THE EFFECTS OF ANTENATAL CORTICOSTEROIDS AND SURFACTANT REPLACEMENT ON NEONATAL RESPIRATORY DISTRESS SYNDROME Introduction

Th e goal of this study was to determine the eff ects of antenatal corticosteroids and surfactant replacement on the severity and frequency of Respiratory Distress Syndrome (RDS) in a cohort of premature infants born in Sarajevo, Bosnia and Herzegovina, from  to . Th e cohort consisted of  premature neonates with estimated gestational age between  and  weeks. Babies with IUGR, babies of diabetic mothers and babies with major congenital defects were excluded. Out of  neonates,  were treated antenatally with corticosteroids (single course of dexamethasone) and / were not. Th ere was no statistical diff erence (p>,) in average gestational age (, vs. , GW) and male/female ratio between investigated groups; there were signifi cantly more male patients (p<,) in both groups. Frequency of RDS was signifi cantly lower in the corticosteroid group (/) in relation to the control group (/) (p<,). Severe RDS was signifi cantly (p<,) more frequent in the control group / (,) then in the corticosteroid group / (,). Bovine surfactant (Survanta) was given as a rescue therapy to  babies with clinical and radiological signs of RDS who required FiO>, and mechanical ventilation. Early surfactant administration within six hours after birth appeared to be eff ective at reducing mortality then later surfactant administration (p<,). In the group of babies requiring FiO≥, at the time of surfactant replacement, the mortality rate was signifi cantly higher (p<,). In conclusion, we confi rm the effi cacy of antenatal corticosteroid treatment and early surfactant treatment in a cohort of premature infants born in Sarajevo.


Introduction
Th e effi cacy of antenatal corticosteroid treatments and early postnatal surfactant replacement has been well established.A National Institutes of Health Consensus Development Conference reported a systematic review of all available clinical trial data regarding administration of antenatal corticosteroids to women with premature onset of labor in  (, , ).As a result, antenatal corticosteroid treatment was recommended for any woman likely to deliver between  and  weeks gestation.At that time, there was little evidence that such treatment was of benefi t to babies of less than  weeks gestation.However, subsequent observational data () indicate that antenatal steroids are also eff ective at reducing the incidence of respiratory distress in babies less than  weeks.Indeed, it appears that giving antenatal steroids to women at less than  weeks gestation shortly before delivery halves the risk of respiratory distress developing after birth, regardless of the gestational age at which delivery occurs (,).While betamethasone was the agent used in the fi rst trial of antenatal steroid treatment (), dexamethasone has been more widely used in many countries.Both drugs (betamethasone and dexamethasone) seem to be of comparable effi cacy in most respects, but there are now observational studies suggesting that while antenatal treatment with betamethasone has no eff ect on, or may actually reduce the risk of subsequent cystic periventricular leukomalacia in the baby, repeated treatment with dexamethasone may increase this risk (,,).Surfactant treatment after birth may augment, but cannot replicate, all the benefi ts associated with antenatal steroid administration.The efficacy of neonatal surfactant therapy is enhanced by antenatal exposure to corticosteroids (,).Although progression of the lung symptoms normally seen in Respiratory Distress Syndrome (RDS) may be modified or halted by ventilatory support, surfactant treatment is still required in about  of all premature babies born before  weeks gestation.In these cases, timing of surfactant administration is of vital importance to improved outcome.The prophylactic administration of surfactant to preterm neonates at risk has signifi cant advantages over rescue therapy (-).Early rescue surfactant replacement, before a complete clinical picture of RDS develops, is preferable to late treatment, although optimal timing of surfactant treatment is not yet clear ().The aim of this study was to determine the effects of antenatal corticosteroids on the severity and the frequency of RDS and the effects of timing of surfactant replacement and O requirement on mortality in a cohort of premature infants.

