Pryhuber GS:
Help in development of the protocol
Evaluation of papers and extraction of data
Providing recommendations for the review; editing final review
Weinberg GA:
Help in development of the protocol
Evaluation of papers and extraction of data
Providing recommendations for the review; editing final review
Phelps DL:
Introduction and guidelines in writing a Cochrane Review
Help in the development of the protocol
Evaluation of papers and extraction of data
Help in entering data in RevMan
Help in writing of the protocol and the review
Providing recommendations for the review; editing final review
More evidence needed on using antibiotics to try and prevent chronic lung disease in preterm babies testing positive for U urealyticum.
Chronic lung disease (CLD) is a major health risk often faced by preterm babies on ventilation (machine-assisted breathing). Ureaplasma urealyticum is a common type of infection that may be one of the causes of CLD, although this has not been proven. Erythromycin is an antibiotic used for other infections caused by U urealyticum. When a baby tests positive for U urealyticum, erythromycin has been tried as a preventive measure. The review found that there is not enough evidence from trials to show whether or not testing preterm babies for U urealyticum and using erythromycin can prevent CLD or mortality.
Controversy exists over whether or not Ureaplasma urealyticum colonization or infection of the respiratory tract contributes to the severity of chronic lung disease (CLD), a major cause of morbidity and mortality in preterm infants.
U. urealyticum is an atypical bacterial organism that lacks a rigid cell
wall, therefore making it resistant to beta-lactam antibiotics. Mucosal surfaces,
particularly the respiratory and genital tracts, are commonly colonized (Tully 1993; Cassell 2001),
but symptomatic infection is relatively uncommon.
In adults, U. urealyticum has been associated with urethritis in males,
urinary calculi (Grenabo 1988; Cassell 2001) and, in immunocompromised patients,
arthritis (Forgacs 1993) and osteomyelitis (Mohiuddin 1991). The organism can be found
in the vagina or cervix of 40-80% of sexually mature, asymptomatic women (McCormack 1986a; Cassell 2001). Colonization is linked to younger
age, lower socioeconomic status, sexual activity with multiple partners, oral
contraceptive use and black ethnicity (McCormack
1986a; McCormack 1986b). The presence
of U. urealyticum in the amniotic fluid and placenta has been associated with
adverse pregnancy outcomes such as chorioamnionitis, preterm delivery, spontaneous
abortion and stillbirths (Cassell 1991). Transmission
of U. urealyticum to the fetus may occur in utero via contamination of the
amniotic fluid with organisms ascending from the vagina or during delivery
by passage through a colonized birth canal (Dinsmoor
1989). Vertical transmission results in colonization rates from 46-89%
in preterm infants and is highest in infants with birthweights less than
1000 grams (Sanchez 1990). Rates of transmission
are somewhat lower (44-55%) in full term infants (Sanchez 1987; Syrogiannopoulos '90). Neonatal morbidity
possibly associated with U. urealyticum includes neonatal pneumonia (Waites 1989) and meningitis (Garland 1987). U. urealyticum has also been implicated
as contributing to the incidence and severity of chronic lung disease in
infants born prematurely. However, whether U. urealyticum infection is causative
of these conditions is unclear.
The lungs of preterm infants are prone to injury leading to CLD. Lung injury may be due to several factors such as use of ventilators, oxygen supplementation and infection. Neonatal CLD was first described as a spectrum of clinical, radiological and pathologic findings in infants requiring mechanical ventilation for respiratory distress syndrome (Northway 1967). The term bronchopulmonary dysplasia (BPD) was used to describe the abnormal pulmonary growth, development and fibrosis evident histologically in infants dying of CLD. Later, the clinical criteria for the diagnosis of BPD in survivors were defined as a requirement for oxygen beyond one month of age plus characteristic x-ray findings. Since the initial description of BPD by Northway, however, the clinical picture has changed. Very premature infants survive more often and the histopathology observed demonstrates fewer airway abnormalities and more alveolar fibrosis and failure of alveolarization. The need for supplemental oxygen at 28 days of life was a good predictor of abnormal pulmonary findings in infants born equal to or greater than 30 weeks of gestation but became less useful as a diagnostic criterion as the gestational age of survivors decreased. For the younger infants the requirement for additional oxygen at 36 weeks postmenstrual age (PMA) is a better predictor of abnormal pulmonary outcomes in the first two years of life (Shennan 1988). It has been proposed that U. urealyticum infection or colonization at birth results in an increased risk of CLD.
