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Antibiotics for neonates born through meconium stained amniotic fluid

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The objectives of this review will be to assess the role of antibiotics for:
i) Prevention of infectious morbidity and mortality in infants born through MSAF and are asymptomatic at birth
ii) Prevention of infectious morbidity and mortality in infants born through MSAF who have signs and symptoms compatible with MAS

Background

Meconium aspiration syndrome (MAS) is a commonly encountered problem in neonates. Meconium is the viscous green material found in the fetal gastrointestinal tract from approximately the tenth week of gestation. Meconium is composed of a mixture of bile, bile acids, mucous, pancreatic secretions and cellular debris (Wiswell 1993). Approximately 10 ‐ 15% of pregnancies are complicated by the passage of meconium around the time of delivery (Wiswell 1993). An adverse intrauterine environment compromising fetal well being can lead to meconium stained amniotic fluid (MSAF) (Ahanya 2005). "Meconium aspiration syndrome" is defined as respiratory distress with compatible chest roentgenographic findings in an infant born through MSAF, whose symptoms cannot be otherwise explained (Wiswell 1990). Despite current interventions such as intubation with tracheal suction, it is estimated that 5 ‐ 12% of infants born through MSAF develop MAS (Wiswell 2000). An estimated 25,000 to 30,000 cases and 1,000 deaths related to MAS occur annually in the United States (Gelfand 2004).

The clinical features of MAS include tachypnea, retractions, grunting and/or cyanosis with or without the radiological features of aspiration pneumonia. The radiological features of MAS consist of areas of atelectasis and consolidation, along with regions of hyperexpansion. Histologically, a significant inflammatory reaction with a diffuse pulmonary infiltrate of polymorphonuclear leukocytes has been observed (Burgess 1996). Although initially sterile, meconium can get secondarily colonized with bacteria following rupture of membranes in utero (Florman 1969) or during neonatal interventions like endotracheal intubation.

Some of the proposed explanations for the widespread use of antibiotics in patients with MAS are the difficulty in radiological differentiation between aspiration pneumonia and bacterial pneumonia (Lee 2004), the possibility of meconium induced inhibition of phagocytic activity and respiratory burst response by alveolar macrophages rendering infants with MAS susceptible to pulmonary infections (Craig 2005), in vitro enhancement of bacterial growth in the presence of meconium in amniotic fluid (Lembet 2003, Florman 1969), the combination of meconium and bacteria aggravating in vivo inflammatory response (Speer 1998), the likelihood of fetal bacterial infection in the causation of in utero meconium passage (Bortolucci 1990; Blot 1983) and apprehension about complications associated with untreated bacterial pneumonia (Wiswell 1992). Several authors have reported increased rates of chorioamnionitis associated with MSAF (Romero 1991; Mazor 1995; Usta 1995; Rao 2001), although it is unclear whether chorioamnionitis is a cause or secondary effect of meconium passage. In a retrospective study of 215 well term babies born through MSAF (of whom 88 patients required tracheal meconium aspiration at birth), no significant difference in the incidence of culture positive sepsis [1 (1.1%) vs 2 (1.6%), p > 0.05] was reported when compared with 127 control infants not requiring tracheal suctioning of meconium passage (Krishnan 1995). The administration of intravenous Ampicillin‐ Sulbactam therapy or cefazolin infusion into the amniotic cavity during amnioinfusion in mothers with MSAF has not shown to be of any benefit in reducing neonatal sepsis (Adair 1996; Edwards 1999). The widespread use of antibiotics in neonates is of some concern (CDC 2004). Excessive use of antibiotics in the neonatal units can lead to emergence of resistant bacterial strains (Tom‐Revzon 2004). Nephrotoxicity has been reported even after brief periods of antibacterial treatment in newborns (Fanos 1999). Ototoxicity has been reported in neonates following aminoglycoside treatment (McCracken 1986). The role of antibiotics in infants born through MSAF has not been systematically evaluated.

Objectives

The objectives of this review will be to assess the role of antibiotics for:
i) Prevention of infectious morbidity and mortality in infants born through MSAF and are asymptomatic at birth
ii) Prevention of infectious morbidity and mortality in infants born through MSAF who have signs and symptoms compatible with MAS

Methods

Criteria for considering studies for this review

Types of studies

Randomized and quasi‐randomized controlled trials of antibiotic administration in infants born through MSAF will be considered for this review.

Types of participants

Two sets of infants will be studied:

i) Term (> 37 weeks gestational age) and preterm (< 37 weeks gestational age) newborn infants with a history of meconium stained amniotic fluid and are asymptomatic at birth

ii) Term (> 37 weeks gestational age) and preterm (< 37 weeks gestational age) newborn infants with a history of meconium stained amniotic fluid and clinical findings of tachypnea, retractions, grunting and cyanosis with or without radiological findings of atelectasis, consolidation and hyperinflation

If a mixed population of term and preterm infants born with a history of meconium stained amniotic fluid who may or may not have symptoms and signs (clinical or radiological) of MAS have been included in studies, authors will be contacted for individual data for symptomatic and asymptomatic infants. This data will be incorporated in the appropriate subgroup comparisons noted above.

