Table 3. Outcomes at 18 to 22 Months of Age by the 4 Hypothermia Groupsa.
| Outcomes | Neonates, No./Total (%) | Adjusted Risk Difference, % (95% CI) |
Adjusted RR (95% CI) |
Neonates, No./Total (%) | Adjusted Risk Difference, % (95% CI) |
Adjusted RR (95% CI) | Neonates, No./Total (%) | Adjusted Risk Difference, % (95% CI) |
Adjusted RR (95% CI)a |
|
|---|---|---|---|---|---|---|---|---|---|---|
| For 72 h at 33.5°C | For 72 h at 32.0°C | For 120 h at 33.5°C | For 120 h at 32.0°C | |||||||
| Primary outcome | ||||||||||
| Death or moderate or severe disability | 27/92 (29.3) | 29/84 (34.5) | 5.0 (−7.8 to 17.8) | 1.23 (0.76-1.98) | 32/93 (34.4) | 6.7 (−5.8 to 19.3) | 1.21 (0.78-1.87) | 22/78 (28.2) | −4.9 (−18.1 to 8.3) | 0.85 (0.53-1.35) |
| Secondary outcomes | ||||||||||
| Death | 8/92 (9) | 15/84 (18) | 9.5 (−0.6 to 19.5) | 2.16 (0.55-8.49) | 18/93 (19) | 12.9 (3.1 to 22.7) | 2.52 (1.06-5.95) | 15/78 (19) | 8.3 (−1.9 to 18.6) | 1.85 (0.79-4.31) |
| Among infants with moderate encephalopathy | 4/71 (6) | 4/64 (6) | 1.2 (−8.0 to 10.4) | 1.06 (0.26-4.29) | 7/75 (9) | 4.4 (−4.4 to 13.2) | 1.55 (0.49-4.92) | 4/53 (8) | 2.3 (−7.4 to 12.0) | 1.27 (0.26-6.20) |
| Among infants with severe encephalopathy | 4/21 (19) | 11/20 (55) | 24.1 (−7.9 to 56.2) | 2.68 (0.61-11.8) | 11/18 (61) | 53.6 (20.1 to 87.1) | 3.14 (1.31-7.51) | 11/25 (44) | 20.8 (−8.7 to 50.3) | 2.25 (1.06-4.77) |
| Death or moderate or severe disability | ||||||||||
| Among infants with moderate encephalopathy | 14/71 (20) | 13/64 (20) | −1.0 (−15.3 to 13.4) | 1.02 (0.48-2.15) | 19/75 (25) | 4.8 (−9.0 to 18.5) | 1.29 (0.74-2.25) | 9/53 (17) | −3.4 (−18.4 to 11.7) | 0.86 (0.41-1.80) |
| Among infants with severe encephalopathy | 13/21 (62) | 16/20 (80) | 2.5 (−28.8 to 33.7) | 1.29 (0.80-2.07) | 13/18 (72) | 17.7 (−15.0 to 50.4) | 1.17 (0.67-2.05) | 13/25 (52) | −14.9 (−43.7 to 13.9) | 0.84 (0.48-1.46) |
| Among survivorsb | ||||||||||
| Moderate or severe disability | 19/84 (23) | 14/69 (20) | −1.0 (−13.5 to 11.5) | 0.95 (0.49-1.85) | 14/75 (19) | −2.4 (−14.7 to 9.9) | 0.89 (0.47-1.69) | 7/63 (11) | −12.2 (−25.1 to 0.7) | 0.44 (0.16-1.16) |
| Moderate disability | 1/84 (1) | 3/69 (4) | 3.2 (−0.6 to 7.0) | 0/75 (0) | −1.0 (−4.8 to 2.7) | 0/63 (0) | −1.2 (−5.1 to 2.7) | |||
| Visual impairmentc | 7/84 (8) | 6/69 (9) | 0.8 (−7.1 to 8.7) | 1.18 (0.53-2.61) | 2/75 (3) | −4.3 (−12.1 to 3.5) | 0.38 (0.08-1.83) | 4/63 (6) | −2.0 (−10.2 to 6.1) | 0.68 (0.17-2.67) |
| Hearing impairmentd | 4/84 (5) | 2/69 (3) | −1.4 (−7.6 to 4.8) | 0.67 (0.15-3.05) | 4/75 (5) | 1.0 (−5.1 to 7.1) | 1.34 (0.45-3.99) | 1/63 (2) | −4.4 (−10.8 to 2.0) | 0.29 (0.03-2.93) |
| No disability (normal)e | 46/81 (57) | 40/69 (58) | 0.4 (−15.5 to 16.4) | 0.99 (0.67-1.47) | 36/72 (50) | −7.2 (−23.1 to 8.7) | 0.82 (0.63-1.08) | 38/63 (60) | 5.9 (−10.5 to 22.3) | 1.03 (0.77-1.39) |
