1. Pediatric Academic Societies and Asian Society for Pediatric Research
2008 Joint Meeting
Platform Session
Neonatal Medicine: Clinical Trials I
Sunday, May 4
7:00am-9:00am
Hawaii Convention Center, Ballroom B

2. Prevalence of cerebral palsy at 3-5 years of age
who participated in an RCT for the prevention of intraventricular hemorrhage by indomethacin in Japanese extremely low birthweight infants
Shinya Hirano, Masanori Fujimura, Satoshi Kusuda,
Hirofumi Aotani.
On behalf of the Neonatal Research Network Japan
Disclosure: The trial vials (indomethacin and placebo) were manufactured by Banyu, a subsidiary of Merck & Co. Inc., NJ, USA.
The research grant from Dept. of Maternal and Child Health, Ministry of Health and Welfare, Japan.
Any real or apparent conflict of interest related to the content of the presentation has been resolved.
It is our pleasure to present the results of first trial compiled by the Neonatal Research Network Japan.
Any real or apparent conflict of interest related to the content of the presentation has been resolved.

3. BACKGROUND:
We reported in 2005 that the prophylactic indomethacin (IND) was effective to reduce the incidence of severe IVH in Japanese ELBW infants in a large RCT (n=419)
Adjusted odds ratio (95% CI)
0.37 ( ) p =0.007
Adjusted for institution, gestational age, sex,
in/out-born, Apgar score at 1 min
HYPOSESIS:
The reduced incidence of severe IVH by prophylactic IND in neonatal period may result in the reduction of cerebral palsy (CP) at 3-5 years of age
We reported in SPR 2005 that the prophylactic indomethacin was effective to reduce the incidence of severe IVH (Grade three and four) in Japanese extremely low birthweight infants in a large randomized controlled trial.
The adjusted odds ratios was 0.37,
From this result, we hypothesized that
the reduced incidence of severe IVH by prophylactic indomethacin in neonatal period may result in the reduction of cerebral palsy at three to five years of age.

4. SUBJECTS: Infants with birthweight 400-1000 g INTERVENTION :
INDOMETHACIN TRIAL
SUBJECTS: Infants with birthweight g
INTERVENTION :
Starting within 6 hours of birth 3 doses of IND or placebo were given with 6 hours continuous intravenous infusion every 24 hours
IND was given at the dose of 0.1 mg/kg-wt/dose
OUTCOMES :
Grade 3 and 4 IVH within 7 days assessed by US.
CP at 3-5 years of age
SUBJECTS of study were infants with birthweight between g
The intervention was to start within six hours of birth,
three doses of indomethacin or placebo were given
with six hours continuous intravenous Infusion every twenty four hours
Indomethacin was given at the dose of 0.1 mg/kg-wt/dose.
OUTCOMES are Grade three and four IVH within 7 days, assessed by Ultrasound scan.
And cerebral palsy at three to five years of age.

5. OBJECTIVE:
To compare the prevalence of CP at 3-5 years between the IND and placebo groups in a follow-up study of a large RCT in Japan
The OBJECTIVE of this study is ,
To compare the prevalence of cerebral palsy at 3 to 5 years of age
between the indomethacin and placebo groups

6. 718 infants assessed for eligibility
50 : Excluded
67 : Not approached
601 infants eligible
Stratified factors
Institution
　 Gestational Age
Sex
In-born / Out-born
Apgar at 1min
132 : No consent
469 infants were assigned randomly
235 IND group
234 placebo group
Seven hundred eighteen infants were assessed for eligibility.
And four hundred sixty nine infants were assigned randomly to the trial.
two hundred thirty five infants were assigned to the indomethacin group, and two hundred thirty four were to placebo group.
Either before or after discharge from the NICU twenty two infants died in indomethacin group and twenty nine infants in Placebo group .
One hundred ninety one children in Indomethacin group, and one hundred eighty seven children in placebo group were assessed for CP in the routine follow-up clinic by qualified pediatricians.
The follow up rate was 90.4 % as a whole.
Death : 22
Drop out, No data : 22
Death : 29
Drop out, No data : 18
191
378 / 418 (90.4%)
187

