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Review
Effect of intrapartum antibiotics on the intestinal microbiota of infants: a systematic review
  1. Petra Zimmermann1,2,3,4,
  2. Nigel Curtis2,3,4
  1. 1 Department of Paediatrics, Fribourg Hospital HFR and Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
  2. 2 Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
  3. 3 Infectious Diseases Unit, The Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia
  4. 4 Infectious Diseases Research Group, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  1. Correspondence to Dr Petra Zimmermann, Department of Paediatrics, Faculty of Science and Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland; petra.zimmermann{at}mcri.edu.au

Abstract

Introduction The use of intrapartum antibiotic prophylaxis (IAP) has become common practice in obstetric medicine and is used in up to 40% of deliveries. Despite its benefits, the risks associated with exposing large numbers of infants to antibiotics, especially long-term effects on health through changes in the microbiota, remain unclear. This systematic review summarises studies that have investigated the effect of IAP on the intestinal microbiota of infants.

Methods A systematic search in Ovid MEDLINE was used to identify original studies that investigated the effect of IAP on the intestinal microbiota in infants. Studies were excluded if: they included preterm infants, the antibiotic regimen was not specified, antibiotics were used for indications other than prophylaxis, probiotics were given to mothers or infants, or antibiotics were given to infants.

Results We identified six studies, which investigated a total of 272 infants and included 502 stool samples collected up to 3 months of age. In all the studies, IAP was given for group B streptococcus (GBS) colonisation. Infants who were exposed to GBS IAP had a lower bacterial diversity, a lower relative abundance of Actinobacteria, especially Bifidobacteriaceae, and a larger relative abundance of Proteobacteria in their intestinal microbiota compared with non-exposed infants. Conflicting results were reported for the phyla Bacteroidetes and Firmicutes.

Conclusions GBS IAP has profound effects on the intestinal microbiota of infants by diminishing beneficial commensals. Such changes during the early-life ‘critical window’ during which the intestinal microbiota and the immune response develop concurrently may have an important influence on immune development. The potential long-term adverse consequences of this on the health of children warrant further investigation.

  • neonate
  • delivery
  • microbiome
  • 16srna
  • prophylaxis

https://doi.org/10.1136/archdischild-2018-316659

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    What is already known on this topic?

    • Intrapartum antibiotic prophylaxis (IAP) has become common practice in obstetric medicine and is used in up to 40% of deliveries, which makes it the most frequent source of antibiotic exposure in neonates. IAP is commonly used in women who are colonised with group B streptococcus (GBS) and also for caesarean section surgical prophylaxis.

    • The intestinal microbiota plays an important role in the development of the immune system. There is an early-life ‘critical window’ during which the intestinal microbiota and the immune response develop concurrently. Changes in the composition of the intestinal microbiota in this critical period may have a significant influence on immune development.

    • The risks associated with exposing a large number of infants to antibiotics, especially potential long-term effects on health through changes in the microbiota, remain unclear.

    What this study adds?

    • This is the first systematic review summarising studies that have investigated the effect of IAP on the intestinal microbiota in infants. All eligible studies used IAP for maternal GBS colonisation.

    • Infants who were exposed to GBS IAP had a lower diversity of bacterial species, a lower relative abundance of Actinobacteria, especially Bifidobacteriaceae, and a larger relative abundance of Proteobacteria in their intestinal microbiota compared with non-GBS-IAP-exposed infants.

    • GBS IAP has profound effects on the intestinal microbiota of infants by diminishing beneficial commensals. The potential long-term adverse consequences of this on the health of children warrant further investigation.

    Introduction

    Intrapartum antibiotic prophylaxis (IAP) has become common practice in obstetric medicine and is used in 30%–40% of deliveries, which makes it the most frequent source of antibiotic exposure in neonates.1–3 IAP is routinely used in both elective and emergency caesarean section (CS). In many settings, IAP is also used in women who are colonised with group B streptococcus (GBS), resulting in an 80% decrease in the incidence of early-onset GBS sepsis in infants.4 5 Despite its benefits, the risks associated with exposing such a large number of infants to antibiotics, especially its long-term effects on health through changes in the microbiota, remain unclear. Since the rates of CS deliveries6 7 and GBS colonisation8 are still rising, there is an urgent need to define these effects.9

