Antibiotics for the management of transient tachypnea of the newborn

Abstract

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

To assess whether:

1. antibiotics ‐ compared to placebo or no intervention ‐ are effective and safe in the management of infants with a suspected diagnosis of transient tachypnea of the newborn;

2. it is safe to withhold exposure to antibiotics for infants with a diagnosis of transient tachypnea of the newborn.

We will perform subgroup analyses regarding gestational age; birth weight; mode of delivery; route of administration; type of antibiotic (see Subgroup analysis and investigation of heterogeneity).

Background

Description of the condition

Transient tachypnea of the newborn was originally described in 1966 as the clinical manifestation of delayed clearance of fetal lung fluid (Avery 1966). It is characterized by tachypnea (respiratory rate greater than 60 breaths per minute) and signs of respiratory distress (grunting, flaring of nostrils, and retraction of skin between, or under, ribs when breathing). The clinical features typically appear immediately after birth or within the first two hours of life in term and late preterm newborns. Transient tachypnea of the newborn is a clinical diagnosis, and is supported by radiologic findings from chest X‐rays, such as increased lung volumes with flat diaphragms, mild cardiomegaly (heart enlargement) and prominent vascular markings in a sunburst pattern originating at the hilum (point at which blood vessels enter the heart). In term and late preterm newborns, transient tachypnea of the newborn is the most common cause of respiratory distress (Clark 2005). Other causes of respiratory distress include surfactant deficiency (respiratory distress syndrome), pneumonia, meconium aspiration syndrome, asphyxia (oxygen deprivation), pneumothorax (collapse of lung caused by air between lungs and chest wall) and congenital heart disease (Ma 2010). The incidence of transient tachypnea of the newborn can reach up to 13% in term infants delivered by elective cesarean section (Kumar 1996; Morrison 1995). Affected infants often undergo evaluation with chest radiography, laboratory exams and close cardiorespiratory monitoring. Although transient tachypnea of the newborn is usually a self‐limited condition, one large retrospective study reported that it is associated with wheezing syndromes in late childhood (Liem 2007). Rarely, affected infants may present persistent with pulmonary hypertension or a pulmonary air leak requiring mechanical ventilation (Miller 1980; Tudehope 1979).

Description of the intervention

It is common practice to start antibiotic prophylaxis in all newborns with respiratory distress, because it is difficult to distinguish transient tachypnea from neonatal pneumonia (Costa 2012; Martin 2011). Bacterial pneumonia is associated with high mortality in newborns (Kumar 1996), and delayed treatment can be fatal. However, it is important to understand whether antibiotics are necessary for this condition because a short course of therapy may also: expose a great number of neonates to ototoxic and nephrotoxic drugs (i.e. medicines that may harm ears and kidneys); increase the population at risk for antibiotic‐mediated alterations in the intestinal microbiome; and promote the development of drug‐resistant organisms (Cipolla 2011; Leibovici 2016). Infections remain a major cause of morbidity and mortality in the neonatal period (Freedman 1981; Gladstone 1990; La Gamma 1983; Laxminarayan 2016). Due to immaturity of the immune system, newborn infants may not elicit all signs of infection, and delay in treatment may lead to severe illness or death (Miller 1977; Siegel 1981). Organisms responsible for infectious pneumonia typically mirror those responsible for early‐onset neonatal sepsis, and are mainly transmitted from the mother. The bacteria most commonly implicated in early neonatal sepsis are Group B streptococci and gram‐negative bacilli (Schrag 2016).

How the intervention might work

In situations where infection is suspected, caregivers in neonatal intensive care tend to choose empirical first‐line antibiotic therapy that will cover both gram‐negative and gram‐positive bacteria. A combination of an aminoglycoside ‐ such as gentamicin, and a beta‐lactam ‐ such as penicillin, has been the treatment of choice in course of transient tachypnea of the newborn (Ramasethu 2017; Randis 2012; Reuter 2014). Aminoglycosides may be associated with important adverse effects such as ototoxicity and nephrotoxicity, and they require frequent monitoring of their blood levels (McCracken 1986; Touw 2009). Moreover, the use of broad spectrum antibiotics in neonates may alter gut flora and may also increase antibiotic resistance in the neonatal unit (Cipolla 2011). Alteration of intestinal flora or sterilization of the gut with these antibiotics may increase the risk of developing necrotizing enterocolitis (Kenyon 2001). Because clinical signs of transient tachypnea of the newborn are not specific for the disease and can be confused with other respiratory morbidities or infections at the early stage of onset, antibiotics could reduce incidence of infectious disease in newborns with this condition. In addition, an untreated infection might complicate the clinical course of the respiratory distress.

Why it is important to do this review

Cesarean section, macrosomia (large baby), maternal diabetes, family history of asthma and twin pregnancy are associated with an increased incidence of transient tachypnea of the newborn (Hansen 2008). Since these prenatal risk factors are widespread, the majority of transient tachypnea of the newborn occurs in level 1 neonatal units, where resources for immediate respiratory support and oxygen supplementation may be scarce, and where nasal continuous positive airway pressure procedures are rarely utilized. Therefore, the availability of a drug that is able to improve the management of transient tachypnea of the newborn, and subsequently to reduce the need for intensive care with or without transport to level 3 neonatal intensive care units would be advantageous. In addition, this would be valuable for both high‐ and low‐income countries, considering the epidemiology of transient tachypnea of the newborn and the relatively wide access to antibiotics worldwide.

Many supportive therapies have been proposed – and have been evaluated or are in the process of being evaluated by Cochrane Reviews, such as fluid restriction (Gupta 2015), furosemide (Kassab 2013), salbutamol (Moresco 2016a), and epinephrine (Moresco 2016b). Though the use of antibiotics in the management of transient tachypnea of the newborn is a common practice, its efficacy and safety have not been studied in any systematic review. In addition, a liberal use of antibiotics might increase resistance, thus resulting in induction and selection of resistant strains (Leibovici 2016).

Objectives

To assess whether:

1. antibiotics ‐ compared to placebo or no intervention ‐ are effective and safe in the management of infants with a suspected diagnosis of transient tachypnea of the newborn;

2. it is safe to withhold exposure to antibiotics for infants with a diagnosis of transient tachypnea of the newborn.

We will perform subgroup analyses regarding gestational age; birth weight; mode of delivery; route of administration; type of antibiotic (see Subgroup analysis and investigation of heterogeneity).

Methods

Criteria for considering studies for this review

Types of studies

We will include prospective randomized controlled clinical trials, quasi‐randomized trials and cluster‐randomized trials.

We will not include cross‐over trials because the intervention might have a lasting effect that compromises entry to subsequent periods of the trial.

Types of participants

Infants:

• born at 34 weeks’ gestational age or more

• less than three days of age

• with transient tachypnea of the newborn, defined as the presence of respiratory distress:

  • starting within six hours after birth with X‐ray findings such as increased lung volumes with flat diaphragms, mild cardiomegaly and prominent vascular markings in a sunburst pattern originating at the hilum;

  • or a normal chest X‐ray with no other apparent reason for respiratory distress (we plan to exclude infants with pneumonia, surfactant deficiency, aspiration syndromes, congenital diaphragmatic hernia, pneumothorax or congenital heart disease).

We will contact the authors of included studies to ascertain their inclusion and exclusion criteria, and, when possible, we plan to report data only for infants matching our eligibility criteria.

We will include all infants with transient tachypnea of the newborn irrespective of the method of respiratory support in place (supplemental oxygen, noninvasive ventilation, or invasive ventilation) at the time of randomization.

Types of interventions

• Primary comparison: any antibiotic or combination of antibiotics compared to placebo or no treatment in the management of infants with a suspected diagnosis of transient tachypnea of the newborn in the first three days of life.

• Secondary comparison: early compared to late suspension of exposure to antibiotics. Suspension might be based on either duration of therapy (i.e. < 72 hours versus > 72 hours) or presence of negative blood culture. Studies with different criteria will not be pooled in the same analysis.

We will include any dose, mode of administration, combination of different antibiotics and duration of therapy in this review.

Types of outcome measures

Primary outcomes

Primary comparison

1. Pneumonia (yes/no): that is, signs of respiratory distress and/or chest radiograph with patchy consolidation with air bronchograms and a lobar distribution of consolidation and/or alteration of markers of inflammation such as C‐reactive protein and white blood cell count

2. Hearing loss: that is, impaired auditory brainstem response (ABR) audiometry, detected by use of otoacoustic emission (OAE) or automated ABR testing in neonatal period and audiological assessment at least once by 24 to 30 months of age as indicated by policy statement of American Academy of Pediatrics (AAP 2007)

Secondary comparison

1. Pneumonia (yes/no): that is, signs of respiratory distress and/or chest radiograph with patchy consolidation with air bronchograms and a lobar distribution of consolidation and/or alteration of markers of inflammation such as C‐reactive protein and white blood cell count

2. Hearing loss: that is, impaired ABR audiometry, detected by use of OAE or automated ABR testing in neonatal period and audiological assessment at least once by 24 to 30 months of age as indicated by policy statement of American Academy of Pediatrics (AAP 2007)

3. Duration of antibiotics exposure (hours)

Secondary outcomes

1. Neonatal mortality (yes/no)

2. Bacterial septicemia (positive blood culture, taken at least 24 hours after study entry; yes/no)

3. Duration of supplemental oxygen therapy (hours)

4. Need for continuous positive airway pressure (yes/no)

5. Need for mechanical ventilation (yes/no)

6. Duration of mechanical ventilation (intermittent positive pressure ventilation, hours)

7. Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure; hours)

8. Duration of hospital stay (days)

9. Age at initiation of oral feeding (days)

10. Duration of tachypnea, defined as respiratory rate greater than 60 breaths per minute (hours)

11. Persistent pulmonary hypertension diagnosed clinically with or without at least one of the following echocardiographic findings: high right ventricular systolic pressure, right to left or bidirectional shunt at the patent foramen ovale or patent ductus arteriosus, severe tricuspid regurgitation

12. Pneumothorax (diagnosis on chest X‐ray)

13. Clinical sepsis, i.e. presence of clinical symptoms and abnormal laboratory findings with no growth from blood culture (yes/no)

14. High levels of serum creatinine (as defined by study authors)

Search methods for identification of studies

We will use the criteria and standard methods of Cochrane and Cochrane Neonatal.

Electronic searches

We will conduct a comprehensive search including: the Cochrane Central Register of Controlled Trials (CENTRAL, current issue) in the Cochrane Library; MEDLINE via PubMed (1996 to present); Embase (1980 to present); and CINAHL (1982 to present) using the following search terms: transient tachypnea of the newborn [MeSH] OR transient tachypnea OR transitory tachypnea OR TTN OR TTNB, plus database‐specific limiters for RCTs and neonates (see Appendix 1 for the full search strategies for each database). We will not apply language restrictions. We will search clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; the World Health Organization’s International Trials Registry and Platform www.whoint/ictrp/search/en/, and the ISRCTN Registry).

Searching other resources

Additionally, we will review the reference lists of all identified articles for relevant articles that were not identified in the primary search.

Data collection and analysis

We will use the criteria and standard methods of Cochrane and the Cochrane Neonatal Review Group.

