Infection (2016) 44:323–327

DOI 10.1007/s15010-015-0858-7

ORIGINAL PAPER

Neonatal Ureaplasma urealyticum colonization increases

pulmonary and cerebral morbidity despite treatment
with macrolide antibiotics
Bernhard Resch1,2 · C. Gutmann1 · F. Reiterer2 · J. Luxner3 · B. Urlesberger2 

Received: 18 August 2015 / Accepted: 17 October 2015 / Published online: 30 October 2015
© Springer-Verlag Berlin Heidelberg 2015

Abstract  non-invasive ventilation (median 11 vs. 6 days p  = 0.006

Objective  To evaluate the influence of Ureaplasma urea-
lyticum (UU) colonization on neonatal pulmonary and cer-
ebral morbidity.
Methods  Single-center case–control study including all
preterm infants with positive UU tracheal colonization
between 1990 and 2012. Cases were matched with con-
trols by birth year, gestational age, birth weight, and sex.
All cases had received macrolide antibiotics for UU infec-
tion starting at the time of first positive culture results from
tracheal aspirates. Main outcome parameters included pres-
ence and severity of hyaline membrane disease (IRDS),
duration of ventilation, bronchopulmonary dysplasia at 36
postmenstrual age and neurological morbidities (seizures,
intra-/periventricular hemorrhages-I/PVH, periventricular
leukomalacia-PVL).
Results  Of 74 cases identified 8 died and 4 had to be
excluded; thus, 62 preterm infants were compared to
62 matched controls. UU was significantly associated
with IRDS (79 vs. 61 %, p  = 0.015), BPD (24 vs. 6 %,
p  = 0.003), seizures (23 vs. 5 %, p  = 0.002) and I/PVH
(45 vs. 24 %, p  = 0.028). Cases had longer duration of
mechanical ventilation and total duration of invasive and
* Bernhard Resch
bernhard.resch@medunigraz.at
1 plasia (BPD) defined as oxygen dependence at 28 days or
Research Unit for Neonatal Infectious Diseases
and Epidemiology, Medical University of Graz, Graz, Austria
2 to develop moderate to severe BPD has been observed
Division of Neonatology, Department of Pediatrics, Medical
University of Graz, Auenbruggerplatz 34/2, 8036 Graz,
Austria
3
Institute for Hygiene, Microbiology and Environmental
Medicine, Medical University of Graz, Graz, Austria
and 25 vs. 16.5 days p = 0.019, respectively).
Conclusion  UU was found to be significantly associated
with pulmonary short- and long-term morbidity and mild
cerebral impairment despite treatment with macrolide
antibiotics.
Keywords  Ureaplasma urealyticum · Erythromycin ·
Respiratory distress syndrome · Bronchopulmonary
dysplasia · Intraventricular hemorrhage
Introduction
Ureaplasma species can be detected in vaginal flora in
40–80 % of healthy women and have been causally linked
to infertility, early pregnancy loss, stillbirth, preterm birth
and neonatal morbidities [1]. Despite its low virulence, evi-
dence by in vitro and in vivo experimental models supports
a significant role for Ureaplasma species in these disor-
ders by vertical transmission from mothers to their infants
occurring both in utero or during delivery [2, 3]. The rate
of respiratory tract colonization with Ureaplasma species
in very low birthweight infants is reported to range from 20
to 45 % [2].
Two meta-analyses published in 1995 [4] and 2005 [5]
observed a significant association between Ureaplasma
respiratory tract colonization and bronchopulmonary dys-
at 36 weeks postmenstrual age. A 7.9-fold increased risk
in infants who had been mechanically ventilated for any
duration and had a positive tracheal aspirate compared to
mechanically ventilated infants with a positive nasopharyn-
geal sample alone [6].

