Infection in the Extremely Preterm Infant — Part 3 of 6: Prevention — Stopping Infection Before It Starts

How NICU teams try to keep the smallest, earliest babies from getting infections — and what the research really shows

Babies born very early — before 28 weeks of pregnancy — are extraordinarily vulnerable to infection, and much of a NICU team's daily work is quietly aimed at preventing it. The encouraging news is that the most dependable protections are not exotic drugs but careful, consistent habits: spotless handling of the tiny tubes that deliver nutrition and medicine, feeding a baby their mother's milk, and using antibiotics thoughtfully. The harder truth is that many "preventive" treatments were mostly tested in larger, slightly older preterm babies, so their benefits are less certain for the smallest infants. This article, Part 3 of the six-part In[Neo]Sight series Infection in the Extremely Preterm Infant, explains what genuinely helps and where the science is still uncertain.

Why infection is such a danger, and how prevention became a science

An extremely preterm baby arrives before the immune system, the skin, and the gut are ready for the outside world. The skin is so thin it barely holds moisture, the immune defences are immature, and lifesaving care itself — a slender catheter threaded into a vein, a breathing tube, days of intravenous nutrition — creates openings that germs can use. For a long time, bloodstream infections from these catheters were treated almost as bad luck, an unavoidable price of intensive care. That view changed in the 2000s, when hospitals discovered that following the same careful steps every single time — a checklist for inserting a line, a strict routine for keeping it clean — could prevent a large share of these infections. The U.S. Centers for Disease Control and Prevention turned that discovery into a formal guide for newborn units, written around the vulnerability of a baby weighing just 500 grams (about 1 pound) born at 24 weeks [1]. One statewide effort in New York cut catheter-related bloodstream infections from 3.5 to about 2.1 for every 1000 days a line was in place [2] — proof that steady, shared routines save lives. Today the same evidence means parents can reasonably expect their baby's unit to follow a written routine for every line, every day.

The protections that work best are habits, not products

The prevention strategies with the strongest track record are built into how a unit works rather than given to the baby. When NICUs adopt "care bundles" — fixed sets of steps for placing and maintaining catheters — bloodstream infections fall by roughly 60% [3]. And unlike many treatments, this benefit holds up even for the very smallest babies: a 2026 review found that quality-improvement programmes still meaningfully reduced late infections in the tiniest infants, cutting the odds by about half [4]. The second great protector is a baby's own mother's milk. Compared with formula, mother's milk dramatically lowers the risk of necrotising enterocolitis — a severe intestinal illness — reducing it by close to 80% in small preterm babies [5], and the American Academy of Pediatrics now treats human milk as the standard, preferred nutrition for these infants [6]. This is why NICU teams work so hard to support pumping and milk supply, and why even a few drops of colostrum — the thick first milk produced in the days after birth — matter. In[Neo]Sight explores the milk evidence further in its article on the exclusive human milk diet.

When a baby needs a breathing machine, and the lung infection that can follow

Many babies born before 28 weeks cannot yet breathe well enough on their own, so the team places a breathing tube — a soft, narrow tube passed through the mouth or nose into the windpipe — and connects it to a ventilator, a machine that gently pushes air and oxygen into the lungs. It is often lifesaving. But the tube also holds open the body's own defences: it bypasses the nose and throat, which normally filter and warm the air, and it gives germs a direct path into the lungs. When a baby on a ventilator develops a lung infection this way, doctors call it ventilator-associated pneumonia. For a family it usually means more days on the machine, more antibiotics, and a longer stay in the NICU.

Here too, steady routines are the best protection. A 2026 review of NICU "care bundles" for babies on ventilators — fixed sets of steps such as strict hand hygiene, careful handling of the tubing, and keeping the head of the bed slightly raised — found that cases of this pneumonia fell by roughly half (a relative risk of 0.52), and that deaths fell by roughly half as well (relative risk 0.53); hand hygiene was part of every single one of the 11 programmes studied [7]. That last detail is worth remembering: the simplest step is the one no successful programme leaves out.

Two honest cautions belong alongside those numbers. The first is that this pneumonia is genuinely hard to identify in a tiny baby. There is no single agreed test for it, and the standard checklists used in hospitals were never written for newborns. In one striking example, when two groups examined the same babies, the hospital's infection-control team counted 37 cases while the unit's own neonatologists counted just 7 [8]. So when a unit reports that its pneumonia rate has fallen, part of that change reflects how cases are counted, not only how well babies were protected — which is why the drop in deaths is the more convincing finding. The second caution is that almost none of this research looked specifically at the earliest babies. In fact, there is no reliable, up-to-date study reporting how often this pneumonia occurs in babies born before 28 weeks at all — the figures that exist describe newborn units as a whole.

