Steroid use in the Neonatal Intensive Care Unit: a preventable cause of cerebral palsy and developmental delay.

Each year some 40,000 infants in the United States are born more than ten weeks prematurely, that is, after a pregnancy of less than 30 weeks in length. Just 20 years ago, the majority of such newborns died shortly after birth, usually because their lungs were too immature to allow them to breathe effectively. Now, at least 80 percent of extremely premature infants survive to hospital discharge. Those that do perish most often succumb in the first week of life, from strokes, infections and birth defects. Death from the typical lung disease of prematurity--Hyaline Membrane Disease (HMD) or Respiratory Distress Syndrome (RDS)--has become quite rare.

The reasons behind this dramatic improvement in the outcome of preemies with HMD/RDS are important to understand, because the improvement in survival has not been associated with a reduction in the rate of brain damage among the survivors. Many extremely premature infants (perhaps 20 percent, or some 6,000 to 7,000 per year in the US) have either developmental delay (DD) or cerebral palsy (CP). Recently, we have learned that some of these disabilities may be preventable by avoiding administration of a drug, dexamethasone, once commonly used in neonatal intensive care units (NICUs). Understanding this requires an overview of the entire subject of DD and its relationship to extreme prematurity.

Extremely premature babies are not just "small" or "early." They're not ready yet. None of their organ systems function as they should. Starting at the top, almost all of the complex pattern of hills and valleys of the cerebral cortex--the thinking part of the brain--are not even visible in the brain of a 26-weeker. Should such an infant come to autopsy, her brain will look as smooth as a cue ball, split just once down the middle and once on each side. The connections that form the thinking part of the brain, connections designed to develop in the dark, warm, wet, pain-free environment of the uterus, now must develop in a bright, dry, painful NICU. The chances for abnormal development are high.

Inside the premature brain, blood vessels in the ventricles--the fluid-filled chambers where spinal fluid is made--are present that would later shrink and disappear naturally, if the pregnancy were to last until the eight month. Prior to that, these vessels, which are thin-walled and not designed to withstand large changes in blood pressure, may burst and cause strokes. Moreover, the blood supply to the brain surrounding these ventricles, the periventricular white matter, is tenuous. Damage to the periventricular area, often caused by low blood pressure or infection, can cause CP.

Premature lungs are both stiff and sticky. In particular, they lack surfactant, the natural lubricant that keeps the walls of the little air sacs where gas exchange occurs from sticking to each other at the end of expiration. If premature labor is detected early enough to allow delivery to be delayed by a few days, the expectant mother may receive two doses of a particular steroid, betamethasone, that induces the fetus to make surfactant. Often, this minimizes the severity of the subsequent HMD/RDS. Of note is that this particular steroid is given briefly to the mother, not to the fetus directly, and rarely more than once.

Surfactant is available as a medicine to be given directly into the newborn's lungs, and better ventilators have been developed that allow gas exchange to occur in the face of severe disease. The problem of premature lungs sticking to themselves internally has basically been solved, so most extremely premature infants now survive their initial lung disease.

After the HMD/RDS has resolved, however, these immature lungs still contain far more connective tissue than adult lungs. They are stiffer--like sponges instead of balloons. Extremely premature infants will often require continued respiratory support (a ventilator or continuous positive airway pressure) for one to six weeks after their initial lung disease has resolved, until the Chronic Lung Disease (CLD)--a developmental phase in which the connective tissue "clears out" and the air sacs grow--improves. During this phase, optimizing nutrition and avoiding hospital-acquired infections facilitates more rapid lung growth.

Let us turn our attention to the premature infant's gut, and the problems of nourishing such a tiny baby. Until approximately 32 weeks gestation, the gut does not move food forward from mouth to anus with any degree of regularity. Not only do premature babies not know how to swallow, but their stomachs don't empty well, their small bowels don't digest well and their colons don't excrete well. Food just seems to slosh around. At a time when human brain growth is supposed to be at its most rapid, the period from 24 to 30 weeks gestation, the fuel for that growth is difficult to process postnatally.

While it is beyond the scope of this article to describe particular methods of encouraging adequate nutrition in the NICU, some generalities may be stated. Early initiation of small volume feedings coupled with aggressive intravenous nutritional support in the first week or two of life, followed by rapid advances in feed volume once the gut "wakes up," seems ideal. Such an approach has its risks--a life-threatening bowel infection called necrotizing enterocolitis may occasionally occur--but these risks are outweighed by the benefits, and can be minimized particularly by feeding the baby his own mothers milk. Necrotizing enterocolitis is much less common in breast-fed newborns. In addition, a rapid transition away from IV nutrition minimizes the risk of blood infection from the intravenous lines themselves.