There are several mechanisms proposed for how U. urealyticum may contribute to the severity of CLD in preterm infants. Neonatal fibroblasts release significant levels of IL-6 and IL-8 in direct response to active infection with U. urealyticum even without the added insult of hyperoxia (Stancombe 1993). Thus, U. urealyticum could initiate or escalate an inflammatory response in the lungs by inducing these cytokines. Increased numbers of polymorphonuclear cells, consistent with reactive inflammation, were detected in endotracheal aspirates from preterm infants colonized with U. urealyticum on the second day of life (Payne 1993). Also, clinical or subclinical Ureaplasma pneumonia may increase oxygen requirements and increase the severity of CLD resulting from oxygen toxicity (Cassell 1988a). Despite the potential for U. urealyticum to cause lung inflammation and injury, published studies do not agree on the role of the organism in the development of CLD. Differences in the patient populations, culture methods and the definition of CLD utilized in the studies contribute to the disparities in reported results.
Several studies have implicated colonization with U. urealyticum in the development of CLD in preterm infants (Cassell 1988b; Sanchez 1988; Wang 1988; Horowitz 1992; Crouse 1993; Payne 1993; Iles 1996; Perzigian 1998; Hannaford 1999). The majority of the studies used a definition of CLD as "the need for supplemental oxygen at 28 days of life." There were differences in defining colonization because of various culture techniques. All of the studies cultured nasopharyngeal aspirates and/or endotracheal aspirates for U. urealyticum. In addition, infant specimens cultured for U. urealyticum included blood (Cassell 1988b) and swabs from the throat, eye, vagina and rectum (Sanchez 1988). Endotracheal aspirates were found to be the most significant marker of colonization in the respiratory tract (Cassell 1988b). U. urealyticum was isolated from endotracheal aspirates in pure culture from 85% of preterm infants and recovered at the same time from blood culture in 26% of these infants (Cassell 1988b). In a recent meta-analysis (Wang 1995), the relative risk (RR) of CLD in colonized compared to non-colonized infants was 1.72 (95% confidence interval, 1.50 - 1.96).
Other studies have suggested that U. urealyticum colonization has no association with the development of CLD (Heggie 2001; Ollikainen 2001; van Waarde 1997; Saxen 1993; Smyth 1993). Ollikainen found no association between U. urealyticum colonization and CLD both at 28 days after birth and 36 weeks PMA. Heggie found no association between colonization with two distinct species of U. urealyticum (U. urealyticum and U. parvum), which have possible differences in pathogenicity in preterm infants, and CLD at 36 weeks PMA. Logistic regression analysis with CLD as the dependent variable, and gestational age, presence of U. urealyticum (van Waarde 1997; Smyth 1993) and birth weight (Smyth 1993) as the independent variables, showed that CLD was significantly related to decreasing gestational age but not to the presence of a positive U. urealyticum culture (van Waarde 1997; Smyth 1993 ) or birth weight (Smyth 1993).
One difference that may contribute to the disagreement between studies concerning the association of U. urealyticum with the development of CLD is the frequency of maternal colonization in the populations studied. The studies implicating U. urealyticum in the development of CLD (Sanchez 1988; Cassell 1988b; Crouse 1993 ) were conducted with inner city populations with high rates of colonization. In contrast, the studies that did not find a relation to CLD (Saxen 1993; Ollikainen 2001; Smyth 1993 ) were conducted in Finnish and British populations utilizing populations with low maternal genital colonization rates. This suggests that U. urealyticum, if not causal of CLD itself, may be a surrogate marker of risk factors affecting lower socio-economic classes, secondarily affecting CLD.
