We identified 3,801 records after excluding of 506 duplicates by using Endnote software version X9. Title and abstract screening resulted in 36 records for further full-text screening. The later yielded 20 eligible papers for inclusion in our study. Two papers were added after performing manual search trials. Finally, we included 22 studies for this systematic review and meta-analysis (Figure 1).
Study characteristics and risk of bias
Out of the 22 included studies; seven were randomized controlled trials and the remaining 15 were cohort in design. The sample size of the included studies was highly variable ranging from 19 and as high as 34,602 pre-term infants. The average mean age in all reported treatment groups was 28 weeks (ranging from 25 to 50 weeks), while it was 27 weeks in control ones (ranging from 26 to 29 weeks). Table 1 shows the main characteristics of the included studies.
The overall risk of bias in the included RCTs was low in more than 50% of all items. The domains with major problems were deviations from intended interventions, randomization processes, and missing outcome data (Figure 2). For non-randomized trials, the risk of bias was higher with more than 50% of all items showing serious of critical risks of bias. Domains with the biggest issues were deviations from intended interventions, selective reporting, and cofounding of the results (Figure 3).
Eight studies, with a total of 20,708 preterm infants, were included in the analysis of patent ductus arteriosus (PDA) rates. Infants with prophylactic doses of indomethacin showed significantly lower rates of PDA compared to those who did not (OR= 0.33; 95% CI= 0.27-0.39; P-value< 0.001). However, there was significant heterogeneity among the included studies (I2= 72%; P-value< 0.001) (Figure 4).
In contrast, there was no significant differences among the two groups when compared in terms of BPD (OR= 1.08; 95% CI= 0.98-1.18; P-value= 106) and pulmonary hemorrhage rates (OR= 0.84; 95% CI= 0.67-1.05; P-value= 0.132). There was no significant heterogeneity among the included studies for both BPD (I2= 48%; P-value= 0.121) and pulmonary hemorrhage (I2= 0%; P-value= 0.786) outcomes (Figure 4).
Nine studies, with 17,949 pre-term infants, and five studies, with 20,116 pre-term infants, were included in the analyses of IVH and cerebral palsy (CP)/neurodevelopmental delay outcomes, respectively. There were no significant differences between prophylactic indomethacin group and the placebo/no treatment group in terms of IVH (OR= 0.90; 95% CI= 0.69-1.18; P-value= 0.460) and CP/neurodevelopmental delay (OR= 1.00; 95% CI= 0.81-1.23; P-value= 0.997). For heterogeneity, there was a significant heterogeneity in both analyses with (I2= 84%; P-value< 0.001) and (I2= 76%; P-value= 0.002) for IV and CP/neurodevelopmental delay, respectively (Figure 5).
Necrotizing enterocolitis/Intestinal perforation, and death
Nine studies, with 35,759 preterm infants, were included in the analysis of necrotizing enter colitis (NEC)/Intestinal perforation (IP) rates. There was a significant increase in NEC/IP rates in prophylactic indomethacin group when compared to the placebo/no treatment group (OR= 1.36; 95% CI= 1.24-1.49; P-value< 0.001). Moreover, there was no significant heterogeneity among the included studies (I2= 44%; P-value= 0.088) (Figure 6).
In the same context, death rates were compared in 47,265 patients of 13 included studies. There were no significant differences in death rates of prophylactic indomethacin group when compared to the placebo/no treatment group (OR= 1.06; 95% CI= 0.94-1.19; P-value= 0.340). However, there was significant heterogeneity among the included studies (I2= 69%; P-value< 0.001). There was no significant risk of bias when tested using Egger’s regression test (P-value= 0.428) (Figure 7).
Two studies of 340 patients were included in the analyses of hospitalization days and days spent of ventilation. On comparing these outcomes among the prophylactic indomethacin and placebo/no treatment groups, there was no statistically significant difference for hospitalization days (MD= 3.67; 95%CI= -11.03-18.37; P-value= 0.625) and days spent of ventilation (MD= -1.00; 95%CI= -6.71-4.71; P-value= 0.732). There was a significant heterogeneity in the analysis of hospitalization days (I2= 56%; P-value= 0.132), while it was not present in the analysis of days spent of ventilation (I2= 0%; P-value= 1.000) (Figure 8).
Prevalence of different outcomes in indomethacin group
For studies with a single prophylactic indomethacin group (no placebo/no treatment group), they were pooled with all other studies (two-armed) with similar outcomes to get the overall prevalence. The highest prevalence observed in pre-term infants with prophylactic indomethacin was the intubation in delivery room/first day (74%; 95%CI= 52.9-100.0), followed by BPD (33.2%; 95%CI= 25.6-43.1), PDA (32.2%; 95%CI= 27.3-38.0) and IVH (26.1%; 95%CI= 19.1-35.7), respectively (Figure 9). All prevalence analyses showed a significant heterogeneity (I2> 50%; P-value< 0.001); however, there was no significant risk of bias in all analyses (Egger’s P-value > 0.10). Table 2 details the prevalence of different outcomes in the prophylactic indomethacin group.