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The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575-1450 g; gestational age: 26.8 weeks, range: 22-31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean +/- SEM) show that apparent volume of distribution (AVd) was 62.1 +/- 3.9 ml/kg, plasma t1/2 beta was 30.5 +/- 4.2 h, elimination rate constant (Kel) was 0.032 +/- 0.004 h-1, plasma clearance was 2.06 +/- 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 +/- 11.1 mg/l. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 +/- 54.5 mg/l and 113.6 +/- 58.2 mg/l, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 +/- 0.39%, n = 26) compared to adult plasma protein (mean +/- SE = 98.73 +/- 0.31%, n = 8, p < 0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.

We report our experience with the use of intra-amniotic thyroxine to accelerate fetal maturation in preterm delivered infants. One hundred and fourteen infants who had received 500 micrograms of thyroxine weekly prenatally until an L/S ratio greater or equal to 2.0 was achieved, were compared to 113 premature infants who had not been given thyroxine or steroids prenatally. After stratification by weight, the relative incidence of respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC) and intraventricular hemorrhage (IVH) were compared. A decrease in the incidence of RDS was observed in the infants with birth weight between 1000 and 1500 g who had received more than one dose of intra-amniotic thyroxine. No difference in the incidence of RDS was observed in infants with birth weight of less than 1000 g or over 1500 g. One dose of thyroxine had no effect in decreasing the incidence of RDS, PDA, NEC, and IVH in any of the groups. We conclude intra-amniotic thyroxine seems to decreases the incidence of RDS in very low birth weight infants.

Objective: To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room., Design: Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation., Results: Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis., Conclusion: The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus.

Aims: To examine the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with patent ductus arteriosus and intraventricular haemorrhage in infants weighing less than 1750 g at birth., Methods: A literature search from 1980 onwards was made of three databases: Medline; Embase; and the Oxford Database of Perinatal Trials. Using strict criteria applied to randomised controlled trials only, two observers independently selected 14 studies for inclusion in the review. The methodological quality of each study was assessed independently by two observers using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions. Where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect., Results: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled estimate of risk difference -0.025 (95% confidence interval (CI) -0.061, 0.010). The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled estimate of risk difference -0.217 (95% CI -0.275, -0.160), but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of grades 3 and 4 intraventricular haemorrhage in treated infants, pooled estimate of risk difference -0.039 (95% CI -0.066, -0.011). However, there is no sound evidence assessing the long term effect of prophylaxis on neurodevelopmental outcome. Although there is a trend in treated infants towards an increased incidence of necrotising enterocolitis, pooled estimate of risk difference 0.015 (95% CI -0.002, 0.033), and some evidence that treatment may transiently impair renal function, there is no evidence that haemostasis is disturbed., Conclusion: Prophylactic treatment with indomethacin has several immediate benefits. However, more data are needed on the incidence of possible adverse effects and neurodevelopmental outcomes before routine use of this therapy can be recommended.