Differing study results concerning the association between U. urealyticum and CLD have led to uncertainty about the possible efficacy of treating infections/colonizations of the respiratory tract in the neonate. Although use of erythromycin to treat U. urealyticum positive cultures in preterm babies is common, no studies have demonstrated the efficacy of such treatment. A causative relationship of U. urealyticum to CLD in preterm infants would be supported if treatment of the organism reduced or prevented the lung disease. Erythromycin has been the drug of choice for U. urealyticum infections in the respiratory tract. A recent review (Buhrer 2001), which was not a meta analysis, examined one non-randomized and two randomized controlled trials using erythromycin for U. urealyticum in preterm infants. The authors concluded that antibiotic treatment failed to reduce chronic lung disease. This Cochrane Review will evaluate studies testing erythromycin therapy for decreasing the incidence and severity of chronic lung disease in preterm infants intubated after birth. Side effects of erythromycin will also be evaluated.
To evaluate the efficacy and safety of erythromycin in preventing chronic
lung disease in intubated preterm infants, when used:
1) prophylactically in infants with unknown U. urealyticum status
2) therapeutically in infants known to be U. urealyticum positive
This objective has been modified from the previously published protocol
to separate prophylactic treatment from treatment of known positive infants.
Intubated preterm infants < 37 weeks and < 2500 grams with unknown U. urealyticum status or with proven U. urealyticum positivity [by culture or polymerase chain reaction (PCR)]. There is no restriction with regards to the site of origin of the samples used for culture or polymerase chain reaction (PCR) tests.
The primary outcome measure is the occurrence of death and/or CLD, defined as a requirement for supplemental oxygen at 36 weeks PMA.
Secondary outcome measures are the days on mechanical ventilation, days on supplemental oxygen, retinopathy of prematurity, necrotizing enterocolitis and the possible side effects of erythromycin treatment including: gastrointestinal disturbances (e.g. diarrhea, vomiting), cardiac tachyarrhythmias, ability of erythromycin to decrease the metabolism of theophylline causing toxicity (e.g. hyperglycemia, hyperreflexia, jitteriness, seizures), or pyloric stenosis.
Search of literature in :
MEDLINE from 1966 - June 9, 2003
EMBASE from 1980 - May 5, 2003
Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library,
Issue 4, 2002)
Previous reviews including cross-references, abstracts (Pediatric Academic
Societies 2000-2003 and American Thoracic Society meetings 2001-2003), expert
informants
Subjects were limited to the human population. There were no language restrictions.
Search terms included these key words and/or MeSH headings: [preterm infant
and limit to human] and [bronchopulmonary dysplasia or chronic lung disease]
and [Ureaplasma or erythromycin]
The standard methods of the Cochrane Neonatal Review Group were used. Titles and abstracts of reports obtained from the databases were initially assessed by one reviewer (CM). The entire article was obtained for studies that were of possible interest and these were assessed independently by the four reviewers for relevance. When needed, authors of abstracts or full reports were contacted for clarification.
The validity of the eligible studies was assessed independently by the
four reviewers. Differences were resolved by consensus. Each eligible study
was evaluated for:
1. Selection bias (blinding of randomization)
2. Performance bias (blinding of intervention)
3. Attrition bias (complete follow-up)
4. Detection bias (blinding of outcome measurement)
Outcome data for the included studies were abstracted independently by the four reviewers. Differences were resolved by consensus. Measures of treatment effect for categorical outcomes were relative risk (RR), risk difference (RD), and number needed to treat (NNT). 95% confidence intervals were used. A fixed effect model was planned for meta-analysis. Tests of heterogeneity were not done as the identified studies could not be combined. Sensitivity analyses were not done.
One hundred forty titles (full reports or abstracts) were screened and, of these, seventeen possibly relevant studies were selected for review by all authors. Two controlled trials (Lyon 1998; Jonsson 1998) were judged to be eligible for inclusion and are described below. Additional data on these two studies were obtained by personal communication with these authors. Fifteen studies were excluded (see the details in the Table of Excluded Studies). One study (Okura 1998) is awaiting assessment.
Included studies (see table, Characteristics of Included Studies, for further details).
