Keywords
bacterial infection - infections - premature birth - pregnancy - normal birth
Abbreviations
AIS:
Amniotic infection syndrome
CNS:
Coagulase-negative staphylococci
CRP:
C-reactive protein
EOS:
Early-onset sepsis
GBS:
Group B streptococci
GW:
Gestational week
LOS:
Late-onset sepsis
PCT:
Procalcitonin
PROM:
Premature rupture of membranes
SIRS:
Systemic inflammatory response syndrome
Introduction
Neonatal sepsis continues to represent a serious clinical picture in neonatal medicine.
The definition of (neonatal) sepsis has changed over time, and pediatric sepsis, especially
in
neonates, differs to sepsis in adults [1]. There are still no screening methods or markers that can reliably
predict or exclude neonatal sepsis [2].
In the case of neonatal sepsis, in contrast to sepsis in adults, a distinction must
be
made between early-onset sepsis (EOS) and late-onset sepsis (LOS); early-onset refers
to cases
that become clinically conspicuous within the first 72 hours after birth, usually
within the
first 24 hours, and late-onset refers to onset after the first 72 hours of life [2]
[3]. In the meantime,
pathogen detection in blood culture is no longer mandatory for the diagnosis of sepsis;
the
unconditional presence of a “systemic inflammatory response syndrome” as a mandatory
component
of the diagnostic criteria has also been abandoned, as this can also arise in other
scenarios,
for example due to severe trauma and other diseases. Serious sequelae of neonatal
sepsis
include septic shock with a high rate of fatality and organ failure, as well as long-term
sequelae due to impaired neurological development of the newborn infant [4].
Premature rupture of membranes should be mentioned as the most prominent prenatal
risk
factor for EOS, affecting approximately 1–5 per 1000 live births [5], especially in the context of the immature
immune system in potential premature births [6]. This reduces the physical barrier between
the fetus and the environment, making it easier for microbial ascension to occur.
Transplacental or transuterine infection is also possible, although this is less common
[7]. Thus, amniotic
infection syndrome, now referred to as triple I (intrauterine infection, inflammation,
or
both), must also be considered a risk to the fetus, in addition to general maternal
infections. In the majority of cases of newborns exposed to amniotic infection syndrome,
there
are no cases of EOS confirmed by blood culture [8]; however, completely asymptomatic cases
with microbial colonization confirmed by blood culture can also occur [9]. In the vast majority
of cases, the site of origin of the pathogens is the maternal anogenital tract; this
explains
the increased occurrence of group B streptococci and Escherichia coli as the pathogens
that
cause neonatal sepsis [10]
[11], with Escherichia coli in particular associated with higher mortality
in EOS [12]
[13]. Especially in the
case of EOS, it is assumed that there is vertical transmission from mother to child
[14]; in the case of LOS,
in addition to vertical transmission, there is also horizontal transmission through
the
environment, for example through (central) venous access or by hospital personnel
[2].
Preventive measures that have already been established include GBS screening between
GW 35
and 37 for the prevention of neonatal infections; this is also universally recommended
in
other countries such as the USA [11]. Considering the predominance of this pathogen in the context of
neonatal sepsis, it is important to continue to advocate for the consistent implementation
of
this screening procedure. While screening certainly leads to a reduction in the number
of
GBS-positive neonatal sepsis cases, the situation with regard to Escherichia coli
as a
pathogen remained constant, so that an absolute increase in Escherichia coli as a
pathogen
causing neonatal sepsis, due to GBS prevention, could be disproved [15]. Empirical antibiotic treatment is
recommended in mothers with suspected triple I. However, although increased antibiotic
use
reduces the number of GBS-positive EOS cases [16], the rate of postpartum complications
such as necrotizing enterocolitis was higher in newborns exposed to this antibiotic
treatment
than in untreated children [7]
[17]. Alternative approaches are also sometimes taken – in such cases,
clinically inconspicuous infants and infants born near GW 37 and whose mother suffered
from
triple I are not automatically treated with antibiotics, but are subject to close
clinical
monitoring in order to avoid unnecessary antibiotic treatment [17]
[18]. The spectrum of pathogens that cause
neonatal sepsis, including both EOS and LOS, is now widely known and can therefore
also be
effectively treated with antibiotics postpartum.
