Milrinone is a pharmacological tool with a distinctive mechanism. Unlike classic vasopressors, which squeeze blood vessels to raise blood pressure, milrinone works by inhibiting an enzyme called phosphodiesterase type 3, or PDE3. This inhibition prevents the breakdown of cyclic AMP, a key intracellular signaling molecule, inside heart muscle cells and vascular smooth muscle. The result is a dual action: the heart contracts more forcefully and relaxes more efficiently between beats, while blood vessels dilate, lowering the resistance against which the heart must pump. In theory, this combination makes milrinone ideal for newborns struggling with acute pulmonary hypertension or with the hemodynamic turbulence that can follow the closure of a patent ductus arteriosus, a fetal blood vessel that sometimes fails to seal after birth. In practice, however, the vasodilating effect that makes the drug attractive can also tip a fragile infant into systemic hypotension—a drop in blood pressure severe enough to threaten blood flow to the brain, kidneys, and gut.

That concern is precisely what motivated the Iowa team, led by neonatologist Trassanee Chatmethakul together with Adrianne Bischoff, Danielle Rios, and Patrick McNamara, to take a closer look. Recent years have seen a marked increase in milrinone use for preterm infants, yet safety data in the extremely low gestational age population remain strikingly thin. Uncontrolled clinical reports had suggested a link between the drug and hypotension, while a small randomized trial using loading doses found tachycardia—abnormally fast heart rate—but no significant blood pressure drop. Animal studies added another layer of uncertainty, hinting that the newborn myocardium, particularly in the early transitional period just after birth, may be relatively unresponsive to the inotropic, or contractility-boosting, effects of PDE3 inhibition. In other words, the very population in which milrinone is increasingly deployed may be the one in which its risks are least understood.

To fill that gap, the researchers conducted a retrospective cohort study at the University of Iowa’s level IV Neonatal Intensive Care Unit, examining the medical records of infants born between 2018 and 2020. They included newborns delivered at a gestational age of 22 weeks and zero days through 28 weeks and six days who received milrinone during the first four postnatal weeks. Crucially, they excluded infants who were already hypotensive when milrinone was started, as well as those with known or suspected genetic syndromes or major congenital malformations, ensuring that the analysis focused on babies whose blood pressure changes could reasonably be linked to the drug exposure itself. The study was approved by the university’s Institutional Review Board, and the team gathered demographic and clinical data from electronic medical records.

The primary outcome was carefully defined: the presence of hypotension lasting at least one hour within the first six hours after the milrinone infusion began. Hypotension was defined either as a diastolic pressure, or both diastolic and mean arterial pressure, falling below the third percentile for gestational age at the time of exposure, or as the need to start or escalate another vasoactive medication. Secondary outcomes included changes in the respiratory severity score—a composite measure of ventilator support and oxygen requirements—the need for new vasopressors, the vasoactive-inotropic score, and a range of neonatal morbidities following exposure.

The cohort comprised 34 extremely low gestational age infants, with a mean gestational age of 24.5 weeks and a mean birth weight of just 676 grams. Of these, eight infants—23.5 percent—developed hypotension or required escalation of vasoactive therapy within the monitoring window. That figure is the study’s central alarm bell. Nearly one in four of these vulnerable newborns experienced a clinically significant blood pressure decline in the hours after milrinone was started, a rate the authors describe as concerning, particularly given that the drug is often administered precisely to stabilize circulation.

What makes the study especially valuable is its identification of who was most at risk. The infants who became hypotensive were, at the time milrinone was initiated, younger and smaller than their counterparts who tolerated the drug well. Their postmenstrual age—the gestational age plus the time since birth—averaged 27.3 weeks compared with 28.8 weeks in the non-hypotensive group, a difference that reached statistical significance. They also weighed less, averaging 796 grams versus 1104 grams. Perhaps most tellingly, the hypotensive infants had a higher respiratory severity score during the first four hours of milrinone exposure, 7.6 versus 4.4, indicating that they were sicker from a respiratory standpoint and required more intensive ventilatory and oxygen support. Taken together, these findings suggest that lower postnatal age, lower weight, and poorer respiratory status all mark infants at heightened risk of a blood pressure crash after milrinone.

The authors are careful to acknowledge the interpretive limits of their data. The hypotension they observed could be a direct pharmacological effect of milrinone’s vasodilating action, or it could reflect the natural course of sicker infants whose underlying pathophysiology—sepsis, pulmonary hypertension, ductal steal, or immature myocardial function—was already driving them toward cardiovascular collapse. With only 34 infants in the cohort, the dataset was too small to disentangle the statistical effect of polypharmacy, the simultaneous use of multiple vasoactive and supportive medications that is routine in this population. Retrospective design adds further constraints: the researchers could observe associations, but not prove causation, and treatment decisions were made by clinicians rather than randomized by protocol.

Even so, the study’s implications for clinical practice are concrete. The findings underscore the importance of close hemodynamic monitoring in the hours immediately following milrinone initiation, particularly for the smallest, youngest, and most respiratory-compromised infants. They also support a philosophy of physiology-based, targeted utilization of milrinone—reserving the drug for infants whose specific pathophysiology genuinely calls for PDE3 inhibition, rather than administering it broadly as a general circulatory tonic. This approach, championed in neonatal hemodynamics literature by McNamara and colleagues, emphasizes matching cardiovascular support to the underlying disease mechanism instead of applying one-size-fits-all protocols.

The broader context makes this work timely. Milrinone’s mechanism—enhancing contractility while reducing afterload—remains uniquely suited to conditions such as pulmonary hypertension of the newborn and the post-closure hemodynamic shifts that increasingly accompany modern PDA treatment. As more extremely preterm infants survive to receive these interventions, the demand for precise safety data will only grow. The Iowa team’s study, though small, provides a crucial first map of the risk landscape: the youngest, lightest, and most ventilator-dependent infants are the ones whose blood pressures deserve the closest watch when milrinone is started. Larger, prospective studies are now warranted to define the drug’s full safety profile and to establish optimal dosing and monitoring parameters for the most fragile patients in the nursery. Until then, the message to neonatal intensivists is clear—milrinone can be a lifeline, but in the tiniest newborns it must be deployed with vigilance, and with a blood pressure cuff never far away.

Subject of Research: Milrinone-associated systemic hypotension risk in extremely low gestational age newborns

Article Title: Characteristics of extremely low gestational age newborns receiving milrinone and possible risk factors associated with the development of systemic hypotension

Article References: Chatmethakul, T., Bischoff, A. R., Rios, D. R., & McNamara, P. J. (2026). Characteristics of extremely low gestational age newborns receiving milrinone and possible risk factors associated with the development of systemic hypotension. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02773-z

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02773-z

Keywords: milrinone, extremely preterm infants, neonatal hypotension, neonatal intensive care, phosphodiesterase inhibitor, patent ductus arteriosus, pulmonary hypertension, hemodynamic monitoring, respiratory severity score, vasoactive medications, retrospective cohort study, neonatal hemodynamics