A Tiny Hole in the Bowel: What Doctors Are Learning About Why It Happens to the Smallest Babies

A ten-year study from a Taiwanese newborn intensive care unit points to two treatments that may raise the risk — and explains what that does and does not mean for your baby

Spontaneous intestinal perforation is a small hole that can open in the bowel of the tiniest premature babies, usually in the first week or two of life. A ten-year study of 858 extremely small newborns in Taiwan found that two common intensive-care treatments — a steroid called hydrocortisone, and the use of three blood-pressure medicines together — were more often given to the babies who went on to develop it. The finding is a reason for closer watching, not a reason to avoid treatments a baby needs.

The problem this research was trying to solve

Babies born weighing less than about two pounds (under 1,000 grams) are, for a few weeks, working with a body that was never meant to be outside the womb yet. Their lungs are unfinished, their blood pressure can be unstable, and — the part that fewer families hear about — the wall of their intestine is extraordinarily thin. In a small number of these babies, a single hole opens in the last stretch of the small intestine, apparently out of nowhere. There is no infection eating through the bowel, no dying tissue around the hole, and often the baby has not been fed at all. Doctors call this spontaneous intestinal perforation, or SIP.

It is not the same thing as necrotizing enterocolitis, the more familiar bowel emergency of prematurity, and understanding that difference matters. Necrotizing enterocolitis involves inflammation and dying tissue and is strongly linked to feeding. SIP is a mechanical failure of a wall that was too thin to hold, and it can happen in a baby who has never had a drop of milk. A 2025 study from Chang Gung Memorial Hospital in Linkou, a large referral centre in northern Taiwan, set out to identify which medicines given before the hole appears might be contributing to it [1].

The question has become more pressing, not less. As neonatal units have improved at preventing necrotizing enterocolitis — largely through feeding babies their mother's own milk or donor milk — and as more babies born at 22 to 24 weeks survive, specialists have predicted that SIP will soon be the most common reason an extremely small baby needs bowel surgery [2]. A large study of hospital records across the United States found it affects a few percent of premature babies [3], which matches what the Taiwanese unit saw: 28 cases among 858 babies, or 3.3%.

How families and doctors used to face this

For a long time, SIP was treated as bad luck — something that happened to very small babies for reasons no one could name. That began to change in 2006, when researchers looking at a large national database noticed that babies who perforated had unusually often received an anti-inflammatory drug called indomethacin in their first days [4]. A second study that same year found that giving indomethacin together with a steroid was worse than either alone [5]. Units around the world stopped combining the two.

Then a large trial testing a low dose of the steroid hydrocortisone, given to protect fragile lungs, had to be stopped early — in part because more babies in the steroid group developed holes in the bowel, especially those who were also getting indomethacin [6]. A later review pooling many trials found that the extra risk clustered in babies given hydrocortisone during their first week of life [7], and a study combining the original records of individual babies from several trials found the same pattern of interaction between the two drugs [8].

But then the picture blurred again. Newer studies from Canada and the United States suggested the real culprit might be a different combination — steroids given to the mother before birth, followed by indomethacin given to the baby [9]. Families and clinicians were left with an honest uncertainty: was hydrocortisone itself risky, or only risky in company?

What this study did

The Taiwanese team reviewed every extremely small baby admitted to their unit over ten years, from January 2014 to December 2023, and identified 28 who developed SIP. To count as a case, a baby needed an X-ray showing free air in the abdomen along with sudden swelling or a bluish-black discoloration of the belly, confirmed by the treating doctor, a surgeon's note, and a separate review of the medical record.

The clever part was the comparison. Rather than comparing the 28 babies with everyone else — which would be unfair, since babies who perforate tend to be smaller and younger to begin with — the researchers used a statistical technique called propensity score matching. For each baby with SIP, they found three babies of nearly identical gestational age, birth weight, sex, and birth year who did not perforate. That gave 84 well-matched comparison babies. They also counted only medicines started at least 24 hours before the hole appeared, so that drugs given in response to a baby already declining would not be mistaken for causes.

The babies who perforated were born at about 25 weeks weighing about 735 grams, and the hole appeared on average at eight and a half days of age. Four babies perforated in the first three days, and interestingly those four were more mature than the ones who perforated later — a pattern first described almost twenty years ago suggesting there may be two different versions of this condition [10].

What they found

Two things stood out. Hydrocortisone — the steroid given to help fragile lungs — had been given to 25% of the babies who perforated, compared with 9.5% of the matched comparison babies. And the use of three blood-pressure medicines together (dopamine, dobutamine, and epinephrine, given in sequence when blood pressure will not come up) appeared in 17.9% of perforation cases versus 2.4% of comparisons. After accounting for other factors, hydrocortisone was linked to roughly three and a half times the odds of perforation, and the triple medicine combination to about twice the odds [1].

Just as important is the long list of things that showed no link: steroids given to the mother before birth, magnesium sulfate, surfactant for the lungs, ibuprofen or paracetamol for a heart-vessel problem called patent ductus arteriosus, caffeine for breathing pauses, and milrinone. This is the first study to look at paracetamol and milrinone in relation to SIP at all, and neither raised a flag — though with only a handful of babies exposed, that reassurance is preliminary.

Why might these two treatments matter? Steroids appear to change the structure of the bowel wall itself, thinning the muscular layer while the inner lining grows — leaving a wall that is, in effect, out of balance [11]. Epinephrine, the strongest of the blood-pressure medicines, raises blood pressure overall but can shunt blood away from the intestine, and laboratory work has shown exactly that effect on the gut's small blood vessels [12]. When blood flow returns, the injury can be worse than the shortage itself.