Infections are one of the most common causes of premature births [19], and premature infants are at a
particularly high risk from neonatal infections due to the immaturity of their immune
system
[7]
[20]. The value of
microbiological diagnosis in the mother in case of imminent premature birth is unclear.
Some
authors recommend general microbiological diagnostics in risk situations, such as
premature
rupture of membranes and in the case of premature contractions [14]. In the German guidelines “Full-Term
Vaginal Birth – S3 guideline” and “Prevention and Therapy of Preterm Birth – S2k guideline”,
this diagnostic procedure is not generally recommended [21]
[22]
[23]
[24]
[25]; nevertheless, it is largely implemented
in clinical practice in Germany. In other guidelines, maternal microbiological diagnostics
are
not mentioned or do not play a role at all, and only preventive maternal antibiotic
administration is recommended [23]
[26]. Studies with data on concordance of smear results between mothers and
their children in the case of sepsis are rare.
The aim of this study was, therefore, to determine the possible rate at which pathogens
causing neonatal sepsis are detected through microbiological vaginal smears taken
from the
mother in the context of routine care in everyday clinical practice in a level 1 perinatal
clinic. For this purpose, we searched for microbial matches in neonates and in their
mothers,
in samples which were collected as part of routine care prior to birth.
Materials and Methods
We identified all newborn and premature infants born in the maternity unit of the
Karlsruhe Municipal Hospital (SKK) who were identified as having a neonatal infection
and
treated in the pediatric clinic of the SKK during the period from 2014 to 2019. Neonates
transferred from outside the SKK were not included. In the case of multiple births,
each child
of a multiple birth was considered individually.
By examining the medical records, we identified the neonates who met the following
definition for neonatal sepsis. The definition of neonatal sepsis was based on the
“IQTIG
guidelines on neonatal care” (QS specification 2021 version 07), which distinguishes
between
three different sepsis groups: 1.) clinical sepsis (without pathogen detection), 2.)
microbiologically confirmed sepsis with pathogen detection without coagulase-negative
staphylococci (CNS), 3.) microbiologically confirmed sepsis with CNS in the pathogen
spectrum.
We also made use of the AWMF guidelines for bacterial infections in neonates (register
no.
024/008, version 4.2); the diagnostic criteria in these guidelines is consistent with
those in
the guidelines mentioned above [27]
[28]. The children who did not meet the diagnostic criteria for neonatal
sepsis were excluded from further analysis.
Based on gestational age, a further subdivision was made between full-term births
(from GW
37 + 0) and premature births (< GW 37 + 0). The clinical parameters and microbiological
smear results were then evaluated on the basis of the mother’s medical records.
We identified the mothers for whom smear results were available, and then identified
mother-child pairs in which there was a microbial match. Based on the time of onset
of the
sepsis, the disease was classified as LOS > 72 hours of life; if the sepsis occurred
prior
to this, it was classified as EOS.
In addition to the bacteriological results, other clinical and laboratory parameters
were
collected from the neonates and mothers. The study protocol is set out in [Fig. 1]. The study protocol was
approved by the Ethics Committee of the National Medical Association of Baden-Württemberg
(file number F-2020–058).
Fig. 1 Flow chart of the study design.
Clinical management
The diagnostic routine during the study period was to perform microbiological
diagnostics based on vaginal and cervical smears for all mothers with premature rupture
of
membranes or premature contractions (GW: < 37 + 0). From the gestational age of 37
weeks
+ 0 days, microbiological diagnostics were usually not performed for the pregnant
women
unless there was suspicion of infection, in which case a smear was performed as described
above.
During the study period, routine treatment in the case of premature rupture of membranes
before GW 37 consisted of prophylactic antibiotic therapy with piperacillin/tazobactam
IV
for 8 days, while from GW 37 onwards, mothers were given prophylactic treatment with
ampicillin or cefuroxime IV. In the case of premature contractions, antibiotic treatment
was
only given if there was clinical suspicion of infection or when a pathological smear
result
was obtained. If necessary, antibiotic therapy was adjusted after obtaining the antibiogram.
No control smears were performed.
According to the PROMPT trial, mothers from GW 34 + 0 with premature rupture of
membranes were given the option of either inducing labor or, in the absence of signs
of
infection, taking a wait-and-see approach with appropriate monitoring, analogous to
the
procedure in the PROMPT trial [29].
Statistics
The statistical program “R” was used for statistical analysis of the available data.