| Mild disabilitye | 16/81 (20) | 15/69 (22) | 1.2 (−13.1 to 15.5) | NA | 22/72 (31) | 9.5 (−4.8 to 23.8) | NA | 18/63 (29) | 6.9 (−7.9 to 21.6) | NA |
| Multiple disabilitiesf | 15/84 (18) | 9/69 (13) | −3.4 (−14.0 to 7.1) | 0.81 (0.34-1.89) | 7/75 (9) | −7.1 (−17.5 to 3.3) | 0.60 (0.28-1.27) | 5/63 (8) | −9.5 (−20.4 to 1.3) | 0.42 (0.12-1.47) |
| Rehospitalizations after discharge | 29/80 (36) | 14/69 (20) | −14.7 (−27.8 to −1.6) | 0.58 (0.30-1.13) | 10/72 (14) | −20.2 (−33.3 to −7.1) | 0.42 (0.21-0.84) | 12/63 (19) | −17.7 (−31.2 to −4.1) | 0.52 (0.30-0.89) |
| Gastrostomy or tube feedingsg | 16/80 (20) | 11/69 (16) | −2.9 (−14.5 to 8.8) | 0.79 (0.49-1.28) | 12/72 (17) | −3.6 (−15.2 to 8.0) | 0.84 (0.48-1.47) | 6/63 (10) | −10.8 (−22.8 to 1.3) | 0.44 (0.16-1.18) |
| Height <10th percentile | 19/75 (25) | 13/69 (19) | −7.0 (−20.2 to 6.2) | 0.77 (0.41-1.46) | 13/70 (19) | −5.4 (−18.6 to 7.9) | 0.76 (0.42-1.39) | 11/62 (18) | −7.8 (−21.4 to 5.9) | 0.65 (0.33-1.30) |
| Weight <10th percentile | 7/78 (9) | 9/69 (13) | 5.0 (−4.8 to 14.8) | 1.46 (0.57-3.77) | 6/70 (9) | 1.4 (−8.4 to 11.2) | 0.98 (0.38-2.49) | 5/63 (8) | 0.5 (−9.6 to 10.6) | 0.85 (0.28-2.57) |
| Head circumference <10th percentile | 15/76 (20) | 18/69 (26) | 6.1 (−7.0 to 19.2) | 1.37 (0.91-2.07) | 9/69 (13) | −5.3 (−18.5 to 7.9) | 0.69 (0.33-1.45) | 12/62 (19) | −1.1 (−14.6 to 12.5) | 0.94 (0.47-1.88) |
| Cerebral palsy | 16/84 (19) | 13/69 (19) | 1.9 (−9.8 to 13.6) | 1.18 (0.63-2.20) | 10/75 (13) | −3.2 (−14.7 to 8.3) | 0.79 (0.35-1.80) | 8/63 (13) | −5.6 (−17.6 to 6.5) | 0.61 (0.26-1.45) |
| Quadriplegic | 6/19 (38) | 8/13 (62) | 3/10 (30) | 3/8 (38) | ||||||
| Diplegic | 2/19 (13) | 1/13 (8) | 2/10 (20) | 0 | ||||||
| Hemiplegic | 1/19 (6) | 1/13 (8) | 1/10 (10) | 1/8 (13) | ||||||
| Dystonic | 1/19 (6) | 2/13 (15) | 2/10 (20) | 1/8 (13) | ||||||
| Athetotic | 1/19 (6) | 0 | 1/10 (10) | 0 | ||||||
| Ataxic | 1/19 (6) | 0 | 1/10 (10) | 1/8 (13) | ||||||
| Unclassified | 1/19 (6) | 1/13 (8) | 0 | 2/8 (25) | ||||||
| Adjudicatedh | 3/19 (19) | 0 | 0 | 0 | ||||||
| Disabling (moderate or severe)i | 14/84 (17) | 10/69 (14) | −0.4 (−11.2 to 10.4) | 0.98 (0.48-2.01) | 3/10 (30) | −2.6 (−13.2 to 8.0) | 0.81 (0.36-1.84) | 5/63 (8) | −7.9 (−19.0 to 3.2) | 0.45 (0.13-1.53) |
| Seizures | 15/84 (18) | 12/69 (17) | −1.6 (−12.6 to 9.4) | 1.03 (0.53-1.99) | 10/74 (14) | −3.7 (−14.5 to 7.2) | 0.83 (0.38-1.82) | 6/63 (10) | −8.6 (−19.9 to 2.7) | 0.54 (0.20-1.44) |
| Bayley III cognitive score | ||||||||||
| Median (IQR) | 90 (80-100) | 90 (75-100) | 90 (80-100) | 90 (80-95) | ||||||
| ≥85 | 51 (65) | 48 (70) | 1 [Reference] | 53 (73) | 1 [Reference] | 44 (70) | 1 [Reference] | |||
| 70-84 | 14 (18) | 10 (14) | −5.7 (−20.3 to 8.9) | 0.80 (0.38-1.68) | 9 (12) | −7.7 (−22.1 to 6.7) | 0.67 (0.41-1.10) | 14 (22) | 0.4 (−14.3 to 15.1) | 1.09 (0.57-2.10) |
