Introduction: Hypoxic-ischemic encephalopathy (HIE), a consequence of perinatal asphyxia, is a major cause of pediatric mortality and morbidity, often leading to neurological conditions like cerebral palsy, mental retardation, and epilepsy. This study aimed to assess the presence or absence of a lactate peak on MR spectroscopy (MRS) in relation to HIE severity and neurodevelopmental outcomes in asphyxiated neonates. Objectives: To examine the trend of brain lactate peaks in asphyxiated neonates over the first 3 months and its relationship with neurodevelopmental outcomes at 6 months. The study also sought to determine the correlation between HIE severity at birth and brain lactate peaks observed on MRS. Methods: This prospective observational clinical study was conducted at Dr. S. N. Medical College, Jodhpur, India, in the Department of Pediatrics and Radiology, following IEC approval. The study spanned December 2020 to May 2021. A total of 89 full-term neonates with clinical HIE were stabilized and underwent MRI with MRS. Repeat MRI/MRS was performed after 4-6 weeks if a lactate peak was initially present. Neurodevelopmental outcomes were assessed using the Hammersmith Infant Neurological Examination (HINE) score at 6-7 months. Results: Of the 89 neonates, 49 (55.1%) showed a lactate peak on the first MRS. Follow-up MRS at a mean age of 67.41±7.91 days showed persistent lactate peaks in 12 (31.5%) of these neonates. In total, 79 neonates completed neurodevelopmental follow-up; 22 (53.65%) with an initial lactate peak exhibited developmental delays. Conclusion: Lactate detected on neonatal MRS often persists until 2-3 months in asphyxiated neonates, correlating with poor neurodevelopmental outcomes, growth, and head circumference. Routine MRS alongside MRI is recommended for all asphyxiated neonates to assess and monitor lactate levels.
Perinatal asphyxia is defined as the failure to initiate and sustain breathing at birth (Basic newborn resuscitation practical guide from WHO) and usually refers to the condition of impaired gas exchange during the first and second stage of labor that leads to fetal acidosis, hypoxemia and hypercarbia1. Each year 4 million neonates die, representing 38% of all deaths of children under 5 years of age. The primary causes of neonatal mortality include prematurity, bacterial infections and birth asphyxia. Perinatal asphyxia and birth trauma are causes of 8% of the total under 5 mortalities. Twenty-three percentage of neonatal deaths in low-income countries are due to perinatal asphyxia and it contributes to highest percentage of neonatal admissions. Perinatal asphyxia stands first with 45% as the cause of mortality in still births2. Approximately 20–30% of infants with HIE (depending on the severity) die in the neonatal period, and 33–50% of survivors are left with permanent neurodevelopmental abnormalities (cerebral palsy, decreased IQ, learning/cognitive impairment)3.
The National Neonatal Perinatal Database, 2000 defined moderate asphyxia as slow gasping breathing or an Apgar score of 4-6 at 1 minute of age. 2 Severe asphyxia was defined as absent breathing or an Apgar score of 0-3 at 1 minute of age2. According to American Academy of Paediatrics and American College of Obstetrics and Gynaecology the diagnosis requires demonstration of prolonged metabolic or mixed acidemia pH < 7.00 on an umbilical cord arterial sample, persistence of an Apgar score of 0-3 for > 5 mins, clinical neurological manifestations in the immediate neonatal period and evidence of multi organ dysfunction in the immediate neonatal period 4.
Lactate peak is also seen in many other conditions like as mitochondrial disorders, infection, high grade brain tumor etc. So, the reasons for persistence of lactate peak in infants is difficult to differentiate from other causes. In the current study, we tried to find out the maximum age where lactate peak due to perinatal asphyxia can persist.
The current study is therefore conceived to evaluate the trends of brain lactate peak in asphyxiated neonates in first 3 months of life and the association between brain lactate peak and neurological outcome at 6 months of age.
AIMS AND OBJECTIVES
To find out the trend of brain lactate peak in first 3 months in asphyxiated neonates and its relationship with neurodevelopmental outcome at 6 months of age.
The present study is observational clinical research with a prospective design and was conducted in the Department of Pediatrics, Pediatric Neurology Clinic and Department of Radiology Dr. S. N. Medical College, Jodhpur, Rajasthan.