A
confidence interval of 95% was chosen in all calculations. Because no statistical
test was
performed, there is no formal significance level; however, the significance level
α = 5% is
indirectly implied in the 95% confidence interval (CI) [(100 − α)% = 95%].
Results
A total of 948 infections in neonates and premature infants were identified during
the
study period. In 209 cases, the diagnostic criteria for neonatal sepsis were met.
Of these, 52
cases (24.9%) were assigned to the full-term birth group, and 157 cases (75.1%) to
the
premature birth group. In the full-term birth group, no pathogens were detected in
31 mothers
(59.6%), and in the premature birth group, no pathogens were detected in 27 mothers
(17.2%).
These mother-child pairs were excluded from further analysis due to the lack of maternal
data.
Among the full-term birth group there were 21 mothers for whom microbiological results
were
available, of which there was a pathogen match in four mother-child pairs. All four
of these
were EOS cases (95% CI = 39.8–100%). In the premature birth group there were 130 mothers
for
whom microbiological results were available, of which there was a pathogen match in
30
mother-child pairs, with 11 cases of EOS (36.7%) (95% CI = 19.9–56.1%) and 19 cases
of LOS
(63.3%) (see flow chart [Fig. 1]).
Rates of detection of neonatal sepsis pathogens based on maternal smear result
The detection rate for sepsis pathogens in full-term infants was 4 out of a total
of 52
cases (7.7%), and in premature infants it was 30 out of a total of 157 cases (19.1%)
([Table 1]).
Table 1 Rate of detection of neonatal sepsis pathogens based on maternal vaginal
smears.
|
Whole cohort
|
Detection rate
|
|
Full-term infants
|
4 out of 52 (7.7%)
|
|
Premature infants
|
30 out of 157 (19.1%)
|
|
Only cases with pathogen detection in the mother
|
|
Full-term infants
|
4 out of 21 (19.0%)
|
|
Premature infants
|
30 out of 130 (23.1%)
|
|
Premature infants, LOS cases excluded
|
|
Whole cohort
|
11 out of 157 (7.0%)
|
|
Pathogen detection in the mother
|
11 out of 130 (8.5%)
|
The detection rates improve if only cases in which a pathogen was detected in the
mother
are included in the calculation of the detection rate. This results in a detection
rate in
full-term infants of 4 in 21 cases (19.0%) and a detection rate in premature infants
of 30
in 130 cases (23.1%) ([Table 1]).
In contrast, the detection rate in premature infants becomes worse if cases with LOS
are
excluded on the assumption that the infection may also have occurred through horizontal
transmission; the rate is 11 out of 157 cases (7%) for all neonates studied, and 11
out of
130 cases (8.5%) if only neonates whose mothers were found to have a pathogen are
included
([Table 1]).
Based on the results in [Table 1], a number needed to test (NNT) was calculated, analogous to the
number needed to treat. This is intended to determine the number of women who would
need to
be tested in order to then find the probable pathogen causing neonatal sepsis. NNT
is
presented in [Table 2] based on
probable success rates of 50%, 80%, and 90% ([Table 2]).
Table 2 “Number needed to test” (NNT) based on the results in [Table 1].
|
|
Detection rate in the study
|
Number of patients required for (at least) one hit
|
|
50% success
|
80% success
|
90% success
|
|
Whole cohort
|
|
Full-term infants
|
7.7% (4 out of 52)
|
9
|
21
|
29
|
|
Premature infants
|
19.1% (30 out of 157)
|
4
|
8
|
11
|
|
Mothers with pathogen detection
|
|
Full-term infants
|
19.0% (4 out of 21)
|
4
|
8
|
11
|
|
Premature infants
|
23.1% (30 out of 130)
|
3
|
7
|
9
|
|
Premature infants, LOS cases excluded
|
|
Whole cohort
|
7.0% (11 out of 157)
|
10
|
23
|
32
|
|
Pathogen detection in the mother
|
8.5% (11 out of 130)
|
8
|
19
|
26
|
General frequency of sepsis pathogens in neonates
Among the full-term infants, 22 neonates (42.3%) were diagnosed with sepsis without
pathogen detection (Group 1 in Materials and Methods), and 30 neonates (57.7%) were
diagnosed with sepsis with pathogen detection (Group 2 + 3 in Materials and Methods).