Objective: To test whether early postnatal (0 to 3 hours) intravenous administration of ibuprofen will prevent patent ductus arteriosus (PDA) in preterm neonates., Design: Prospective sequential controlled trial with three treatment arms., Setting: Level 3 perinatal-neonatal intensive care nursery., Patients: Thirty-four premature newborn infants born from February to August 1993 with a mean birth weight of 913 g (range, 565 to 1460 g) and gestational age of 26.9 weeks (range, 22.4 to 31.0)., Intervention: Infants were consecutively assigned within 3 hours of age to treatment with either one dose of ibuprofen lysine (10 mg/kg intravenously) followed by 5 mg/kg per dose intravenously at 24 and 48 hours of age (n = 12), one dose of ibuprofen lysine (10 mg/kg intravenously; n = 11), or saline (n = 11)., Outcome Variables: Primary outcome variable was the presence of ductus arteriosus by echocardiography and clinical assessments at 3, 7, and 21 days of life. Secondary outcome variables included presence of intraventricular hemorrhage, renal function, ventilatory and oxygen needs, hematologic changes, gastrointestinal function, time to full enteral feeding, duration of hospitalization, and age at discharge., Results: The three groups of patients were comparable in birth weight, gestational age, antenatal administration of betamethasone, and other perinatal characteristics. Ibuprofen treatment significantly reduced plasma levels of prostaglandins, and the levels remained low for 72 hours in newborns who received three doses of the drug. The incidence of PDA and other variables did not differ between patients who received a single dose of ibuprofen and those given saline. However, compared with the saline-treated newborns, babies who received three doses of ibuprofen had no PDA (0/12 vs 7/11 for saline; P < .02), had lower daily mean airway pressures (mean +/- SD, 5.2 +/- 1.1 cm H2O vs 8.3 +/- 2.8 cm H2O for saline; P < .02) and better oxygenation index (2.6 +/- 0.6 vs 4.7 +/- 1.8 for saline; P < .02) at the end of the first week of life, and required fewer days of ventilation (25 +/- 14 days vs 44 +/- 26 days for saline; P < .03). Babies given three doses of ibuprofen tended to tolerate full oral feedings earlier (35 +/- 19 days vs 56 +/- 34 days for saline; P = .09), had shorter duration of hospitalization (71.2 +/- 22.6 days vs 127.3 +/- 74.7 days for saline; P < .05), and were discharged to home at an earlier postconceptional age (37.8 +/- 2.0 weeks vs 44.8 +/- 9.8 weeks for saline; P < .05). ibuprofen treatment in this phase I trial was not associated with any apparent early neurological, intestinal, renal, hepatic, or hematologic complications., Conclusions: Administration of three doses of ibuprofen within 3 hours after birth in preterm neonates reduced the incidence of PDA without causing notable early adverse drug reactions in this phase I trial. Early closure of the ductus arteriosus was also associated with better respiratory outcome and earlier discharge from the hospital.

To study the effect of antenatal indomethacin or nylidrin hydrochloride treatment on the fetal and neonatal ductus arteriosus and tricuspid valve function, 84 pregnant women with threatened premature birth between 22.9 and 34.0 wk gestation and 94 of their offspring born at 24.7 to 41.6 wk of gestation were studied by Doppler echocardiography. Forty-six women were treated with indomethacin and 38 with nylidrin. Both peak systolic and peak diastolic velocities in the ductus increased after administration of indomethacin and exceeded the corresponding velocities in the fetuses of the nylidrin group (p = 0.0001). Ductal constriction occurred in 42 of 49 fetuses treated with indomethacin (86%). Tricuspid valve regurgitation (TR) was evident in 11 of 49 fetuses treated with indomethacin (22%). The mean gestational age of the fetuses with TR (30.0 wk) tended to be higher than those without TR (28.3 wk, p = 0.056). In the nylidrin group, no fetus had ductal constriction or TR. A significant increase in peak systolic velocity (r = 0.54, p = 0.0001) and in peak diastolic velocity (r = 0.46, p = 0.0001) in the ductus with advancing gestational age was demonstrated in the indomethacin group; however, in the nylidrin group, there was a less remarkable increase in peak systolic velocity (r = 0.35, p = 0.04) and no increase in peak diastolic velocity (r = 0.02, p = 0.93). In infants born at or before 35 wk gestation, incidences of both spontaneous closure and indomethacin-induced closure of ductus were similar in both study groups (p > 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To determine whether antenatal dexamethasone sodium phosphate administration constricts the fetal ductus arteriosus or improves spontaneous closure of the ductus in premature infants., Design: A randomized double-blind study., Setting: University hospital of Helsinki, Finland., Participants: Sixty-one pregnant women with threatened preterm delivery between 24 and 31.9 weeks' gestation and 57 of their offspring (28 in the dexamethasone and 29 in the placebo group), born at 24 to 34.9 weeks' gestation, were studied using Doppler echocardiography., Interventions: None., Measurements and Main Results: Between the dexamethasone and placebo groups, there were no significant differences in systolic or diastolic flow velocity values in the fetal ductus arteriosus. Of the 29 infants with respiratory distress syndrome, 26 (90%) had hemodynamically significant patent ductus arteriosus and received indomethacin sodium: 12 (92%) of 13 dexamethasone-treated infants and 14 (88%) of 16 placebo-treated infants. One placebo-treated infant was ligated. Of the 28 infants without respiratory distress syndrome, only four (14%) had hemodynamically significant patent ductus arteriosus. In infants born at or before 30 weeks' gestation, spontaneous closure of the ductus occurred more frequently after administration of prenatal dexamethasone (in six of 17 infants; 35%) than placebo (in none of 10 infants; P < .05)., Conclusions: Our data indicate that antenatal dexamethasone administration had no constrictive effect on the ductus arteriosus of the fetus between 24 and 31 weeks' gestation. However, antenatal dexamethasone had a beneficial effect on ductal closure in very premature infants.