7. RESULTS : Baseline Characteristics
IND
(N=235)
Placebo
(N=234)
p value
Birth weight(g)
775.2±130.6
784.0±139.8 NS
Apgar score at 5 min
6.7 ±1.9
6.8 ±1.9
Primipara
119 (50.6%)
109 (46.6%)
Singleton / Multiple
189 / 46
188 / 46
Vaginal / C-section
64 / 171
68 / 166
Antenatal steroids
103 (43.8%)
102 (43.6%)
This table shows the baseline characteristics of infants and mothers for two groups.
There was no evidence of differences between two groups in birthweight, Apgar score at 5 min, and Obstetric characteristics, between two groups .
Mean±1SD NS: not significant

8. RESULTS: Outcomes IND Placebo odds ratio p value Death 22 / 235
(95% CI) p
value
IVH 3 or 4 <7 days
16 / 235
(6.8%)
32 / 234 (13.7%)
0.37
( )
0.007
Death
22 / 235
(9%)
29 / 234
(12.4%)
0.75
( )
0.34 CP
31 / 235
(13.2%)
32 / 234
(13.7%)
0.95
( )
0.82
CP or death
53 / 235
(22.5%)
61 / 234
(26.0%)
( )
0.37
This slide shows the result.
Grade 3 or 4 IVH within 7 days was significantly reduced in IND group.
Up to the time of final follow up, there were 22 deaths in IND group and 29 in Placebo group.
The number of children who either died or showed the sign of CP were 53 in indomethacin and 61 in placebo group.
There is no evidence of difference.

9. Severity of IVH and Prevalence of CP
IND
Placebo
This slide shows the percentage of CP in relation with the severity of IVH.
Each pink bar shows the ratio of CP with number of cases and blue is without CP.
In IND group on the left, there is a significant correlation between the grade of IVH and the percentage of CP. The severer the IVH, the higher the rate of CP.
There is a same trend in the Placebo group, and there is no evidence of difference in the prevalence of CP between the IND and Placebo groups in relation with the severity of IVH.
It is well known that periventricular leukomalacia is one of the major cause of CP.
Therefore we specified each case of PVL on this figure in the next slide.. CP
Without CP

10. Severity of IVH , PVL, and Prevalence of CP
IND
Placebo
Here the PVL cases are shown with highlighted bars.
In IND group with IVH nil or grade 1, there were 6 cases of PVL. In placebo group there were 5 cases. There were no PVL in IVH grade 2 and 3, and in IVH grade4, 3 cases of PVL all together.
There could be seen no bias in the distribution of PVL In indomethacin or placebo groups.
We therefore can conclude from these data thatthe distributions of CP both in IND and Placebo groups may be similar in relation with the severity of IVH.
If this is true we may wonder why the reduction of IVH did not result in the reduction of CP? CP
Without CP
with PVL

11. Subgroup Analysis as for “CP or Death”
IND
Placebo
Odds ratio (95% CI)
p value
Male
25 / 105
31 / 105
0.75 ( )
0.34
Female
28 / 130
40 / 129
0.90 ( )
0.74 g
7 / 22
18 / 27
0.23 ( )
0.015 g
39 / 164
34 / 150
1.06 ( )
0.81 g
7 / 49
9 / 57
0.88 ( )
0.82
GW 22-23w
9 / 23
15 / 22
0.30 ( )
0.051
GW 24-26w
35 / 136
39 / 135
0.85 ( )
0.56
GW 27w-
9 / 76
7 / 77
1.34 ( )
0.57
Outborn
6 / 45
13 / 44
0.36 ( )
0.06
Inborn
47 / 190
48 / 190
0.97 ( )
0.91
Apgar score 1min <3
28 / 97
33 / 96
0.77 ( )
0.41
Apgar score 5min <3
5 / 15
4 / 14
1.25 ( )
0.78
antenatal steroids
19 / 103
18 / 102
1.05 ( )
0.88
RDS
48 / 182
43 / 187
1.19 ( )
0.45
We then made subgroup analysis wondering if we could find any subgroups who might have had a favorable effect on “CP or Death” by the use of IND.
In Birthweight g, IND was effective to reduce CP or death.
For those who are weeks of gestation, and outborn, the IND group shows the trend to reduce CP or death.
Then we analyzed the birthweight subgroups.