Among
the premature infants, 72 neonates (45.9%) were diagnosed with sepsis without pathogen
detection (Group 1 in Materials and Methods), and 85 neonates (54.1%) were diagnosed
with
sepsis with pathogen detection (Group 2 + 3 in Materials and Methods). In addition,
[Table 3] shows the frequencies of
identifiable sepsis pathogens independent of maternal results, broken down by premature
and
full-term births. The pathogens were either detected in blood cultures or, if the
blood
cultures did not reveal the presence of pathogens, they were detected in smear results
from
body surfaces. For the sake of clarity, we have listed no more than 10 of the most
common
pathogens per group ([Table 3]).
Table 3 Frequency of pathogen detection (10 most common pathogens [from blood culture, or
from body surface smears if the blood culture was negative]).
|
|
Premature infants
Frequency (n)
|
|
Clinical sepsis (without pathogen detection)
|
72
|
|
Sepsis with pathogen detection
|
85
|
|
|
Full-term infants
|
|
Clinical sepsis (without pathogen detection)
|
22
|
|
Sepsis with pathogen detection
|
30
|
|
|
Premature infants
Frequency (n)
|
|
Staphylococcus epidermidis
|
31
|
|
Staphylococcus haemolyticus
|
28
|
|
Escherichia coli
|
27
|
|
Klebsiella oxytoca
|
22
|
|
Enterococcus faecalis
|
21
|
|
Klebsiella pneumoniae
|
20
|
|
Enterobacter cloacae
|
19
|
|
CNS
|
19
|
|
Bacillus cereus
|
15
|
|
Staphylococcus capitis
|
13
|
|
|
Full-term infants
Frequency (n)
|
|
Escherichia coli
|
11
|
|
CNS
|
4
|
|
Staphylococcus epidermidis
|
4
|
|
GBS
|
3
|
|
Bacillus cereus
|
2
|
|
Enterococci
|
2
|
|
Enterococcus faecalis
|
2
|
|
2MRGN Escherichia coli
|
2
|
|
Miscellaneous pathogens
|
1 in each case
|
Frequency of pathogens in pathogen matches between mothers and neonates
Four cases of EOS occurred in full-term infants. Three out of four cases showed matching
results for group B streptococci and one out of four cases showed a match for Escherichia
coli, with these pathogens being detected in both the mother and the neonate. No cases
of
LOS occurred in full-term infants ([Table 4]).
Table 4 Frequency of microbial matching in mother and child (full-term births).
|
|
EOS
Frequency (n)
|
|
GBS
|
3
|
|
Escherichia coli
|
1
|
|
|
LOS
Frequency (n)
|
|
None
|
None
|
Among the premature infants, there were 11 cases of EOS with a total of 16 matching
results (multiple mentioning was possible). The following frequencies were found:
3 × group
B streptococci, 3 × Escherichia coli, 2 × 3MRGN Escherichia coli, 1 × Enterococcus
faecalis,
1 × Enterobacter aerogenes, 1 × Streptococcus mitis, 1 × group A streptococci, 1 ×
Morganella morganii, 1 × Ureaplasma urealyticum, 1 × Staphylococcus haemolyticus,
1 ×
coagulase-negative staphylococci ([Table 5]).
Table 5 Frequency of microbial matching in mother and child (premature births).
|
|
EOS
Frequency (n)
|
|
GBS
|
3
|
|
Escherichia coli
|
3
|
|
2MRGN Escherichia coli
|
2
|
|
Enterococcus faecalis
|
1
|
|
Enterobacter aerogenes
|
1
|
|
Streptococcus mitis
|
1
|
|
Group A streptococci
|
1
|
|
Morganella morganii
|
1
|
|
Ureaplasma urealyticum
|
1
|
|
Staphylococcus haemolyticus
|
1
|
|
CNS
|
1
|
|
|
LOS
Frequency (n)
|
|
Staphylococcus haemolyticus
|
6
|
|
Enterococcus faecalis
|
6
|
|
CNS
|
4
|
|
Escherichia coli
|
4
|
|
Staphylococcus epidermidis
|
3
|
|
GBS
|
3
|
|
Klebsiella pneumoniae
|
2
|
|
Staphylococcus capitis
|
2
|
|
Ureaplasma urealyticum
|
1
|
Among the premature infants, there were 19 cases of LOS with a total of 31 matching
results (multiple mentioning was possible). The following frequencies were found:
6 ×
Staphylococcus haemolyticus, 6 × Enterococcus faecalis, 4 × coagulase-negative
staphylococci, 4 × Escherichia coli, 3 × Staphylococcus epidermidis, 3 × group B
Streptococci, 2 × Klebsiella pneumoniae, 2 × Staphylococcus capitis, 1 × Ureaplasma
urealyticum ([Table 5]).
