine contractions—and subsequent preterm birth.

The researchers also found that molecular signaling pathways triggered by μ-opioid and TLR4 receptors played a role in regulating inflammatory and membrane weakening responses as well.

The study, says Abrahams, will provide the basis for further investigation into the mechanistic link between opioid use in pregnancy and the elevated risk of preterm birth. It could also pave the way for studies on other—both therapeutic and unregulated—and provide insights to clinicians on the safest therapies for pregnant women with OUD or ways to keep them on their medication, while making their pregnancy safer .

Abrahams’ team is now studying the effects of methadone, another therapy for opioid use disorder, on fetal membranes. “Methadone is used like buprenorphine, but it has an even stronger impact on preterm birth,” she explains. Her team also has plans to study unregulated opioids, such as fentanyl, that are commonly used by people who struggle with opioid use disorder.

“Adverse pregnancy outcomes can impact the health of a baby long-term, as well as the mother,” Abrahams says. “If we can find ways to prevent issues like preterm birth, then we’re making everybody healthier in the long run.”

This study was supported in part by a Next Gen Pregnancy Research Grant from the Burroughs Wellcome Fund and grants R01DA062540 and R01DA051390 from the National Institute on Drug Abuse, NIH.