    The human intestine is the habitat for a large community of microbes, consisting of archaea, bacteria, eukaryotes (fungi, helminths and protozoans) and viruses. Microbes are already present at a low diversity in the placenta and amniotic fluid,10–12 and the detection of bacteria in meconium suggests that the foetal intestine becomes colonised in utero.13–25 After delivery, colonisation of the intestine increases rapidly, and the microbes to which infants are first exposed play a crucial role in the subsequent establishment of microbial communities.26 The infant intestine is colonised by microbes from breast milk, caregivers, family members and the environment.27 The composition of the intestinal microbiota can be described on different taxonomic levels (for bacteria, these comprise phylum, class, order, family, genus and species). The use of modern sequencing techniques, especially metagenomic sequencing, allows for detailed analysis down to the species level. It also enables the detection of antibiotic resistance genes and the identification of other components of the microbiota such as fungi and viruses. Another way to analyse the intestinal microbiota is by measuring bacterial diversity, which entails richness (number of different bacteria) and evenness (relative abundance of different bacteria). A higher bacterial diversity has been associated with beneficial effects, for example, stronger vaccine responses,28 whereas a lower diversity has been associated with the development of chronic inflammatory bowel disease,29 obesity,30 diabetes mellitus31 and allergic diseases.32 A higher abundance of Bifidobacterium (belonging to the phylum Actinobacteria) and Lactobacillus (phylum Firmicutes) has also been associated with beneficial health benefits,33 34 while the role of other bacteria is less clear. On a species level, a high prevalence of Bifidobacterium infantis has been associated with increased vaccine responses28 and with a reduced risk of infection in infancy, as well as a reduced risk of chronic illnesses later in life.35–37 In contrast to bacteria, there is much less known about the abundance of archaea, eukaryotes or viruses in the intestinal microbiota (especially in infants) and their association with health outcomes. Changes in numbers of bacteriophages have been associated with chronic inflammatory bowel diseases,38 and a perturbed intestinal virome has been associated with severe malnutrition in infants.39 However, in addition to the abundance and diversity of different microbes their metabolites may also affect health outcomes. For example, bacteria in the colon, especially anaerobic bacteria, metabolise undigested carbohydrates into short-chain fatty acids (SCFAs). A lack of SCFAs can disrupt the integrity of colonic epithelial cells, the function of the mucosa and the regulation of T cells.40–42 In adults, antibiotic use has been associated with a decrease in SCFAs.43–47

    While the effect of delivery mode and feeding methods on the establishment of microbial communities in the intestine has been well studied, much less is known about the effects of intrapartum and postpartum antibiotics on the intestinal microbiota.27 In this review, we systematically review studies that have investigated the effect of IAP on the intestinal microbiota of infants.

    SYSTEMATIC REVIEW METHODS

    In May 2019, MEDLINE (1946 to present) was searched using the Ovid interface with the following search terms: (anti-bacterial agents OR antibiotic OR prophylaxis OR penicillin OR ampicillin OR amoxicillin OR amoxycillin OR macrolides OR streptococcal OR Streptococcus agalactiae) AND (microbio* OR feces OR faeces OR gastrointestinal microbiome OR culture OR polymerase chain reaction OR RNA, ribosomal, 16S OR high-throughput nucleotide sequencing) AND (perinatal OR intrapartum OR pregnancy OR delivery OR labor OR labour OR obstetric OR maternal OR neonat* OR newborn OR infant) without any language limitations. This identified 328 articles. Studies were excluded if: they included preterm infants, the antibiotic regimen was not specified, antibiotics were used for indications other than prophylaxis, probiotics were given to mothers or infants, or antibiotics were given to infants. References were hand-searched for additional publications and no further relevant studies were found. The selection of studies is summarised in figure 1. The following variables were extracted from the included studies: year of study, country, study design, number of participants, delivery mode, feeding method, antibiotic regimen (substance, dose, administration route, duration), antibiotic use in pregnancy or in infants, probiotic use, number of collected stool samples, age at the collection of samples, stool analysis technique (including sequenced region, sequencing machine, database used for identification), diversity and relative abundance of microbiota in stool, changes in bacterial resistance and changes in concentrations of SCFAs in stool. Diversity in study design and reporting precluded quality evaluation according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

    Figure 1
    Figure 1

    Selection of studies.

