Indian Pediatrics 1999; 36:653-658 

ROLE OF ETHAMSYLATE IN PREVENTING PERIVENTRICULAR-INTRAVENTRICULAR HEMORRHAGE IN PREMATURE INFANTS BELOW 34 WEEKS OF GESTATION

Periventricular intraventricular hemorrhage (PVH-IVH)  has been documented to occur in 40% of very low birth weight infants (VLBW)(l). The neurodevel­opmental sequelae of PVH-IVH remain a major cause for concern. Approximately half of PVH-IVH occur within the first day of life an 90% occur before 4 days of age. Further pro­gression in the size of the hemorrhage may be found in 20-40% of the infants in the first week of life(2,3).

The efficacy of antenatal and postnatal interventions in the form of drugs like phenobarbitone(4-6), vitamin E(7), indome thacin(8), ethamsylate(9-12) and vitamin K(13) for prevention of PVH-IVH have been studied. However, no consensus exists regarding the value of drug prophylaxis for prevention of PVH-IVH.

Ethamsylate (Diethyl ammonium 2.5- dihydroxybenzene sulphonate) is a capillary stabilizing agent and an inhibitor of prostaglandin synthesis. It lowers Prostaglandin 12 and vasoconstrictor thromboxane levels, thereby reducing baseline cerebral blood flow(14). This effect may in part, explain the means by which it can prevent PVH-IVH in preterm infants. Ethamsylate is a safe cheap and an easily available drug. There have been few studies that have defined the role of this drug in the prevention ofPVH-IVH(9-12). The present study was carried out to evaluate the efficacy of ethamsylate in preventing PVH-IVH in preterm infants <34 weeks gestation age, in an attempt to find a safer and cheaper alternative to the other known drugs.

Subjects and Methods

Study Group

This randomized, controlled trial was carried out on infants <34 weeks gestational age, which was determined by the best obstetrical estimate. Inborn infants between 1st December 1996 and 28th February 1998 were included in the trial. Newborns with congenital malformations, family history of bleeding disorders and with Apgar scores <5 at 5 minutes were excluded from the trial. Infants who did not complete the drug schedule were also excluded. Each eligible neonate was randomized into 'ethamsylate' [Group A] or 'control' [Group B] groups using opaque envelopes.

Administration of the Study Drug

The infants in Group A received 12.5 mg! kg (0.1 ml/kg) of ethamsylate (Ethamsyl - Mejda Pharmaceuticals) intravenously within the first hour of birth and thereafter 6 hourly for 4 days. The Group B infants did not receive any medication other than routine therapy.

Evaluation of Infants

Cranial ultrasounds were obtained on all study infants by a pediatric sonologist, who was blinded to the patient group, on days 3-5, 10-14 and 28-30 of post natal age and before discharge using a WIPRO Scanner 2000 ultra- sound real time machine with 7.5 and 5 Hz probes. Scans was performed weekly if PVH- IVH or its complications were found on initial scans. Ultrasound appearances of PVH-IVH were graded from I-IV by a system based on that of Papi1e et al.(1).

Clinical data relating to factors known to be associated with an increased incidence of peri ventricular-intra ventricular hemorrhage (PVH-IVH) were noted. Antenatal history of pregnancy induced hypertension, other maternal medical disorders, drug administration (steroids, phenobarbitone, vitamin K, indomethacin), delivery details including fetal distress, instrumentation and Apgar scores, and the clinical course of the infants with specific regards to ventilation, surfactant therapy, PDA, sepsis and medications (phenobarbitone, vitamin E, indomethacin) administered were noted. Side effects of ethamsylate i.e., skin rashes, hypotension, and deep vein thrombosis were recorded. Other known adverse reactions of ethamsylate such as nausea and headaches could not be noted due to the age constraints of the patient group.

Outcome Measures

The outcome mesures were the incidence and severity of PVH-IVH during the neonatal period in the two groups during the neonatal period.

Statistical Analysis

Statistical analysis was done using the Student's t-test for continuous variables and the Chi-square test for discrete variables. A p value <0.05 was taken as statistically significant.

Results

A total of 208 infants < 34 weeks delivered at the hospital during the study period met the inclusion criteria. Of these four infants with congenital heart disease, two infants with geni- tourinary tract anomaly and two with intestinal obstruction were excluded after randomization. Eight infants died before completing the drug schedule, five due to congenital sepsis and three due to respiratory distress syndrome. Of the remaining 192 infants, 93 belonged to Group A and 99 to Group B.

Maternal Characteristics

The frequency of antenatal administration of corticosteroids and the mode of delivery were not found to be statistically different amongst the two groups (Table /). None of the mothers received phenobarbitone, vitamin K or indomethacin antenatally. There were two twins and one set of triplets in Group A, as com- pared to three twin pairs in Group B. Five twin pairs were split with one infant in Group A and the other in Group B.

