The Journal of Infectious Diseases MAJOR ARTICLE
Placental Infection With Ureaplasma species Is Associated With Histologic Chorioamnionitis and Adverse Outcomes in Moderately Preterm and Late-Preterm Infants Emma L. Sweeney,1 Suhas G. Kallapur,2 Tate Gisslen,2 Donna S. Lambers,3 Claire A. Chougnet,4 Sally-Anne Stephenson,1 Alan H. Jobe,2 and Christine L. Knox1 1 Institute of Health and Biomedical Innovation, Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; 2Division of Neonatology, 3Division of Maternal and Fetal Medicine, and 4Division of Immunobiology, Cincinnati Children’s Hospital Medical Centre, Ohio
Objective. The human Ureaplasma species are the microbes most frequently isolated from placentae of women who deliver preterm. The role of Ureaplasma species has been investigated in pregnancies at 6 h; 12/57, 21.0%), when compared with infants whose placentae had no detectable microorganisms (43/478, 9%; P = .009; Table 2).
Because the Ureaplasma species were the microorganisms most frequently isolated in our study, we also correlated the presence of these species with adverse pregnancy or neonatal outcomes. Owing to the small number of microorganisms other than Ureaplasma species present, it was not possible to analyze these other species individually; therefore, we compared the outcomes of women with placentae infected or colonized with Ureaplasma species and those with placentae infected with microorganisms other than Ureaplasma (referred to as ‘other’ microorganisms throughout the paper). In some cases, women
Table 2. Pregnancy Outcomes for 474 Women Whose Pregnancies Were Complicated by Chorioamnion Infection and Neonatal Outcomes for Infants (535 Placentae) After Pregnancies Complicated by Infection, Compared With Those for Whom No Infection Was Identified Outcome
No Chorioamnion Infection
25.0 ± 0.7 (17–38)
27.8 ± 0.3 (15–43)
2.2 ± 0.2 (1–5)
2.5 ± 0.1 (1–11)
1.9 ± 0.1 (1–4)
2.1 ± 0.1 (1–10)
Maternal No. evaluatedb Maternal age, y Mean ± SEM (Range)
Clinical pregnancies, no. Mean ± SEM (Range)
Viable offspring from all pregnancies, no. Mean ± SEM (Range)
At least 1 sign/symptom of infectionc
Cervical incompetence and/or preterm labor
Antibiotics administered during labord
35.7 ± 0.3 (32–41)
35.6 ± 0.1 (32–41)
2642.4 ± 84.6 (1380–3925)
2658.0 ± 29.8 (1060–4530)
441.3 ± 16.2 (199–710.7)
428.7 ± 5.8 (132–1099)
Maternal stage, median (range)
Fetal stage, median (range)
Mode of delivery
Neonatal No. evaluated Gestational age at delivery, wks Mean ± SEM (Range)
Birth weight, g Mean ± SEM (Range)
Placental weight, g Mean ± SEM (Range)
Histologically confirmed chorioamnionitise 6 h
7.0 ± 1.1 (1–37)
6.1 ± 0.3 (1–43)
Length of hospital stay, wks Mean ± SEM (Range)
Data are no. (%) of subjects, unless otherwise indicated. Abbreviations: CPAP, continuous positive airway pressure; NS, not significant; PCR, polymerase chain reaction; pPROM, preterm premature rupture of membranes; RDS, respiratory distress syndrome; SEM, standard error of the mean. a
By logistic regression analysis.
Some women (n = 3) delivered multiple placentae and one placenta was found to be infected, while the other was shown to be uninfected by culture and 16S rRNA PCR. Data from these women with contrasting placental microbiology results were excluded from this analysis.
Defined as maternal temperature of >38°C, uterine or abdominal tenderness, foul-smelling vaginal discharge, maternal tachycardia (heart rate, >120 beats/minute), or fetal tachycardia (heart rate, >160 beats/minute).
Data are for antibiotics administered for >3 hours before delivery. The types and doses were not recorded.
Assessed using tissue sections from each placenta according to criteria set out by Redline et al . Maternal and fetal grades of chorioamnionitis are listed as median and range.