    SYSTEMATIC REVIEW OVERVIEW

    A total of six studies (all prospective cohort studies) reporting results from 502 stool samples from 272 infants (127 exposed to IAP and 145 not exposed to IAP) met the inclusion criteria of this review (table 1).48–53 All studies were done in west European countries and all used IAP for GBS colonisation. Studies were rated to be at low risk of bias. None of the studies had any detection, attrition or reporting bias (table 2). However, two studies were deemed to have performance bias because antibiotic use in pregnancy was not reported.51 52 Four studies were done by the same research group in the same time frame, so they have made a potential selection bias, as it is unclear if there was an overlap of participants.49–52

    View this table:
    Table 1

    Summary of the main findings of studies investigating the effect of GBS IAP on the infant intestinal microbiota

    View this table:
    Table 2

    Risk of bias summary of studies included in the review

    The number of infants in each study ranged from 20 to 84 (median 45, mean 45). The longest follow-up (time at the collection of last stool sample) was 3 months.48 Antibiotic regimens were intravenous ampicillin (n=4),49–52 amoxicillin (n=1)53 and penicillin (n=1).48 Seventy-four per cent of infants (200 of 272) were exclusively breast fed at the time of stool collection. Only one child was born by CS.53

    Multiple methods were used to determine the bacterial intestinal microbiota, including bacterial culture (n=1),53denaturing gradient gel electrophoresis (DGGE) (n=1),52 quantitative PCR (n=3),49 50 52 16S rRNA gene sequencing (n=3) (Illumina MiSeq (n=2)48 49 and Ion Torrent Personal Genome Machine (n=1).51 Bacterial diversity was assessed in three of the six studies.48 49 Results were reported down to the lowest taxonomic level analysed in each study.

    Systematic review results

    Diversity

    All three studies that investigated alpha diversity (a measure of intrasample diversity) of the intestinal microbiota reported significantly lower diversity in infants who were exposed to GBS IAP compared with those who were not.48 49 51 The observed numbers of operational taxonomic units (a measure of richness through observed taxa without correction for non-observed taxa), the Chao1 index (a measure of estimated richness corrected for relative uncertainty of predicting taxa) and the Shannon index (a measure of estimated richness and evenness corrected for relative uncertainty of predicting taxa) were significantly lower in GBS IAP-exposed infants at a number of time points between 2 days and 3 months of age.48 49 51

    Differences at the phylum level

    Three studies reported statistically significant differences in relative bacterial abundance at the phylum level.48 49 52 In one study, a higher relative abundance of Verrucomicrobia was reported in infants at 2 days of age who were exclusively breast fed and exposed to GBS IAP (BF-GBS IAP).48 In all three studies, infants exposed to GBS IAP, independent of breast feeding, had a lower relative abundance of Actinobacteria at 7 to 10 days of age.48 49 52 At the same age, BF-GBS IAP infants were reported to have a lower relative abundance of Bacteroidetes than BF-no-GBS IAP infants.48 52 In contrast, a higher relative abundance of Bacteroidetes was observed in a small number of infants (n=11) who were partly or exclusively formula fed and exposed to GBS IAP (FF-GBS IAP) in one study.48 Additionally, BF-GBS IAP infants were reported to have a higher relative of Proteobacteria at 7 days52 and Firmicutes at 10 days and 3 months of age than BF-no-GBS IAP infants.48

    Differences at the family level

    Only two of the six studies reported differences in relative bacterial abundance at the family level.48 49 A higher relative abundance of Muribaculaceae was reported in infants exposed to GBS IAP at all measured time points (2, 10 days, 1 and 3 months) in one study.48 Additionally, infants exposed to GBS IAP were reported to have a higher relative abundance of Prevotellaceae at 7 days and 3 months,48 Rikenellaceae at 2 days,48 Enterobacteriaceae at 7 days,49 Clostridiaceae at 10 days,48 Veillonellaceae at 1 month49 and Campylobacteraceae and Helicobacteraceae at 3 months of age.48 In contrast, infants exposed to GBS IAP were reported to have a lower relative abundance of Bifidobacteriaceae at the age of 10 days.48

    Differences at the genus level

    All, but one study reported differences in the relative abundance of bacteria at the genus level.49 50 52–54At 7 days of age, a higher relative abundance of Escherichia and a lower relative abundance of Bifidobacterium were reported in infants exposed to GBS IAP.49 In the same group, a lower abundance of Clostridium (proportion of infants colonised) at the age of 3 days53 and a lower relative abundance of Bifidobacterium at 7 days50 52 and Streptococcus at 1 month of age were reported.49 In contrast, a higher relative abundance of Bacteroides and Parabacteroides was reported at 3 months of age.54