Clinical parameters of mothers and full-term or premature infants with a microbial
match
The clinical parameters of mothers and full-term and premature infants are shown in
[Table 6] and [Table 7]. Among mothers of premature
infants with sepsis (n = 157), there was a total of 26 cases of AIS (16.6%), whereas
in
mothers of full-term infants with sepsis (n = 52), there was only one case of postpartum
fever (1.9%). Premature infants with EOS were born at an average gestational age of
31 weeks
+ 0 days, and premature infants with LOS were born at an average gestational age of
30 weeks
+ 2 days. Among the full-term infants, there was no difference in the mode of delivery;
in
the case of premature infants, no statement can be made as only two children from
the group
of premature infants with LOS were born spontaneously; all other premature infants
were born
by caesarean section. The maternal CRP and WBC values did not show any clustering
of
particularly high results; the values appear fairly evenly distributed ([Table 6]).
Table 6 Clinical parameters of mothers in the case of microbial matching between
mother-child pairs.
|
|
Premature rupture of membranes
Frequency (n)
|
|
Full-term infants
|
2/4
|
|
Premature infants (EOS)
|
7/11
|
|
Premature infants (LOS)
|
8/19
|
|
|
Mode of delivery
Frequency (n)
|
|
Full-term infants
|
2/4 by vacuum extraction
2/4 by spontaneous delivery
|
|
Premature infants (EOS)
|
6/11 by caesarean section
4/11 by emergency section
1/11 by forceps
|
|
Premature infants (LOS)
|
15/19 by caesarean section
2/19 by emergency section
2/19 by spontaneous delivery
|
|
|
Average delivery time
|
|
Premature infants (EOS)
|
GW 31 + 0
|
|
Premature infants (LOS)
|
GW 30 + 2
|
|
|
CRP
Peripartal maximum (mg/dl)
|
|
Full-term infants
|
2/4 < 10
1/4 10–20
1/4 > 20
|
|
Premature infants (EOS)
|
7/11 < 10
1/11 10–20
3/11 > 20
|
|
Premature infants (LOS)
|
17/19 < 10
2/19 10–20
0/19 > 20
|
|
|
White blood cells (WBC)
Peripartal maximum (per nl)
|
|
Full-term infants
|
0/4 < 20
3/4 20–30
1/4 > 30
|
|
Premature infants (EOS)
|
4/11 < 20
5/11 20–30
2/11 > 30
|
|
Premature infants (LOS)
|
12/19 < 20
7/19 20–30
0/19 > 30
|
|
|
Maternal infections
|
|
Mothers of premature infants
|
26 AIS (16.6%)
|
|
Mothers of full-term infants
|
1 postpartum fever (1.9%)
|
Full-term infants predominantly showed a good clinical course. There were four deaths
among the premature infants with EOS, and one death among the premature infants with
LOS.
Full-term infants and premature infants with EOS and LOS did not show any clustering
of
particularly high CRP, WBC, or interleukin-6 levels ([Table 7]).
Table 7 Clinical parameters of neonates in the case of a microbial match between the
mother-child pair.
|
* Neonates in a stable condition were transferred for further treatment to
another pediatric clinic closer to the parents’ place of residence.
