Intra-Amniotic Infection with Ureaplasma parvum Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin.

Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a taxonomic characterization of Ureaplasma isolates from women with intra-amniotic infection, which revealed that Ureaplasma parvum is the most common bacterium found in this clinical condition. Next, using animal models, we provided a causal link between intra-amniotic inoculation with Ureaplasma species and preterm birth. Importantly, the intra-amniotic inoculation of Ureaplasma species induced high rates of mortality in both preterm and term neonates. The in vivo potency of U. parvum to induce preterm birth was not associated with known virulence factors. However, term-derived and preterm-derived U. parvum isolates were capable of inducing an intra-amniotic inflammatory response. Both U. parvum isolates invaded several fetal tissues, primarily the fetal lung, and caused fetal inflammatory response syndrome. This bacterium was also detected in the placenta, reproductive tissues, and most severely in the fetal membranes, inducing a local inflammatory response that was replicated in an in vitro model. Importantly, treatment with clarithromycin, a recently recommended yet not widely utilized antibiotic, prevented the adverse pregnancy and neonatal outcomes induced by U. parvum These findings shed light on the maternal-fetal immunobiology of intra-amniotic infection.IMPORTANCE Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species.

Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial.

OBJECTIVE: Since preventive therapies for bronchopulmonary dysplasia (BPD) are limited we treated preterm infants with azithromycin to decrease the incidence of BPD. METHODS: Infants less than 1,250 g birth weight were randomized to azithromycin or placebo within 12 hr of beginning mechanical ventilation and within 72 hr of birth. The treatment group received azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for a maximum of 6 weeks. Aspirates were collected during the study to assay for Ureaplasma. The primary endpoints were incidence of BPD or mortality. (Clinical Trials Identifier: NCT00319956.) RESULTS: A total of 220 infants were enrolled (n=111 azithromycin, and 109 placebo). Mortality was 18% for the azithromycin group versus 22% for the placebo group (P = 0.45). Incidence of BPD was 76% for the azithromycin group versus 84% for the placebo group (P=0.2). The multiple logistic regression analysis demonstrated an odds ratio of 0.46 decrease in the chance of developing BPD or death for the azithromycin group, but was not statistically significant. The incidence of BPD in the Ureaplasma subgroup was 73% in the azithromycin group versus 94% in the placebo group (P=0.03). Analysis of patients in the Ureaplasma subgroup only, using the exact logistic model demonstrated a decrease in BPD or death in the azithromycin group with an estimated odds ratio of 0.026 (0.001-0.618, 95% confidence interval). CONCLUSIONS: Routine use of azithromycin therapy for the prevention of BPD cannot be recommended. The early treatment of Ureaplasma colonized/infected patients might be beneficial, but a larger multi-centered trial is required to assess this more definitively.

Role of pulmonary infection in the development of chronic lung disease of prematurity.

We studied the role of ante- and post-natal infection in the development of chronic lung disease (CLD) of prematurity. 192 newborn infants (61 term and 131 pre-term of <34 weeks gestation: 88 with respiratory distress syndrome, 35 developed CLD and eight died) were recruited. 16S ribosomal RNA (rRNA) genes were identified by PCR of DNA isolated from 840 gastric and lung fluid samples. Ureaplasma spp. were also cultured. Presence of 16S rRNA genes (OR 1.6, 95% CI 1.2-2.2) and Ureaplasma spp. (OR 3.6, 95% CI 1.7-7.7) was significantly associated with the development of CLD. This association remained if the 16S rRNA genes and Ureaplasma spp. were first identified within the first 3 days of life (OR 2.4 (95% CI 1.4-4.1) and 3.8 (95% CI 1.4-10.0), respectively) or if first identified after 3 days of age (OR 1.7 (95% CI 1.1-2.8) and OR 5.1 (95% CI 1.3-19.8), respectively). Peak lung fluid interleukin (IL)-6 and IL-8 were significantly associated with presence of microbes (p<0.0001 and p=0.0001, respectively) and development of CLD (p=0.003 and 0.001, respectively). Both early and late microbial presence in neonatal lung fluid samples was significantly associated with the development of CLD suggesting that both ante- and post-natal infection play a role in the development of CLD.

Experimental intrauterine Ureaplasma infection in sheep.

OBJECTIVE: Prenatal Ureaplasma spp exposure is associated with preterm birth and modulates the neonates' susceptibility to respiratory distress syndrome and bronchopulmonary dysplasia. We hypothesized that intra-amniotic ureaplasmas would cause lung inflammation and alter fetal lung development. STUDY DESIGN: Pregnant ewes bearing singleton fetuses were given an intra-amniotic injection of 20 x 10 6 CFUs of U parvum (serovar 3) or vehicle, either 1, 3, 6, or 10 weeks before the delivery of preterm lambs at 124 days of gestation (n = 4-10 per group) for evaluation of inflammation and fetal lung maturation. RESULTS: Ureaplasmas were recovered from amniotic and fetal lung fluids after intra-amniotic injection. Body weight and umbilical arterial pH were reduced by Ureaplasma exposure for 10 weeks ( P < .05). Ureaplasmas caused progressive lung inflammation and improvements in lung function that were associated with increased surfactant lipids (control, 0.13 +/- 0.02 micromol/kg; 10 weeks of Ureaplasma exposure, 7.43 +/- 3.0 micromol/kg; P < .001) and surfactant protein messenger RNA expression. CONCLUSION: Long-term exposure to ureaplasmas in amniotic fluid alters ovine fetal development.

Surgical infections with Mycoplasma: a brief review.

Mycoplasma hominis and Ureaplasma urealyticum are common inhabitants of the human genital tract. Evidence for an aetiological role in pyelonephritis, pelvic inflammatory disease, post-abortion and post-partum fever has been presented. There are sporadic reports of Mycoplasma causing serious extragenital infection such as septicemia, septic arthritis, neonatal meningitis and encephalitis. We review 38 cases of surgical infections with Mycoplasma.

Ureaplasma urealyticum infection associated with acute respiratory insufficiency and death in premature infants.

The incidence and outcome of Ureaplasma urealyticum infection were studied in 98 infants born before 34 weeks of gestational age. Infection was defined as the presence of one or more isolations of U. urealyticum in samples obtained from trachea, blood, cerebrospinal fluid, or postmortem brain or lung biopsies. Forty-seven infants were infected. Intact amniotic membranes had no protective effect against infection; intrauterine U. urealyticum infection was detected in 19 infants who were born by cesarean section with intact amniotic membranes. Respiratory distress syndrome, the need for assisted ventilation, severe respiratory insufficiency, and death were significantly more common among infected than among noninfected infants. Our results suggest that U. urealyticum infection is associated with an unfavorable short-term outcome in preterm infants.