Preterm Infants and Medication Side Effects: What NICU Teams Need to Know

When a baby is born too soon, their body isn’t ready for the world - and that includes handling medications. Preterm infants, especially those born before 28 weeks, face a unique challenge: they need drugs to survive, but their underdeveloped organs can’t process them the way older babies or adults can. Every dose carries risk. Every pill, injection, or IV drip could cause harm - sometimes in ways that don’t show up until years later.

Why Medications Are Riskier for Preterm Infants

It’s not just about being small. A preterm baby’s liver, kidneys, and brain are still growing. Their enzymes, which break down drugs, are barely active. Their blood vessels are leaky. Their gut is fragile. These aren’t minor differences - they change how every medication behaves.

Take caffeine citrate, one of the most common drugs given to preterm babies to stop apnea. It’s usually safe - but not always. Around 18.7% of infants on standard doses develop fast heart rates. Nearly 7.3% stop feeding well. These aren’t rare side effects. They’re common enough that nurses monitor for them daily.

And that’s just one drug. More than 90% of respiratory medications used in NICUs are given off-label. That means they were never tested in babies this young. The FDA hasn’t approved them for this use. But there’s no choice. So doctors use them anyway - with guesses based on weight, gestational age, and gut feeling.

The Hidden Toll of Pain Management

For decades, doctors believed newborns didn’t feel pain the way adults do. That myth led to surgeries without anesthesia. Today, we know better. But the solution has its own dangers.

A 2021 study in JAMA Network Open found that 100% of extremely preterm infants received some kind of pain or sedation drug during their NICU stay. Over 40% got opioids. Nearly 30% got benzodiazepines. These drugs help them tolerate breathing tubes, IVs, and procedures. But they also affect brain development.

The American Academy of Pediatrics now says routine use of these drugs isn’t recommended. Why? Because repeated exposure may change how neural connections form. The long-term effects aren’t fully understood, but early evidence points to higher risks of attention problems, learning delays, and even autism spectrum traits later in life.

Now, NICUs are shifting toward targeted, short-term use - only when absolutely necessary. Weaning protocols have cut average opioid exposure from nearly 29 days down to 14. And pain is still managed just as well. That’s progress.

Antibiotics: Saving Lives, Changing Microbiomes

One in three preterm infants gets antibiotics in the first week of life - often for suspected infection, even when there’s no proof of it. That’s because sepsis can kill fast, and waiting for test results isn’t an option.

But antibiotics don’t just kill bad bacteria. They wipe out good ones too. A 2021 study from Washington University showed that preterm babies exposed to antibiotics had 47% more harmful bacteria in their guts - especially Enterobacteriaceae - and 32% fewer beneficial species like Bifidobacterium. These changes didn’t go away. They lasted 18 months after discharge.

And it gets worse. These babies also had 2.8 times more antibiotic-resistant genes in their gut. That means future infections might be harder to treat. One parent on a preemie support forum described her son: “He got 28 days of antibiotics for possible sepsis that was never confirmed. Now at age 2, he’s had five ear infections and two rounds of antibiotics.” That’s not rare.

Experts like Dr. Gautam Dantas warn that the gut microbiome is mostly set by age three. What happens in the NICU can shape a child’s health for life.

Anti-Reflux Drugs: A Common Practice with Dangerous Consequences

It’s common to see preterm infants on acid-reducing medications like proton pump inhibitors (PPIs). Parents and doctors worry about spitting up, crying, or discomfort. But here’s the truth: there’s almost no evidence these drugs help.

A 2022 Cochrane review found no benefit for anti-reflux meds in preterm infants. And yet, 41% of NICU graduates are still prescribed them. Why? Because it feels like the right thing to do.

The cost? A 1.67 times higher risk of necrotizing enterocolitis (NEC), a deadly gut disease. An 1.89 times higher chance of late-onset sepsis. And a 2.3 times greater risk of bone fractures. These aren’t small risks. They’re life-altering.

The AAP updated its guidelines in January 2024 to say: don’t use anti-reflux meds routinely in preterm infants. If a baby spits up, it doesn’t mean they need a pill. There are safer ways to manage feeding - positioning, slower feeds, thickened milk. Those should come first.

The Hidden Problem: Dosing Errors

Most NICU meds are dosed by weight - in milligrams per kilogram. Sounds simple. But for a baby weighing 800 grams? One decimal point wrong means a 10% overdose. That’s enough to stop breathing.

Nurses report that 68.4% see at least one dosing error per month. Over 20% of those lead to real harm: low blood pressure, seizures, organ stress. Many errors happen because formulas aren’t built for tiny weights. Or because the same drug has different dosing rules depending on gestational age.

For example, morphine clearance in a 26-weeker is 60% lower than in a 34-weeker. Fentanyl behaves differently too. But most hospitals still use one standard dose for all preemies. That’s changing. NICUs using pharmacokinetic modeling software like DoseMeRx have cut dosing errors by over half. But only 37% of Level IV NICUs use it. Most still rely on paper charts and mental math.

What’s Being Done - And What’s Next

Change is slow, but it’s happening. The FDA’s Best Pharmaceuticals for Children Act has led to 15 new neonatal labeling changes since 2002. The NIH’s Neonatal Research Network now has a dedicated pharmacology core. And in 2023, the Neonatal Precision Medicine Initiative launched - aiming to build personalized dosing models for 25 high-risk drugs by 2026.

There’s also hope in new formulations. NeoFen, the first fentanyl designed specifically for preterm infants, is in FDA Fast Track review. Approval is expected in mid-2025. It could mean safer pain control without the spikes in blood pressure or breathing trouble that current versions cause.

And researchers are testing microbiome-sparing antibiotics - drugs that target only the bad bugs, leaving the good ones alone. Early trials are promising. If they work, they could prevent years of digestive and immune problems.

The Bottom Line

Medications save preterm babies. But they also hurt them - sometimes silently, sometimes years later. The key isn’t to avoid drugs. It’s to use them wisely.

Every time a preterm infant gets a drug, three questions should be asked:

1. Is this absolutely necessary?
2. Have we tried non-drug options first?
3. Is the dose tailored to their exact gestational age and weight?

The answer to all three should be yes - every time. Because for these tiny patients, the line between healing and harm is thinner than a strand of hair.