Ureaplasma and Chorioamnionitis
JID 2016:213 (15 April)
mean age, 27.8 ± 0.3 years). There were no other differences in maternal demographic data (Table 2) or incidence of adverse pregnancy outcomes between these groups of women. The presence of Ureaplasma species (n = 38), but not other microorganisms in placentae (n = 535) correlated with histologically conﬁrmed chorioamnionitis (26 of the 38 Ureaplasma positive placentae; 68.4% vs 4/15 of the placentae infected with other microorganisms, 26.7%, respectively; P < .001). Of the placentae infected with ureaplasmas, 12/38 (31.6%) showed no evidence of inﬂammation, 14/38 (36.8%) showed only mild evidence of chorioamnionitis (grade 1), and 12/38 (31.6%) demonstrated histologically conﬁrmed severe chorioamnionitis (grades 2 or 3; Figure 1B). There was no difference in the prevalence of U. parvum or U. urealyticum clinical isolates in placentae with or without histologically conﬁrmed chorioamnionitis (P = .10) or in placentae that were delivered late preterm or at term (P = .076; data not shown). Interestingly, the presence of histologically conﬁrmed chorioamnionitis was signiﬁcantly associated with spontaneous (but not medically indicated) M/LPT birth when Ureaplasma species infection was present (22.5% vs 3.1%; P < .001 data not shown). There were no other signiﬁcant correlations between the presence of other microorganisms and spontaneous delivery in the presence and absence of histologically conﬁrmed chorioamnionitis (3.4% and 1.8%, respectively). Placental Infection With Ureaplasma species and Other Microorganisms Was Associated With Elevated Cord Blood Cytokine Levels
Figure 1. A, The severity of chorioamnionitis was similar among moderately preterm and late-preterm (M/LPT) placentae and term placentae. B, Ureaplasma species but not other microorganisms were associated with histologically confirmed chorioamnionitis, and the severity of inflammation was greater when ureaplasmas were present. Data are presented as the mean and data were analyzed using analysis of variance.
delivered multiple infants/placentae in which 1 placenta was infected but the other was not (n = 3) or had placentae that contained both ureaplasmas and other microorganisms (n = 4); data from these women were excluded from these analyses. Women testing positive for the presence of Ureaplasma species within a placenta (n = 32) had a decreased maternal age (mean age, 24.2 ± 0.8 years; P = .002), compared to women - positive for the presence of other microorganisms (n = 12; mean age, 28.2 ± 1.4 years) and those women who had an absence of microorganisms in placentae (n = 427; 1344
JID 2016:213 (15 April)
Sweeney et al
Chorioamnion infection, irrespective of etiology, was associated with elevated cord blood factors. Placentae with chorioamnion infection demonstrated signiﬁcantly higher concentrations of IL-8 (536 pg/mL) and G-CSF (403 pg/mL), compared with cord blood from pregnancies in which no chorioamnion infection was detected (56 pg/mL [P = .03] and 231 pg/mL [P = .04], respectively; data not shown). We also investigated whether speciﬁc cord blood cytokines were associated with infection with particular microorganisms. Detection of Ureaplasma species in the chorioamnion was associated with elevated levels of G-CSF (P = .02; Figure 2D) but not IL-6 (Figure 2A), IL-8 (Figure 2B), and MCP-1 (Figure 2C). By contrast, cord blood collected from pregnancies in which the chorioamnion was infected by microorganisms other than Ureaplasma demonstrated higher levels of IL-8 (P = .01; Figure 2B). DISCUSSION
Infections of the female upper genital tract are associated with preterm birth, and up to 40% of all preterm births are attributed to infection . While previous studies have identiﬁed an association between upper genital tract infections in pregnancy and early preterm births (ie, 32 weeks of gestation). We identiﬁed chorioamnion infection in 10.6% of all M/LPT and term pregnancies. We also found no differences in the incidence of chorioamnionitis in M/LPT or term placentae and no major differences in the prevalence of signs/symptoms of infection in women experiencing chorioamnionitis. This highlights why it is so difﬁcult to identify and treat women with asymptomatic upper genital tract infection and chorioamnionitis during pregnancy. Within our study, colonization and infection of placentae were predominantly caused by a single microorganism. The human Ureaplasma species were the most prevalent microorganisms identiﬁed in the chorioamnion, accounting for >68% of all isolates in the study. While 70% of the women in our study delivered vaginally, we isolated no Lactobacillus species in any chorioamnion tissue specimens tested. Lactobacillus species have been isolated in up to 90% of vaginal specimens , and the absence of this microorganism in placental tissue conﬁrms that our methods of collection and sampling have eliminated or circumvented vaginal microﬂora contamination. Furthermore, the majority of the microorganisms detected in
these placentae are consistently associated with intraamniotic infection. Some studies have demonstrated the presence of these species in early preterm births (