Some trials in premature infants with respiratory distress syndrome have shown an increased incidence of patent ductus arteriosus after exogenous surfactant therapy. The effect of prophylactic ethamsylate on patent ductus arteriosus after intratracheal administration of a single dose of porcine surfactant preparation (Curosurf, 2.5 ml/kg) was studied in a group of 20 preterm infants with severe respiratory distress syndrome. Gestational age of the patients was 29.2 +/- 2.5 weeks (mean +/- SD), and birth weight was 1158 +/- 319 gm. Ethamsylate (12.5 mg/kg) was given prophylactically within the first 4 hours of life followed by 6-hourly doses for 4 days. Hemodynamically significant patent ductus arteriosus occurred more frequently in the untreated group (8 of 10) than in the ethamsylate group (2 of 10) (p < 0.02). No acute adverse effects were attributed to the therapy. This preliminary experience suggests that ethamsylate, an inhibitor of prostaglandin biosynthesis, could be useful in reducing the incidence of patent ductus arteriosus in very low birth weight infants treated with exogenous surfactant.

In a multicenter, double-blind, placebo-controlled trial conducted at 23 hospitals in the United States, a single prophylactic 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal) or air placebo was administered shortly after birth to 215 infants with birth weights of 500 to 699 gm. Despite stratification at entry by birth weight and gender, by chance female infants predominated in the air placebo group and male infants predominated in the surfactant group. Among infants receiving synthetic surfactant, improvements in oxygen requirements were significant at 2 hours after birth (p = 0.014) and persisted for 3 days (p = 0.001); improvements in the alveolar-arterial partial pressure of oxygen gradient were significant at 6 hours after birth (p = 0.01) and persisted for 3 days (p = 0.008). Improvements in mean airway pressure were not significant at 2 or at 6 hours after birth (p = 0.622 and 0.083, respectively), but became significant thereafter and persisted for 3 days (p = 0.002). Pneumothorax was reduced by slightly more than half (25 vs 11; p = 0.014); death from respiratory distress syndrome (RDS) was also reduced (26 vs 15; p = 0.046). Overall neonatal mortality, however, was not significantly reduced (58 vs 46; p = 0.102). Other complications of RDS and prematurity were not altered, except that pulmonary hemorrhage occurred significantly more frequently in infants receiving synthetic surfactant (2 vs 12; p = 0.006). These findings indicate that a single prophylactic dose of synthetic surfactant in infants weighing 500 to 699 gm at birth improves lung function, incidence of air leak, and death from RDS but not overall mortality. The only safety problem identified was an increase in pulmonary hemorrhage.