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A twofold increased risk for necrotizing enterocolitis
(NEC) in preterm infants of <33 weeks gestational age with
respiratory infection with Ureaplasma species had been
reported recently [7]. Ureaplasma species have also been
detected in blood, cerebrospinal fluid (CSF), and brain
tissue, suggesting the potential for invasive disease [2].
Although the risk of severe intraventricular hemorrhage
(IVH ≥ grade III) has been reported to be 2.5-fold higher
in serum Ureaplasma PCR-positive compared to PCR-
negative infants [8], results are divergent [2]. Additionally,
ureaplasma detection in CSF has not been observed to be
clearly associated with cranial ultrasound abnormalities
[2].
Despite in vitro susceptibility of Ureaplasma species to
erythromycin and favorable pharmacokinetic activity, trials
of erythromycin therapy in colonized preterm infants have
failed to demonstrate efficacy in the prevention of BPD or
to eradicate respiratory tract colonization [9–13]. Clarithro-
mycin has been assessed in a single-center study of at-risk
preterm infants to successfully prevent BPD [14] but results
have not been confirmed by others.
Aim of this retrospective case–control study was to eval-
uate the influence of Ureaplasma urealyticum (UU) colo-
nization and subsequent treatment with erythromycin on
neonatal pulmonary and cerebral morbidity.
Patients and methods
This was a single-center retrospective case–control study
including all preterm infants with positive UU tracheal
colonization between 1990 and 2012. Setting was a two
ward tertiary care NICU at the Medical University of Graz
located in the southern part of Austria covering a region
with 8500 to 10,000 births per year. During the study time
period, approximately 7000 preterm infants were hospital-
ized at the two wards of the NICU.
Cases were collected from a local electronic data base,
and data regarding positive UU aspirate confirmed by
review of the medical charts and the bacterial result pro-
tocols. A commercial kit, Mycoplasma IST-2 (BioMer-
ieux, Marcy l’Etoile, France), was used according to the
manufacturer’s instructions (performed at the Institute
for Hygiene, Microbiology and Environmental Medicine,
Medical University of Graz, Austria), as described else-
where [15]. Cases were matched with controls by birth
year, gestational age (±1 week), birth weight (±100 g), and
sex. All cases had received macrolide antibiotics (erythro-
mycin 50 mg per kg body weight 3 times a day for 10 days)
for UU infection starting at the time of first positive culture
results from tracheal aspirates.
Main outcome parameters included presence and
severity of hyaline membrane disease (infant respiratory
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B. Resch et al.
distress syndrome-IRDS, grade 1–4), duration of ventila-
tion (mechanical ventilation and CPAP), bronchopulmo-
nary dysplasia with oxygen dependency at 36 postmen-
strual age and neurological morbidities (seizures, intra-/
periventricular hemorrhages-I/PVH, periventricular leu-
komalacia-PVL). Secondary outcome parameters included
necrotizing enterocolitis-NEC, early and late onset sepsis,
and neonatal treatment with steroids for chronic lung dis-
ease of prematurity.
Data were collected regarding gestational age in weeks,
birth weight, gender, small for gestational age (birth weight
below the 10 ‰), multiple gestation, breech presentation,
antenatal steroids, maternal antibiotics, maternal age, cho-
rioamnionitis, sectio caesarea, preterm premature rup-
ture of the membranes-PPROM, Apgar scores at 1, 5, and
10 min, neonatal steroids, neonatal seizures, and apneas.
Exclusion criteria were death during neonatal
hospitalization
The study was approved by the local ethic committee of the
Medical University of Graz (Nr. 27-080 ex 14/15).
Statistical analyses were done with t test and Wil-
coxon test for numerical data after checking the normality
assumption with the Kolmogorov–Smirnov test. Categori-
cal data were tested with Chi square using Yates correction
and Fisher’s exact test as appropriate. Analysis was done
with SPSS version 17 (SPSS Inc., 2008, Chicago, USA)
and Microsoft Excel 2007 (Microsoft Corporation, 2007,
Redmond, USA). A p value <0.05 was considered to be
significant.
Results
During the study period, 74 preterm infants were diagnosed
as having UU colonization by positive tracheal aspirate.
Eight of them died during their neonatal hospitalization. Of
the remaining 66 cases another 4 had to be excluded due to
lack of matching controls. Thus, the study population com-
prised 62 cases with 62 matched controls.
Perinatal data of cases and controls are depictured in
Table  1. Significant differences were found regarding
higher presence of PPROM and chorioamnionitis in cases
and higher rates of multiple gestations in the controls.
Main outcome parameters differed significantly regard-
ing IRDS (79 vs. 61 %, p  = 0.015), BPD (24 vs. 6 %,
p  = 0.003), presence of neonatal seizures (23 vs. 5 %,
p = 0.002), and I/PVH (45 vs. 24 %, p = 0.028). The lat-
ter was influenced by significant differences regarding IVH
grade I (57 vs. 41 %, p = 0.019). IVH grades 2 and 3 and
PVH did not differ between groups, see Table 2. Cases
had longer duration of mechanical ventilation and total
Neonatal Ureaplasma urealyticum colonization increases pulmonary and cerebral morbidity… 325