    Differences at the species level

    One study used DGGE to differentiate which Bifidobacterium spp. were most affected by GBS IAP and showed that the species which were most depleted in IAP-exposed infants were B. breve, B. bifidum and B. dentium.52 Additionally, these infants also had a lower diversity of Bifidobacterium spp.52

    Differences in bacterial antibiotic resistance

    A recent study used PCR to identify and quantify resistance genes.48 It reported that infants exposed to GBS IAP have a higher numbers of beta-lactamase coding genes at all four time points tested (2 and 7 days, 1 and 3 months), but no increase in genes coding for resistance to tetracyclines.48 The oldest study included in the review, which used culture for the identification of bacteria, did not observe any effect of GBS IAP exposure on the proportion of beta-lactamase resistant bacteria.53

    Differences in faecal short-chain fatty acids

    One study compared faecal SCFAs between GBS IAP-exposed and non-exposed infants. The former had significantly lower levels of propionate at 2 days, acetate at 10 days and butyrate at 1 and 3 months of age. In contrast, GBS IAP-exposed infants  had significantly higher propionate levels at 10 days, 1 and 3 months of age and higher butyrate levels at 10 days of age.48

    Discussion

    The intestinal microbiota plays an important role in the development of the immune system. There is an early-life ‘critical window’ during which the intestinal microbiota and the immune response develop concurrently. The development of intestinal microbiota is easily disrupted by external factors,27 and perturbation of the intestinal microbiota during this vulnerable period may have a large influence on immune development.21 55–59 Numerous studies suggest that the composition of intestinal microbiota is associated with many immune- mediated and non-immune-mediated diseases, including sepsis18 and necrotising enterocolitis (NEC) in neonates.60 It is suggested that the intestinal microbiota also play an important role in the development of chronic inflammatory bowel disease,29 diabetes mellitus31 and allergic diseases in children.34

    IAP has been associated with adverse clinical outcomes. For example, administration of amoxicillin/clavulanate as IAP leads to increased rates of NEC in preterm infants.61 IAP has also been associated with amoxicillin-resistant late-onset E. coli infections.62 63 Furthermore, antibiotic exposure in the first 6 months of life has been associated with long-term adverse health outcomes, such as a 20% increased risk of obesity64 and an increased risk of developing allergic diseases and asthma later in life.65–68

    This review shows that GBS IAP has profound effects on the intestinal microbiota in infants (summarised in figure 2). Infants who are exposed to GBS IAP have a lower bacterial diversity of their bacterial intestinal microbiota, a lower relative abundance of Actinobacteria, especially Bifidobacteriaceae, and a larger relative abundance of Proteobacteria compared with infants who are not exposed to GBS IAP. Similarly, a study which was not included in this review because some of the infants were treated with antibiotics after delivery also reported a delay in expansion of Bifidobacteriumduring the first 12 weeks of life in infants whose mothers received GBS IAP. This study also reported a persistence of Escherichia in these infants.69 Furthermore, it is likely that GBS IAP also reduces the numbers of Bacteroidetes as reported in two studies in this review.48 52 Additionally, another study which was also not included in this review because it included infants who were given antibiotics after birth also reported a significantly lower relative abundance of Bacteroidetes at the age 3 and 12 months and an over-representation of Enterococcus and Clostridium in infants exposed to IAP.54 Although one study reported the opposite (a higher relative abundance of Bacteroidetes in FF-GBS IAP-exposed infants), it only included 11 samples.48 Studies investigating the relative abundance of Firmicutes report conflicting results. This might be attributable to heterogeneity in study design, stool analysis techniques, as well as the DNA isolation, amplification and sequencing protocols in those studies which used sequencing. Only one study reported changes in Verrucomicrobia, which is likely because of its very low abundance in the first few weeks of life.

    Figure 2
    Figure 2

    Summary of the main differences in the intestinal microbiota between infants who were or were not exposed to GBS IAP (reported at the lowest taxonomic level that was analysed in each study).