Lyon 1998 - The objective of the study was to determine if erythromycin given prophylactically from birth in preterm infants reduced the inflammatory response and the incidence and severity of CLD. Intubated infants equal to or less than 30 weeks gestation (n=75) were randomized (used sealed envelopes containing random number table allocation) at birth to receive erythromycin (15/mg/kg/dose) three times a day for 7 days or not. The primary outcome was to compare the levels of interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) between the treatment and control groups. Culture and PCR for U. urealyticum were obtained from tracheobronchial secretions on admission. Nine infants (13%) proved to be positive for U. urealyticum of which three were in the treatment group and six were in the control group. The clinical staff in the NICU did not know the culture or PCR results until after the study was completed. CLD was defined as the need for supplemental oxygen at 36 weeks PMA. Alveolar arterial oxygen difference (AaDO2) at 36 weeks PMA, which correlates with the degree of pulmonary dysfunction at 1 year of age in babies with CLD, was measured to assess the severity of lung disease (Iles 1997).
Jonsson 1998 - The aim of the study was
to investigate U. urealyticum colonization and the effect of erythromycin
treatment in culture positive infants less than 30 weeks gestation. Other
risk factors influencing respiratory morbidity and the need for supplemental
oxygen were also evaluated. One hundred fifty-five intubated infants <30
weeks gestation were screened in the study. Cultures for U. urealyticum
from endotracheal aspirates and nasopharyngeal swabs were taken as soon as
possible after birth. 29/155 (19%) of infants were culture positive. One
colonized infant died due to severe IVH at day 3, was not allocated to treatment
or control and was, therefore, not included in the trial (personal communication).
As soon as culture results were known (an average of 7 days after birth),
every other colonized infant was treated with erythromycin (n=14). The 14
treated babies received a 10-day course of erythromycin 40 mg/kg/day orally
(PO) n=10, or, if they did not tolerate oral feeds, intravenously (IV) n=4.
The remaining 14 infants did not receive erythromycin or placebo.
Blinding of randomization - Yes (used sealed envelopes)
Blinding of intervention - No (placebo not used)
Complete follow-up - Yes
Blinding of outcome measurement - Yes
Jonsson 1998:
Blinding of randomization - No (quasi-randomization by alternate assignment)
Blinding of intervention - No (placebo not used)
Complete follow-up - Yes
Blinding of outcome measurement - No
PROPHYLACTIC ERYTHROMYCIN VS NO TREATMENT OR PLACEBO IN BABIES AT RISK FOR U. UREALYTICUM COLONIZATION OR INFECTION (Lyon 1998)
1. CLD
CLD occurred in 13/34 treated babies and 11/41 controls. There was no significant effect of erythromycin prophylaxis on CLD [RR=1.40, 95% CI: 0.72, 2.70]. Since the effect may have differed among those who subsequently turned out to be culture/PCR positive, we also looked at the subgroups of positive and negative infants. There was no significant effect in either subgroup:
Culture/PCR Positive - 1/3 infants had CLD in the treatment group and 1/6 infants in the control group [RR=2.00, 95% CI: 0.18, 22.06].
Culture/PCR Negative - 12/31 infants had CLD in the treatment group and 10/35 in the control group [RR=1.35, 95% CI: 0.68, 2.69].
2. Death
Deaths occurred in 4/34 treated infants, and 8/41 controls. There was no significant effect of erythromycin either in all infants enrolled [RR=0.64, 95% CI: 0.22, 1.83] or in either subgroup:
Culture/PCR Positive - 0/3 infants died in the treatment group and 1/6 died in the control group [RR=0.58, 95% CI: 0.03, 11.21].
Culture/PCR Negative - 4/31 infants died in the treatment group and 7/35
infants died in the control group [RR=0.65, 95% CI: 0.21, 2.00].
3. Death or CLD
Combining Death or CLD is necessary because these are competing outcomes. Among the treated infants, 17/34 vs 19/41 control infants experienced death or CLD. There was no significant effect of erythromycin either in all infants enrolled [RR=1.06. 95% CI: 0.66, 1.69] or in either subgroup:
Culture/PCR Positive - 1/3 infants died or had CLD in the treatment group and 2/6 infants died or had CLD in the control group [RR=1.00, 95% CI: 0.14, 7.10].
Culture/PCR Negative - 16/31 infants died or had CLD in the treatment group and 17/35 infants died or had CLD in the control group [RR=1.06, 95% CI: 0.66, 1.72].
4. Side effects of erythromycin
There were no recognized side effects of erythromycin observed in the treated infants (personal communication).
5. Number of days on mechanical ventilation
In Lyon's study, these parameters were not reported by treatment group. However, among all culture positive infants, the median number of days on mechanical ventilation was 14 days (range 2-80 days) and in the culture negative group, the infants were ventilated for a median of 6 days (range 1-63 days).
