Early exposure to infection may benefit preterm infants

A new study detailing the impact of early infection, antibiotics, and vaccines in preterm infants also offers hope that new vaccine therapies could help decrease sepsis and long-term damage in this vulnerable population.

The study, published in Frontiers in Immunology, outlines the current practice and treatment for early infection exposure in preterm infants while hinting at new discoveries on the horizon.¹

All neonates are exposed to infections, antibiotics, or vaccines early in their lives. Unlike adults and older children for whom sepsis results in an increased risk of subsequent infection, the researchers note that subsequent infection is of lesser concern in neonates. Instead, septic infants run a greater risk of developing long-term neurodevelopmental problems.

Early onset sepsis in neonates usually develops as a result of maternal ascending vaginal infection, with untreated group B Streptococcus infection, prolonged rupture of membranes, and chorioamnionitis all increasing the risk of infection.

Some of these infections may prove beneficial, however, with research indicating that sepsis among preterm infants appears to have a protective effect against childhood asthma. Another recent study referenced in the report found that children who had reduced exposure to bacteria in their first year of life were more likely to develop atopy by age 3 years.

For this reason, the researchers caution against the current practice of administering empiric antibiotics in preterm infants. Antibiotics can increase length of stay and also the risk of necrotizing enterocolitis or death when given long-term, according to the study findings. Most neonates, out of concern for infectious complications, are given empiric antibiotics shortly after birth, the study notes.

There is evidence of resistance attributed to intrapartum antibiotic use or maternal antibiotic prophylaxis, according to the report, and empiric antibiotic use is a standard of practice among preterm infants, making these medications the most commonly used medications in neonatal intensive care units.

“This phenomenon is largely due to the difficulty of accurately diagnosing neonatal sepsis in symptomatic neonates with developmental immaturity,” the researchers write. “A retrospective cohort analysis of 5693 extremely low birth weight neonates demonstrated that 98% of neonates received antibiotic treatment in the first 3 postnatal days, while <2% of neonates had positive blood cultures and clinical symptoms of early onset sepsis.”

The majority of neonates with negative cultures who received more than 5 days of empiric antibiotics were found to have a 4% increase in the odds of developing necrotizing enterocolitis and a 16% increase in the odds of death, according to the study.

Shawn D. Larson, MD, FACS, from the division of Pediatric Surgery in the Sepsis and Critical Illness Research Center and a surgeon at the University of Florida College of Medicine, Gainesville, co-authored the report and says widespread antibiotic use may do more harm than good.

“The use of empiric, long-term antibiotics without a proven infectious source can have detrimental effects on the newborn including increased risk of subsequent infections and even neonatal death,” Larson says. “The improper use of antibiotics likely has long-term, negative effects as well, including increased risk of developing asthma, diabetes, and obesity as referenced in the review article. Our laboratory, along with others, [is] exploring ways to develop new immune therapies that act by promoting or strengthening the newborn's ability to fight off dangerous bacteria and viruses.”

Early exposure to nonlethal infections actually can have short-term and long-term benefits for most premature infants, but there are also risks, Larson says. “In order to harness the benefits without the risks associated with exposure to live virulent pathogens, vaccines have been developed. There is overwhelming evidence of the clear long-term benefits of vaccines,” he says.

“Unfortunately, newborns do not respond to vaccines in the same way as infants and children given differences in their immune system. The belief is that premature infants and newborns do not have the ability to develop ‘immunological memory,’ meaning that their bodies will not remember exposure to the antigen or infection,” Larson says.

Immunization with vaccines containing adjuvants may be the key to harnessing the power of the infant’s own immune system.

Vaccines typically have been of little use in the first month of life with the exception of vaccines against hepatitis B and tuberculosis, according to the study, but adjuvants may offer additional benefit. Some adjuvants currently being used with some success in the United States and Europe include aluminum salts, oil-in-water emulsions (MF59, AS03, AF03), virosomes, and AS04 (monophosphoryl lipid A [MPLA] preparation with aluminum salt), the study notes.

The key to understanding how to prevent infection and early onset sepsis in neonates is to understand the mechanisms of the immune function, and to investigate interventions like the addition of adjuvants to vaccines, according to the report.

“Administration of [bacillus Calmette-Guérin (BCG)] vaccine at birth in Guinea-Bissau led to a 41% reduction in all-cause mortality at 12 months among very low birth weight neonates. This reduction was attributed not to reduced tuberculosis but to fewer cases of neonatal sepsis and respiratory infections,” the report states. “It is likely that the success of this vaccine in early life is due to the induction of a strong immune response . . . . These findings require further investigation and may lead to the development of novel immune agonists that can augment the host immune response early in life with an associated reduction in the infectious burden in neonates.”

“Evidence from long-term vaccine studies demonstrated that vaccination shortly after birth with the [BCG] vaccine had fewer infections overall, and not just to tuberculosis,” Larson adds. “As such, we recommend continued research of novel agents to help improve the newborn's immune response to vaccines.”

This evidence may provide the key to treating infections such as sepsis, which has traditionally been understudied in the infant population.

“We believe that the best way to treat sepsis is by preventing it from happening particularly in the very vulnerable premature neonates. Our laboratory has currently seen evidence that a common immune adjuvant improves survival to sepsis in neonatal mice,” Larson says, adding that the research is currently under review for publication and more research will be needed to uncover the differences in how mice responded in comparison with humans.

Larson says he hopes pediatricians will continue to investigate the interventions they use and that research into this area will continue to make progress. “​We hope that this report will help educate pediatric practitioners on the impact of early exposures to the newborn, promote the responsible use of vaccines and antibiotic stewardship, and encourage additional investigations in this important field,” he says. “We have a current, ongoing NIH-funded study that aims to better understand the neonatal immune response, develop improved diagnostic tests, and to investigate new therapeutic strategies.”

Larson is concerned about the ability to continue his research. “Importantly, investigations into neonatal and pediatric sepsis are extremely limited compared to adult studies despite the lifelong impact including long-term disability and increased mortality in children,” he says. “Additional funding is needed; however, like all researchers, we are concerned that the NIH and other sources will be negatively impacted by proposed budget cuts.”

REFERENCE

1. Raymond SL, Rincon JC, Wynn JL, Moldawer LL, Larson SD. Impact of early-life exposures to infections, antibiotics, and vaccines on perinatal and long-term health and disease. Front Immunol. 2017;8:729.