Neonatal sepsis caused by intestinal pathogens is a serious complication of early infancy that may often be lethal, especially for premature infants. But is this linked to prenatal antibiotics often used to prevent infection following preterm premature rupture of membranes (PPROM)?

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

A preprint posted to the medRxiv* server presents evidence for this hypothesis.

Introduction

Late-onset sepsis (LOS) in neonates is defined as an infection of the blood occurring seven days after birth.

It is a major cause of neonatal death, especially in infants with risk factors. These include being born very small (very low birth weight, VLBW), with one in ten such babies being diagnosed with the condition. These babies, who weigh less than 1.5 kg at birth, fail to survive in about a fifth of LOS cases.

In many LOS babies, the infection is caused by intestinal bacteria, indicating a failure of mucosal immunity that allows the pathogens to cross the intestinal epithelial barrier, entering the bloodstream and potentially causing infection at multiple sites all over the body. This has been demonstrated in animal models.

The bacterium called Escherichia coli (E. coli) is the cause of the second-highest number of LOS cases. This bacterium has often been found to be part of the gut microbiota in the neonate before causing infection.

Breastfeeding ought to be protective against the translocation of this opportunistic pathogen by supplying maternal mucosal antibodies, namely, immunoglobulin A (IgA).

These antibodies bind to numerous opportunistic pathogens in the gut and help to develop the neonatal gut microbiome composition. They are produced by plasma cells originally resident in the maternal gut, thus forming a link between the breast milk and the gut microbiome.

Antibiotics given to the mother before delivery, as well as those used for the neonate, are associated with an increased risk of LOS. Unfortunately, these drugs are used in over a quarter of all pregnancies. In PPROM, they are recommended in current guidelines.

Nowadays, broad-spectrum antibiotics are being used more often in pregnancy. This is despite the evidence of earlier studies showing that the risk of LOS, necrotizing enterocolitis (NEC), and poor neonatal outcomes is enhanced with broad-spectrum antibiotic use in PPROM.

The current study aimed to identify any association between prenatal antibiotic use and a higher risk of LOS and NEC in at-risk premature infants who were receiving breast milk from their mothers. The researchers identified a cohort of infants born after PPROM.

All babies had received recommended antibiotics. This was either penicillin combined with a macrolide or in case of penicillin allergy, another antibiotic.

All babies in this cohort were delivered at about the same gestational age after the same delay following PPROM, which occurred at the same gestational age. The mothers all received antibiotics for the same number of days, and the neonates were given maternal breast milk for the same duration.

What did the study show?

The findings show a fivefold increase in the risk of LOS in neonates following prenatal treatment with cephalosporins and other broad-spectrum antibiotics like azithromycin in a cohort of infants at risk for this event. The infants were also at higher risk for positive blood cultures. These figures are in comparison to penicillin use.

Interestingly, these antibiotics are more active against E. coli than penicillin is.

There was no difference in early-onset sepsis, which is caused by organisms transmitted from outside and occurs within 72 hours of delivery.

The preclinical mouse model showed a fourfold higher risk of fatal LOS with prenatal cephalosporin therapy that was not seen with penicillins. This was associated with reduced levels of IgA in the breast milk but not serum IgA. This led to a reduction in the amount of IgA in the gut lumen of the infants breastfed by these women.

In turn, this led to reduced IgA binding of E. coli in the neonatal gut, with increased colonization by these bacteria, resulting in their translocation beyond the gut wall. The risk for mortality was higher in these animals. Human IgA from breast milk was shown to bind to multiple strains of the bacterium, including commensal and pathogenic strains isolated from neonatal samples.

While this cross-reactive binding to E. coli was also seen with immunoglobulin G (IgG), it was five times less cross-reactive than IgA. Pathogenic strains were more efficiently bound by the maternal IgA, indicating a possible enhancement of cross-reactivity.

This effect was not seen with other bacteria, such as group B streptococci, indicating an E. coli-specific decrease in mammary IgA production.

What are the implications?

We propose maternal administration of select antibiotics could limit maternal IgA availability by disrupting mammary IgA, leading to increased risk of LOS in infants by allowing for pathogen colonization in the neonatal intestine.

McDonald et al. (2023)

PPROM is a significant risk factor for premature birth and its complications. The benchmark recommendations for antibiotic prophylaxis in the case of PPROM have successfully increased the gestational age at delivery. However, they are based on a trial that did not consider LOS as a potential complication.

Non-penicillin prophylaxis has not been well studied either. In this situation, the authors suggest the need for better evidence when using broad-spectrum antibiotics in a patient without any signs of infection.

The findings of this study, which suggest a higher LOS risk with cephalosporin use compared to penicillin, corroborate those of the prior ORACLE trial on poorer neonatal outcomes with broader spectrum antibiotics.

Earlier studies showed that a decrease in maternal IgA was linked to a higher abundance of Enterobacteriaceae and subsequent NEC. The current study extends this to show that maternal IgA not only prevents intestinal colonization of pathogenic bacteria but also prevents translocation and systemic sepsis. Of course, other factors may also be at work to protect neonates from intestinal pathogens.

It is important for scientists to modify antibiotic recommendations in light of such potential repercussions on infant mortality and neonatal gut dysbiosis, which could affect long-term immunity as well.

Further studies in how antibiotics can cause a perturbation of the microbiome-immune axis and lead to consequences in maternal-child health are warranted.

McDonald et al. (2023)

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.