Material and Methods
One hundred seventy two () premature neonates (gestational age - weeks, aged between - hours) admitted to the Neonatology Department of the Paediatric Clinic, Clinical University Centre Sarajevo during the two year period from  to  were enrolled in this study.Babies with intra-uterine growth restriction (IUGR), babies of diabetic mothers and babies with major congenital defects were excluded.Comparisons were made between infants treated antenatally with single course of antenatal corticosteroids (four doses of dexamethasone  mg, given intramuscularly  hours apart) and infants with no antenatal corticosteroid treatment.Bovine surfactant (Survanta,  ml/kg) was given to infants with radiological and clinical signs of RDS (tachypnea and cyanosis on room air) who required mechanical ventilation with FiO more than . following radiological confi rmation of correct endotracheal tube placement.Each dose was administered over  sec.into each lung quadrant.If oxygen saturation fell below  installation was discontinued, and then resumed after the oxygen saturation improved.A second dose of surfactant was given  hours later at the discretion of the treating physician.Oxygen requirement was recorded.Severe RDS was defi ned as O requirement more then  (FiO≥,).Clinical outcomes were assessed at  days.Standard statistical parameters were used: determination of means and standard deviations for normally distributed variables, median and range for vairables without a normal distribution, t-test for continuous variables, and x-test for categorical and dichotomous variables.

Results
A summary of epidemiologic data for the infants enrolled in the study is presented in Table  and Table  .While there was no statistical signifi cance in average gestational age between the two groups, the infants who developed RDS had approximately one week lower gestational age in both groups.We found no statistical diff erence in male/female ratio between the two groups, though there were signifi cantly more male then female patients in both groups (p<.).Consistent with other published studies, we found a signifi cant decrease in RDS and severe RDS in the infants treated with antenatal corticosteroids (Table ).
SUADA HELJIĆ ET AL.: THE EFFECTS OF ANTENATAL CORTICOSTEROIDS AND SURFACTANT REPLACEMENT ON NEONATAL RESPIRATORY DISTRESS SYNDROME Mortality data are presented in Table  and  Table .We note significant associations between both late surfactant therapy and higher oxygen requirement and increased mortality.

Discussion
We present a summary of the incidence of RDS and the mortality rates of a cohort of premature infants born in Sarajevo, Bosnia and Herzegovina from  to .Our results are similar to other published data and add to the studies available for inclusion in meta-analyses.We found that infants treated with corticosteroids antenatally were less likely to develop RDS.Th e target group for the antenatal corticosteroid treatment in our study was the group of preterm babies born before  weeks gestation.A Cochrane meta-analysis of  randomized trials () concluded that antenatal corticosteroid therapy reduces the incidence of RDS, neonatal death and intraventricular haemorrhage.Th ere was evidence of benefi t in all major subgroups of preterm babies, regardless of race or gender.Infants born after  weeks did not show a statistically signifi cant decrease in RDS although the trend was positive ().At less than  weeks, the numbers of infants studied were small (, , , ).An analysis of 'the number needed to treat' suggests that after  weeks,  women will need to be treated to prevent one case of RDS, while before  weeks one case of RDS is prevented for every fi ve women treated ().We investigated two predictors of mortality: time of surfactant dose and maximum oxygen requirement.A regression analysis to correct for potential confounders was not possible, however we did fi nd a strong association between later administration of surfactant and increased mortality and between higher oxygen requirement and increased mortality.It is important to give surfactant as soon as the diagnosis of RDS is established, before the complete clinical picture develops.Early treatment when RDS is moderately severe prevents or reverses the natural progression of the disease in at least  of the cases and lowers the risk of serious complications (,,).Whether increased oxygen requirement is simply a marker of more severe disease, a marker of delay in surfactant treatment, or a contributing factor to mortality could not be determined with this study design.Th e prophylactic administration of surfactant in the delivery room is preferable, but should be reserved for the smallest infants with the highest risk of developing RDS and should be given by a person experienced in neonatal resuscitation and surfactant administration.

Conclusion
. Antenatal corticosteroid administration signifi cantly reduces the incidence and severity of RDS in premature neonates.Every eff ort should be made to initiate antenatal corticosteroid therapy in women between  and  weeks of gestation as soon as preterm delivery appears likely, .Our study confi rms the benefi ts of early surfactant use in the treatment of RDS in premature infants.Early surfactant use reduces mortality in preterm babies - weeks gestation with RDS..In neonates who require FiO >,, surfactant should be given as soon as possible, before the complete clinical picture of RDS is developed.

TABLE 1 .
Average gestational age in weeks in Corticosteroid (CS) and Control group

TABLE 4 .
Outcome of the illness related to the timing of the fi rst surfactant dose

TABLE 5 .
Outcome of the illness in dependency of O 2 requirements

TABLE 2 .
Male/female ratio in Corticosteroid (CS) and Control group

TABLE 3 .
Frequency and severity of RDS resulting from antenatal cor-