    Unfortunately, the studies included in this review followed up infants only until the age of 3 months. The above-mentioned study, which was not included, showed that IAP-induced changes in the intestinal microbiota were still evident at the age of 12 months in infants who were born by emergency CS, but not in infants exposed to IAP for other reasons.54 However, since the first few weeks of life are important in training mucosal immunity, the effect of IAP might have profound effects on health in later childhood.

    A likely explanation for the observed patterns of differences in the intestinal microbiota induced by GBS IAP is that penicillin and ampicillin have stronger activity on Gram-positive bacteria, allowing overgrowth of Gram-negative bacteria such as Proteobacteria. GBS IAP leads to a decrease in bacteria which are considered beneficial commensals, such as Bifidobacteriaceae, but to an increase in potentially pathogenic bacteria, including Enterobacteriaceae,49 Campylobacteriaceae and Helicobacteriaceae.48 These changes (higher rates of Enterobacteriaceae and lower rates of Bifidobacteriaceae), which are also found in children born by CS, have been associated with an increased risk of developing allergic diseases and asthma.34

    Additionally, a higher relative abundance of the phylum Proteobacteria has been associated with lower vaccine responses, while a higher relative abundance of the phylum Actinobacteria has been associated with higher vaccine responses.33 Both these changes (higher relative abundance of Proteobacteria48 52 and lower abundance of Actinobacteria)48 49 52 have been associated with IAP. Furthermore, Bifidobacteriaceae, which are suppressed through antibiotics have been associated with beneficial health outcomes, such as inhibiting the growth of potentially pathogenic bacteria and preventing intestinal infection70 71 and alleviation of constipation.72 73

    Some of the studies included in this review reported a larger effect of IAP on the intestinal microbiota in infants who are exclusively breast fed,49 while others found less changes in breastfed infants born by CS.54

    As only one study investigated the effect of GBS IAP on SCFA (reporting lower butyrate and higher propionate levels) precludes drawing any firm conclusion on the effect of GBS IAP on SCFA.48 Higher butyrate and propionate levels in early life have been associated with protection against developing allergic diseases later in life.74 Butyrate and propionate have also been shown to protect against obesity.75

    The use of IAP is rising as a result of increasing rates of both CS and GBS colonisation. In the USA alone, GBS IAP leads to approximately 1 million infants exposed to antibiotics each year.76 There is still debate about whether universal GBS screening and routine administration of antibiotics to colonised mothers leads to better outcomes than risk-based screening.77–79 Furthermore, IAP is often used in situations in which it has not been proven to have a clear benefit, such as prelabour rupture of membranes in term deliveries80 and preterm labour with intact membranes.81 A minority of countries, such as Norway, do not use IAP for elective CS, without adverse outcomes.82 None of the studies included in this review commented on adverse outcomes of infants whose mothers did not receive IAP.

    The strengths of this review are that the included studies used similar antibiotic regimens (intravenous ampicillin or penicillin), the homogeneity of infants included in the studies (mostly vaginally born, exclusively breastfed infants) and the use of advanced DNA sequencing techniques in most studies. The main limitation of this review, apart from the relatively low number of studies, is that many of the studies were limited by small sample size, short follow-up and inadequate accounting for potential confounding factors. A further limitation is that four of the six studies were done by the same research group, and there was potentially an overlap of participants.49–52 However, different stool analysis techniques were used in these studies (PCR50 52 and 16S rRNA gene sequencing49 51).

    Further studies are needed to clarify whether restricted use of IAP has adverse outcomes for neonates. The benefits of IAP need to be weighed against the potential (especially long-term) adverse effects. This will require larger studies with longer follow-up to investigate the effect of IAP on the intestinal microbiota of infants and relate changes with clinical outcomes later in life. Once the relationship between the intestinal microbiota and the development of the immune system is clearer, interventions such as exclusive breast feeding, targeted probiotic administration or phage therapy might be used as adjuvant therapy in infants exposed to antibiotics. Furthermore, the successful development of a GBS vaccine would help reduce the necessity for IAP.

    Acknowledgments

    PZ greatly acknowledges funding recieved from the European Society of Paediatric Infectious Diseases (ESPID) and the University of Melbourne.

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    Footnotes

    • Contributors PZ drafted the initial manuscript. NC critically revised the manuscript and both authors approved the final manuscript as submitted.

    • Funding PZ is supported by a Fellowship from EPSID and an International Research Scholarship from the University of Melbourne.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.