Table 3.
Prespecified Secondary Outcomes to Hospital Discharge and at 2 Years.*
| Outcome | Higher Hemoglobin Threshold | Lower Hemoglobin Threshold | Adjusted Relative Risk, Hazard Ratio, or Mean Difference (95% CI)† | |
|---|---|---|---|---|
| Outcomes to hospital discharge | ||||
| Survival to discharge without severe complications — no./total no. (%)‡ | 257/901 (28.5) | 274/888 (30.9) | 0.93 (0.81 to 1.06) | |
| Bronchopulmonary dysplasia at 36 wk postmenstrual age — no./total no. (%)§ | 469/795 (59.0) | 453/805 (56.3) | 1.04 (0.96 to 1.13) | |
| Retinopathy of prematurity stage ≥3 or treatment for that condition received — no./total no. (%)¶ | 157/797 (19.7) | 137/797 (17.2) | 1.14 (0.94 to 1.39) | |
| Grade 3 or 4 intraventricularhemorrhage, cystic periventricular leukomalacia, or ventriculomegaly diagnosed on ultrasonographic examination — no./total no. (%) | 146/855 (17.1) | 154/859 (17.9) | 0.94 (0.77 to 1.16) | |
| Necrotizing enterocolitis, Bell’s stage ≥2 — no./total no. (%)∥ | 91/907 (10.0) | 95/906 (10.5) | 0.95 (0.73 to 1.25) | |
| No. of transfusions per infant | 6.2±4.3 | 4.4±4.0 | 1.71 (1.37 to 2.05) | |
| Anthropometric measures** | ||||
| Weight for age | ||||
| No. of infants | 769 | 774 | ||
| Change in z score | −1.2±0.8 | −1.3±0.8 | 0.04 (−0.04 to 0.11) | |
| Length for age | ||||
| No. of infants | 715 | 715 | ||
| Change in z score | −1.9±1.0 | −1.9±0.9 | 0.07 (−0.01 to 0.16) | |
| Head circumference for age | ||||
| No. of infants | 754 | 766 | ||
| Change in z score | −1.4±1.0 | −1.4±1.0 | −0.01 (−0.10 to 0.08) | |
| Postmenstrual age at final tracheal extubation in infants who were intubated | ||||
| No. of infants | 796 | 804 | ||
| Wk | 30.1±3.4 | 30.2±3.3 | −0.11 (−0.43 to 0.21) | |
| Postmenstrual age at final caffeine dose in infants who received caffeine treatment | ||||
| No. of infants | 882 | 887 | ||
| Wk | 33.8±3.0 | 34.0±2.8 | −0.19 (−0.45 to 0.07) | |
| Length of hospital stay†† | ||||
| No. of infants | 908 | 906 | ||
| Median days (IQR) | 96 (72 to 129) | 97 (75 to 127) | −1.25 (−6.96 to 4.48) | |
| Time to full enteral feeding‡‡ | ||||
| No. of infants | 808 | 824 | ||
| Median days (IQR) | 19.5 (14 to 29) | 19.0 (15 to 30) | 0.96 (0.87 to 1.05) | |
| Outcomes at 2 yr — no./total no. (%) | ||||
| Severe cerebral palsy§§¶¶ | 20/710 (2.8) | 11/720 (1.5) | 1.85 (0.90 to 3.82) | |
| Hydrocephalus shunt¶¶ | 20/717 (2.8) | 22/728 (3.0) | 0.92 (0.51 to 1.67) | |
| Microcephaly∥∥ | 61/700 (8.7) | 52/710 (7.3) | 1.17 (0.83 to 1.66) | |
| Seizure disorder*** | 42/714 (5.9) | 41/726 (5.6) | 1.04 (0.68 to 1.57) | |
| Respiratory disease necessitating readmission before follow-up | 248/715 (34.7) | 230/726 (31.7) | 1.09 (0.95 to 1.26) | |
| Developmental delay assessed with BSID-III††† | ||||
| Composite language score <85 | 355/671 (52.9) | 368/691 (53.3) | 1.01 (0.91 to 1.11) | |
| Composite motor score <85 | 255/678 (37.6) | 280/695 (40.3) | 0.96 (0.84 to 1.09) | |
| Composite cognitive score <70 | 88/695 (12.7) | 96/712 (13.5) | 0.96 (0.74 to 1.25) | |
| Composite language score <70 | 164/671 (24.4) | 163/691 (23.6) | 1.06 (0.88 to 1.27) | |
| Composite motor score <70 | 87/678 (12.8) | 99/695 (14.2) | 0.91 (0.70 to 1.18) | |
Plus–minus values are means ±SD. Outcomes to hospital discharge are reported for 908 infants in the higher-threshold group and 906 infants in the lower-threshold group. These numbers were calculated as the number of infants in each group who underwent randomization (911 and 913, respectively), minus the number of infants in each group (3 and 7, respectively) for whom consent for data collection was withdrawn. Outcomes at 2 years are reported for 699 infants in the higher-threshold group and 712 infants in the lower-threshold group (some of the denominators shown are larger than the number of patients who had a complete follow-up assessment because partial data from incomplete assessments were included). Estimates are adjusted for birth-weight and center stratum. IQR denotes interquartile range.
For categorical outcomes, adjusted differences are adjusted relative risks, with the lower-threshold group as the reference. For time to full enteral feeding, differences are adjusted hazard ratios; for the remaining continuous outcomes, they are adjusted mean differences. The 95% confidence intervals are not adjusted for multiplicity and should not be used to infer definitive treatment effects.
Severe complications were defined as bronchopulmonary dysplasia, retinopathy of prematurity of stage 3 or higher or for which treatment was warranted, and an adverse finding on ultrasonographic examination of the head.
Bronchopulmonary dysplasia was diagnosed on the basis of the need for supplemental oxygen after a standardized oxygen reduction test at 36 weeks of postmenstrual age.
Retinopathy of prematurity was recorded for infants who underwent a retinal examination before discharge from the neonatal intensive care unit.
Bell’s stages range from 1 to 3, with higher stages indicating greater severity of disease.
Z scores are derived from Olsen growth curves.17
Length of stay was up to hospital discharge or death, whichever occurred first.
A total of 808 of 907 infants (89.1%) in the higher-threshold group and 824 of 906 infants (90.9%) in the lower-threshold group attained full enteral feeding during the period of observation. The hazard ratio may be interpreted as the odds of attaining full enteral feeding faster at any point in time. Deaths were considered to be a censoring event.
Severe cerebral palsy was defined as Gross Motor Function Classification System (GMFCS) levels IV or V on an ordinal scale on which levels range from I (mild impairment) to V (most severe impairment).
The trial centers with low incidences of this condition were pooled with their nearest geographic center.
Microcephaly was defined as a head circumference-for-age z score of less than −2, according to growth curves developed by the World Health Organization (WHO) (WHO Multicentre Growth Reference Study Group, Geneva; www.who.int/toolkits/child-growth-standards/standards/head-circumference-for-age) in infants in whom age was corrected for prematurity.
A seizure disorder was defined as a report of having one or more seizures since discharge or of regular use of anticonvulsants or seizure medications.
BSID-III composite language and motor scores range from 40 to 160, and BSID-III composite cognitive scores range from 55 to 145, with higher scores indicating better performance.10 Composite BSID-III scores of less than 85 are less than 1 SD below the mean of 100. Composite BSID-III scores of less than 70 are less than 2 SD below the mean of 100.