|
|
|
Discharge state
Frequency (n)
|
|
Full-term infants
|
4/4 clinically unremarkable
|
|
Premature infants (EOS)
|
4/11 fatal outcome
6/11 clinically unremarkable
1/11 Transfer to external clinic, stable, close to
home*
|
|
Premature infants (LOS)
|
1/19 fatal outcome
14/19 clinically unremarkable
1/19 Transfer to external clinic, stable, close to
home*
|
|
|
CRP
Maximum (mg/dl)
|
|
Full-term infants
|
3/4 < 10
1/4 10–20
|
|
Premature infants (EOS)
|
11/11 < 10
|
|
Premature infants (LOS)
|
16/19 < 10
3/19 10–20
|
|
|
White blood cells (WBC)
Maximum (per nl)
|
|
Full-term infants
|
2/4 < 20
1/4 20–30
1/4 > 30
|
|
Premature infants (EOS)
|
5/11 < 20
2/11 20–30
3/11 > 30
|
|
Premature infants (LOS)
|
8/19 < 20
7/19 20–30
4/19 > 30
|
|
|
Interleukin-6
Maximum (pg/ml)
|
|
Full-term infants
|
1/4 < 1000
1/4 1000–2000
2/4 > 2000
|
|
Premature infants (EOS)
|
6/11 < 1000
4/11 1000–2000
1/11 > 2000
|
|
Premature infants (LOS)
|
14/19 < 1000
4/19 1000–2000
1/19 > 2000
|
Discussion
Neonatal sepsis represents a very serious and severe clinical picture that can lead
to
permanent impairment [1]
[4]
[22]
[23]. Therefore, efforts are made to diagnose and treat the condition as
early as possible [27]. For this reason, seeking to identify possible pathogens as early as
possible so as to allow a targeted treatment is an understandable approach [14].
There is a lack of data on the extent to which the pathogen spectrum in the case of
neonatal sepsis matches that of the mother. There is a large and good body of data
on the
general pathogen spectrum in neonatal sepsis, which is consistent with our results,
as well as
with the theoretical pathways of transmission [11]
[30]
[31]
[32]. However, to date there has been no data
on how often there is a match between the pathogen spectrum of mother and child; we
are
presenting this kind of data for the first time in this study.
To our knowledge, this is the first study to demonstrate match rates between the pathogen
spectrum in neonatal sepsis and in maternal smear results. Overall, the match rates
are low,
which means the probability of early detection of neonatal sepsis pathogens based
on a
maternal smear is very low, and the NNT is correspondingly high. In full-term infants,
59% of
mothers had no smear result, and in premature infants, 17% of mothers had no smear
result. A
limiting factor is that the smear result is not always available in a timely manner
when the
treatment of the neonate needs to be started; in other words, the result comes too
late. While
this aspect was not considered in this study, it would further reduce the clinical
value of
the maternal smear.
In cases of EOS in particular, pathogen transmission from mother to child is assumed,
although the route of infection is unclear; while an ascending infection seems likely
in the
case of premature rupture of membranes, there are also cases of infection in the child
in
which the mother has intact membranes or lacks other risk factors. In contrast, in
cases of
LOS, interventions such as ventilation and central venous access must also be considered
as
possible routes of infection.
The pathogen spectrum found in cases of neonatal sepsis that were not consistent with
pathogens found in the mother was largely composed of skin bacteria such as Staphylococcus
epidermidis and Staphylococcus haemolyticus. However, as we have included LOS cases
here,
horizontal colonization cannot be ruled out. If only EOS cases are considered, and
if pathogen
match between mother and child is taken into a count, a shift can be seen in the bacterial
spectrum towards group B streptococci and Escherichia coli and other bacteria of the
anogenital region; in these cases, vertical transmission from mother to child therefore
appears the most likely scenario.
Overall, rates of detection of neonatal sepsis pathogens based on a maternal smear
of
approximately 7% in full-term infants and 19% in premature infants can be achieved
under
routine conditions within the framework of normal care structures; if a pathogen can
be
detected in the mother, then the rates are slightly higher. However, since it is not
always
possible to identify a pathogen in the mother, the detection rate in the overall cohort
drops
to 7.7% and 19.1% respectively for full-term infants and premature infants, and if
cases with
LOS are excluded, the detection rate drops further to 8.5% and 7% respectively. Again,
this
seems to argue against the clinical significance of a maternal smear result.
The smear results were not obtained under study conditions, but reflect the care situation
in obstetrics in a level 1 perinatal center. Overall, rates of detection of neonatal
sepsis
pathogens from maternal smears are low, especially when we exclude LOS cases in which
horizontal pathogen transmission cannot be excluded. Therefore, the importance of
maternal
smear diagnostics in pregnancy with regard to early identification of neonatal sepsis
pathogens seems questionable, especially considering that unnecessary antibiotic treatment
in
pregnancy can promote resistance [33]; also, the possibility of transplacental antibiotic therapy having an
effect on the fetus cannot be ruled out [7]. Furthermore, according to current studies, pathogen detection is not
considered a mandatory diagnostic criterion for neonatal sepsis. A distinction is
made between
“clinical sepsis” and bacteriologically “confirmed sepsis”; accordingly, it is questionable
where there is a need to start searching for causative pathogens already during pregnancy
[5]
[26]. Given the severity
of the clinical picture, it is also debatable whether broad, empirical antibiotic
treatment of
the neonate should be abandoned due to questionable findings in the mother during
pregnancy.