The incidence and type of cerebral lesions in 159 infants born before 30 weeks gestation were studied, using ultrasound. Indomethacin was given as part of tocolytic management to mothers with a high incidence of early rupture of membranes and preterm labour; and 76 fetuses were exposed to the drug as a result. For the remaining 83 pregnancies, in which there was a high incidence of chronic fetal distress and in utero hypoxia, tocolysis was either not started or limited to fenoterol. The neonatal course was similar for both groups of infants, except that patent ductus arteriosus was less commonly diagnosed in the 76 infants exposed to indomethacin. However, the incidence of periventricular leukomalacia was increased among infants exposed to any tocolytic agent; and cystic lesions occurred more commonly in those exposed to indomethacin.

To assess the efficacy of prophylactic indomethacin in reducing the incidence of symptomatic patent ductus arteriosus, thirty two preterm infants weighing 750-1500 gm at birth were randomized to receive oral indomethacin or placebo. Fifteen infants received oral indomethacin with a dosage of 0.2 mg/kg at the 24th, 36th and 60th hour of age as the study group. The other 17 infants received 1 ml 0.33% saline in 5% G/W solution at the same schedule. Birth weight, gestational age, male/female ratio and severity of respiratory distress syndrome were similar for both groups. Nine of the 16 survivors of control group developed symptomatic patent ductus arteriosus. On the contrary, only two of the 14 survivors who received prophylactic indomethacin developed symptomatic PDA (P less than 0.05). There were no significant difference in the development of bronchopulmonary dysplasia, duration of oxygen therapy, duration of endotracheal intubation, days required to regain birth weight or complication between these two groups. The results indicated that the use of prophylactic oral indomethacin is beneficial in the prevention of symptomatic PDA in very low birth weight infant.

The effect of indomethacin on systolic and diastolic cardiac function was assessed in 15 premature infants. Seven infants (group 1) received indomethacin to treat a clinically significant patent ductus arteriosus (PDA), and eight infants (group 2) received indomethacin prophylactically at 24 hours of age because of their high risk for PDA. Diastolic cardiac function was assessed using instantaneous rates of change of left ventricular (LV) cavity dimension, derived from M-mode echocardiography. The maximum velocity of lengthening of the LV cavity dimension, an index of early diastolic function, fell from 63 +/- 19 mm/sec before indomethacin to 48 +/- 16 mm/sec 1 hour after indomethacin in group 1 (P less than 0.01), with the ductus still patent and the LV chamber still dilated, and also decreased in group 2, from 52 +/- 7 mm/sec to 38 +/- 6 mm/sec (P less than 0.01). This index, when normalized for loading conditions, was decreased 1 hour after indomethacin at 12 +/- 2 sec-1 and 12 +/- 1 sec-1 for groups 1 and 2, respectively, compared with values before indomethacin of 15 +/- 3 sec-1 and 15 +/- 2 sec-1. There was no effect of indomethacin on the indices of systolic function. We conclude that indomethacin decreases early diastolic function in premature infants.

Early treatment of premature infants with indomethacin has been proposed as a means of reducing the morbidity associated with respiratory distress syndrome complicated by symptomatic patent ductus arteriosus. We identified 26 infants less than 48 hours old with severe respiratory distress syndrome who had an asymptomatic patent ductus arteriosus. These infants were treated with either indomethacin or placebo. There was a significant difference in the frequency of ductal closure after receiving indomethacin treatment. No significant difference was observed in the time required for mechanical ventilation, time receiving supplemental oxygen, or time in the hospital, and there were no significant differences in the incidence of bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, or death between the two groups.

The incidence of clinically detectable patient ductus arteriosus (PDA) in a group of preterm infants whose birth weights were less than 2,000 g was compared with that of a similar group of infants whose mothers received antenatal glucocorticoids. A PDA was diagnosed on the basis of a typical heart murmur, increased precordial activity, and bounding peripheral pulses beyond the third day of life. Whereas 14 (44%) of 32 infants who were not exposed to antenatal glucocorticoids showed evidence of a PDA, only one (6.5% of 15 infants whose mothers received antenatal glucocorticoids had similar findings. The incidence of ruptured membranes (greater than 72 hours), the number of infants who were small for gestational age, and clinical management of the infants in the two groups were similar.