What this means for your baby — and what it does not

The most important thing to understand is that this is a study of association, not proof of cause. Hydrocortisone and triple blood-pressure support are given to the sickest babies in the unit. It is genuinely difficult to separate the effect of the medicine from the effect of the illness that made the medicine necessary. The researchers took this seriously and found that the pattern held even among babies who had never been fed [13], but they are careful not to overstate what 28 cases can prove. The statistical range around the steroid finding was wide, meaning the true effect could be much smaller than the headline number.

The second thing worth knowing is that fewer of the babies who perforated had started milk feeds. This is not evidence that feeding causes harm or that withholding milk protects. The researchers interpreted it the other way round: babies too sick to start feeding are the same babies most at risk. Feeding your baby breast milk remains one of the clearest goods in newborn intensive care.

What the study reasonably changes is watchfulness. If your baby is started on hydrocortisone for their lungs, or if the team escalates to a third blood-pressure medicine, that is a period — roughly the following three to seven days — when the team should be examining your baby's abdomen carefully at every shift and taking new swelling or discoloration seriously. It is entirely appropriate to ask, "Is my baby in a higher-risk window for a bowel perforation right now, and what are you watching for?" Recent work focused on babies born at 22 to 24 weeks suggests the risk profile may differ at the very earliest gestations [14], so the answer may depend on how early your baby arrived.

What researchers are working on next

Three questions are open. Does the dose and timing of hydrocortisone matter — is the first week uniquely dangerous, as the pooled trial data hint? Can doctors measure blood flow to the gut directly, and identify at-risk babies before a hole forms, rather than inferring risk from a medication list? And do the reassuring results for paracetamol, ibuprofen, and milrinone hold up when many more babies are studied? Larger multi-centre studies would be needed to answer any of these confidently, and the antenatal steroid question in particular remains actively contested [15].

There is one more reason this research matters beyond the operating room. Babies who experience a bowel perforation tend to have more developmental difficulties at 18 to 22 months than similar babies who do not [16]. Preventing even a few of these events would mean more than avoiding a surgery. It would mean protecting the long arc of a child's development — which is, in the end, what every decision in a neonatal unit is trying to do.

References

  1. Cheng W-H, Tu L-H, Chiang M-C, Chen Y-N, Wu W-H, Hsu K-H. The Association Between Perinatal Pharmacologic Treatments and Spontaneous Intestinal Perforation in Extremely Preterm Infants: A Propensity Score Matching Study. Children (Basel). 2025;12(2):142. doi:10.3390/children12020142 ↩
  2. Swanson JR, Hair A, Clark RH, Gordon PV. Spontaneous intestinal perforation (SIP) will soon become the most common form of surgical bowel disease in the extremely low birth weight (ELBW) infant. J Perinatol. 2022;42:423–429. doi:10.1038/s41372-022-01347-z ↩
  3. Elgendy MM, Othman HF, Heis F, Qattea I, Aly H. Spontaneous intestinal perforation in premature infants: a national study. J Perinatol. 2021;41:1122–1128. doi:10.1038/s41372-021-00990-2 ↩
  4. Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol. 2006;26:93–99. doi:10.1038/sj.jp.7211429 ↩
  5. Paquette L, Friedlich P, Ramanathan R, Seri I. Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous intestinal perforation in very low birth weight neonates. J Perinatol. 2006;26:486–492. doi:10.1038/sj.jp.7211548 ↩
  6. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics. 2004;114:1649–1657. doi:10.1542/peds.2004-1159 ↩
  7. Morris IP, Goel N, Chakraborty M. Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis. Eur J Pediatr. 2019;178:1171–1184. doi:10.1007/s00431-019-03398-5 ↩
  8. Shaffer ML, Baud O, Lacaze-Masmonteil T, Peltoniemi OM, Bonsante F, Watterberg KL. Effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone in very preterm infants: an individual patient data meta-analysis. J Pediatr. 2019;207:136–142.e5. doi:10.1016/j.jpeds.2018.10.004 ↩
  9. Kandraju H, Kanungo J, Lee K-S, et al. Association of co-exposure of antenatal steroid and prophylactic indomethacin with spontaneous intestinal perforation. J Pediatr. 2021;235:34–41.e1. doi:10.1016/j.jpeds.2021.03.012 ↩
  10. Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol. 2006;26:185–188. doi:10.1038/sj.jp.7211439 ↩
  11. Gordon PV. Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res. 2009;65:138–144. doi:10.1203/PDR.0b013e31818c7920 ↩
  12. Krejci V, Hiltebrand LB, Sigurdsson GH. Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis. Crit Care Med. 2006;34:1456–1463. doi:10.1097/01.CCM.0000215834.48023.57 ↩
  13. Rayyan M, Myatchin I, Naulaers G, Ali Said Y, Allegaert K, Miserez M. Risk factors for spontaneous localized intestinal perforation in the preterm infant. J Matern Fetal Neonatal Med. 2018;31:2617–2623. doi:10.1080/14767058.2017.1350161 ↩
  14. Thakkar PV, Sutton KF, Detwiler CA, et al. Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22–24 weeks' gestational age. J Perinatol. 2024;44:94–99. doi:10.1038/s41372-023-01782-6 ↩
  15. Laptook AR, Weydig H, Brion LP, et al. Antenatal steroids, prophylactic indomethacin, and the risk of spontaneous intestinal perforation. J Pediatr. 2023;259:113457. doi:10.1016/j.jpeds.2023.113457 ↩
  16. Wadhawan R, Oh W, Vohr BR, et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indomethacin therapy and effects on neurodevelopmental outcomes at 18–22 months corrected age. Arch Dis Child Fetal Neonatal Ed. 2013;98:F127. doi:10.1136/archdischild-2011-300659 ↩