Original research
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
1
Department of Paediatrics,
Fribourg Hospital HFR and
Faculty of Science and Medicine,
University of Fribourg, Fribourg,
Switzerland
2
Department of Paediatrics,
The University of Melbourne,
Parkville, Victoria, Australia
3 long-­term effects on health through changes in the
Infectious Diseases Unit,
The Royal Children’s Hospital
Melbourne, Parkville, Victoria,
Australia
4
Infectious Diseases Research
Group, Murdoch Children’s
Research Institute, Parkville,
Victoria, Australia
Correspondence to
Dr Petra Zimmermann,
Department of Paediatrics,
Faculty of Science and Medicine,
University of Fribourg, CH-1700 given to infants.
Fribourg, Switzerland;
p​ etra.z​ immermann@m ​ cri.e​ du.a​ u a total of 272 infants and included 502 stool samples
Received 4 December 2018
Revised 29 May 2019
Accepted 31 May 2019
Published Online First
11 July 2019
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Zimmermann P,
Curtis N. Arch Dis Child Fetal
Neonatal Ed
2020;105:F201–F208.
Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659
Effect of intrapartum antibiotics on the intestinal
microbiota of infants: a systematic review
Petra Zimmermann ‍ ‍ ,1,2,3,4 Nigel Curtis2,3,4
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
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
Results  We identified six studies, which investigated
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.
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 expo-
sure 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
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.
Organisation (HINARI) - Group A. Protected by copyright.
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.
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 proto-
zoans) and viruses. Microbes are already present
at a low diversity in the placenta and amniotic
fluid,10–12 and the detection of bacteria in meco-
nium suggests that the foetal intestine becomes
   F201
 Original research

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
colonised in utero.13–25 After delivery, colonisation of the intes-
tine 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 rich-
ness (number of different bacteria) and evenness (relative abun-
dance 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 Acti-
nobacteria) and Lactobacillus (phylum Firmicutes) has also been

Organisation (HINARI) - Group A. Protected by copyright.

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 intes-
tinal 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 abun-
dance and diversity of different microbes their metabolites may
also affect health outcomes. For example, bacteria in the colon,
especially anaerobic bacteria, metabolise undigested carbohy-
drates 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 anti-
biotic regimen was not specified, antibiotics were used for indi-
cations other than prophylaxis, probiotics were given to mothers
F202 Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659
Figure 1  Selection of studies.
or infants, or antibiotics were given to infants. References were
hand-­searched for additional publications and no further rele-
vant 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 abun-
dance 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.
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 detec-
tion, 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
The number of infants in each study ranged from 20 to 84
(median 45, mean 45). The longest follow-­up (time at the collec-
tion 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
 Table 1  Summary of the main findings of studies investigating the effect of GBS IAP on the infant intestinal microbiota
No of:
Author Infants, samples
Country IAP, no-­IAP Analysis techniques Higher abundance in infants with IAP Lower abundance in infants with IAP
Year Characteristics of participants (including region, (relative abundance IAP, relative abundance (relative abundance IAP, relative abundance
Study design Antibiotic regimen machine, database) Age no-­IAP) no-­IAP) Other findings in infants with IAP
Nogacka et al48 40, 160 16S rRNA 2 days Phylum level Lower alpha diversity at all time points (numbers of
Spain 18, 22 V3–V4 Verrucomicrobia (BF-­IAP 0.16, BF-­no-­IAP 0.04, OTUs, Chao1 index and Shannon index)
2017 CS: – MiSeq Illumina p<0.05) Higher number of beta-­lactamase coding genes at
PCS BF: IAP 11/18, no-­IAP 18/22 (3 months) SILVA database Family level all time points
Penicillin intravenous 5 million units followed by Muribaculaceae (0.43, 0.04, p<0.01) Lower propionate levels at 2 days
2.5 million units every 4 hours until delivery PCR for resistance genes Prevotellaceae (0.12, 0.02, p=0.04) Lower levels of propionate at 2 days, acetate
No antibiotics in pregnancy Rikenellaceae (0.28, 0.12, p=0.02) at 10 days and butyrate at 1 and 3 months
No antibiotics given to infants 10 days Phylum level Phylum level Higher levels of propionate at 10 days, 1 month
Bacteroidetes (FF-­IAP 11.8, FF-­no-­IAP 0.32, p<0.05) Actinobacteria (BF-­IAP 12.30, BF-­no-­IAP 22.66, and 3 months and butyrate at 10 days
Firmicutes (BF-­IAP 45.29, BF-­no-­IAP 21.65, p<0.05) p<0.05, FF-­IAP 6.06, FF-­no-­IAP 34.01, p<0.05)
Family level Bacteroidetes (BF-­IAP 1.66, BF-­no-­IAP 22.03,
Muribaculaceae (0.24, 0.04, p=0.05) p<0.05)
Clostridiaceae (16.04, 0.59, p=0.03) Family level
Bifidobacteriaceae (8.87, 22.14, p=0.01)
1 month Family level
Muribaculaceae (0.46, 0.22, p=0.04)
3 months Phylum level
Firmicutes (BF-­IAP 40.41, BF-­C 22.23, p<0.05)
Family level
Campylobacteraceae (0.03, 0.00, p=0.04)
Helicobacteraceae (0.87, 0.03, p=0.04)
Muribaculaceae (0.25, 0.03, p=0.03)
Prevotellaceae (0.08, 0.03, p=0.03)
Mazzola et al49 26, 52 16S rRNA 7 days Family level Phylum level Lower alpha diversity at 7 days (numbers of
Italy 13, 13 V3–V4 Enterobacteriaceae (BF-­IAP 52, BF-­no-­IAP 14, Actinobacteria (BF-­IAP 0, BF-­no-­IAP 17%, p≤0.01) OTUs, Chao1 index and Shannon index)
2016 CS: – MiSeq Illumina p=0.04, FF-­IAP 52, FF-­no-­IAP 15, p=0.13) Genus level
PCS BF: IAP 7/13, no-­IAP 7/13 (1 month) SILVA database Genus level Bifidobacterium (BF-­IAP 0, BF-­no-­IAP 16, p<0.01)
Ampicillin intravenous 2 g, followed by 1 g every Escherichia  (BF-­IAP 52, BF-­no-­IAP 14, p=0.04, MF-­
4 hours until delivery qPCR (Bifidobacterium) IAP 52, MF-­no-­IAP 15, p=0.13)
No antibiotics or probiotics given to infants 1 month Family level Genus level
Veillonellaceae (n.s., p=0.04) Streptococcus (n.s., p=0.04)
Corvaglia et al50 84, 168 qPCR 7 days Genus level No difference in aubundance of Bifidobacterium

Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659

Italy 35, 49 Bacteroides, ­ Bifidobacterium (6.61, 7.80, p<0.01) at 1 month
2016 CS: – Bifidobacterium, ­ No differences in abundance of Bacteroides or
PCS BF: IAP 26/35, no-­IAP 30/49 (7 days), IAP 22/35, no-­ Lactobacillus ­ Lactobacillus at both time points
IAP 29/49 (1 month) ­
Ampicillin intravenous 2 g, followed by 1 g every ­
4 hours until delivery ­
No antibiotics given to mothers in last 4 weeks of 1 month
pregnancy
No antibiotics or probiotics given to infants
Aloisio et al51 20, 20 16S rRNA 6–7 days Phylum level Phylum level Lower alpha diversity (numbers of OTUs, Chao1
Italy 10, 10 V2–V4, V6–V9 Proteobacteria (54.7, 15.5, p<0.05) Actinobacteria (0.4, 3.8, p<0.05) index and Shannon index)
2016 CS: – Ion Torrent Personal Bacteroidetes (16, 47.8, p<0.05) Higher abundance of Gram-­negative bacteria
PCS BF: 20/20 (7 days) Genome Machine Genus level
Ampicillin intravenous 2 g, followed by 1 g every Ion Reporter Software Bifidobacterium (0.00, 0.07, p<0.05)
4 hours until delivery
Antibiotic use in pregnancy not reported
No antibiotics or probiotics given to infants

Continued
Original research

F203
Organisation (HINARI) - Group A. Protected by copyright.
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
 Original research

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
Multiple methods were used to determine the bacterial intes-

No difference in number of beta-­lactamase resistant

Bifidobacterium, Enterobacteria., Enterococcus, and

16S rRNA, 16S rRNA gene sequencing; BF, exclusively breast fed; CS, caesarean section; DGGE, denaturing gradient gel electrophoresis; FF, partly or exclusively formula fed; IAP, intrapartum antibiotic prophylaxis; n.s., not specified; OTU, operational taxonomic unit; PCS, prospective cohort study; qPCR,
tinal microbiota, including bacterial culture (n=1),53denaturing

B. breve, B. bifidum and B.dentium were most

gradient gel electrophoresis (DGGE) (n=1),52 quantitative PCR

No difference in abundance of Bacteroides,

(n=3),49 50 52 16S rRNA gene sequencing (n=3) (Illumina MiSeq

Lower diversity of Bifidobacterium spp.

Other findings in infants with IAP
(n=2)48 49 and Ion Torrent Personal Genome Machine (n=1).51

No differences of other bacteria

Bacterial diversity was assessed in three of the six studies.48 49
Results were reported down to the lowest taxonomic level anal-
ysed in each study.