Hydrocortisone, prednisolone, and betamethasone were injected into a rat that was 21 days pregnant, and the fetal ductus arteriosus was studied using the rapid whole-body freezing technique. All these glucocorticoids constricted the fetal ductus arteriosus in a dose-dependent relationship. Fetal ductal constriction was maximum 1 to 4 hr after injection and was significantly more prominent in premature fetuses than in mature ones.

Patent ductus arteriosus is common among premature neonates, especially those with birth weights less than 1,500 g. In vitro, room light inhibits the contraction of immature piglet's ductal rings. Because phototherapy is used frequently from the first days of life to treat jaundice in preterm neonates, we compared the occurrence of patent ductus arteriosus among premature infants exposed to this intense light source with those whose chests were shielded. Seventy-four babies with respiratory distress syndrome were randomly assigned to either a treatment group (chest shielded with aluminum foil while on phototherapy, 36 babies) or control group (no shield, 38 babies). All were on radiant warmers, received mechanical ventilation for respiratory distress syndrome, and phototherapy (Air Shields model PTU 78-1) from day 1 of life. Irradiance was maintained at greater than 4.0 microW/cm2/nm in all cases. Although both groups had similar birth weights, gestational ages, severity of respiratory distress syndrome, intravenous fluid intake, and duration of phototherapy, the incidence of patent ductus arteriosus was significantly less in the shield group (shield 11/36 v No shield 23/38; P = .009). Patent ductus arteriosus murmurs developed in shielded patients at a later date, they required less vigorous treatment (ie, indomethacin), and they had shorter hospitalizations (74 v 85 days; P less than .05). The significant reduction of patent ductus arteriosus with shielding suggests that phototherapy may play a role in the occurrence of patent ductus arteriosus in premature infants. Shielding may be a practical method to decrease this common complication should this initial observation be confirmed.

Prenatal maternal glucocorticoid treatment has been reported to reduce the incidence of patent ductus arteriosus in prematurely born infants. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE2 both in utero and in prematurely born infants, and lung is a major source of PGE2 in fetuses and neonates. 15-Hydroxy-prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reaction in converting biologically active PGE2 to its inactive analogue, 15-keto-PGE2. In the present study, effect of prenatal dexamethasone treatment on the activity of fetal rat lung 15-PGDH was studied at 20, 21 and 22 days of gestation. Activity of fetal lung 15-PGDH more than doubled from 20 to 22 days of gestation. Dexamethasone treatment at 0.4 mg/kg and 0.8 mg/kg significantly increased the activity of 15-PGDH in both 20- and 21-day fetuses but had no effect on 22-day fetuses. We speculate that the clinical observation that prenatal glucocorticoid treatment reduces the incidence of patent ductus arteriosus in premature infants may in part be due to the stimulatory effect of glucocorticoid on the activity of 15-PGDH in fetal and neonatal lung and possibly other organs.

To determine the efficacy of indomethacin to prevent the occurrence of symptomatic patent ductus arteriosus (PDA), a randomized clinical trial was conducted involving 32 preterm infants weighing 750 to 1500 g at birth who had hyaline membrane disease. By random assignment, 15 infants were given a single dose of indomethacin, 0.2 mg/kg intravenously, 24 hours after birth. Seventeen infants composed a control group for which indomethacin was reserved as treatment for symptomatic PDA. Birth weight, gestational age, male/female ratio, black/white ratio, and severity of disease were similar for both groups. Only one of the 14 survivors who received prophylactic indomethacin had symptomatic PDA, compared with nine of the 16 survivors in the control group (P = 0.007). There was no difference between the groups in development of bronchopulmonary dysplasia, duration of time endotracheal intubation, was required, duration in oxygen, duration to reach full feedings and regain birth weight, and duration of hospital stay. There was no difference between the two groups in incidence of intraventricular hemorrhage, and none developed necrotizing enterocolitis. These results indicate that the use of prophylactic indomethacin is beneficial in prevention of symptomatic PDA; the lack of differences in pulmonary sequelae or other complications may have been related to a population sample size not large enough to impart sufficient statistical power.