Any Term AGA newborn admitted in Neonatal ICU and in Intermediate ICUs/Neonatal Wards having:
After enrollment informed consent was taken from the caregiver. All epidemiological data including registration number, name of baby, mother’s name, father’s name, detailed address, contact telephone number were recorded on a predesigned proforma. Date and exact time of birth, date and exact time of admission, date and exact time of MRI brain with MR Spectroscopy were recorded on the predesigned proforma.
Detailed antenatal and perinatal history was recorded. The time period between the onset of labour pains and delivery, significant intervention by the obstetrician during this period were also taken into account. Resuscitation of the neonates was done as per NNF guidelines (NRP) and the resuscitation details and were recorded in the proforma to include use of initial steps only, requirement of positive pressure ventilation and/or use of medication. In extramurally born babies the resuscitation details as available from their referral ticket were recorded.
All babies were managed as per National Neonatology forum protocol and any deviation from the protocol was recorded with reasons thereof.
Cord blood from umbilical artery wherever feasible in intramurally born babies or blood from radial artery within 6 hours of birth were collected using a pre heparinized syringe for blood gas analysis.13 Samples were drawn for laboratory investigations that included complete blood count, C Reactive protein, blood sugar, calcium, urea, creatinine, CPK-MB, LDH.
A neurological examination was performed and staged for hypoxic ischemic encephalopathy based on the Sarnat & Sarnat classification1. HIE staging done at time birth in intramurals neonates and at the time of admission in extramural neonates. The changes in the HIE staging in the course were noted at hours of life. The same was repeated at 24 hours interval and maximum HIE stage was recorded with exact age of neonates in hours. At the time of discharge, HIE stage was recorded
MRI brain with MR spectroscopy done in Department of Radiology as soon as possible after stabilization of neonate. MRI brain with Proton MR spectroscopy were be carried out on a 1.5 Tesla Philips MRI scanner. MRI brain with MR spectroscopy was done in Department of Radiology as soon as possible after stabilization of neonate. If lactate peak presented on MRS, then repeat MRI brain with MR spectroscopy was done after 4-6 week of first MRS.
Surviving neonates were reviewed in Follow up at 6 -7 months of age in the Neurology Clinic. At the time of follow-up, the child’s general condition was noted. The neurological assessment and the development of these children was done as per Hammersmith Infant Neurological Examination (HINE) for neurodevelopmental assessment.
STATISTICAL ANALYSIS:
The data was analysed with the help of Microsoft Excel 2016 and statistical analysis was performed with window SPSS version 23. Numerical data were expressed as Mean±SD, median and categorical data were expressed as percentage. Correlation coefficient was used to assess the correlation between variables. To demonstrate this correlation, we used scatter plots with a regression line where R2 is coefficient of determination. The appropriate p value was calculated and difference between the two values was considered to be significant if p value was <0.05 and correlation coefficient was calculated and r value of >0.5 was considered to have significant correlation.
The present study is an observational clinical study with a prospective design and was conducted in the Department of Pediatrics and Pediatric Neurology Clinic and Department of Radiology Dr. S. N. Medical College, Jodhpur, Rajasthan after approval from Institutional Ethics Committee (IEC) from December 2020 to May 2021.
A total of 89 asphyxiated neonates (21 intramural and 68 extramural) were included in the study. Maximum number of asphyxiated neonates (40, 44.94%) were admitted at 0-12 hours of life. Mean age of asphyxiated neonates at the time of admission was 33.91±3.45 weeks and female children presented earlier than male child. There were 53 (59.55%) males while the rest 36 (40.45%) were females with male to female ratio of 1.47:1.
The mean gestational age of neonates in our study was comparable in both groups. Neonates in gestational age group from 36-38 and >38 weeks were 45 (50.56%) and 44(49.44%) respectively. The mean gestational age was in 36-38 and >38 weeks group was 37.64±0.64, 39.43±0.62 respectively. Mean birth weight of asphyxiated neonates in our study was 2856.48±428.21 gms. Asphyxiated Neonates with weight of 2500-3000 gm were significantly higher (47.19%) as compared to other weight group.
Image 1: Gender wise distribution of cases
Among 89 enrolled asphyxiated neonates, 79.78% of neonates had Head circumference ≤ 35cm while 20.22% had HC >35 cm and mean head circumference of the study population was 33.70±1.10 and Median Head Circumference was 34.00 cm.