Staphylococcus,
Systematic review results
affected

bacteria
Diversity
All three studies that investigated alpha diversity (a measure
of intrasample diversity) of the intestinal microbiota reported
Clostridium (infants colonised 12%, 40%, p<0.05)
(relative abundance IAP, relative abundance

significantly lower diversity in infants who were exposed

to GBS IAP compared with those who were not.48 49 51 The
Lower abundance in infants with IAP

observed numbers of operational taxonomic units (a measure

Bifidobacterium (5.85, 7.29, p<0.01)

of richness through observed taxa without correction for non-­

observed taxa), the Chao1 index (a measure of estimated rich-
ness corrected for relative uncertainty of predicting taxa) and
the Shannon index (a measure of estimated richness and even-
ness corrected for relative uncertainty of predicting taxa) were
Genus level

Genus level

significantly lower in GBS IAP-­exposed infants at a number of

Organisation (HINARI) - Group A. Protected by copyright.

no-­IAP)

time points between 2 days and 3 months of age.48 49 51

Differences at the phylum level

(relative abundance IAP, relative abundance

Three studies reported statistically significant differences in rela-

tive bacterial abundance at the phylum level.48 49 52 In one study,
Higher abundance in infants with IAP

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
no-­IAP)

infants.48 52 In contrast, a higher relative abundance of Bacte-

roidetes was observed in a small number of infants (n=11) who
were partly or exclusively formula fed and exposed to GBS IAP
6–7 days

(FF-­GBS IAP) in one study.48 Additionally, BF-­GBS IAP infants

3 days
Age

were reported to have a higher relative of Proteobacteria at

7 days52 and Firmicutes at 10 days and 3 months of age than
B. fragilis, Bifidobacterium,

BF-­no-­GBS IAP infants.48

Analysis techniques

machine, database)
(including region,

Differences at the family level

Lactobacillus
C. difficile,

Only two of the six studies reported differences in relative bacte-

Culture
E. coli,

DGGE

rial abundance at the family level.48 49 A higher relative abun-

qPCR

dance of Muribaculaceae was reported in infants exposed to GBS

IAP at all measured time points (2, 10 days, 1 and 3 months)
Amoxicillin intravenous 2 g, followed by 1 g every

No antibiotics given to mothers in last 15 days of

Ampicillin intravenous 2 g, followed by 1 g every

in one study.48 Additionally, infants exposed to GBS IAP were

No antibiotics or probiotics given to infants

reported to have a higher relative abundance of Prevotellaceae at

Antibiotic use in pregnancy not reported

7 days and 3 months,48Rikenellaceae at 2 days,48 Enterobacteri-

BF: IAP 26/26, no-­IAP 26/26 (7 days)

aceae at 7 days,49 Clostridiaceae at 10 days,48 Veillonellaceae at

Characteristics of participants

1 month49 and Campylobacteraceae and Helicobacteraceae at 3

months of age.48 In contrast, infants exposed to GBS IAP were
CS: IAP 1/25, no-­IAP 1/25
4 hours until delivery

4 hours until delivery

Antibiotic regimen

reported to have a lower relative abundance of Bifidobacteria-

BF: 34/50 (3 days)
Infants, samples

ceae at the age of 10 days.48

quantitative polymerase chain reaction.
IAP, no-­IAP

pregnancy
No of:

52, 52
26, 26

50, 50
25, 25
Table 1  Continued

Differences at the genus level

CS: –

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
Jauréguy et al53

relative abundance of Escherichia and a lower relative abun-

Study design
Aloisio et al52

dance of Bifidobacterium were reported in infants exposed to

Country
Author

GBS IAP.49 In the same group, a lower abundance of Clostridium

France
2014

2004
Year

Italy

PCS

PCS

(proportion of infants colonised) at the age of 3 days53 and a

F204 Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659

Table 2  Risk of bias summary of studies included in the review
Reference Publication year Selection bias
Nogacka et al48 2017 − −
Mazzola et al49 2016 +*
Corvaglia et al50 2016 +*
Aloisio et al51 2016 +*
Aloisio et al52 2014 +*
Jauréguy et al53 2004 − −
*Potential overlap in participants.
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 devel-
opment 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 pertur-
bation 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 intes-
tinal 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
Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659
Original research
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
Performance bias Detection bias Attrition bias Reporting bias
− − −
− − − −
− − − −
+ − − −
+ − − −
− − −
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
Organisation (HINARI) - Group A. Protected by copyright.
with antibiotics after delivery also reported a delay in expan-
sion 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 Bacteroi-
detes 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 Bacteroi-
detes 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
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).
F205
 Original research
likely because of its very low abundance in the first few weeks
of life.
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 immu-
nity, 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 peni-
cillin 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 Helicobacteri-
aceae.48 These changes (higher rates of Enterobacteriaceae and
lower rates of Bifidobacteriaceae), which are also found in chil-
dren 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 patho-
genic bacteria and preventing intestinal infection70 71 and allevi-
ation 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 vagi-
nally 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
F206 Zimmermann P, Curtis N. Arch Dis Child Fetal Neonatal Ed 2020;105:F201–F208. doi:10.1136/archdischild-2018-316659
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2018-316659 on 11 July 2019. Downloaded from http://fn.bmj.com/ on November 2, 2022 at World Health
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.
Correction notice  The article type has been changed to Original article since this
paper was published Online First.
Acknowledgements  PZ greatly acknowledges funding recieved from the
Organisation (HINARI) - Group A. Protected by copyright.
European Society of Paediatric Infectious Diseases (ESPID) and the University of
Melbourne.
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.
Patient consent for publication  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
ORCID iD
Petra Zimmermann http://​orcid.​org/​0000-​0002-​2388-​4318
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