Infection in the Extremely Preterm Infant — Part 1 of 6: Pathophysiology & Epidemiology — How Infection Takes Hold

A plain-language walk through what large hospital-network studies and laboratory research tell us about why the tiniest babies catch infections so easily, and how often it happens

Babies born before 28 weeks of pregnancy get infections far more often than babies born at term, because their skin, gut and immune system are all still under construction when they arrive. In the largest recent study, covering more than 118,000 very preterm babies in 774 American hospitals, about 9 in every 100 developed a bloodstream infection after their first three days of life — and among the very smallest, born at 23 weeks or less, it was closer to 1 in 3. Understanding why this happens is the first step towards preventing it, and this article explains the biology and the numbers in everyday language.

The Problem, and How Families and Doctors Used to Face It

Thirty years ago, the great fear in newborn infection was a bacterium called group B Streptococcus, which mothers can carry harmlessly and pass to their baby during birth. From the 1990s onwards, hospitals began giving antibiotics to mothers during labour when that bacterium was detected, and it worked. Among very small babies (under 1,500 g), infections in the first three days of life fell from roughly 19–32 cases per 1,000 births in the early 1990s to around 9–11 per 1,000 in more recent years. But there was a group the improvement barely reached. Among babies born between 22 and 28 weeks, the rate stayed at about 20–24 per 1,000 across two decades. The official American guidance still records this steep staircase: about 0.5 cases per 1,000 births at full term, about 6 per 1,000 below 34 weeks, about 20 per 1,000 below 29 weeks, and about 32 per 1,000 at 22–24 weeks [1]. At the same time, medicine got much better at helping the smallest babies survive, so the very group that prevention helped least became the group neonatal units now care for most. That is the gap this article is about.

Modern research has filled in the picture. A large American study followed 936 babies born between 24 and 28 weeks who took part in the Preterm Erythropoietin Neuroprotection Trial (PENUT) — a research study run across 19 sites and 30 newborn intensive care units in 13 US states between December 2013 and September 2016. It found that only 64 of 909 babies (7%) went through their whole hospital stay without either a proven or a suspected infection [2]. Infection is not an unlucky exception in this population. It is close to the norm.

Why Their Defences Are Not Ready

Think of a full-term baby as arriving with a starter kit of protection. Most of that kit is delivered in the last weeks of pregnancy, and a baby born at 24 weeks simply leaves before the delivery is complete.

The clearest example is antibodies — the proteins a mother's body makes to recognise infections she has met before. These cross the placenta to the baby, but slowly: a baby has only about 10% of the mother's antibody level at 22 weeks, about 50% at 32 weeks, and receives most of the rest in the final four weeks. Only one type of antibody crosses the placenta at all; the type that normally guards the lining of the gut and airways never crosses [3]. A baby born at 24 weeks therefore arrives with borrowed protection that was only a tenth delivered.

Skin is the second gap. We think of skin as a simple wrapper, but it is a sophisticated barrier that is only finished at about 34 weeks of pregnancy. Extremely preterm babies also have very little vernix — the creamy white coating, roughly 80% water, that carries natural germ-killing substances and protects the skin surface. Healthy skin is slightly acidic, which discourages bacteria; preterm skin is not, and the warm humid air inside an incubator that stops these babies drying out also delays that protective acidity from developing [4]. A German study measured natural germ-killing substances on the skin of 55 newborns and found one of them, called RNase 7, was about half as concentrated on the first day of life in preterm babies as in term babies [5].

Third, the white blood cells that fight infection are present but slow to arrive where they are needed. Their ability to actually swallow and kill bacteria is largely intact — the problem is getting them to the site fast enough [3], and the body runs out of reserves quickly during a serious infection [6]. Some of the chemical "flares" that help summon them sit at only about half of adult levels [7].

Finally, the gut. A term baby's intestine fills with a friendly, diverse community of bacteria; a preterm baby's often does not. In a careful study of 32 very small preterm babies in Taiwan, one bacterial family that includes many troublesome germs made up about 16% of the gut community in term babies by weeks four to seven of life, but had climbed to 73–80% in the preterm babies. Most strikingly, when researchers genetically matched the germ found in a baby's bloodstream to the germs living in that baby's gut, they matched in 4 out of 10 cases — direct evidence that the infection came from inside, crossing an immature intestinal wall [8].

How Often, and What It Means

Infections are grouped by timing. Early infections appear in the first three days and usually come from the birth process. Later infections appear after that and usually come from the baby's own skin or gut, or from the tubes and lines that keep them alive.