| <70 | 13 (17) | 11 (16) | −1.1 (−14.8 to 12.6) | 0.95 (0.41-2.20) | 11 (15) | −2.2 (−15.7 to 11.3) | 0.92 (0.50-1.71) | 5 (8) | −9.9 (−24.4 to 4.6) | 0.45 (0.16-1.28) |
| Bayley III language score | ||||||||||
| >85 | 39 (53) | 39 (57) | 39 (54) | 40 (65) | ||||||
| 70-84 | 18 (25) | 16 (24) | −7.9 (−25.0 to 9.2) | 0.87 (0.45-1.70) | 19 (26) | 1.1 (−15.8 to 18.0) | 1.05 (0.59-1.88) | 11 (18) | −13.2 (−30.9 to 4.4) | 0.64 (0.32-1.28) |
| <70 | 16 (22) | 13 (19) | −4.2 (−21.3 to 12.9) | 0.87 (0.44-1.70) | 14 (19) | −1.2 (−18.3 to 15.9) | 0.94 (0.53-1.69) | 11 (18) | −8.2 (−25.5 to 9.0) | 0.70 (0.30-1.61) |
| Bayley III motor score | ||||||||||
| >85 | 53 (68) | 47 (71) | 55 (77) | 53 (85) | ||||||
| 70-84 | 10 (13) | 7 (11) | −2.6 (−14.6 to 9.3) | 0.88 (0.44-1.78) | 3 (4) | −11.1 (−22.9 to 0.6) | 0.35 (0.15-0.82) | 5 (8) | −9.3 (−21.0 to 2.5) | 0.53 (0.17-1.63) |
| <70 | 15 (19) | 12 (18) | 0.1 (−13.2 to 13.4) | 1.02 (0.48-2.16) | 13 (18) | −1.5 (−14.4 to 11.3) | 0.89 (0.46-1.69) | 4 (6) | −14.5 (−28.0 to −0.9) | 0.29 (0.09-0.97) |
Abbreviations: IQR, interquartile range; NA, not applicable due to small sample size; RR, relative risk.
Adjusted risk differences and RRs compare each experimental group with the usual care group (cooling for 72 hours at 33.5°C). For definitions of encephalopathy and severe, moderate, mild, or no disability, see footnote a in Table 2.
Missing data: 17 neonates were lost to follow-up 3 in the group with 72 hours of cooling at 33.5°C; 6 in the group with 72 hours of cooling at 32.0°C; 3 in the group with 120 hours of cooling at 33.5°C; and 5 in the group with 72 hours of cooling at 32.0°C.
Visual impairment is defined as bilateral blindness with some/no useful vision.
Hearing impairment is defined as hearing impairment despite amplification.
Six infants were missing data for no disability (normal) and mild disability. These infants were adjudicated to no/mild disability, but sufficient information was unavailable to distinguish between normal and mild disability. These include 3 infants in in the group with 72 hours of cooling at 33.5°C and 3 in the in the group with 120 hours of cooling at 33.5°C.
Multiple disabilities was defined as ≥2 of the following: disabling cerebral palsy, Gross Motor Function Classification System level 3-5, Bayley III cognitive score <70, blindness, or deafness. Multiple disabilities occurred only in the severe disability group.
Exploratory outcome.
Adjudicated cerebral palsy is based on review caretaker interview/medical chart review by a small group of investigators unaware of treatment status.
Disabling cerebral palsy was defined as that which was moderate or severe, with infants requiring support for sitting, unable to crawl, or requiring adult assistance to move.