6. Number of days on supplemental oxygen
Not reported
7. Retinopathy of prematurity
Not reported
8. Necrotizing enterocolitis
Not reported
9. Effects on inflammatory responses were reported in this study, but are not included in this review
THERAPEUTIC ERYTHROMYCIN VS NO TREATMENT OR PLACEBO IN U. UREALYTICUM COLONIZED OR INFECTED PRETERM INFANTS (Jonsson 1998)
1. CLD
9/14 infants had CLD in the treatment group versus 10/14 infants in the control group. Erythromycin had no significant effect [RR=0.90, 95% CI: 0.54, 1.50].
2. Death
There were no deaths in either group.
3. Death or CLD
9/14 infants had CLD or died in the treatment group versus 10/14 infants in the control group. Erythromycin had no significant effect [RR=0.90, 95% CI: 0.54, 1.50].
4. Side effects of erythromycin
There were no recognized side effects in the treated infants (personal communication).
5. Number of days on mechanical ventilation
The treated, culture-positive infants were ventilated for 9 days (median; range 1-47 days) and CPAP was used for a further 41 days (median; range 25-60 days). The infants who were not treated and culture-positive were ventilated for 6 days (median; range 1-29 days) and CPAP was used for a further 52 days (median; range 23-130 days).
Among all of the culture-positive infants, ventilation was used for 6.5 days (median; range 1-47 days) and CPAP was used for a further 42 days (median; range 23-130 days). Among the culture-negative infants, ventilation was used for 7 days (median; range 1-420 days) and CPAP was used for a further 30 days (median; range 1-159 days).
6. Number of days on supplemental oxygen
The treated, culture-positive infants required supplemental oxygen for 82 days (median; range 37-180 days) and the infants who were not treated and culture-positive needed supplemental oxygen for 74 days (median; 48-180 days).
Comparing the culture-positive infants with the culture-negative infants, culture-positive infants required supplemental oxygen for 80 days (median; range 37-180 days) while culture-negative infants required supplemental oxygen for 67 days (median; range 2-315 days).
7. Retinopathy of prematurity
Not reported
8. Necrotizing enterocolitis
Not reported
The results of this review found no evidence that erythromycin decreased the incidence or severity of CLD in intubated preterm infants, whether used prophylactically or in infants known to be colonized or infected with U. urealyticum. Due to the small sample sizes, even a large benefit could have been missed by these studies. The means of detection of colonization (culture and/or PCR) and timing of treatment in both studies varied. Jonsson treated the colonized infants after the culture results were known (mean=7 days) while Lyon treated infants at birth with erythromycin prior to the results of the cultures or PCR. We cannot combine the results of the two identified studies because they are different in the populations and the timing of treatment. Awaiting the results of culture delayed treatment by about 7 days in one study, while the prophylactic study was able to treat from birth. Therefore, we did a separate analysis for infants who were given erythromycin prophylactically in contrast to therapeutically. The infants were divided into subgroups in Lyon's study to see if there was a differential effect in those who were U. urealyticum positive
Although routine cultures for Ureaplasma are not done in pregnant women, it would be interesting to know the mothers' colonization status. Transmission of the organism may occur in utero or during delivery; therefore, early treatment of a culture positive mother might decrease the risk of colonization or infection in the fetus or infant. In a Cochrane Review, erythromycin use in women who have preterm premature rupture of membranes showed a significant reduction in the number of babies born within 48 hours of membrane rupture [RR 0.84, 95% CI 0.76, 0.93], requiring oxygen therapy [RR 0.87, 95% CI 0.78, 0.98] and with a positive blood culture for any organism [RR 0.70 CI 0.52, 0.94] (Kenyon 2002).
Results of cultures for Ureaplasma can take a long time and the benefits of early treatment, if any, may be missed if treatment is delayed. PCR is equal to, if not more sensitive than culture for detection of Ureaplasma and gives more rapid results [< 24 hours] (Blanchard 1993). In a study where PCR was done in 100 endotracheal aspirates from 54 intubated, preterm babies, PCR showed a sensitivity of 93% (Cunliffe 1996). Use of PCR could achieve prompt diagnosis and permit trials of early treatment in colonized mothers and/or infants. However, cultures will still be important to determine drug sensitivities.