The largest picture comes from the Vermont Oxford Network, a quality-improvement network of newborn units. Across 774 centres in 49 US states between 2018 and 2020, 118,650 very preterm babies who survived their first three days were tracked. Of these, 10,501 (8.9%) had a later bloodstream infection — but among those born at 23 weeks or under, the rate was 322 per 1,000, roughly one in three. Babies who had an infection stayed in hospital a median of 102 days compared with 62 days for those who did not. Survival was 78.2% among babies who had a late infection, compared with 94.9% among those who did not [9]. A review focused on the smallest band estimates that 12–28% of babies born at 22 to 26 weeks develop a late infection; that figure is an informed estimate rather than a hard measurement [6].

Parents naturally ask what infection means for the longer term. A Canadian study followed 6,322 babies born before 29 weeks at 26 specialist units and assessed them at 18 to 21 months of age. Significant developmental difficulty was found in 15.0% of babies who had no infection, 22.9% of those who had a bloodstream infection, and 32.0% of those who had meningitis (infection of the fluid around the brain) [10]. The honest reading is that infection shifts the odds — meaningfully, and most of all for meningitis — but it does not decide the outcome. The great majority of babies in every one of those groups did not have significant difficulty.

One thing worth knowing is that most suspected infections are never confirmed by a laboratory test. Worldwide, only about 32% of babies treated for infection ever have the germ actually grown from their blood [11]. When a doctor starts antibiotics on suspicion and then stops them two days later, that is not a mistake — it is the system working as designed, because waiting for certainty in a very small baby is dangerous.

It also matters where in the world a baby is born. A study of 3,204 babies with infection across 19 hospitals in 11 countries, mostly in Asia and Africa, found that the germs there are more often the hard-to-treat kind, and that many no longer respond to standard antibiotics [12]. A second study across Bangladesh, Ethiopia, India, Nigeria, Pakistan, Rwanda and South Africa found that 60% of the germs tested were resistant to the two antibiotics most commonly used first [13]. Meanwhile, in a country with a mature prevention programme, group B Streptococcus infection in Norway occurred in only 0.62 per 1,000 births [14] — proof that prevention can work at national scale when it is properly funded.

When the Body's Own Alarm Causes Harm

One of the most important recent insights is that much of the harm from infection in these tiny babies comes not from the germ itself but from the baby's own inflammation — the emergency response the immune system switches on to fight infection. In very preterm babies this response sometimes begins before birth. When infection or irritation reaches the womb, the unborn baby can mount a body-wide inflammatory reaction that doctors call the fetal inflammatory response syndrome, whose fingerprints can often be seen afterwards in the placenta and umbilical cord [15]. It can affect many organs at once — the blood, the adrenal glands, the heart, the lungs, the skin and, most importantly, the brain [16]. The concern is that this inflammation is one of the main reasons very premature babies are at risk of longer-term difficulties with movement and learning: inflammatory signals can interfere with the cells that build the brain's insulation, called myelin, at exactly the stage when that insulation is being laid down [17]. There is also a "two-hit" pattern, in which inflammation before birth leaves the brain more sensitive, so that a later infection after birth does more damage than it otherwise would [17]. This is encouraging in one respect — it means that preventing and quickly treating infection is not only about clearing germs, it is a way of protecting the developing brain. It is another reason the care team acts fast, and another reason the gentle, everyday things families do to lower infection risk genuinely matter.

What Researchers Are Working On Next

Several open questions are being actively pursued. One is measurement: units around the world define and count infection differently, and agreeing a shared definition would let results be compared honestly. A second is the gut and skin — if the germ that causes infection is often already living on the baby, then feeding, skin care and gentle handling become genuine anti-infection tools rather than comfort measures, and this is exactly where research on breast milk, protective proteins and helpful bacteria is concentrated. A third is fairness: nearly all the detailed data on the very smallest babies come from wealthy countries, while the hardest-to-treat germs are concentrated elsewhere.

This article is Part 1 of the six-part In[Neo]Sight series Infectious Diseases in the Extremely Preterm Infant. Part 2 looks at what infection does inside the body, Part 3 at prevention, Part 4 at treatment, Part 5 at long-term outlook, and Part 6 at nursing perspectives. If you want more on specific prevention tools, In[Neo]Sight has separate articles on the early-onset sepsis calculator, early antibiotics and the microbiome, lactoferrin, the neonatal sepsis nomogram, oropharyngeal colostrum, and zinc.

If your baby is in intensive care, the most useful thing to take from all of this is that the care team's caution is proportionate — and that the skin-to-skin contact, hand hygiene and breast milk you contribute are not side details. They act on exactly the three barriers this research shows are unfinished.

References

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