12. Incidence of IVH 3, 4 and “CP or Death “ Stratified by Birth weight
IND
Placebo
Odds ratio(95% CI) g
2 /22
11 / 27
7 / 22
18 / 27
0.14 ( )
0.23 ( ) g
12 / 164
19 / 150
39 / 164
34 / 150
0.58 ( )
1.06 ( ) g
2 / 49
2 / 57
7 / 49
9 / 57
1.17 ( )
0.88 ( )
This slide shows the incidence of IVH grade three and four, and CP or death for each birth weight groups.
In g group the number of CP or death in the IND group was 7 in twenty 22, whereas it was 18 in 27 in the placebo group. The odds ratio is 0.23 and the IND is effective to reduce CP or death.
In other birthweight groups there could be seen no effect.

13. Incidence of IVH 3, 4 and “CP or Death “
Stratified by Gestational Weeks
IVH 3, 4
CP or Death
IND
Placebo
Odds ratio (95% CI)
22-23w
2 /23
11 / 22
9 / 23
15 / 22
0.10 ( )
0.30 ( )
24-26w
13 / 136
19 / 135
35 / 136
39 / 135
0.65 ( )
0.85 ( )
27w-
1 / 76
2 / 77
9 / 76
7 / 77
0.5 ( )
1.34 ( )
On the gestational weeks of birth, in weeks group, the indomethacin was seem to be effective to reduce IVH grade three or four
and CP or death.
From these results
In most premature group of babies;
that is either g birthweight or weeks gestation, indomethacin is shown to be effective to reduce
both severe IVH and CP or death at 3-5 years of age.

14. and Gestational Age Groups
IVH 3, 4
and Gestational Age Groups N=
P=0.0034
We showed this figure in the previous SPR in 2005.
There can be seen a trend that the smaller the gestation the more the preventive effect of Indomethacin to IVH grade 3 or 4.
It could be that infants above 25 weeks the indomethacin is not necessary for the prevention of IVH.

15. and Birthweight Groups
Cerebral Palsy
and Birthweight Groups N=
odds ratio=0.23 ( )
In this presentation
we have shown the evidence that
the use of prophylactic IND could be indicated
only for those who are born between g.

16. CONCLUSIONS:
For the whole study subjects, there was no evidence of difference in the number of infants with “CP or death” by the prophylactic use of IND compared with placebo
The prevalence of CP in each grade of IVH showed no evidence of difference between IND and placebo groups
The prevalence of PVL showed no evidence of difference in IND and placebo groups
In a subgroup analysis, the prevalence of “CP or death” was significantly lower in infants with birthweight g in IND group than placebo group
Application of prophylactic IND to the smallest group of ELBW g is shown as effective in preventing the development of CP at 3-5 years
We thank Naohiro Yonemoto and Rintaro Mori for kind advice for statistical analysis.
In CONCLUSION :
1. For the whole study subjects, there was no evidence of difference in the number of infants with “CP or death” by the prophylactic use of IND compared with placebo.
2. The prevalence of CP in each grade of IVH showed no evidence of difference between IND and placebo groups.
3. The prevalence of PVL showed no evidence of difference in IND and placebo groups.
4. In a subgroup analysis, the prevalence of “CP or death” was significantly lower in infants with birthweight g in IND group than placebo group.
5. Application of prophylactic indomethacin to the smallest group of Extremely Low Birth Weight g is shown as effective in preventing the development of CP at 3-5 years
We thank Naohiro Yonemoto and Rintaro Mori for kind advice for sta tistical analysis
THANK YOU VERY MUCH FOR YOUR ATTENTION.