To summarize: premature infants are at risk of brain damage because of environmental stress, strokes, particularly vulnerable brain tissues, malnutrition and infection. Until the NICU can more closely resemble a uterus (and efforts to reduce environmental stress are underway), or until premature birth itself can be prevented, some premature infants will inevitably be at risk for serious developmental delay. Doctors have just learned, however, that one of the medicines in common use in NICUs increases that risk markedly.

Let us return to chronic lung disease, CLD, the state of the premature lung after the initial HMD/RDS has been treated with surfactant. Lungs with CLD are stiff; the preemie with CLD may be too weak to move enough air to survive. We know this stiffness will lessen over the course of weeks of patient attention to nutrition and avoidance of infection. In the meantime, though, the infant must be attached to a breathing machine--an uncomfortable life for both the baby and her parents. In addition, correct respiratory support is labor-intensive, expensive, and risky in its own right, predisposing to pneumonia and trauma to the airway. All these risks, too, can be minimized, but only if there are enough experienced nurses to allow for constant and careful observation of every infant.

In the early 1990s a serious nursing shortage developed in the United States. At the same time, hospital reimbursement for the care of premature infants declined, as HMOs and other third-party payers pressured physicians to shorten lengths of stay. If the duration of chronic lung disease could be shortened, money could be saved and, perhaps, outcomes improved. A drug to treat CLD was needed.

An old medical aphorism states that "in times of desperation atheists turn to God, and doctors turn to steroids." Pediatricians already knew that, given prenatally, steroids could help prevent HMD/RDS. Why, then, not try steroids after birth to treat chronic lung disease? In fact, there was every reason to think that dexamethasone--a powerful synthetic steroid that reliably loosens up connective tissues--might improve CLD. That dexamethasone treatment also causes high blood pressure and ulcers and predisposes to fungal infection may be true, but we have other drugs to treat those complications. That dexamethasone also stunts growth--well, that is the tradeoff for keeping the premature infant alive. So dexamethasone was tried, and it worked. A few days of steroids and many ventilator-dependent infants can come off their machines. Their parents can hold them more easily, their sore mouths and noses heal, they can learn to eat earlier, and then, perhaps, even go home sooner. Parents are happier. Money is saved.

The problem is that premature infants treated with steroids are approximately twice as likely to have DD or CP as those not treated. No drug can treat that period of stunted growth the steroids cause. Developmental delay in the premature infant is usually the result of many cumulative insults. Harsh environment, inadequate nutrition, and infection all may contribute. Steroid treatment of CLD seems, often, to be the final straw.

The data are new, and still somewhat controversial, but most neonatologists, the American Academy of Pediatrics and the Canadian Paediatric Society now accept them. From the February 2002 issue of Pediatrics:

"On the basis of limited short-term benefits, the absence of long-term benefits, and the number of serious short and long-term complications, the routine use of systemic dexamethasone for the prevention or treatment of CLD in extremely premature infants is not recommended.... Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support). In those circumstances, parents should be fully informed about the known short- and long-term risks and agree to treatment."

In short, while dexamethasone does help get preemies "off the ventilator," that small benefit is not worth the long-term risk.

So how was is it that perhaps one-third of extremely premature infants born in the US in the 1990s were treated with a drug that we now learn may cause DD and CP?. The answer is simple: only large, long-term studies, many just completed, could reveal the added risk. Individual neonatologists rarely treat NICU graduates beyond a few months after discharge. Low IQ and cerebral and motor delay are generally diagnosed after the baby is one year of age. As is often the case, a promising treatment only later has been shown to have serious, unanticipated side effects.

What, then, can we learn from the data regarding post-natal steroid use in the premature infant? As of 2002, we know that such treatment should be restricted to those rare, life-threatening cases of CLD that may, on occasion, occur in the tiniest and sickest of preemies. More important, however, parents and professionals alike must learn to accept better the dual nature of modern neonatal care.

For the first few days of life, most extremely premature infants are critically ill--so sick they may die. Almost any intervention is justified in order to keep the baby alive. After the crisis has passed, however, aggressive interventions are more likely to harm than help. The rest of a tiny preemie's hospitalization must be focused on growth, establishing good nutrition and avoiding infections. The change in emphasis--for parents, for doctors, for nurses--is both necessary and profound. Patience, not action, becomes a virtue. Less truly becomes more.

Regardless of how they are cared for, many infants born after pregnancies of less than 30 weeks will have handicaps and some, tragically, will die. We can minimize the suffering of the survivors only by remembering what our grandmothers knew:

Babies need to be kept warm and clean. They need to be held and well fed. And once a baby is growing, only rarely does it need strong medicine.