Pre-term infants receive numerous medical procedures, usually without any painkillers at all. New research shows this may cause them lifelong problems with stress.

As medical technology advances, infants born prematurely can be kept alive at younger and younger ages. However, their lungs, heart, and other organs may not be fully formed, requiring a great deal of medical attention. And what many parents may not know is that the majority of these medical procedures are done without any kind of painkiller.

“Preterm infants (born before 37 gestational weeks) are small, often sick, and require medical attention,” explained Dr. Nicole Victoria, a postdoctoral associate at the University of Minnesota, in an interview with Healthline. “They spend, on average, 25 days in the Neonatal Intensive Care Unit (NICU) where they experience an average of 10 to 18 procedures per day. These procedures are painful and inflammatory, yet 65 percent of these procedures are performed without pre- and/or post-emptive anesthesia or analgesia.”

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To find out what effect this rough treatment has on premature newborns, Victoria teamed up with Dr. Anne Murphy.

To simulate what the newborns experience, Victoria and Murphy took newborn rat pups and gave them a single injection of an inflammatory agent, which creates not just pain but also a physical response similar to the way human babies react to injury.

As it turns out, once was enough. Any such injection administered within eight days of the pups’ birth—the equivalent of three to six months of age in human babies—caused the rats’ brains to rewire, permanently changing the way they processed stress and pain.

“We found that not only does early life injury blunt acute response to stress, but also to acute pain stimuli,” said Murphy, Associate Director of the Neuroscience Institute at Georgia State University.

At first, the changes might seem beneficial. As adults, it took more pain to stress the rats out, and their stress system returned to baseline much faster. But this also meant that it took the rats longer to respond to and avoid pain, foul odors, or other stressors in their environment.

“If you are less responsive to something that is supposed to produce anxiety or something that is supposed to be aversive, that could be a problem,” Victoria said. “It could result in serious harm.”

In new research that Victoria is preparing for publication, she followed up on the long-term effects of stress in these afflicted rats, and confirmed her suspicions: in the long run, they were very vulnerable to stress.

Because they were unable to respond properly to pain, the rats never learned to deal with stress. Their chronic stress response was activated more easily, and they showed far more anxious and antisocial behaviors.

“These changes in response to the early life pain are maintained long term into adulthood,” Murphy said.

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So what does this mean for premature infants, who will experience not just one but dozens of painful medical procedures?

“The studies coming out now show that…outcomes are better if anesthesia and analgesia are given for infant pain,” Victoria said. “There is a good amount of evidence showing that administration of opioid analgesia to preterm infants during surgery decreases sepsis, decreases the release of stress hormones and endorphins, and increases the likelihood of survival.”

This might offer hope for premature infants in the future, since their long-term outcomes bear a disturbing resemblance to the injured rats’. “By middle school, former preterm infants are at least 28 percent more likely to suffer from disorders of anxiety, depression, or inattention,” explained Victoria. “As young adults, they are at high risk for disorders of internalization and externalization, like anxiety, depression, or ADHD, and have problems with cognitive and behavioral flexibility.“

But this doesn’t have to be the case. “Currently, the majority of infant pain is not treated,” Victoria said. “A recent study showed that if you actually do treat their pain in the NICU with morphine, their outcomes are better in the long-term for executive functioning and externalization behavioral.”

So why don’t premature infants receive painkillers? It comes down to history, Murphy says. “It was always assumed that a newborn infant was incapable of responding to any pain because the sensory system was underdeveloped,” she explained. Moreover, opiate painkillers make it harder to breathe, and for a pre-term infant whose lungs are already struggling to function, any impact on breathing might be lethal.

The consensus began to change in the 1980s, after it came out that a series of premature babies had undergone major surgery without any anesthetic or analgesia.

One famous case, Baby Jeffrey received heart surgery with only paralytics in his system, leaving him fully awake while his chest was cut open. The child soon died of sepsis, unable to withstand the terrible shock to his body. Still, the field is slow to change. “It was common practice, and in some cases still is standard practice to provide respiratory support and paralytics that provide no analgesia for surgical procedures,” Victoria said.

“What we’re really trying to do is get the word out,” Murphy said. “Something needs to be done in order to modulate this pain early in life.”