Types of interventions

Two intervention strategies will be studied:

i) Prophylactic systemic administration of antibiotics started immediately after birth in infants born through MSAF and are asymptomatic at birth compared with no antibiotics or placebo

ii) Therapeutic administration of antibiotics started at the time of initial clinical suspicion of MAS in infants born through MSAF compared to no antibiotics or placebo

Types of outcome measures

The outcomes will be similar for both sets of intervention/ populations.

Primary outcome:

Incidence of sepsis in first 28 days (neonate would be considered to have sepsis if the blood or CSF culture is positive for bacterial organism in a symptomatic neonate). This would be classified in two groups:

(i) Early onset neonatal sepsis (symptomatic before 72 hours)
(ii) Late onset neonatal sepsis (symptomatic after 72 hours of age)

Secondary outcomes:

1. Mortality prior to discharge
2. Duration of mechanical ventilation (days)
3. Maximum ventilatory requirements [(Oxygenation index (OI), mean airway pressure (MAP), Fraction of inspired oxygen (FiO2)] during first seven days of life
4. Duration of oxygen therapy (days)
5. Treatment with HFV
6. Treatment with inhaled nitric oxide
7. Treatment with surfactant lavage
8. Treatment with bolus surfactant administration
9. Treatment with extra corporeal membrane oxygenation (ECMO)
10. Incidence of pulmonary air leak syndromes (pneumothorax, pulmonary interstitial emphysema)
11. Incidence of intracranial hemorrhage
12 Incidence of intraventricular hemorrhage
13. Incidence of periventricular leukomalacia
14. Duration of hospital stay till discharge home in survivors (days)
15. Incidence of oliguria (< 1 ml/kg/hr)
16. Incidence of azotemia (> 1.5 mg/dl)
17. Incidence of diarrhea
18. Incidence of hearing impairment associated with antibiotics
19. Incidence of suspected sepsis (neonate would be considered to have suspected sepsis if one ore a combination of following markers of sepsis is abnormal i.e. total white blood cell count, absolute neutrophil count, immature to total neutrophil ratio, C reactive protein, cytokines IL6, gastric aspirates for neutrophils or bacteria).
20. Proportion of infants born through MSAF initiated on antibiotics before discharge

Subgroup analysis:

For both of the above comparisons, subgroup analyses will be performed to assess the effects of antibiotic regimen, duration of antibiotics and gestational age.

Search methods for identification of studies

MEDLINE (1966 ‐ present) will be searched using following terms with all the subheadings connected by "AND"
Population: Infant‐Newborn (MeSH) OR Infant, Newborn, Meconium Aspiration (MeSH) OR Infant, Newborn, MAS (MeSH) OR newborn (text word) OR infant (text word) OR neonate (text word) OR meconium aspiration (text word) OR MAS
Intervention: Anti ‐Bacterial Agents (MeSH), antibiotics (text word)
Comparison: Clinical Trial (MeSH) OR Controlled Clinical Trial (MeSH) OR Randomized Controlled Trial (MeSH)

Other databases that will be searched include EMBASE (1980 to the latest); CINAHL (1982 to the latest); The Cochrane Central Register of Controlled Trials (CENTRAL, latest issue of The Cochrane Library), the reference list of identified trials and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies, published in Pediatric Research (2002 ‐ 2006). Editorials, commentaries, reviews, lectures abstracts and letters to the editor will only be included if they contain original data. No language restrictions will be applied. Authors will be contacted for additional/missing information.

Data collection and analysis

Two reviewer authors (SS and MP) will independently search for and assess trials for inclusion and methodological quality. Discrepancy will be resolved by involvement of the third review author (PSS). Quality of the studies will be assessed using the following criteria: masking of randomization, masking of intervention, completeness of follow up and blinding of outcome measurement. Data will be extracted independently by two reviewer authors. In the event of discrepancy or differences third reviewer author (PS) will independently extract the data and the differences will be resolved by discussion and consensus of the reviewers. Meta‐analysis would be performed using RevMan 4.2. Mean difference (MD) and weighted mean differences (WMD) will be reported for continuous variables. For categorical outcomes the relative risk (RR) and risk differences (RD) will be reported. For significant findings, number needed to treat (NNT) will be calculated along with 95% confidence intervals. We will estimate the treatment effects of individual trials and examine heterogeneity between trial results by inspecting the forest plots and quantifying the impact of heterogeneity in any meta‐analysis using a measure of the degree of inconsistency in the studies' results (I2 statistic). If we detect statistical heterogeneity, we will explore the possible causes. We plan to use a fixed effect model for meta‐analysis.