1. (mean±SD, n (%) or n/N (%)) (n (%), mean±SD or median [IQR])
Prospective Research in Infants with Mild Encephalopathy – the PRIME study .
J Garfinkle1, C Prempunpong2, L Chalak3, N Rollins3, S Thayyil4, P Sanchez5, A Pappas6, KA Nguyen1, B Shah7, V Kalra6, I Mir3, R. Boyle1,
S Shankaran6, A Laptook7, G Sant'Anna1
1McGill University, Montreal, Canada; 2Mahidol University, Bangkok, Thailand ; 3UT Southwestern Medical Center, Dallas, TX; 4Imperial College London, London, United Kingdom;
5Nationwide Children's - Ohio State University, Columbus, OH; 6Wayne State University, Detroit, MI; 7Women’s and Infant’s Hospital, Providence, RI, United States.
No disclosures
Background
Results
Hypothermia for neonatal Hypoxic-Ischemic Encephalopathy (HIE) accompanied by severe acidosis/birth resuscitation is standard of care for term neonates with moderate or severe encephalopathy manifesting at <6 hours of age.
Term infants with severe acidosis/birth resuscitation with mild HIE currently do not undergo hypothermia; however, retrospective studies report that infants with mild HIE have abnormal short term outcomes1.
Outcomes of these infants need further investigation.
Between Dec 2012-Oct 2015 a total of 63 infants were enrolled.
Complete primary outcome data was obtained in 54 infants.
Table 4: Primary and other outcomes
Figure 1: Abnormal modified Sarnat exam and its components
Outcomes
Results
(n=54)
Primary outcome
Any of abnormal aEEG, MRI or neurologic exam
21 (39)
Components of the primary outcome
Abnormal aEEG
2 (4)
Abnormal brain MRI
4 (7)
Abnormal neurological exam
11 (20)
Abnormal aEEG and MRI
Abnormal aEEG and neurologic exam
1 (2)
Abnormal MRI and neurologic exam
Abnormal aEEG, MRI and neurologic exam
Other outcomes
Death
Seizure (at 36 hours of life)
Gavage feed at discharge
Length of stay (days)
5 [3.3,9]
Table 1: Maternal and perinatal characteristics
Table 2: Neonatal characteristics
Characteristics
(mean±SD, n (%) or n/N (%))
Results
(n=54)
Maternal
Age (years)
31 ± 6
Primigravida
27 (50)
Ethnicity: white
18 (33)
Education: college
29/53 (55)
Gestational hypertension
2 (4)
Preeclampsia
Diabetes mellitus
3 (6)
Gestational diabetes mellitus
6 (11)
Perinatal
Fever
5 (9)
GBS positive
11 (20)
GBS unknown
17 (31)
Prolonged rupture of membrane
10 (19)
Chorioamnionitis
7 (13)
Maternal antibiotics
20 (37)
Antepartum hemorrhage
Abnormal fetal heart rate pattern
41 (76)
Meconium stained amniotic fluid
Cord accidents
Nuchal cord
Maternal hemodynamic instability
1 (2)
Shoulder dystocia
Cesarean section
26 (48)
Vaginal delivery with forceps or vacuum
Vaginal delivery without forceps or vacuum
17 (32)
Characteristics
(n (%), mean±SD or median [IQR])
Results
(n=54)
Apgar score:
1 minute
2 [1,3]
5 minutes
5 [3,6]
10 minutes
7 [5,8]
Neonatal resuscitation within the first 10 minutes of life 
Positive pressure ventilation
48 (89)
Intubation
24 (44)
Chest compression
8 (15)
Epinephrine administration
1 (2)
Assisted ventilation at 10 minutes
36 (67)
Cord or postnatal blood gas (first hour of life) pH
6.99 ± 0.14 (50)
pCO2
75.4 ± 24.8 (46)
HCO3
18.3 ± 4.9 (43)
Base deficit
14.6 ± 4.9 (49)
Gestational age (week)
39.4 ± 1.4
Birth weight (gram)
3,262 ± 597
Head circumference (cm)
34.2 ± 1.8 (53)
Male
34 (63)
Inborn
22 (41)
Objectives
Primary : to determine whether infants with mild HIE at < 6 hours of age have abnormalities on any of the following: amplitude integrated EEG (aEEG) at < 9hrs of age, MRI at < 30 days of life or neurological examination at discharge.
Secondary : (1) to evaluate abnormalities in all 3 outcomes and (2) 18 month neurodevelopmental outcome.
Methods
Prospective study performed at 6 NICUs offering therapeutic hypothermia, per current standard of care for infants with moderate or severe HIE.
Inclusion criteria: gestational age ≥ 36 weeks, birth weight ≥1,800g; acidemia and/or resuscitation at birth; and abnormal neurologic exam (modified Sarnat) with ≤ 2 categories at stages 2 or 3 (level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic system)2.
Exclusion criteria: > 6hrs of age, completely normal neurological exam, and treatment with hypothermia.
Outcome measures were:
aEEG: suppressed background pattern (discontinuous, burst suppression, or flat) or seizures at < 9h of age3
MRI < 30 days of life with NICHD-NRN score4 > 0: 1a and b = minimal or more extensive cerebral lesions only; 2a = basal ganglia and thalami/internal capsule/infarction; 2b = 2a + cerebral injury; and 3 = hemispheric devastation
Abnormal neurological exam at discharge: abnormality on the modified Sarnat, clonus, fisted hand, persistent ATNR, or abnormal movements2.
aEEG and MRI analyses were performed by central readers blinded to the clinical data, and neurological examination performed by certified examiners.
Sample size: 50 infants was necessary to obtain a precision of 10% (10-30%) based on an expected rate of 20% of brain injury and using a CI of 95%.
Table 3: aEEG and MRI findings
Conclusions
Findings
(n (%) or median [IQR])
Results
(n=54)
aEEG
Background pattern*
Continuous
50 (92.6)
Discontinuous
4 (7.4)
Age when aEEG was done (hr of life)
5.5 [4.8, 6.4]
MRI pattern of injury (NICHD scoring)**
47 (87)
1a (minimal cerebral lesions)
2 (3.7)
1b (more extensive cerebral lesions)
2a (BGT/IC/infarction)
1 (1.9)
Age when MRI was done (day)
13 [7, 23]
39% of infants with mild HIE had either an abnormal aEEG at < 9h of age, MRI, or neurological exam at discharge.
Neurological abnormalities at discharge, especially abnormal tone and primitive reflexes, were the most frequent abnormal findings (Figure 1).
Abnormal MRI was found in 13% of infants and all but one were of lower severity categories.
Only one infant (2%) had abnormal aEEG, MRI and neuro exam at discharge.
Among infants with mild encephalopathy at ≤ 6hrs of age, the neurologic examination improves over time.
The months outcome is ongoing.
References:
DuPont TL, Chalak LF, Morriss MC, et al. J Pediatr 2013;162:35-41.
Shankaran S, Laptook AR, Ehrenkranz RA, et al. N Eng J Med 2005;353:
Hellstrom-Westas L. Clin Perinatol 2006;33:
Shankaran S, Barnes PD, Hintz SR, et al. Arch Dis Child Fetal Neonatal Ed 2012;97:F
*No aEEG with burst suppression, low voltage, flat tracing or seizures was observed.
**No MRI stage 2b or 3 was reported.