Table 1: Maternal characteristics of asphyxiated neonates
Maternal characteristics |
Number (%) / Mean±SD |
Age of the mother [in years] |
24.51±3.55 |
Gravidity Status |
|
Number of Primigravida mother |
56 (62.92%) |
Number of second gravida mother |
20 (22.47%) |
Number of third gravida mother |
07 (7.87%) |
Number of multigravida mother |
06 (6.74%) |
Parity |
|
0 |
59 (66.29%) |
1 |
17 (19.10%) |
2 |
07 (7.87%) |
3 or more |
06 (6.74%) |
Booked /Unbooked |
72 (80.89%) |
Pregnancy Induced Hypertension [Y/N] |
12/77 [13.48/86.52] |
Gestational Diabetes Mellitus [Y/N] |
03/86 [3.37/96.36] |
Infections during pregnancy [Y/N] |
00/89 [0/100%] |
Ultrasound Normal [Y/N] |
76/13 [85.39/14.61] |
Table no. 1 describes the maternal characteristics of enrolled newborns. Most asphyxiated neonates were born to Primigravida mother (66.29%). 14.61% of mothers had an abnormal antenatal scan. 12 (13.48%) mothers had pregnancy induced hypertension while 3 (3.37%) had gestational diabetes mellitus.
Table 2: Distribution of asphyxiated neonates with perinatal characteristics duration of Labour, complications during labor and other labour characteristics
PERINATAL HISTORY |
Mean±SD [%] |
Onset of labour pains [in hrs] Mean±SD |
16.39±5.81 |
Obstructed labour [Y/N] |
33/56 [37.08/62.92] |
Failed progress [Y/N] |
05/84 [5.62/94.38] |
Difficult labour [Y/N] |
21/68 [23.60/76.40] |
Mode of delivery [Normal/LSCS] |
70/19 [78.65/21.35] |
Apgar score if available at: 1 min 5 min |
3.11±0.91 4.62±1.00 |
In the current study average time taken between onset of labour pain and delivery was 16.39±5.81 hrs. Majority of asphyxiated babies were born by vaginal delivery (78.65%) as compared to LSCS. APGAR scores and The Sarnat & Sarnat HIE staging at birth were available for all intramural neonates and were not available in most of the extramural neonates because some of them were delivered at home or in facility where it was not documented. The average Apgar score at 1 minute was 3.11±0.91 and at 5 minutes was 4.62±1.00. On admission and during hospitalization HIE stage II asphyxiated neonates were significantly higher.
In the current study, all the asphyxiated neonates received IV fluids. Vasopressors and inotropes used were dopamine, dobutamine, adrenaline and noradrenaline. 11.23% of total asphyxiated neonates needed vasopressor support. Oxygenation, anticonvulsants and antibiotics were required in 89.8%, 82.02% and 83.14% neonates respectively. 20.22% of neonates required mechanical ventilation.
Table 3: - Presence or absence of Lactate peak in asphyxiated neonates at the time of 1st and 2nd MRS (1st MRS correlating with stabilization of the neonate)
Age on admission of asphyxiated neonates (in hours) |
Lactate peak on 1ST MRS |
P value |
Lactate peak on 2nd MRS |
P value |
|
|
|
Present No. (% of asphyxiated neonates) [age of stabilization in days Mean score±SD] |
Absent No. (% of asphyxiated neonates [age of stabilization in days Mean score±SD] |
|
Present No. (% of asphyxiated neonates) [age of neonates at MRS in days Mean score±SD] |
Absent (% of asphyxiated neonates [age of neonates at MRS in days Mean score±SD] |
|
0 - 12 hrs [n=40] |
22 (55.0%) (13.18±7.55) |
18 (45.0%) (9.1±3.98) |
0.0006 |
6 (35.29%) (64.5±7.20) |
11 (64.70%) (85±11.34) |
<0.001 |
12 – 24 hrs [n=9] |
03 (33.33%) (19.66±5.13) |
06 (66.67%) (8.16±2.11) |
0.009 |
1(33.33%) (64) |
2 (66.66%) (86.5±1.5) |
<0.001 |
24 – 48 hrs [n=12] |
07 (58.33%) (11.28±6.08) |
05 (41.67%) (8.60±4.22) |
0.003 |
4(80%) (74±6.59) |
1 (20%) (74) |
1 |
>48 hrs [n=28] |
17 (60.71%) (11.17±5.10) |
11 (39.29%) (8.63±3.02) |
0.001 |
1(7.70%) (62) |
12 (92.3%) (71.58±12.20) |
<0.001 |
Total n=89 N=79 |
49(55.05%) [12.61±6.84]
|
40 (44.94%) [8.90±3.62] |
0.005 |
12 (31.57%) 67.41±7.91 |
26 (68.42%) 79.5±13.00 |
0.005 |
Figure 8: - Presence or absence of Lactate peak in asphyxiated neonates at the time of 1st and 2nd MRS (1st MRS correlating with stabilization of the neonate)
Figure 9: - MR spectroscopy obtained in 2-day-old Asphyxiated neonates with Single voxel and multi voxel MR spectroscopy performed in bilateral basal ganglia and occipital parietal white matter using PRESS technique with TE of 31 ms and 144 ms reveals decreased level of normal metabolites (Choline, creatine and NAA) with elevated lactate peaks.
