Caroline Helwick

October 21, 2012

NEW ORLEANS — Caffeine therapy initiated for prevention of apnea of prematurity shortly after birth reduces gross motor function impairment and, in infants who are small for gestational age (SGA), improves many hospital-related outcomes, new research suggests.

Here at the 2012 American Academy of Pediatrics National Conference and Exhibition, Barbara Schmidt, MD, principal investigator of the Caffeine for Apnea of Prematurity (CAP) study, presented 5-year follow-up results. Other investigators reported new information on its benefits in SGA premature infants.

"Striking" Reduction in Length of Stay

In a study led by Pradeep Alur, MD, of WellSpan Health in York, Pennsylvania, caffeine therapy initiated within 3 days of life in premature (≤ 29 weeks) SGA infants reduced the duration on mechanical ventilation and shortened hospital length of stay.

"We believe that ours is the first study to compare the effect of early caffeine on neonatal outcomes in SGA preterm infants," he said.

SGA infants have significantly higher mortality and risk for chronic lung disease (CLD) and longer hospital stays than premature infants whose size is appropriate for gestational age (AGA).

The retrospective chart review (2007 - 2011) included data for 198 premature infants surviving to discharge or to 36 weeks corrected gestational age. Caffeine was prescribed at the discretion of the attending neonatologist for either periextubation prophylaxis or for treatment of apnea.

The study evaluated the benefit of initiating caffeine started ≤3 days of life (the "early caffeine" group), compared with control participants, who could have received caffeine on day 4 or later.

The study examined not only the benefit of caffeine but also differences in various outcomes between SGA infants and AGA infants.

The early-caffeine group had a lower incidence of CLD, a shorter hospitalization, and shorter duration of ventilation, said Dr. Alur.

The incidence of CLD was 52% among SGA infants and 19.7% among AGA infants (P ≤ .001); 24% of SGA infants vs 5.8% of AGA infants needed oxygen at discharge (P = .002).

Mean length of stay was 110.3 days for the SGA group vs 73.1 days for the AGA infants (P < .001), and mean duration of mechanical ventilation was 42 vs 16, respectively (P < .001).

Caffeine therapy provided a number of benefits for these SGA infants, of whom 90% developed CLD in the control group, compared with 25.4% in the early-caffeine group (P ≤ 0.001); 33.8% vs 17.4%, respectively, were on oxygen at discharge (P = .008).

Differences in length of stay were "striking," Dr. Alur noted. Length of stay was 152 days in the control group vs 82 days (P = .004) with early caffeine therapy, and 51 vs 19 days, respectively, on the ventilator (P < .001).

Confounding Factors?

"Our results strongly suggest that starting caffeine within 3 days of life is beneficial in the SGA preterm infants," said Dr. Alur.

"The fact that 90% of our SGA infants compared to 25% of the AGA infants in the control group developed CLD, which is statistically significant, is very concerning," he added. "It may be important to start caffeine in these vulnerable preterm infants soon after birth to reduce morbidities."

Dr. Schmidt, who is with the Hospital of the University of Pennsylvania, in Philadelphia, and who is principal investigator of the CAP trial, commented on the new findings. She said this is "interesting information," but there could be confounding factors that cloud the conclusions.

"The problem is there may be reasons why you gave the caffeine earlier to some babies. It could well be true that earlier is better in SGA babies, but it could also be that if you have a baby who is fully ventilated, you would not be so inclined to give caffeine early.

"That child would be sicker and therefore would get it later, and because he is sicker to begin with, he or she automatically has a worse outcome," she explained. "You can't really tease out these confounding factors, but the study raises an interesting hypothesis," she said.

Data Mining

CAP investigators are mining the data of this landmark study to determine the implications of its finding and to uncover factors that may lead to better outcomes for subgroups of infants, said Dr. Schmidt.

Starting in 1999, the global study randomly assigned 2000 preterm infants weighing 500 g to 1200 g to receive caffeine citrate or saline to treat or prevent apnea. Initial results showed that caffeine improved the rate of survival without neurodevelopmental disability at a corrected age of 18 months.

The 5-year follow-up, published this year (Schmidt B et al, JAMA 2012;307:275-282), showed that the benefit of the intervention in reducing the composite of death or disability — although still favorable — was no longer significantly higher for babies receiving caffeine compared with those receiving placebo.

However, significant benefit was derived in the area of gross motor function, which Dr. Schmidt described in her presentation.

Rates of the primary outcome — death or survival with at least 1 impairment (motor impairment, cognitive impairment, behavior problems, poor general health, severe hearing loss, or bilateral blindness) — were 21.1% with caffeine therapy and 24.8% with placebo (odds ratio, 0.82; P = .09).

However, a secondary analysis indicated that caffeine therapy was associated with better gross motor function, manual dexterity, and visual perception. Gross motor function, as determined by the Gross Motor Functional Classification System (GMFCS), was normal in 91% of the caffeine group vs 86% in the placebo group, for a 36% reduction in risk that was statistically significant (P = .006).

GMFCS levels between 1 and 5 indicate increasing limitations of gross motor function. A total of 1553 children were assigned a GMFCS level at both ages. Of the 30 children with a GMFCS level greater than 2 at 18 months, 26 (86.7%) had a level greater than 2 at 5 years. Of the remaining 1523 children with a GMFCS level of 2 or less at 18 months, 1515 (99.5%) remained unimpaired or mildly impaired at 5 years.

With caffeine therapy, "there was a reduction in the severity of impairment related to motor disorders," she said.

The CAP investigators are currently evaluating social factors that may be influencing cognitive gains at 5 years, and Dr. Schmidt said they are finding some "striking observations" that will be published soon. They are also evaluating means of intervening to produce better outcomes.

Important Study

Carl Bose, MD, professor of pediatrics at the University of North Carolina, in Chapel Hill, commented to Medscape Medical News following the lecture.

"This was terrific presentation. There has been some misunderstanding of the 5-year follow-up because there was no difference in the primary outcome, but I think Dr. Schmidt explained why CAP is a very important study," said Dr. Bose.

"There were some people who have pointed out that caffeine therapy made a difference at 2 years but not at 5. But it is important to recognize that while the cognitive benefits seemed to disappear, the motor outcomes persisted."

"And if you ask parents, they will argue that this is a very important outcome, particularly severe motor disability, which is something they all want to avoid. That alone would be worth giving the treatment," he added.

Dr. Schmidt, Dr. Alur, and Dr. Bose have disclosed no relevant financial relationships.

The American Academy of Pediatrics National Conference and Exhibition. Abstract 16162. Presented October 21, 2012.