Side effects of erythromycin were not systematically reported in the included trials, or in other studies detected but excluded. Potential toxicity of the antibiotic is an important consideration especially if infants are to be treated prophylactically, prior to knowing the culture results. Since vertical transmission results in colonization rates among preterm infants of 46-89% (Sanchez 1990), a significant number of non-infected infants would be treated if prophylaxis were used, even if restricted to the infants of Ureaplasma positive mothers. Erythromycin use for pertussis in newborns has been associated with an increased risk of infantile hypertrophic pyloric stenosis, which raises concerns for the safety of this drug if it were to be used in a prophylactic manner. In a study of prophylactic erythromycin to prevent pertussis, the rate of pyloric stenosis was 32.3/1000 liveborn infants. This was about 7-fold higher than the rate of 4.7/1000 observed in infants born in the same hospital in the prior two years [RR=6.8; 95% CI 3.0-15.7] (Honein 1999).
Based on current evidence from controlled trials, we cannot recommend the routine use of either prophylactic or therapeutic erythromycin for the purpose of reducing CLD secondary to U. urealyticum in intubated preterm infants. No evidence of benefit of treatment has been shown and the incidence of side effects from the antibiotic is unknown. The decision to treat an individual patient, however, is based on clinical status as well as culture results, and individual decisions may thus vary since the data lack the power to rule out a true benefit. The fact that the rate of side effects of erythromycin in preterm infants is unknown cannot be overlooked.
Additional controlled clinical trials are required to determine whether antibiotic therapy of Ureaplasma reduces CLD/death in preterm infants.
Methods of detection of colonization and timing of treatment are important factors to consider in the design of trials to study efficacy of treatment of U. urealyticum in preventing CLD. Studies are needed to test 1) treatment of proven U. urealyticum colonization/infection, and 2) prophylaxis in high risk infants with unknown U. urealyticum status. Rapid PCR results from either the mother or the infant could be used to identify groups of subjects who are most likely to benefit from early treatment. Given the suggestions that in utero fetal pulmonary inflammation may predispose to CLD, further consideration should be given to randomized treatment of women who are carriers of U. urealyticum, or who are documented to have the organism in amniotic fluid, with follow-up not only of effect on risk of preterm delivery but also for sequelae, including CLD, in their newborns. It should also be considered that treatment of U. urealyticum infection/colonization of premature lungs may not affect the multifactorial disease that is CLD but may reduce the severity of the disease. Severity of CLD as well as its occurrence should be considered as study outcomes. All trials should also report other common neonatal morbidities such as NEC and IVH, and should specifically look for and report potential side effects of erythromycin.
Gail Cassell, M.D., for providing references.
Luis Rodriguez, M.D., Chief of Pediatric Pulmonology and Critical Care, Elmhurst Hospital Center-Mt. Sinai Services, Mt. Sinai School of Medicine, New York, USA for help in translating the Spanish articles.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Jonsson 1998 | Quasi - randomized (alternate assignment). Concealed randomization- No. Masked intervention-No (placebo not used). Complete follow-up-Yes. Masked outcome-No. | 28 intubated preterm infants <30 weeks gestation culture positive for U. urealyticum. 14 treated, 14 control | Treated every other colonized infant with a 10 day course of erythromycin, 40 mg/kg/day, orally (n=10) or intravenously (n=4). Average age at treatment 7 days. Controls received no treatment. | Primary outcome: Oxygen dependency at 36 weeks PMA. Secondary outcome: Side effects of erythromycin treatment (GI, hepatic, cardiovascular) | C | |
| Lyon 1998 | Randomized trial (sealed envelopes). Concealed randomization - Yes. Masked intervention-No (placebo not used). Complete follow-up-Yes. Masked outcome-Yes. |
75 intubated infants equal to or less than 30 weeks gestation. Of the 75 randomized infants, 9 infants proved to be positive for U. urealyticum by culture and/or PCR. | Erythromycin (45 mg/kg/day TID, IV for 7 days) treatment versus
no treatment before culture/PCR results were known. Cytokine levels and differential counts done on bronchoalveolar lavage. |
Primary outcome: Inflammatory cytokine response after birth in bronchoalveolar lavage fluid. | A |
| Study | Reason for exclusion |
| Agarwal 2000 | No control group. |
| Alfa 1995 | Treatment was not randomized. |
| Bowman 1998 | No control group. |
| Cordero 1994 | Treatment was not randomized. |
| Cordero 1996 | Treatment was not randomized. |
| Da Silva 1997 | Treatment was not randomized. |
| Galetto Lacour 2001 | Treatment was not randomized. |
| Garland 1996 | Treatment was not randomized. |
| Heggie 1994 | Treatment was not randomized. |
| Izraeli 1991 | Treatment was not randomized. |
| Pacifico 1997 | Treatment was not randomized. |
| Patterson 1998 | Treatment was not randomized. |
| Rudd 1984 | No treatment with erythromycin was involved. |
| Sanchez 1988 | No treatment with erythromycin was involved. |
| Tay 1997 | No treatment with erythromycin was involved. |
Jonsson B, Rylander M, Faxelius G. Ureaplasma urealyticum, erythromycin and respiratory morbidity in high-risk preterm neonates. Acta Paediatr 1998;87:1079-84.