Figure10: - MR spectroscopy obtained in 15-day-old Asphyxiated neonates with severe HIE with Single voxel and multi voxel MR spectroscopy performed in bilateral basal ganglia and occipital parietal white matter using PRESS technique with TE of 31 ms and 144 ms reveals decrease level of normal metabolites (Choline, creatine and NAA) with elevated lactate peaks.
1st MR spectroscopy was done as soon as possible after cardiopulmonary stabilization in all the 89 asphyxiated neonates. A lactate peak was present in 49 neonates and in 38 of these neonates’ 2nd MRS could be done. Amongst these 38 neonates, 12 had a lactate peak persisting in the 2nd MRS even at a mean age of 67.41±7.91 days. Mean age of asphyxiated neonates at the time of 1st MRS in neonates having lactate was 12.61±6.84 (in days) and in neonates not having lactate was 8.90±3.62 (in days); the difference being statically significant (p value=0.002). [Table no. 3]
A total of 8.16% (n=4) neonates having a lactate peak on 1st MRS expired at a mean age of 20.50±34.65 hours as compared to 2.50% (n=1) neonate not having a lactate peak on 1st MRS (p-value <0.0001). Odd ratio for death in presence of a lactate peak was 3.46, Relative risk for death in presence of a lactate peak was 3.25 and Attributable risk for death in presence of a lactate peak 69% [Table no. 4] Mean Hammersmith global score (HINE) was found to be significantly higher in neonates without lactate peak as compared to the 41 neonates having lactate peak on 1st MRS. [Table no. 4]
Table 4: Comparison between brain Lactate peak on 1st MRS in asphyxiated neonates with outcome and Hammersmith global score
Lactate peak on 1st MRS in asphyxiated neonates |
Outcome |
|
|
|
Expired N= (%) |
Survivors Number of neonates (%) Number of neonates] |
Hammersmith global score at 6-7 months of age Mean±SD |
LACTATE PEAK Present [n=49] |
04 (8.16%) |
45 (91.84%)
|
41 [57.36±12.04] |
LACATE PEAK Absent [n=40] |
01 (2.50%) |
39 (97.50%)
|
38 [71.15±1.68] |
P value |
NA |
<0.0001 |
|
In the current study we did not observe any significant difference in the APGAR scores at 1 minute and 5 minutes in asphyxiated neonates having a lactate peak as compared to those not having a lactate peak on 1st MRS. (p value = 0.226 & 0.307 for 1 min and 5 min respectively)
Table 5: Hammersmith Global score at 6 to 7 months of age in asphyxiated neonates with or without lactate peak on 1st MRS
Age on the admission of asphyxiated neonates (in hours) |
Lactate peak on 1ST MRS |
P value |
|
|
Present No. (% of asphyxiated neonates) No. [Mean ±SD of Global score] |
Absent No. (% of asphyxiated neonates) No. [Mean±SD of global score] |
|
0 - 12 hrs [n=40] |
22 (55.0%) 17 (58.76±13.00) |
18 (45.0%) 17 (70.88±1.57) |
0.0006 |
12 – 24 hrs [n=9] |
03 (33.33%) 3 (55.0±11.79) |
06 (66.67%) 06 (71.33±1.75) |
0.009 |
24 – 48 hrs [n=12] |
07 (58.33%) 06 (50.50±11.39) |
05 (41.67%) 05 (70.40±1.34) |
0.003 |
>48 hrs [n=28] |
17 (60.71%) 15 (59.00±11.34) |
11 (39.29%) 10 (71.90±1.91) |
0.001 |
Total n=89 N=79 |
49(55.05%) 41 [57.36±12.04]
|
40 (44.94%) 38 [71.15±1.68] |
<0.0001 |
Out of 89 asphyxiated neonates, only 79 could complete follow up at 6 to 7 months of age. Hammersmith infant neurological score was calculated in these 79 infants. Mean global score was 41 [57.36±12.04] in infants having lactate peak on 1st MRS and was 38 [71.15±1.68] in infants who did not have a lactate peak on 1st MRS, the difference being statistically significant overall in between both groups and, in all groups, as per their age of admission.