Characteristics of Infants

The mean birth weights and gestational ages were 1190:!: 290 grams (range 760-1600 grams) and 31.9:!: 2.3 weeks (range 26-34 weeks) in Group A and 1230:!: 310 grams (range 820-1740 grams) and 32.3 :!: 2.2 weeks (range 26-34 weeks) in Group B, respectively (Table I). In Group A and Group B, 76.3% and 77 .8% of the infants respectively were greater than 28 weeks of gestation. No infant received phenobarbitone, or indomethacin during the first seven days or prophylactic Vitamin E for prevention of retinopathy of prematurity during the study period. The frequency of respiratory failure requiring ventilation in the two groups was similar. There were no significant differences in the incidence of complications of prematurity (PDA, pulmonary hemorrhage, pneumothorax, sepsis) amongst the two groups. Hypotension needing ionotropic support was seen in six infants in Group A and eight infants in Group B which could not be attributed to ethamsylate. Infants with PDA were treated with oral mefenamic acid for ductal closure after partial feeding was established. None of the infants exhibited any side effects of ethamsylate.

Outcome Measures

A total of 55 babies (28.5%) developed PVH-IVH (Table II). The incidence and the severity of PVH-IVH did not differ significant (p >0.05) in Group A (27.9%) and Group B (29.2%) though the babies in Group B had a higher mean birth weight and gestational age. Periventricular leukomalacia and ventriculitis with progressive hydrocephalus were detected in one infant each in group B.

Mortality

Eleven infants in Group A and nine infants in Group B died in hospital. In Group A causes of mortality were necrotising enterocolitis - three, sepsis-three, PVH-IVH- three, RDS- one, and pulmonary hemorrhage- one. Group B had nine deaths which were inclusive of six due to sepsis, two due to PVH- IVH and one due to pulmonary hemorrhage.

Discussion

Four studies relating to ethamsylate prophylaxis for PVH-IVH have been published(9-12). One study(9) enrolled 70 infants in a randomized double-blind trial and demonstrated a significant reduction (50%) in the frequency of PVH-IVH. Forty-five ventilated infants given ethamsylate in another study were found to have a reduction in both the incidence and severity of PVH-IVH as compared to controls(10). Two large randomized controlled multi-centric trials(11-12) were conducted to evaluate the role of ethamsylate in the prevention of PVH-IVH. The study by Benson et al. (1 J) demonstrated a 50% reduction in major bleeds whereas the EC ethamsylate trial group( 12) found no differences either in the incidence or in the severity of PVH-IVH with the use of postnatal prophylactic ethamsylate.

The duration and dosage of ethamsylate administered to the newborns in our study was similar to other studies(9-12). The mean birth weights of the infants enrolled in these studies was comparable but the mean gestational age was higher in our study as more than 80% of the infants were >28 weeks gestation. The incidence of PVH-IVH decreases with increasing gestational age and weight(1). The overall incidence of PVH-IVH in this study was lower than 25-45% reported by other studies on ethamsylate(9,1 J, 12). Severe grades were seen in one-fifth of the infants who developed PVH- IVH in our study as compared to almost one- third of the infants in the previous trials(9- 12).The incidence of RDS, ventilation, pneumothoraces and clinical PDA in babies <34 weeks gestation (Table I) at our institute was low as compared to the two multicentric trials(ll, 12) which have reported an incidence of RDS (68%), ventilation (70-80%), pneumo- thoraces (15%) and PDA (20%) all of which are known to increase the risk of PVH-IVH. Antenatal steroids were administered to 35% of the babies in our trial as compared to 16% in the EC ethamsylate trial group study(12). The other studies(9-ll) have not reported data regard- ing antenatal steroid use or any other drug administered for prevention of PVH-IVH. Prenatal steroids are known to decrease the incidence of PVH-IVH(15). Prophylactic vitamin E, phenobarbitone, and indomethacin were not received by any of the mothers or infants in this study. Postnatal vitamin E was not found to affect the incidence or severity of PVH-IVH(lI, 12), and as a unit policy we do not use prophylactic vitamin E for prevention of retinopathy of prematurity except for multi- vitamin supplementation after the infant is on full oral feeds. The combined effect of higher coverage of mothers in preterm labor with antenatal steroids, the lower incidence of RDS and ventilation and its complications, and the higher gestational age of our study infants may have resulted in the decreased- incidence and severity of PVH-IVH in the present study.

We did not include newborns with low Apgar scores to avoid a confounding factor at study entry. This also precluded the use of phenobarbitone in asphyxiated infants with convulsions which is known to affect PVH- IVH(6). Hospital records of the previous' two years showed that PVH-IVH occurred in 30.8% of infants <34 weeks gestation. Power calculations suggested that to attain a statistical significance level of p <0.05 with a power of 80%, a total number of 174 infants would be required in each group to decrease the incidence of PVH-IVH to 15% with prophylactic ethamsylate. A review was requested by the sponsors midway through the study and when no obvious advantage was found the study was stopped with mutual consent.

In conclusion, this study could not conclusively prove or disprove the efficacy of ethamsylate in prevention of PVH-IVH as the incidence of severe grades of PVH-IVH was low in the study infants. We feel that °v:erall improvements in care in the perinatal and early neonatal period, including antenatal cortico steroid therapy, preventing RDS and the complications of ventilation may contribute more to decrease the severity of PVH-IVH rather than postnatal ethamsylate therapy though it was not the subject of comparison in our study.