Table 1  Perinatal data of 62 preterm infants with Ureaplasma urea- Table 2  Short-term outcome data of 62 preterm infants with Urea-
lyticum infection and 62 matched controls plasma urealyticum infection and 62 matched controls
Cases Controls p value Cases Controls p value

Number 62 62 Number 62 62
Gestational age 27 [23–36] 27 [24–36] 0.229 Bronchopulmonary dysplasia 15 (24) 4 (6) 0.003
(weeks) Infant respiratory distress syn- 49 (79) 38 (61) 0.015
Gender (male:female) 36:26 (58:42) 36:26 (58:42) 0.500 drome (IRDS)
Birth weight (g) 945 [532–2948] 1000 [470–2950] 0.487  IRDS grade I 9 (18) 5 (13)
Small for gestational 2 (3) 2 (3) 0.500  IRDS grade II 16 (33) 9 (24)
age  IRDS grade III 15 (31) 11 (29)
Multiple gestation 6 (10) 15 (24) 0.019  IRDS grade IV 9 (18) 13 (34) *
Breech presentation 1 (2) 1 (2) 0.257 Mechanical ventilation (MV) 59 (95) 50 (81) 0.005
Antenatal steroids 48 (78) 33 (53) 0.051 Duration of MV (days) 11 [0–95] 6 [0–50] 0.006
Maternal antibiotics 35 (57) 26 (42) 0.064 CPAP (days) 10 [0–59] 6 [0–55] 0.166
Maternal age 27 29 0.368 MV and CPAP (days) 25 [0–95] 16.5 [0–71] 0.019
Chorioamnionitis 33 (53) 22 (35) 0.028 Early onset sepsis 11 (18) 5 (8) 0.059
Sectio caesarea 35 (56) 42 (68) 0.099 Late onset sepsis 10 (16) 14 (23) 0.184
PPROM 46 (74) 30 (48) 0.002 IVH total 28 (45) 17 (27) 0.028
Apgar 1 6,5 [2–9] 6 [2–9] 0.142  IVH grade I 16 (57) 7 (41) 0.019
Apgar 5 8 [3–10] 8 [5–10] 0.362  IVH grade II 3 (11) 3 (18) 0.326
Apgar 10 9 [6–10] 9 [5–10] 0.196  IVH grade III 4 (16) 3 (20) 0.350
Data are given as n (%) or median [range]  PVH 4 (14) 2 (12) 0.326
PPROM preterm premature rupture of the membranes Cystic periventricular leukoma- 10 (16) 6 (10) 0.144
lacia
Necrotizing enterocolitis 1 (2) 4 (6) 0.087
Neonatal steroids 30 (48) 12 (19) <0.001
duration of invasive and non-invasive ventilation (median
Neonatal seizures 14 (23) 3 (5) 0.002
11 vs. 6 days p = 0.006 and 25 vs. 16.5 days p  = 0.019,
Apnoeas 50 (81) 49 (79) 0.482
respectively).
Secondary outcome parameters differed significantly Data are given as n (%) or median [range]
regarding rates of neonatal treatment with steroids for pre- CPAP continuous positive airway pressure, I/PVH intra-/periventricu-
vention and treatment of chronic lung disease of prematu- lar hemorrhage
rity (48 vs. 19 %, p < 0.001). There were no differences * IRDS differences regarding grading (p = 0.201)
regarding rates of NEC or early and late onset sepsis, see
Table 2.
chorioamnionitis on the course of pulmonary disease in
the case group by being unaware of maternal UU coloni-
Discussion zation results. This finding compares to a study reporting
on infection-related chronic lung disease that was associ-
In this retrospective case–control study UU was found to ated with neonatal colonization of UU (OR 43.7, 95 % CI
be significantly associated with pulmonary short- and long- 2.84–673.8) in 105 infants below 32 weeks of gestational
term morbidity and mild cerebral impairment despite treat- age [21]. A small study including 20 babies colonized with
ment with macrolide antibiotics. UU found no association with BPD and, thus, stated that
The impact of UU on BPD is documented by a total of UU played no significant role in development of BPD in
3 meta-analyses [4, 5, 16] for both definitions of chronic Indian preterm infants [22]. But even appropriate designed
lung disease (defined as oxygen dependence at 28 days prospective studies could not confirm the association of UU
or at 36 weeks postmenstrual age). Nevertheless, some with BPD [23].
studies found results strongly influenced by lower gesta- Erythromycin for the prevention of chronic lung dis-
tional age [17, 18], others not [19, 20], and some reported ease in intubated preterm infants at risk for BPD or colo-
on an increased mortality rate [18, 19]. Our study design nized or infected with UU failed to demonstrate efficacy as
excluded the influence of different gestational age between reported in a 2003 Cochrane review [24]. One reason might
UU colonized and non-colonized preterm infants on be the fact that half of UU strains demonstrated to be resis-
BPD. We only found a possible influence of PPROM and tive against erythromycin in vitro [25]. In a further study,