Lyon 1998 {published and unpublished data}
Lyon AJ, McColm J, Middlemist L, Fergusson S, McIntosh N, Ross PW. Randomised trial of erythromycin on the development of chronic lung disease in preterm infants. Arch Dis Child Fetal Neonatal Ed 1998;78:F10-14.
Agarwal P, Rajadurai VS, Pradeepkumar VK, Tan KW. Ureaplasma urealyticum and its association with chronic lung disease in Asian neonates. J Paediatr Child Hlth 2000;36:487-90.
Alfa 1995 {published data only}
Alfa MJ, Embree JE, Degagne P, Olson N, Lertzman J, Macdonald KS, Macdonald NT, Hall PF. Transmission of Ureaplasma urealyticum from mothers to full and preterm infants. Pediatr Infect Dis J 1995;14:341-5.
Bowman 1998 {published data only}
Bowman ED, Dharmalingam A, Fan WQ, Brown F, Garland SM. Impact of erythromycin on respiratory colonization of Ureaplasma urealyticum and the development of chronic lung disease in extremely low birth weight infants. Pediatr Infect Dis J 1998;17:615-20.
Cordero 1994 {published and unpublished data}
Cordero L, Warner W, Ayers L. Ureaplasma urealyticum tracheal colonization of mechanically ventilated newborn (abstract). Pediatr Res 1994;35:267A.
Cordero 1996 {published data only}
Cordero L, Davis K, Warner D, Ayers L. Ureaplasma urealyticum tracheal colonization and respiratory disease in newborn. Neonatal Intensive Care 1996;9:24-31.
Da Silva 1997 {published data only}
Da Silva O, Gregson D, Hammerberg O. Role of Ureaplasma urealyticum and Chlamydia trachomatis in development of bronchopulmonary dysplasia in very low birth weight infants. Pediatr Infect Dis J 1997;19:364-9.
Galetto Lacour 2001 {published data only}
Galetto Lacour A, Zamora S, Bertrand R, Brighi Perret L, Auckenthaler R, Berner M, Suter S. Colonization by Ureaplasma urealyticum and chronic lung disease in premature newborn infants under 32 weeks of gestation. Arch Pediatr 2001;8:39-46.
Garland 1996 {published data only}
Garland SM, Bowman ED. Role of Ureaplasma urealyticum and Chlamydia trachomatis in lung disease in low birth weight infants. Pathology 1996;28:266-69.
Heggie 1994 {published data only}
Heggie AD, Jacobs MR, Butler VT, Baley JE, Boxerbaum B. Frequency and significance of isolation of Ureaplasma urealyticum and Mycoplasma hominis from cerebrospinal fluid and tracheal aspirate specimens from low birth weight infants. J Pediatr 1994;124:956-61.
Izraeli 1991 {published data only}
Izraeli S, Samra Z, Sirota L, Merlob P, Davidson S. Genital mycoplasmas in preterm infants: prevalence and clinical significance. Eur J Pediatr 1991;150:804-7.