The step experts rate most highly is the simplest to describe and the hardest to achieve: avoid the breathing tube altogether where it is safe to do so, using gentler support such as pressure delivered through soft prongs in the nose [9]. A lung that never has a breathing tube in it cannot get this kind of pneumonia. Even here, though, no study has directly tested whether choosing gentler breathing support prevents this pneumonia in extremely preterm babies — and for babies born before 26 weeks there is, at present, no research at all on any way of preventing it. That is a real gap, and one families deserve to hear stated plainly. What you can do is ask your team how long they expect your baby to need the tube, whether a trial off it is being considered, and how they protect the airway day to day — and, as always, insist that every pair of hands is cleaned before they touch your baby.

The treatments that look promising but are less certain for the smallest babies

Some preventive treatments given directly to the baby seem to work well overall but fade when researchers look specifically at the tiniest infants. Probiotics — supplements of "good" gut bacteria — reduce serious intestinal disease and death when studied across preterm babies as a group, but in the smallest babies the benefit shrinks until it is no longer clear [10]. These products are also genuinely debated among experts: after one baby died from an infection linked to a contaminated probiotic, the U.S. Food and Drug Administration issued a warning in 2023, while European specialist groups argued the smallest babies might benefit most — a disagreement that remains unresolved [11]. The sensible takeaway for families is not alarm but honesty: this is an area where thoughtful experts disagree, and each unit makes a careful policy choice. If your baby's team uses or avoids probiotics, it is reasonable to ask why.

Using antibiotics carefully is its own kind of prevention

It may seem surprising, but giving fewer antibiotics can be a form of prevention. Antibiotics are essential when a baby has an infection, but using them longer than necessary disturbs the developing gut and encourages resistant germs. For years, doctors believed long courses of early antibiotics directly caused death and intestinal disease in tiny babies. More recent, careful studies temper that claim: a large U.S. research-network study of 5730 babies born at 22–28 weeks did not find a clear link between longer early antibiotics and death or intestinal disease [12]. What the research does show clearly is that antibiotic use varies enormously from one hospital to another for no good reason, and that national use has fallen substantially without any sign of harm [13]. This is why many NICUs now schedule an "antibiotic time-out" after 36 to 48 hours to stop the drugs promptly when cultures are negative. If you notice your baby is still on antibiotics after a couple of days, it is perfectly reasonable to ask whether the cultures have come back and whether the antibiotics are still needed; good units welcome that question.

Protection that begins before birth, and one that is still hard to get right

Some prevention starts during labour. Group B streptococcus (GBS) is a common bacterium that can cause dangerous newborn infection, and giving the mother antibiotics during labour prevents a large share of these cases — across more than 10 million births, this practice roughly halved early GBS infection [14]. Honest guidelines note, though, that there is little direct evidence about how well it protects the very earliest babies specifically, even though preterm infants are far more likely to die if they do get GBS [15]. A different challenge is cleaning a baby's skin before procedures. Antiseptics prevent infection, but a tiny baby's paper-thin skin can be burned by the very solutions meant to protect it — nearly all reported antiseptic skin injuries in newborns happened in extremely preterm babies [16]. NICU teams manage this by using the smallest amount of antiseptic, keeping it from pooling under the baby, wiping away any residue, and watching the skin closely. It is a good example of how, for the tiniest babies, even a routine protective step has to be balanced against a real risk of harm.

What this means for families, and what researchers are working on next

If your baby was born extremely early, the strongest protections are the steady, everyday ones: meticulous handwashing and catheter care, your own milk whenever possible, and careful, limited use of antibiotics. These are not dramatic, but they are what the evidence supports most firmly for the smallest infants. It is also fair to know that some prevention practices are borrowed from research on larger babies, and a good team will say so rather than overpromise. Researchers are now designing studies that specifically enrol babies born before 28 weeks, so that one day every prevention strategy can be tested in the infants who need it most. Until then, you can be an active partner: ask about your baby's lines, provide milk if you are able, and never hesitate to remind anyone approaching your baby to clean their hands. In prevention, consistency is the quiet hero.

References

  1. Centers for Disease Control and Prevention; Healthcare Infection Control Practices Advisory Committee. Recommendations for Prevention and Control of Infections in Neonatal Intensive Care Unit Patients: Central Line-associated Blood Stream Infections. Atlanta, GA: CDC; 2022 (web version reviewed 2024). https://www.cdc.gov/infection-control/hcp/nicu-clabsi/introduction.html ↩
  2. Schulman J, Stricof R, Stevens TP, et al.; New York State Regional Perinatal Care Centers. Statewide NICU central-line-associated bloodstream infection rates decline after bundles and checklists. Pediatrics. 2011;127(3):436–444. doi:10.1542/peds.2010-2873 ↩
  3. Payne V, Hall M, Prieto J, Johnson M. Care bundles to reduce central line-associated bloodstream infections in the neonatal unit: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2018;103(5):F422–F429. doi:10.1136/archdischild-2017-313362 ↩
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  13. Flannery DD, Zevallos Barboza A, Mukhopadhyay S, et al. Antibiotic use among infants admitted to neonatal intensive care units. JAMA Pediatr. 2023;177(12):1354–1356. doi:10.1001/jamapediatrics.2023.3664 ↩
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