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erythromycin and clindamycin demonstrated the lowest
activity (MIC90 of 8 mg/L) compared to clarithromycin
and josamycin which were the most potent macrolides
(MIC90 of 0.5 mg/L) against Ureaplasmas [26]. Another
reason might be that erythromycin was shown to be effec-
tive against only one of four UU strains in a mouse model
of Ureaplasma sepsis [27].
In a study enrolling 257 preterm infants below 34 weeks
of gestational age being born by cesarean section infants
were divided into two groups according to detection of
Ureaplasma species by culture-based and/or polymerase
chain reaction techniques [20]. Significant differences were
observed between both groups for all IVH (p = 0.032) and
severe IVH grades 3 or 4 (p = 0.013), and Ureaplasma spe-
cies was a significant predictor (p < 0.001) of BPD after
correcting for birth weight (p  = 0.003) and positive pres-
sure ventilation (p = 0.001). Interestingly, we found com-
parable results but significant differences between groups
only regarding low-grade IVH. No influence on respira-
tory distress syndrome, severe intraventricular hemorrhage
grades 3 and 4, or death was found in another study includ-
ing 351 mother/infant dyads with deliveries between 23
and 32 weeks of gestational age who had cord blood cul-
tures for UU and M. hominis [28].
The analysis of tracheal aspirate or nasopharyngeal fluid
samples from 24 preterm babies with and 26 without respira-
tory distress syndrome for the detection of UU and U. par-
vum by culture identification assay and PCR revealed a sig-
nificant association with respiratory distress syndrome [29]
as found in our study. This is in contrast to an analysis of 60
ventilated babies below 30 weeks gestation, who had tracheal
secretions tested for UU, and retrospective review of chest
radiographs within the first 10 days of life for the presence of
acute lung injury [30]. The UU negative group showed sig-
nificantly more changes characteristic of respiratory distress
syndrome, as shown by the degree of diffuse granularity, on
the first radiographs. Interestingly, by day 5 the UU positive
group was showing early emphysematous changes, which
were more obvious by day 10 and significantly different
from the UU negative babies. At 36 weeks corrected gesta-
tion, there was no significant difference between the groups
[30]. Comparable to our findings UU positive babies were
more likely to experience chorioamnionitis and PPROM, and
additionally more often required ventilation to be restarted,
had a higher proportion being ventilated on day 10 including
higher oxygen demands, and needed a higher mean airway
pressure [30]. An association with NEC as described else-
where [7] could not be confirmed by our findings.
In conclusion, we found erythromycin being un-effec-
tive in the prevention of short- and long-term respiratory
morbidity of preterm infants colonized with UU. In con-
trast to other studies, UU was only associated with mild
cerebral impairment.
13
B. Resch et al.
Compliance with ethical standards 
Conflict of interest  The authors declare that they have no conflict
of interest.
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