Pacifico 1997 {published data only}
Pacifico L, Panero A, Roggini M, Rossi N, Bucci G, Chiesa C. Ureaplasma urealyticum and pulmonary outcome in a neonatal intensive care population. Pediatr Infect Dis J 1997;16:579-86.
Patterson 1998 {published data only}
Patterson AM, Taciak V, Lovchik J, Fox RE, Campbell AB, Viscardi RM. Ureaplasma urealyticum respiratory tract colonization is associated with an increase in interleukin 1-beta and tumor necrosis factor alpha relative to interleukin 6 in tracheal aspirates of preterm infants. Pediatr Infect Dis J 1998;17:321-8.
Rudd 1984 {published data only}
Rudd PT, Carrington D. A prospective study of chlamydial, mycoplasmal, and viral infections in a neonatal intensive care unit. Arch Dis Child 1984;59:120-5.
Sanchez 1988 {published data only}
Sanchez PJ, Regan JA. Ureaplasma urealyticum colonization and chronic lung disease in low birth weight infants. Pediatr Infect Dis J 1988;7:542-6.
Tay 1997 {published data only}
Tay ST, Boo NY, Khoo TB, Koay AS, Rohani MY. Prevalence and antibiotic susceptibility of Ureaplasma urealyticum in Malaysian neonates with respiratory distress. Med J Malaysia 1997;52:409-11.
Okura M, Sato Y, Takeuchi Y, Ono T, Hashimoto T, Nishigaki K. Multicenter study on clinical effects of a small dose of erythromycin on chronic lung disorders of premature infants-single blind comparison of treated and treated groups. A committee for the Study of EM Therapy for Chronic Lung Disease of Premature Infants. Jpn J Antibiot 1998;51 Suppl 1:103-6.
* indicates the primary reference for the study
Blanchard A, Hentschel J, Duffy L, Baldus K, Cassell GH. Detection of Ureaplasma urealyticum by polymerase chain reaction in the urogenital tract of adults, in amniotic fluid, and in the respiratory tract of newborns. Clin Infect Dis 1993;17:S148-53.
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01.01 CLD
01.02 Death
01.03 CLD or death
01.04 Side effects of erythromycin
02 Erythromycin vs placebo in U. Urealyticum culture positive babies
02.01 CLD
02.02 Death
02.03 CLD or death
02.04 Side effects of erythromycin
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Prophylactic erythromycin vs placebo in babies at risk for U. Urealyticum colonization or infection | ||||
| 01 CLD | 2 | 75 | RR (fixed), 95% CI | 1.40 [0.72, 2.70] |
| 02 Death | 2 | 75 | RR (fixed), 95% CI | 0.64 [0.22, 1.83] |
| 03 CLD or death | 2 | 75 | RR (fixed), 95% CI | 1.06 [0.66, 1.69] |
| 04 Side effects of erythromycin | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 02 Erythromycin vs placebo in U. Urealyticum culture positive babies | ||||
| 01 CLD | 1 | 28 | RR (fixed), 95% CI | 0.90 [0.54, 1.50] |
| 02 Death | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 03 CLD or death | 1 | 28 | RR (fixed), 95% CI | 0.90 [0.54, 1.50] |
| 04 Side effects of erythromycin | 0 | 0 | RR (fixed), 95% CI | No numeric data |
Dr Gloria S. Pryhuber
Associate Professor
Pediatrics-Neonatology
Strong Children's Research Center, University of Rochester
601 Elmwood Avenue, Division of Neonatology, Box 651
Rochester
NY USA
14642
Telephone 1: 585 275 5884
Facsimile: 585 461 3614
E-mail: gloria_pryhuber@urmc.rochester.edu
Secondary contact person's name: Dale L. Phelps, M.D.
Dr Geoffrey A. Weinberg
Associate Professor
Pediatrics-Infectious Diseases
Strong Children's Research Center, University of Rochester
601 Elmwood Avenue, Box 690, Division of Pediatric Infectious Diseases
Rochester
NY USA
14642
Telephone 1: 585 275 2623
E-mail: geoff_weinberg@urmc.rochester.edu
Secondary contact person's name: Dale L. Phelps, M.D.
| This review is published as a Cochrane review in
The Cochrane Library 2003, Issue 4, 2003 (see www.CochraneLibrary.net for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |
