More research needed to show whether corticosteroids could reduce complications and mortality in newborn babies with meconium aspiration syndrome
A bowel movement (meconium) from an unborn baby in stress during labour can enter the lungs when the baby starts to breathe after birth. Suction and/or intubation are used to try and remove the meconium from the baby's breathing passages, but some babies will still develop meconium aspiration syndrome. Those babies will have breathing difficulties which can lead to breathing failure and death. Corticosteroids are anti-inflammatory drugs that have been tried for babies with meconium aspiration syndrome. However, the review of trials found that there is not enough evidence to assess the potential benefits and harms of this treatment.
Meconium is a viscous green substance found in the fetal gastrointestinal tract from approximately the 10th week of gestation. It is an heterogenous substance composed of a mixture of bile, bile acids, mucous, pancreatic secretions and cellular debris (Wiswell 1993). Approximately 10 to 15 % of pregnancies will be complicated by the passage of meconium around the time of delivery (Wiswell 1993). It is estimated that despite current interventions such as intubation with tracheal suction, five to 12% of infants born through meconium stained amniotic fluid will still develop meconium aspiration syndrome (Wiswell 2000).
Meconium aspiration syndrome is defined as respiratory distress associated with the passage of meconium around the time of birth, with characteristic radiological changes and without an alternative etiology for the respiratory symptoms. The radiological features consist of areas of atelectasis and consolidation, along with regions of hyperexpansion. Histologically, a significant inflammatory reaction is seen, with a diffuse pulmonary infiltrate of polymorphonuclear leukocytes. Release of cytokines from these leukocytes, along with the direct toxicity of bile salts, has been postulated to result in a chemical pneumonitis (Oelberg 1990). Hypoxemia and hypercapnia may occur, requiring respiratory support. Secondary pulmonary vasoconstriction may follow, resulting in persistent pulmonary hypertension of the newborn (Wiswell 1993).
There has been considerable interest in the therapeutic potential of steroids in the management of meconium aspiration syndrome, due to their anti-inflammatory properties. In a randomised controlled trial of cortisol in a rabbit model of meconium aspiration syndrome, a slight decrease in both respiratory rate and the severity of pulmonary histopathological changes was seen in the cortisol treated rabbits, but there was also increased mortality in the treatment group (Frantz 1975). A more recent animal study on a newborn piglet model of meconium aspiration found improvement in lung function following treatment with dexamethasone (Khan 1999).
The objective of this review was to determine whether steroid therapy for meconium aspiration syndrome decreases the incidence of chronic lung disease and mortality associated with this disease, without an associated increase in adverse effects such as neurodevelopmental disability.
Primary outcome measures:
1. Chronic lung disease (oxygen dependency at 28 days of age)
2. Mortality (before hospital discharge, before age 1 year)
3. Long term growth, and neurodevelopmental outcome assessed at age 1, 2
and 5 years with validated assessment tools
Secondary outcome measures:
1. Duration of mechanical ventilation
2. Duration of oxygen therapy
3. Pulmonary air leak syndromes (pneumothorax, pulmonary interstitial emphysema)
4. Intraventricular haemorrhage and/or periventricular leukomalacia on head
ultrasound studies
5. Duration of hospital stay
Post-hoc outcome measures:
1. Acute adverse steroid effects (weight loss, hyperglycaemia, hypertension
and gastrointestinal haemorrhage)
2. Treatment with extra-corporeal membrane oxygenation (ECMO)
Using MeSH search terms ' meconium aspiration syndrome ' and 'exp infant, newborn' searches were made of PREMEDLINE and MEDLINE from 1966 to April 2003, CINAHL from 1992 to April 2003, Current Contents from 1998 to April 2003, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003) and the Oxford Database of Perinatal Trials. The search included cross-referencing of previous reviews, and a review of abstracts, conference and symposia proceedings published in Pediatric Research from 1993 to April 2003.
We sought clarification of the data from the authors of both studies but did not receive additional information. As the variation around the mean duration of oxygen therapy reported by Yeh 1977 was so small, and because standard error was used elsewhere in the paper to describe variance, this was assumed to be the standard error and was converted to standard deviation for our analysis.
Three randomised controlled trials were identified with the Search Strategy. Two randomised controlled studies were included in this systematic review, Yeh 1977 and Wu 1999. The third study, Davey 1995 which examined dexamethasone versus placebo therapy in the treatment of meconium aspiration syndrome was excluded as it was published in abstract form only. We contacted the authors who were unable to provide sufficient data for inclusion in this review.
Of note is the time difference of 22 years between the studies by Yeh 1977 and Wu 1999. There were 35 infants in the study by Yeh 1977, and 50 infants in the study by Wu 1999, giving a total of 85 infants in the two studies. Similar diagnostic criteria were used in each study, with the definition of meconium aspiration syndrome based on the presence of meconium staining of the skin, with associated respiratory distress and radiological findings consistent with meconium aspiration syndrome. The type of intervention and duration of treatment varied between the two studies. Yeh 1977 compared a two day course of intravenous hydrocortisone with lactose placebo, whereas Wu 1999 compared a seven day reducing course of intravenous dexamethasone to saline placebo. Both studies examined the outcomes of mortality, need for mechanical ventilation and duration of oxygen therapy. Yeh 1977 also assessed the incidence of air leak syndromes. Assisted ventilation was reported as an outcome, but the study did not define whether this included or excluded continuous positive airways pressure. The study did not report the incidence of chronic lung disease, hyperglycaemia, hypertension, weight loss, duration of mechanical ventilation, length of hospital stay or long term outcome. Wu 1999 reported the duration of mechanical ventilation, length of hospital stay, weight loss, hypertension and hyperglycaemia, but did not report the incidence of air leak syndromes. Neither study reported outcome data following hospital discharge.
In Yeh 1977 allocation concealment was adequate, using a random number table with master code in a sealed envelope. There were no exclusions after randomisation. Blinding of intervention was achieved using identical treatment and placebo vials. While the trial was described as double blind, the methods of blinding of outcome assessment were not described.
The study by Wu 1999 was described as a double blind randomised trial, but the methods of allocation concealment and blinding of intervention and outcome assessment after randomisation were not clearly outlined by the authors. There were no exclusions after randomisation.
2. Mortality
Mortality before hospital discharge was assessed by Yeh 1977 and Wu 1999 (85
infants). Neither study reported a significant difference between the steroid-treated
compared to control groups. On meta-analysis there was no significant difference
in the mortality rate before hospital discharge between the steroid-treated
and control groups [typical RR 0.95 (0.2-4.58)].
Mortality at one year follow up was not reported in either study.
3. Long-term growth and neurodevelopmental outcome assessed at age 1, 2
and 5 years with validated assessment tools.
These outcomes were not reported in either of the included studies.
Secondary outcome measures:
1. Duration of mechanical ventilation
Only Wu 1999 reported this outcome (50 infants).
In this trial the duration of mechanical ventilation was reported as significantly
shorter in the steroid treated group (mean 3.5 days) compared to control group
(4.6 days). Our analysis, however, found this difference not to be statistically
significant.
2. Duration of oxygen therapy
Both Yeh 1977 and Wu 1999
reported this outcome (85 infants). Yeh 1977 reported
that infants in the steroid-treated group took longer to wean to room air
(68.9 +/- 38.6 hours) than infants in the control group (36.6 +/- 29.3 hours).
Wu 1999 reported no significant difference in duration
of oxygen therapy. On meta-analysis there was a significant increase in hours
on oxygen therapy in the steroid-treated group compared to the control group
[WMD 30.0 hours (8.4-51.6)].
3. Pulmonary air leak syndromes (pneumothorax, pulmonary interstitial emphysema)
The incidence of air leak was only reported by Yeh
1977 (35 infants) who found no significant difference between the steroid-treated
and control groups [RR 0.64 (0.18-2.26)].
4. Intraventricular haemorrhage and/or periventricular leukomalacia on
head ultrasound studies
Neither of the included studies reported data on this outcome.
5. Duration of hospital stay
Duration of hospital stay was only reported by Wu 1999
(50 infants) who found no significant difference in the number of days in
hospital between with those treated with steroids and those receiving placebo
[MD 0.0 days (-3.09-3.09)].
Post-hoc outcome measures:
1. Acute adverse steroid effects (weight loss, hyperglycaemia, hypertension
and gastrointestinal haemorrhage)
Only Wu 1999 reported weight loss. While more weight
loss was seen on days 5 to 10 in the steroid-treated group, this weight loss
was not quantified, and the statistical and clinical significance were not
described.
Wu 1999 reported that transient elevations of blood
glucose and blood pressure were noted on days 2, 3, 5 and 7 in the steroid-treated
group; data were not available. Yeh 1977 did not
report blood glucose levels or blood pressure measurements.
Neither Wu 1999 nor Yeh 1977
reported the incidence of gastrointestinal haemorrhage.
2. Treatment with extra-corporeal membrane oxygenation (ECMO)
Neither Wu 1999 nor Yeh 1977
reported ECMO as an outcome in their studies.
No significant difference was seen in mortality with steroid treatment. In fact a surprising small but significant increase in days of oxygen therapy was found. Limited data were available regarding acute adverse effects of steroid therapy such as hyperglycaemia and hypertension with Wu 1999 suggesting there was no effect, while neither study provided information regarding long term respiratory and neurodevelopmental outcome.
In contrast to the statistically significant result reported in the paper by Wu 1999, our analysis of the difference in duration of mechanical ventilation using the data reported showed that the difference between the two groups was not significant. Data published in the paper suggest that the mean duration of mechanical ventilation reported for the steroid treated group may be incorrect, as there were no infants on mechanical ventilation at four days. The authors were contacted but were unable to provide additional information.
It has previously been noted that survivors of meconium aspiration may
develop symptoms of obstructive airways disease in later childhood (MacFarlane 1988, Swaminathan 1989). An increased incidence
of cerebral palsy has also been noted in infants with a history of meconium
staining at delivery (Nelson 1989) compared to
the general population. These outcomes are therefore important when planning
studies involving infants with meconium aspiration syndrome. A recently published
case series of 14 patients treated with intravenous dexamethasone for ventilated
infants with meconium aspiration syndrome intends to follow up longer term
developmental outcome (da Costa 2001). Endeavours
to assess long term respiratory and neuro-developmental sequelae of meconium
aspiration syndrome within the context of randomised controlled trials are
also desirable.
There remains considerable interest in the possible benefits of steroid
therapy for meconium aspiration syndrome. Previous animal studies and a prospective
case series have shown encouraging results (Khan 1999,
da Costa 2001). Given current concerns regarding
the possible role of postnatal dexamethasone in the aetiology of cerebral
palsy in preterm infants, caution is required in the use of steroids during
the neonatal period. However, in view of the significant mortality and morbidity
associated with meconium aspiration syndrome, including respiratory failure
requiring ECMO therapy (Davey 1995), steroids
continue to be prescribed in the clinical setting for infants with this condition
(Davey 1995, da
Costa 2001). At present there is insufficient evidence available to fully
evaluate the risks and benefits of steroid treatment. A larger randomised
controlled trial including careful assessment of short and long term adverse
effects would be required to further delineate the role of steroid therapy
in the management of meconium aspiration syndrome.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Wu 1999 | Randomised controlled trial- double blind. Blinding of randomisation - can't tell. Randomised assigment list used for randomisation, but concealment unclear. Intervention adequately blinded, with equal volumes of treatment and saline placebo. Follow up complete for all enrolled subjects. Method of blinding outcome assessment not clearly defined. |
50 newborn infants with meconium aspiration syndrome and severe
respiratory distress. |
Intervention group n=27; Control group n=23. Intravenous dexamethasone
or saline placebo of equivalent volume given immediately after diagnosis of
meconium aspiration syndrome, then q12h for 7 days Initial dose: 1mg/kg/dose; day 1-3: 0.5mg/kg/dose; day 4-7: 0.25mg/kg/dose. |
Pulmonary hypertension, mortality, intubation, duration of mechanical ventilation, duration of oxygen therapy, length of hospitalisation, acid base status, weight loss, blood glucose, blood pressure. | Study assumed to have been conducted in Taiwan, dates unknown | B |
| Yeh 1977 | Randomised controlled trial-double blind. Blinding or randomization - yes. Random number sequence with master code in sealed envelope. Blinding of intervention achieved with identical vials of treatment and placebo. Outcome data available for all enrolled subjects. Methods of blinding of outcome assessment not clearly defined. |
35 newborn infants with meconium staining of the skin and positive tracheal aspiration of meconium who had one of two criteria: 1: clinical signs of respiratory distress in the first 4 hours and/or 2: radiographic findings of aspiration syndrome. | Intervention group n=17; Control group n=18. Identical vials of hydrocortisone or placebo (lactose hydrous) in similar diluent administered at same intervals. Hydrocortisone 20mg/kg initially then q12h for 4 doses given immediately after diagnosis. |
Need for mechanical ventilation, incidence of air leak, mortality, alveolar-arterial oxygen gradient, duration of oxygen therapy, length of respiratory distress. | Study conducted between October 1974 and September 1975 in hospital setting in Illinois, USA. | A |
| Study | Reason for exclusion |
| Davey 1995 | Abstract contained insufficient information about methodology and results. Two authors contacted but could not provide additional data. |
Wu JM, Yeh TF, Wang JY, Wang JN, Lin YJ, Hsieh WS, Lin CH. The role of pulmonary inflammation in the development of pulmonary hypertension in newborn with meconium aspiration syndrome. Pediatric Pulmonology - Supplement 1999;18:205-208.
Yeh 1977 {published data only}
Yeh TF, Srinivasan G, Harris V, Pildes RS. Hydrocortisone therapy in meconium aspiration syndrome: A controlled study. Journal of Pediatrics 1977;90:140-143.
Davey AM, Kueser TJ, Turner HF. Randomised controlled trial of early dexamethasone therapy in the treatment of meconium aspiration syndrome. Pediatric Research 1995;37:329A.
* indicates the primary reference for the study
Burke-Strickland M. Tracheobronchial lavage in small infants. Minnesota Medicine 1973;56:287-89.
da Costa DE, Nair AK, Pai MG, Al Khusaiby SM. Steroids in full term infants with respiratory failure and pulmonary hypertension due to meconium aspiration syndrome. European Journal of Pediatrics 2001;160:150-53.
Frantz ID, Wang NS, Thach BT. Experimental meconium aspiration: effect of glucocorticoid treatment. Journal of Pediatrics 1975;86:438-41.
Khan AM, Shabarek FM, Kutchback JW, Lally KP. Effects of dexamethasone on meconium aspiration syndrome in newborn piglets. Pediatric Research 1999;46:179-83.
MacFarlane PI, Heaf DP. Pulmonary function in children after neonatal meconium aspiration syndrome. Archives of Disease in Childhood 1988;63:368-72.
Nelson KB. Relationship of intrapartum and delivery room events to long-term neurologic outcome. Clinics in Perinatology 1989;16:995-1007.
Oelberg DG, Downey SA, Flynn MM. Bile salt-induced intracellular calcium accumulation in type II pneumocytes. Lung 1990;168:297-308.
Swaminathan S, Quinn J, Stabile MW et al. Long-term pulmonary sequelae of meconium aspiration syndrome. Journal of Pediatrics 1989;114:356-61.
Wiswell TE, Bent RC. Meconium staining and the meconium aspiration syndrome. Unresolved issues. Pediatric Clinics of North America 1993;40:955-81.
Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szlyd E et al. Delivery room management of the apparently vigorous meconium-stained neonate: Results of the multicenter, international collaborative trial. Pediatrics 2000;105:1-7.
01.01 Chronic lung disease (oxygen dependency at 28 days)
01.02 Mortality (before hospital discharge)
01.03 Duration of mechanical ventilation (days)
01.04 Duration of oxygen therapy (hours)
01.05 Pulmonary air leak syndrome
01.06 Duration of hospital stay (days)
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Steroid vs placebo in the treatment of meconium aspiration syndrome | ||||
| 01 Chronic lung disease (oxygen dependency at 28 days) | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 02 Mortality (before hospital discharge) | 2 | 85 | RR (fixed), 95% CI | 0.95 [0.20, 4.58] |
| 03 Duration of mechanical ventilation (days) | 1 | 50 | WMD (fixed), 95% CI | -1.10 [-2.79, 0.59] |
| 04 Duration of oxygen therapy (hours) | 2 | 85 | WMD (fixed), 95% CI | 30.00 [8.40, 51.61] |
| 05 Pulmonary air leak syndrome | 1 | 35 | RR (fixed), 95% CI | 0.64 [0.18, 2.26] |
| 06 Duration of hospital stay (days) | 1 | 50 | WMD (fixed), 95% CI | 0.00 [-3.09, 3.09] |
| 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 msot recent version of the Review. |