We admitted 48 preterm neonates (600 to 1250 gm birth weight, normal 6-hour echoencephalograms) to a randomized prospective indomethacin or placebo trial for the prevention of neonatal intraventricular hemorrhage. Beginning at 6 postnatal hours, indomethacin or placebo was administered intravenously every 12 hours for a total of five doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, and renal and clotting functions were monitored. No differences in birth weight, gestational age, Apgar scores, or ventilatory needs were noted between the two groups. Six infants given indomethacin had intraventricular hemorrhage, compared to 14 control infants (P = 0.02). The indomethacin-treated group had significant decreases in serum prostaglandin values 30 hours after the initiation of therapy. The overall incidence of patent ductus arteriosus was 82% at 6 postnatal hours; 84% of the indomethacin-treated infants experienced closure of the ductus, compared to 60% of the placebo-treated patients. Closure of the ductus was not related to incidence of intraventricular hemorrhage. We speculate that indomethacin may provide some protection against neonatal intraventricular hemorrhage by acting on the cerebral microvasculature.

The impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants (less than or equal to 1300 g birth weight) was prospectively investigated. The trial was controlled, the infants were randomized, and the investigators were unaware of the group assignments. Patients with minimal (grade I) or no periventricular-intraventricular hemorrhage determined by prestudy echoencephalography were randomized within two birth weight subgroups (500 to 899 and 900 to 1300 g) to receive either prophylactic indomethacin (n = 99) or an equal volume of saline-vehicle placebo (n = 100). The first dose (0.2 mg/kg) was given within 12 hours of delivery and two subsequent doses (0.1 mg/kg) were administered at 12 hourly intervals. Prophylactic indomethacin significantly reduced the incidence of grades II to IV periventricular-intraventricular hemorrhage. Intraventricular hemorrhage was half as common in infants given prophylactic indomethacin as in control infants (23% v 46%, P less than .002). The reduction was manifested in both birth weight subgroups. Results of this study also confirmed a lower incidence of clinically significant patent ductus arteriosus in infants who received prophylactic indomethacin in contrast to those who received placebo (11% v 42%, P less than .001). No significant differences were found between treatment and control groups in the duration of oxygen therapy, mechanical ventilation, or hospitalization or in the incidence of pneumothorax, chronic lung disease, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. Early prophylactic indomethacin initiated within 12 hours of delivery is effective in reducing the incidence of intraventricular hemorrhage as well as clinically significant patent ductus arteriosus in very low birth weight premature infants.

A cohort of 678 consecutive very low birth weight infants, liveborn in one tertiary institution during a 63-month period, was studied to investigate whether antenatal steroid therapy had any beneficial or harmful effects on mortality or morbidity over the first 2 years of life. Comparing the 244 babies who received treatment with the 434 controls, 195 (79.9%) and 265 (61.1%), respectively, were discharged home (P less than 0.001). Mortality in the treated group remained substantially lower and was almost halved after adjustment for birth weight, extreme immaturity, lethal malformations, and confounding obstetric variables (P = 0.001). Fatal cases of respiratory distress syndrome were less common in the treated group (P = 0.044). Of in-hospital survivors, those in the treated group required less positive pressure respiratory support (P = 0.003) and fewer days in oxygen (P = 0.018), and the incidences of bronchopulmonary dysplasia (P = 0.003) and patent ductus arteriosus (P = 0.002) were lower. Two-year survivors who had received treatment were heavier (P = 0.016) and had larger head circumferences (P = 0.029). These beneficial associations in the treated group were not at the expense of increased rates of infection or adverse neurologic outcome. We did not detect any adverse effects of antenatal steroid therapy on any relevant aspect of mortality or morbidity in infancy under circumstances in which the chances of finding substantial differences were high.