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

When a baby is born too soon, every decision matters-even the smallest dose of medicine. Preterm infants, born before 37 weeks, don’t just need extra care-they need medications that are carefully matched to their tiny, still-developing bodies. But here’s the hard truth: most drugs given in the NICU weren’t designed for them. And the side effects? They can last far longer than the hospital stay.

Why Preterm Infants Are So Sensitive to Medications

A preterm baby’s liver, kidneys, and brain are still under construction. Their ability to absorb, break down, and get rid of drugs is nothing like a full-term infant’s, let alone an adult’s. At 28 weeks, a baby’s cytochrome P450 enzymes-responsible for metabolizing over 70% of medications-are only at 30% of adult function. They won’t reach full maturity until the child is a year old. That means a drug that clears quickly in a 1-year-old can build up dangerously in a 29-week-old preemie.

Add to that the fact that many preterm infants have conditions like patent ductus arteriosus (PDA), which changes how drugs spread through their bodies. One study found that PDA can increase the volume of distribution for certain medications by up to 80%. That’s not a small tweak-it’s a complete shift in how the drug behaves. Without adjusting for this, you’re not just underdosing or overdosing-you’re flying blind.

The Most Common NICU Medications and Their Hidden Risks

Let’s look at the drugs you’ll see in nearly every NICU-and what they’re really doing to these tiny patients.

• Caffeine citrate is the go-to for apnea of prematurity. It works. But 18.7% of babies on standard doses develop tachycardia. Another 7.3% can’t feed properly because of stomach irritation. Dose adjustments aren’t optional-they’re necessary.
• Opioids and benzodiazepines are used to manage pain and sedate babies during procedures. Yet a 2021 JAMA study found that 100% of extremely preterm infants received at least one of these drugs during their NICU stay. That’s not rare-it’s standard. But we now know these drugs can interfere with brain development. The AAP now advises against routine use, yet many units still default to them.
• Antibiotics are given to nearly half of preterm infants, often for suspected sepsis that never gets confirmed. But research shows these babies end up with gut microbiomes packed with 47% more harmful bacteria and 32% fewer good ones. These changes don’t fix themselves. They can persist for years, increasing risks for infections, allergies, and even obesity later in life.
• Proton pump inhibitors (PPIs), used to treat reflux, are prescribed to 41% of NICU graduates. But they come with a steep cost: 1.67 times higher risk of necrotizing enterocolitis (NEC), 1.89 times higher risk of late-onset sepsis, and 2.3 times higher fracture risk. The 2022 Cochrane review found no real benefit. And yet, they’re still widely used.
• Magnesium sulfate, given to moms before preterm birth to protect the baby’s brain, reduces cerebral palsy risk by 30%. But in infants under 26 weeks, it’s linked to a 2.4-fold increase in meconium-related ileus-a dangerous bowel blockage.

Off-Label Use Is the Norm, Not the Exception

Only 35% of medications used in NICUs have FDA approval for infants. For respiratory drugs? That number drops to 8%-meaning 92% are prescribed off-label. That doesn’t mean they’re unsafe. It means we’re guessing.

Doctors and pharmacists rely on outdated formulas, adult dosing scaled down, or small studies with limited data. One NICU pharmacist reported that 76.3% of medication protocols need to be adjusted based on gestational age. A 28-week baby isn’t just a smaller 36-week baby. Their metabolism, fluid balance, and organ function are fundamentally different. Yet most hospitals still use weight-based dosing alone, ignoring the critical role of gestational age.

Medication Errors Are More Common Than You Think

Nurses in NICUs report that 68.4% see at least one medication error per month. Most are due to miscalculating weight-based doses-sometimes by just a few milligrams. In a baby weighing 800 grams, that’s enough to cause a seizure, a dangerous drop in blood pressure, or cardiac arrest.

One parent shared on a support forum: “My son got 28 days of antibiotics for suspected sepsis that was never confirmed. Now, at age 2, he’s had five ear infections and two rounds of antibiotics.” That’s not an isolated story. It’s a pattern. Early antibiotic exposure alters immune development, making these babies more vulnerable long after they leave the hospital.

What’s Changing-And What’s Working

Thankfully, things are shifting. NICUs that use standardized weaning protocols for opioids and benzodiazepines cut medication exposure by nearly two weeks-without increasing pain or distress. That’s huge.

Pharmacokinetic modeling software like DoseMeRx is now used in 37.2% of Level IV NICUs. It cuts dosing errors by almost 60% in the tiniest babies. It doesn’t replace clinical judgment-it supports it. It takes into account gestational age, postnatal age, kidney function, and even the presence of PDA to calculate safer doses.

The AAP updated its guidelines in January 2024 to specifically recommend against routine use of acid-suppressing drugs in preterm infants. That’s a direct response to the growing evidence of harm. And the NIH’s Neonatal Precision Medicine Initiative is working on building gestational age-specific models for 25 high-risk medications by 2026.

What Families Should Know

Parents aren’t just observers-they’re essential partners. Ask:

• Why is this medication being given?
• Is there evidence it helps preterm infants like mine?
• Are there alternatives?
• What side effects should I watch for?

Don’t assume a drug is safe because it’s in the NICU. Many of the most common medications have little to no proven benefit-and real risks. If your baby is on antibiotics for more than 48 hours without confirmed infection, ask if the course can be shortened.

The Bigger Picture: Why This Matters Beyond the NICU

The drugs given in the first weeks of life don’t just affect a baby’s stay in the hospital. They shape their future. Gut microbiome changes from antibiotics can influence immune health for years. Neurotoxic medications may contribute to learning delays or attention issues. Even small doses of opioids may alter pain sensitivity later in life.

The Institute of Medicine estimates that medication-related complications currently account for 18.3% of neurodevelopmental impairments in extremely preterm infants. That’s more than 1 in 5. And the cost? $2.4 billion a year in extra care through age five.

We’re not just treating a sick baby-we’re shaping a child’s long-term health. That demands more than good intentions. It demands precision, evidence, and courage to question the status quo.

What’s Next?

The future is coming. A new neonatal-specific fentanyl formulation (NeoFen) is on track for FDA approval in early 2025. Microbiome-sparing antibiotics are in Phase II trials. Researchers are finally building dosing models that reflect real biology-not guesses.

But until then, the best tool we have is awareness. Every dose matters. Every decision counts. And the most powerful question in the NICU isn’t “What should we give?”-it’s “Do we really need to give this at all?”