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

• by Malcolm Hitchcock
• Nov 16, 2025
• 0 Comments

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

Preterm infants are not small adults - and their medications shouldn’t be treated like they are

Every year, over 1 in 10 babies in the U.S. are born too soon. These preterm infants, especially those born before 28 weeks, face a battlefield of medical interventions just to survive. One of the most dangerous? Medications. What seems like a routine dose of pain relief, antibiotics, or acid blockers can have lasting consequences - not because the drugs are bad, but because preterm infants’ bodies handle them in ways doctors still don’t fully understand.

Here’s the hard truth: 100% of extremely preterm infants in the NICU get at least one medication during their stay. Many get multiple. Opioids. Benzodiazepines. Antibiotics. Caffeine. Proton pump inhibitors. But here’s what most parents - and even some clinicians - don’t realize: most of these drugs were never tested on babies this small. Over 60% of medications used in NICUs have no FDA approval for infants under one year. That means doctors are guessing. And sometimes, those guesses hurt.

Why dosing preterm infants is like navigating a minefield

It’s not just about weight. A 1,000-gram baby born at 24 weeks doesn’t metabolize drugs like a 3,000-gram baby born at 36 weeks. Their liver is still learning how to break things down. Their kidneys can’t filter waste the way older babies can. Their blood-brain barrier is leaky. Their gut is a fragile ecosystem.

Take caffeine, the go-to drug for apnea of prematurity. It’s effective - but 18.7% of infants on standard doses develop fast heart rates. About 7% can’t tolerate feeding because of it. That’s not rare. That’s common enough that every NICU nurse needs to watch for it. But what if the baby also has a patent ductus arteriosus (PDA)? That single condition can increase the volume of distribution for some drugs by 80%. A dose that’s perfect for one preterm infant could be toxic for another - just because of a heart defect.

And then there’s the clock. Cytochrome P450 enzymes, the liver’s main drug-processing system, are only 30% mature at 32 weeks. They don’t hit adult levels until the baby is 12 months old. That means drugs like morphine or fentanyl - commonly used for pain - stick around longer. The risk of respiratory depression? Higher. The window for safe dosing? Narrower.

The hidden cost of antibiotics: A gut that never recovers

Antibiotics are the most prescribed drugs in the NICU. But they’re not harmless. A 2021 study from Washington University showed that preterm infants exposed to antibiotics had gut microbiomes packed with 47% more harmful bacteria and 32% fewer good ones. These changes didn’t go away after discharge. They lasted 18 months.

Why does that matter? Because the gut microbiome shapes immunity, brain development, and even metabolism. Babies who get broad-spectrum antibiotics early are more likely to develop allergies, asthma, and recurrent infections later. One parent on Reddit shared: “My son got 28 days of antibiotics for suspected sepsis - never confirmed. At age 2, he’s had five ear infections and two rounds of antibiotics.” That’s not an outlier. It’s the pattern.

And here’s the kicker: many of these antibiotics are given for “possible sepsis” - a diagnosis based on vague signs like temperature swings or low blood pressure. But in preterm infants, those signs are often just normal stress responses. Yet, 70% of these babies still get antibiotics. The risk? A gut microbiome that’s permanently altered. The reward? Sometimes, nothing at all.

Anti-reflux drugs: Prescribed often. Proven useless. Dangerous always

One of the most shocking practices in the NICU? Giving proton pump inhibitors (PPIs) like omeprazole to preterm infants for reflux. It’s done in 41% of NICU graduates. Why? Because parents and nurses see spit-up and assume it’s pain. But here’s what the science says: there’s no evidence these drugs help.

The 2022 Cochrane review - the gold standard in medical evidence - found no benefit from acid-suppressing meds in preterm infants. Yet, the risks are real. These drugs increase the chance of necrotizing enterocolitis (NEC) by 67%, late-onset sepsis by 89%, and bone fractures by 130%. Why? Because stomach acid isn’t just for digestion - it’s a barrier. Lowering it lets bad bacteria grow. And in a preterm gut, that’s a recipe for disaster.

Despite this, many NICUs still start PPIs routinely. The AAP updated its guidelines in January 2024 to say: stop. But change moves slowly. And while it does, babies are being put at unnecessary risk.

Neurotoxic drugs: Pain relief that might harm the brain

Preterm infants feel pain - and they feel it deeply. But for decades, doctors avoided giving them pain meds, fearing addiction or breathing problems. That changed in the 1990s. Now, 42.7% get opioids. 28.3% get benzodiazepines. Both are powerful. Both are neurotoxic.

Studies show repeated exposure to these drugs during critical brain development windows can alter neural connections. The result? Higher risk of attention deficits, learning delays, and behavioral issues later in life. The AAP now says: don’t use them routinely. Use them only when pain is confirmed - and then, use the lowest dose for the shortest time.

That’s easier said than done. Pain assessment in nonverbal infants is hard. But tools like the CRIES scale and the CRIES-2 are now standard in top NICUs. Nurses are trained to look for facial grimacing, limb withdrawal, and changes in heart rate - not just crying. And when pain is confirmed, non-drug options come first: swaddling, skin-to-skin contact, sucrose drops. Drugs are the last resort.

What’s changing - and what’s working

Change is happening, but it’s slow. Some NICUs are using pharmacokinetic modeling software like DoseMeRx. It takes into account gestational age, weight, kidney function, and even the presence of PDA to calculate precise doses. In units using it, dosing errors dropped by nearly 60% in babies under 28 weeks.

Standardized weaning protocols for opioids and sedatives are another win. One study found that when NICUs used structured plans to taper these drugs, infants spent 14 fewer days on them - without more pain or distress. That’s a win for the brain and the body.

And then there’s the future. The FDA has fast-tracked NeoFen, the first fentanyl formulation designed specifically for preterm infants. It’s expected to be approved in mid-2025. Researchers are testing “microbiome-sparing” antibiotics that target harmful bugs without wiping out the good ones. The Neonatal Precision Medicine Initiative aims to create individualized dosing models for 25 high-risk drugs by 2026.

What parents should ask

If your baby is in the NICU, you have the right to know what’s being given - and why. Don’t be afraid to ask:

• Is this medication FDA-approved for preterm infants?
• Is there evidence this helps - or is it being used because it’s “what we’ve always done”?
• What are the risks? Can we try non-drug options first?
• How long will my baby be on this? Is there a plan to stop it?

Parents are the most powerful advocates. When they ask these questions, care improves. Studies show NICUs with strong parent engagement have lower rates of medication errors and shorter hospital stays.

The bottom line: Less is often more

Preterm infants don’t need more drugs. They need smarter ones. They need fewer, better-timed, and better-monitored doses. They need clinicians who understand that their bodies aren’t broken adults - they’re developing systems, vulnerable and unique.

The good news? We’re learning. The bad news? Too many babies are still being exposed to drugs with known risks and unproven benefits. The goal isn’t to avoid all medications. It’s to avoid the ones that do more harm than good.

Every dose matters. Every decision counts. And for preterm infants, the right choice today might mean a healthier brain - and a better life - tomorrow.