The Role of Serotonin in Persistent Pulmonary Hypertension of the Newborn

Research study background

More than 30 years ago, neonatologists at Children’s Hospital Colorado pioneered the use of inhaled nitric oxide to treat persistent pulmonary hypertension of the newborn (PPHN). This groundbreaking intervention has become the standard, notably improving outcomes, particularly for newborns with mild to moderate disease. Yet, PPHN still carries a concerning 8% overall mortality rate, and survivors often face serious complications.

In an effort to develop targeted, individualized therapies for severe PPHN, neonatology experts at Children’s Colorado have set out to identify new mechanisms driving this devastating disease, turning their focus to the neurotransmitter serotonin. Serotonin is increasingly recognized as a key contributor to pulmonary hypertension (PH) in adults, but its role in neonatal PH is less clear, as evidenced by the team’s earlier findings in animal models.

“PPHN is a complex disease, and while caring for these babies is deeply rewarding, it is often heartbreaking because even our best therapies sometimes fall short,” says Jamie Archambault, MD, neonatologist at Children’s Colorado. “When standard pulmonary vasodilators fail, it signals that deeper mechanisms are driving the disease. We urgently need to move beyond existing treatments to uncover new biologic pathways that could improve survival and long-term outcomes for these vulnerable newborns."

In this study, published in The Journal of Pediatrics, investigators built on the known link between serotonin and PH to test the hypothesis that newborns with PPHN would have higher levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), compared to age-matched controls. They enrolled term or near-term newborns that required monitoring in neonatal intensive care units at Children’s Colorado and the University of Colorado Hospital between 2021 and 2022. Of the 64 newborns initially eligible for the study, 30 (17 with PPHN and 13 controls with no respiratory disease) were included in the final cohort. In the PPHN group, 71% had congenital diaphragmatic hernia (CDH) and six required extracorporeal membrane oxygen (ECMO) support. 

The team collected spot urine samples on days one and three of life to non-invasively measure serotonin and 5-HIAA concentrations, which are directly linked to plasma and serum concentrations. Samples were analyzed by mass spectrometry and adjusted for urine creatinine to account for variation in renal function.

At day one of life, there was no difference in urine serotonin between the groups. At day three, urine serotonin was actually lower in the PPHN group compared to controls. When examining percent changes over time, infants with PPHN showed a decrease in urine serotonin levels and an increase in urine 5-HIAA between days one and three of life, a change not observed in the control group. 

Relevance to future research

After the study was complete, the team conducted a subgroup analysis based on disease severity and also compared PPHN secondary to CDH against other causes. There was no difference in urine serotonin and urine 5-HIAA between either variable across both timepoints.

“These findings challenge some of our assumptions and points to a more complex role for serotonin signaling in neonatal pulmonary vascular disease,” Dr. Archambault says.

In their conclusion, the study authors speculated that the observed changes of decreased serotonin and increased 5-HIAA in PPHN may be a result of enhanced pulmonary tissue uptake and metabolism, but the exact mechanism is still not clear. They noted that further studies are needed to verify this relationship in PPHN and other causes of neonatal PH.

Currently, the research team is investigating how platelet activation contributes to lung disease and PH, with early evidence showing platelets actively worsen disease in neonatal mice. They are launching a clinical study in infants with BPD-associated PH, which could lead to anti-platelet therapies for this vulnerable group.