In this context, pretreatment of the mother with the chosen antibiotic regimen plays
a role
that must not be underestimated; while bacterial selection in the case of a neonatal
infection
cannot be ruled out in this way, Schilling et al. nevertheless showed that 65% of
all pregnant
women received antibiotic treatment during pregnancy or birth [17].
To our knowledge, the advantage of this study is that we were able, for the first
time, to
identify the correspondence between pathogen detection in infants with neonatal sepsis
and in
maternal vaginal smear findings, and thus to calculate possible rate of detection
of neonatal
sepsis pathogens from a maternal smear. To date, no other results of this kind have
been
published in the literature. Our study also included a large case number of 200 infants;
moreover, the distinction between EOS and LOS in the data analysis is not always commonly
made.
The disadvantage of this study is its retrospective design, and thus the lack of data
in
some cases. Bacterial detection was not available from all mothers. Also, smears were
not
taken at precisely defined times, and bacterial determination was performed according
to
general bacteriological diagnostic criteria and not by genetic testing. Thus, even
in the case
of a bacterial match, this does not necessarily prove that the maternal bacterium
is also the
sepsis pathogen in the neonate.
One instrument used for sepsis prophylaxis in neonates is GBS screening in GW 35–37,
during which colonization with group B streptococci can be detected by vaginal and
rectal
smear. The risk of sepsis in the case of maternal colonization is reported to be approximately
1–2/100 births, with an increased risk in the case of premature labor (< GW 37), premature
rupture of membranes, or if the mother develops an elevated temperature or fever during
birth
[11]
[33]; however, the
infection rate of GBS-positive cases regardless of maternal colonization is estimated
to be
2–5/1000 births [34].
In the case of a positive finding, antibiotic prophylaxis is administered; this has
been
found, at least in studies, to reduce the incidence of EOS [35]. However, it should also be remembered
that antibiotic prophylaxis can trigger a disorder of the enteral microbiome, and
can thus
become the causative agent of serious neonatal diseases such as necrotizing enterocolitis
[7]
[17]
[36]. It remains unclear
to what extent this screening process, which is not part of the care mandated by the
EU
Pregnant Workers Directive, and the treatment given in case of a positive finding,
actually
leads to a reduction in sepsis cases in real care settings; also, in the cohort studies
we
conducted, group B streptococci were the most common pathogens causing EOS in both
premature
and full-term infants [37]
[38].
Other risk assessment instruments, such as the “EOS Calculator” used in the USA, which
includes not only the risk of infection by group B streptococci but also by other
pathogens,
should make it possible to calculate the general risk of EOS from a gestational age
of 34
weeks + 0 days, thus enabling a reduction in unnecessary antibiotic treatments [39]
[40]
[41]
[42].
Despite all the limitations of the retrospective study design and the fact that we
could
only include results obtained or available in the context of routine care, we were
able to
demonstrate, for the first time, matches in pathogen detection between children with
neonatal
sepsis and pregnant mothers, and calculate possible rates of detection of sepsis pathogens
based on maternal smears.
Considering the severity of the clinical picture for neonatal sepsis, a detection
rate of
approximately 20% in premature infants may be an argument for continuing to perform
routine
smears; however, if cases of LOS are excluded, the detection rate falls below 10%,
and the
risk/benefit ratio then needs to be critically discussed, as well as the potential
risk
arising from unnecessary antibiotic treatment.
Conclusion
The causes of neonatal sepsis cannot always be clearly determined. However, due to
the
severity of the clinical picture, early diagnosis and treatment are important. Nevertheless,
starting diagnostics already during pregnancy by taking vaginal smears from the mother
seems
very questionable, since the rate of detection of neonatal sepsis pathogens by this
method is
very low. The value of the maternal smear for identifying neonatal sepsis pathogens
must be
critically questioned. It is likely that it makes more sense to start the diagnostic
procedure
in neonates, and focus on these examination results.
Acknowledgements
This study was performed to meet the requirements for obtaining the title “Dr. med.”
by Mr. Rafael Kuld at the Medical Faculty of the Friedrich-Alexander
University Erlangen-Nuremberg.
