A new study by an international team of scientists has found an association between antibiotic use in the first few days of life and reduced height and weight in boys in early childhood.
In the study, published yesterday in Nature Communications, a team led by scientists from Finland and Israel looked at the impacts of neonatal antibiotic use on two large cohorts of children and found in both that boys exposed to antibiotics within the first 14 days of life gained less weight and height during the first 6 years of life compared with boys who were not exposed to antibiotics. The findings were not observed in girls, however.
In contrast, when the researchers looked at antibiotic exposure in infancy after the neonatal period, they found that in both boys and girls, antibiotic use was associated with increased weight during first 6 years of life—a finding that is in line with previous studies.
"The impact of antibiotics on child growth thus seems to be age-dependent," Samuli Rautava, MD, study co-author, neonatologist, and instructor of clinical pediatrics at the University of Turku in Finland, said in an email.
Additional findings from the study suggest the impact of antibiotic use on height and weight is linked to antibiotic-induced changes in the infant gut microbiome, the collection of microbes that inhabit the gastrointestinal tract.
Shortages increasing risk of infections
The study adds to a growing body of research that links antibiotic exposure in early life to potential long-term impacts on growth and weight gain. Many studies have found a positive association with weight gain but with notable differences in the observed effect.
Unlike previous research that focuses on antibiotic use in the first months of life, said Rautava, this study breaks new ground because of its focus on newborns, who are highly susceptible to invasive bacterial infections and receive empiric antibiotic therapy if they show clinical signs of infection. It also looked at the effects beyond the first few weeks of life.
"Our study is the first to concentrate on the long-term effects of antibiotic exposure in the very first days of life," he said.
For the study, Rautava and his colleagues analyzed data on 12,422 children from the Southwest Finland Birth Cohort, which includes nearly 15,000 children born at Turku University Hospital from 2008 through 2010. Of these children, 1,151 (9.3%) had received antibiotics within the first 14 days of life. To differentiate between the impact of antibiotic exposure and the underlying infection, they categorized these children as having either brief empirical antibiotic treatment (513 newborns) or antibiotics administered for confirmed or clinical infection (638 newborns).
After controlling for potential confounders that might be associated with antibiotic exposure and could affect growth, they found that boys exposed to either brief empiric exposure or antibiotic treatment for infection exhibited significantly lower weight, height, and body mass index (BMI) compared to non-exposed children through the first 6 years of life. Growth impairment appeared to be slightly more pronounced in newborns who had received a full course of antibiotics.
The researchers then confirmed this finding in the children from the PEACHES (Programming of Enhanced Adiposity Risk in Childhood-Early Screening) cohort, which consists of 1,707 German children and mothers recruited from 2010 through 2015. Of the 535 children analyzed, 6.4% (34 newborns) had an infection and antibiotic therapy. The results showed boys exposed to antibiotics in the neonatal period, but not girls, exhibited significantly lower weight and height in the first 5 years of life compared with those who didn't receive antibiotics as newborns.
When the researchers went back to the Finnish cohort and looked at antibiotic exposure after the newborn period, they found that the cumulative number of antibiotic courses during the first 6 years of life was associated with significantly higher BMI scores in both boys and girls, and higher weight just in boys. There was no association found between height development and antibiotic use.
Rautava said they don't yet have an explanation yet for the sex-specific association between neonatal antibiotic use and impaired growth. But he noted that previous research has suggested boys are more prone to an antibiotic-associated increase in BMI after the neonatal period—a finding that's also been observed in mice.
"Taken together, boys seem to be more susceptible to the long-term adverse effects of antibiotics, but the reason is currently unknown," he said.
Antibiotic impact on the gut microbiome
Knowing that previous research has shown that newborns who receive antibiotics exhibit altered gut microbiome composition during the first few weeks of life, the researchers then obtained and analyzed fecal samples from 13 infants exposed to antibiotics as newborns and 20 non-exposed infants at Turku University Hospital. They wanted to see if those changes persisted for longer than a few weeks.
They found that at 1 month, the antibiotic-treated infants had significantly lower gut microbiome richness compared with the non-exposed infants. At 6 months, however, the antibiotic-treated infants had the same level of bacterial richness as the control infants. By 12 and 24 months, they had higher levels of bacterial richness compared with the control infants.
Taxonomic and metagenomic analysis revealed that the biggest difference in the gut microbiomes of the infants treated with antibiotics was in the relative abundance and diversity of Bifidobacterium, one of the major genera of bacteria that make up the gastrointestinal tract in mammals. Bifidobacterium is highly abundant in the gut during infancy, especially when infants are breastfeeding, but Rautava and his colleagues noted this was less so in infants who had received antibiotics as newborns at all time points, except for 6 months after treatment.
Study co-author Omry Koren, PhD, a professor at Bar Ilan University in Israel who studies the role of the microbiome in disease, said future research will delve further into the role that Bifidobacterium might play in reduced growth.
"We definitely think it plays a role and are currently running experiments to try and tease out the mechanism," he said.
Taking their investigation a step further, the researchers discovered a similar impact on growth in germ-free mice after they introduced gut microbiome bacteria from the antibiotic-exposed and non-exposed infants using fecal microbiota transplantation (FMT). During the 43-day follow-up period, and even after 24 months, the male mice who received FMT from the exposed infants gained less weight than the male mice who received FMT from the non-exposed infants. Again, the effect was not observed in female mice.
"These data suggest that the reduced growth in boys and the long-term perturbations in the gut microbiome after neonatal antibiotic exposure are causally linked," they wrote in the study.
Further research needed
Rautava and his colleagues caution that there are limitations to these findings. One is that, despite their efforts to differentiate between newborns who had brief empiric antibiotic therapy and those who had infections, the results could be confounded by the underlying causes that led to antibiotic exposure.
The other is a lack of breastfeeding data. Because breast milk can affect specific Bifidobacteria in the gut, differences in the rate and duration of breastfeeding could explain the reduced abundance observed in the antibiotic-treated infants.
Nonetheless, they say the results suggest neonatal antibiotic administration may have detrimental consequences since impaired childhood growth is known to be associated with poor neurodevelopmental outcomes. They call for further research as well as quicker methods to determine which newborns need antibiotics and which don't.
"The impact of neonatal antibiotic exposure on long-term health warrants detailed study with both epidemiological and experimental approaches," they wrote. "In the clinical setting, rapid means of accurately identifying neonates with bacterial infection are needed to limit antibiotic use in these vulnerable subjects."
