For the first time in large, multicenter clinical studies, a therapy has been shown to significantly lower the risk of lung and brain damage in some very low birthweight premature infants. Results from two randomized clinical trials demonstrate that when given within the first few weeks of life, inhaled nitric oxide helps prevent chronic lung disease in some low birthweight premature infants. In addition, when used within 48 hours after birth, treatment appears to protect some premature newborns from brain injury.

Combined, the two new, independent studies involved nearly 1,400 very low birthweight premature infants treated at 37 medical centers. The studies represent the largest clinical research effort of inhaled nitric oxide therapy in premature infants, and they offer promising advances in the care of very small premature babies, who are at high risk for delayed growth, lasting problems with their breathing and brain development, and other complications. Other studies of therapies to prevent these potentially debilitating long-term complications have yielded conflicting results. Supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), the studies' results are published in the July 27, 2006, issue of the New England Journal of Medicine in conjunction with a related editorial.

"Medical science has dramatically improved our ability to help very small and premature babies survive. But as the rate of premature births continues to rise, it is even more critical that we develop ways to prevent many of the complications related to prematurity so that these children can lead healthy, robust lives," NIH Director Elias A. Zerhouni, M.D., says.

In 2004, more than one-half million babies in the United States (about 12.5 percent) were born prematurely (less than 37 weeks of pregnancy) — the highest number reported since comparable national data have been available, according to the Centers for Disease Control and Prevention (CDC). Last year, costs associated with premature births in the United States totaled approximately $26.2 billion, or $51,600 per infant, according to a report released July 13 by an independent panel convened by the Institute of Medicine of the National Academies.

Breathing problems at birth are common among babies born very prematurely and at very low birthweight (under 3 pounds). Because their lungs are not fully developed, premature infants are likely to have trouble breathing continuously or on their own, a condition known as respiratory failure. Oxygen and, in many cases, use of a mechanical breathing machine, or ventilator, is used to help them breathe and to protect other organs such as the brain, heart, liver, and kidneys from damage while the lungs have a chance to mature.

However, high levels of extra oxygen or prolonged use of ventilators can damage the lungs and interrupt normal development, leading to a chronic lung disease known as bronchopulmonary dysplasia (BPD). Very small babies (those born weighing less than 1250 grams, or about 3 pounds) are at high risk for BPD even if they do not require a ventilator. BPD is associated with increased risk of ongoing lung problems such as pulmonary hypertension (high blood pressure in the arteries that supply blood to the lungs), sensitivities to secondhand smoke, asthma, and respiratory infections; neurodevelopmental problems such as cerebral palsy; learning disabilities; impaired growth; and cardiovascular problems. In the United States, more than 10,000 babies develop BPD each year.

Previous studies have shown that inhaled nitric oxide (iNO) can help full-term newborns with severe respiratory failure survive without the need for treatment with a heart-lung machine, thereby lowering their risk of developing BPD and related long-term complications. But the benefits and risks of treatment in premature and very low birthweight babies have been uncertain.

The two new trials were conducted independently at different medical centers. Both involved infants born at less than 34 weeks of pregnancy who weighed between 500 and 1250 grams (about 1 pound to 3 pounds) at birth and who needed a ventilator to help them breathe. In one study, patients were treated with iNO within the first 48 hours of life; in the other study, treatment began between 1 week and 3 weeks of age. Combined, the studies reveal important benefits without adverse effects from iNO treatment.

"The findings from these two large, multicenter trials should help us better identify which babies might benefit from inhaled nitric oxide," noted Elizabeth G. Nabel, MD, director of NHLBI. “Successful and early treatment of breathing problems in these babies would represent a significant advance in improving the health and quality of life of a growing number of premature babies.”

In the first study, nearly 800 babies were given either low-dose iNO or placebo (a harmless gas) starting within the first 48 hours of life and continuing through 21 days or until they no longer needed breathing assistance. Researchers found that the effects of iNO on survival without BPD were related to birthweight. Although treatment did not lower the overall incidence of BPD at 36 weeks, iNO appeared to cut the risk of BPD in half among the babies who weighed 1000 grams to 1250 grams (about 2.5 pounds) at birth.

In addition, significantly fewer babies treated with iNO developed brain damage, as indicated by head ultrasound. In particular, treated babies who weighed between 750 grams and 1000 grams (about 2 pounds) when they were born had half the risk of brain damage compared to babies of similar size who did not receive treatment.

"When given within the first 48 hours of life, low-dose inhaled nitric oxide reduced the risk of brain injury in very low birthweight premature newborns who required mechanical ventilation after birth,” said John P. Kinsella, MD, lead author of the study, which was conducted at 16 clinical sites. Kinsella is a neonatologist with the Pediatric Heart Lung Center at Children's Hospital in Denver and professor of pediatrics in the School of Medicine at the University of Colorado at Denver and Health Sciences Center. "We are optimistic that this therapy could prevent long-term developmental and neurological problems in many of these children."

Kinsella cautions that children need to be studied for longer periods to better understand the long-term effects of treatment and to confirm the protective effects on brain development. He and his colleagues will continue to follow these participants for another 4.5 years.

In the second study, nearly 600 very low birthweight premature babies at very high risk of developing BPD were randomly selected to begin iNO treatment or placebo beginning at between 7 days and 21 days of age. They were treated for at least 24 days. Overall, more babies treated with iNO survived without BPD at 36 weeks than those who did not receive treatment (44 percent versus 37 percent). The benefits were even more apparent among the group of infants who began treatment between 7 and 14 days after birth — these babies had twice the rate of survival without BPD compared to their peers who did not receive treatment. All participants will continue to be followed for an additional 2 years.

"In addition to improving the rate of survival without BPD in these premature infants, we found that inhaled nitric oxide was associated with less severe lung disease among the treated infants who did develop BPD," noted Roberta A. Ballard, MD, professor of pediatrics and obstetrics and gynecology and formerly chief of the Neonatology Division at The Children’s Hospital of Philadelphia and the University of Pennsylvania, and lead author of the study. "At 40 and 44 weeks, the treated infants had shorter hospitalizations and less need for mechanical ventilation or oxygen therapy than those who did not receive treatment."

Mary Anne Berberich, PhD, NHLBI project officer for the two studies commented, "Inhaled nitric oxide appears to play a role in preventing breathing problems and possibly brain damage related to prematurity and very low birthweight. The results of these two studies highlight the effects of treatment on premature newborns of different ages and sizes."

INO Therapeutics, of Clinton, N.J., supplied nitric oxide and gas delivery equipment for the two NHLBI-supported studies.

To schedule an interview with NHLBI experts, please call the NHLBI Communications Office at (301) 496-4236. To reach Dr. Kinsella, please call Deborah Méndez-Wilson, UCDHSC Office of Public Relations, (303) 724-1520, or Natalie Goldstein, media relations manager, The Children's Hospital, 303-861-3970. To speak with Dr. Ballard, send email to ballard@email.chop.edu or contact Joey McCool at (267) 426-6070 or at MCCOOL@email.chop.edu.

Bronchopulmonary dysplasia:
http://www.nhlbi.nih.gov/health/dci/Diseases/Bpd/Bpd_WhatIs.html

The National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at: www.nhlbi.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.