Selection of studies

Two review authors (LM, MB) will independently search and identify eligible trials that meet the inclusion criteria. We will screen the titles and abstracts to identify potentially relevant citations. We will retrieve the full texts of all potentially relevant articles, and independently assess the eligibility of the studies by filling out eligibility forms designed in accordance with the specified inclusion criteria. We will review studies for relevance based on study design, types of participants, interventions and outcome measures. We will resolve any disagreements by discussion and, if necessary, by consulting a third author (MGC). We will provide details of studies excluded from the review in the 'Characterists of excluded studies' table along with the reasons for their exclusion. We will contact the trial authors if the details of the primary trial reports are not clear, or to request additional data.

Data extraction and management

Two authors (LM, MGC) will independently extract data using a data extraction form integrated with a modified version of the Cochrane Effective Practice and Organisation of Care Group data collection checklist (EPOC 2013).

We will extract the following characteristics from each included study.

• Administrative details: author(s); published or unpublished; year of publication; year in which study was conducted; details of other relevant papers cited

• Details of the study: study design; type, duration and completeness of follow‐up; country and location of study informed consent and ethics approval

• Details of participants: sex, birth weight, gestational age, and number of participants

• Details of intervention: initiation, dose, duration and class of antibiotic treatment

• Details of outcomes as mentioned above in Types of outcome measures.

We will resolve any disagreement by discussion. We will describe ongoing studies identified from our search, where available, detailing the primary author, research question(s), methods and outcome measures together with an estimate of the reporting date.

Should any queries arise or, in cases where additional data are required, we will contact the study investigators/authors for clarification. Two review authors (MGC, MB) will use the Cochrane software, Revman 5 (RevMan 2014), for data entry.

Assessment of risk of bias in included studies

Two review authors (MB, MGC) will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool for the following domains (Higgins 2011).

• Sequence generation (selection bias)

• Allocation concealment (selection bias)

• Blinding of participants and personnel (performance bias)

• Blinding of outcome assessment (detection bias)

• Incomplete outcome data (attrition bias)

• Selective reporting (reporting bias)

• Any other bias

Any disagreements will be resolved by discussion or by a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We will carry out statistical analysis using the standard methods of the Cochrane Neonatal Review Group. We will extract categorical data for each intervention group and calculate risk ratios (RRs) and absolute risk differences (RDs). We will obtain means and standard deviations for continuous data, and perform analyses using mean differences (MDs). For each measure of effect we will also calculate the corresponding 95% confidence intervals (CI). We will present the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) when RDs are found to be statistically significant (P value < 0.05).

Unit of analysis issues

The unit of randomization will be the intended unit of analysis, i.e. the individual neonate.

If we find any cluster‐RCTs, we will adjust them for effects that result from their design using the methods stated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We will obtain a dropout rate for each study. If we find a significant dropout rate, we will contact the author(s) to provide additional data. We will perform a sensitivity analysis to evaluate the overall results with and without the inclusion of studies with a significant dropout rate. If a study reports outcomes only for participants completing the trial, or only for participants who followed the protocol, we will contact author(s) and ask them to provide additional information to facilitate an intention‐to‐treat analysis and, in instances where this is not possible, we will perform a complete case analysis.

Assessment of heterogeneity

We plan to assess clinical heterogeneity by comparing the distribution of important participant factors between trials and trial factors (randomization concealment, blinding of outcome assessment, loss to follow‐up, treatment type, co‐interventions). We will assess statistical heterogeneity by examining the I² statistic (Higgins 2011), a quantity that describes the proportion of variation in point estimates that is due to variability across studies rather than sampling error.

We will interpret the I² statistic as described by Higgins 2003:

• < 25%: no (none) heterogeneity;

• 25% to 49%: low heterogeneity;

• 50% to 74%: moderate heterogeneity;

• ≥ 75%: high heterogeneity.

We will consider statistical heterogeneity to be substantial when I² exceeds 50%. In addition, we will employ the Chi² test of homogeneity to determine the strength of evidence that heterogeneity is genuine. We will explore clinical variation across studies by comparing the distribution of important participant factors among trials and trial factors (randomization concealment, blinding of outcome assessment, loss to follow‐up, treatment type and co‐interventions). We will consider a threshold of P value of < 0.1 as an indicator of whether heterogeneity (genuine variation in effect sizes) is present.

Assessment of reporting biases

We will assess reporting/publication bias by visual inspection of funnel plot asymmetry where there are 10 or more studies included in a meta‐analysis. If we find significant asymmetry in the funnel plot, we will report this in the corresponding results. (Egger 1997; Higgins 2011).

Data synthesis

We will perform statistical analyses according to the recommendations of the Cochrane Neonatal Review Group (neonatal.cochrane.org/en/index.html). We will analyses all infants randomized on an intention‐to‐treat basis. We will analyze treatment effects in the individual trials. We will use a fixed‐effect model in the first instance to combine the data. For any meta‐analyses we will synthesize data using RR, RD, NNTB, NNTH, and 95% CI. We plan to analyze and interpret individual trials separately when we judge meta‐analysis to be inappropriate.

Quality of evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes: pneumonia, hearing loss, duration of supplemental oxygen therapy, septicemia, need for mechanical ventilation, duration of hospital stay and duration of tachypnea.

Two authors will independently assess the quality of the evidence for each of these outcomes. We will consider evidence from randomized controlled trials as high quality but downgrade the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We will use the GRADEpro GDT Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.

The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades.

1. High: we are very confident that the true effect lies close to that of the estimate of the effect.

2. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

3. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

4. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

We plan to present data from the following subgroups.

1. Gestational age: term (≥ 37 weeks) versus late preterm infants ( ≥ 34 weeks, but < 37 weeks)

2. Birth weight: < 2500 g versus ≥ 2500 g

3. Mode of delivery: vaginal versus cesarean section

4. Route of administration of antibiotic: enteral versus intravenous administration

5. Type of antibiotic (e.g. penicillins, macrolides, aminoglycosides, cephalosporins, glycopeptides, or combinations)

Sensitivity analysis

We will conduct sensitivity analyses to explore the effect of the methodological quality of the trials, checking to ascertain whether studies with a high risk of bias overestimate the effect of treatment.

Appendices

Appendix 1. Cochrane Neonatal standard search strategy

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

Appendix 2. Risk of bias tool

We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of the trials. For each trial, we will seek information regarding the method of randomization, blinding and reporting of all outcomes of all the infants enrolled in the trial. We will assess each criterion as being at a low, high, or unclear risk of bias. Two review authors will separately assess each study. We will resolve any disagreement by discussion. We will add this information to the table Characteristics of included studies. We will evaluate the following issues and enter the findings into the risk of bias table:

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we will categorize the method used to generate the allocation sequence as:

• low risk (any truly random process e.g. random number table; computer random number generator);

• high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we will categorize the method used to conceal the allocation sequence as:

• low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk, high risk or unclear risk for participants; and

• low risk, high risk or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we will categorize the methods used to blind outcome assessment. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re‐include missing data in the analyses. We will categorize the methods as:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data); or

• unclear risk.

6. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we will compare prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we will contact study authors to gain access to the study protocol. We will assess the methods as:

• low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

• unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?

For each included study, we will describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk;

• unclear risk

If needed, we plan to explore the impact of the level of bias through undertaking sensitivity analyses.

Contributions of authors

LM and MB reviewed the literature and wrote the protocol.

MGC commented on and reviewed the protocol.

Sources of support

Internal sources

• Pediatric and Neonatology Unit, Ospedale San Paolo, Savona, Italy.

  LM is employed by this organization

• Istituto Giannina Gaslini, Genoa, Italy.

  MGC is employed by this organization

• Institute for Clinical Sciences, Lund University, Lund; Research & Development, Section for HTA Analysis, Skåne University Hospital, Lund, Sweden.

  MB is employed by this organization

External sources

• No sources of support supplied

Declarations of interest

LM: no conflict of interest

MB: no conflict of interest

MGC: no conflict of interest

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