Table 6: - Correlation between Lactate peak on 1st & 2ND MRS with development delayed and global score.
Development delay at 6-7 months of age asphyxiated neonates |
Lactate peak on 1ST MRS |
Lactate peak on 2ND MRS |
|
|
|
Present No. of neonates (%) [Mean±SD of global score] |
Absent No. of neonates (%) [Mean±SD of global score] |
Present No. of neonates (%) [Mean±SD of global score] |
Absent No. of neonates (%) [Mean±SD of global score] |
YES |
22 (53.65%) [48.95±10.39] |
0 |
11 [42.36±4.00] 1 expired |
9 (42.85%) [59.47±7.18] |
NO |
19 (46.34%) [67.10±3.17] |
38(100%) [71.15±1.68] |
0 |
12(57.14%) [67.47±2.99] |
P VALUE |
<0.0001 |
<0.0001 |
|
<0.0001 |
In the current study 22 (53.65%) infants out of 41 asphyxiated neonates having lactate peak on 1st MRS had development delay with mean global score of 48.95±10.39 at 6-7 months of age. 19 (46.34%) infants out of these 41 asphyxiated neonates having a lactate peak did not have a neurodevelopmental abnormality/delay with a mean global scope 67.10±3.17 at 6-7 months of age. 38 out of 40 asphyxiated neonates who not having a lactate peak on 1st MRS had a significantly higher (p-value <0.0001) mean global score of 71.15±1.68 with no development delay at 6-7 months of age as compared to mean global score of 67.10±3.17 in 19 out of 41 asphyxiated neonates who did not have developmental delay but had a lactate peak on 1st MRS brain. 11 (91.66%) out of 12 asphyxiated neonates having lactate peak in 2nd MRS had development delay with mean global score were 42.36±4.00 and 1 neonate was expired. 9 (42.85%) out of 21 asphyxiate neonates having no lactate peak on 2nd MRS had development delay with mean global score were 59.47±7.18 as compared to 12 (57.14%) out of 21 had no development delay with mean global score were 67.47±2.
In our study present or absent lactate peak on 1st MRS with gender-wise distribution, weight of asphyxiated neonates, mode of delivery NORMAL/LSCS, maternal GDM and PIH had no statistical significance but 66.66%, 75% of asphyxiated neonates which had lactate peak on 1st & 2nd MRS respectively, associated with maternal PIH.
Table 7: comparison between MRS I and MRS II with weight, head circumference and HINE score at 6 months of age (follow up) in asphyxiated neonates
Weight, head circumference and hine score at 6- 7-month age of asphyxiated neonates in follow up |
Brain lactate peak on 1ST MRS |
P value |
Brain lactate peak on 2ND MRS |
P value |
|
|
|
Present (n=41) |
Absent (n=38) |
|
Present (n=11) |
Absent (n=26) |
|
Weight |
4.96±0.56 |
5.68±0.33 |
<0.0001 |
4.35±0.42 |
5.24±0.42 |
<0.0001 |
HC |
38.18±1.01 |
39.63±0.93 |
<0.0001 |
37.30±0.80 |
38.49±0.90 |
0.0006 |
Posture |
11.82±2.20 |
14.00±0.69 |
<0.0001 |
9.09±1.30 |
13.11±1.10 |
<0.0001 |
Cranial nerve function |
13.21±2.60 |
16.26±0.60 |
<0.0001 |
10.27±1.27 |
14.57±1.50 |
<0.0001 |
Movements |
4.39±0.97 |
5.44±0.60 |
<0.0001 |
3.36±0.50 |
4.84±0.78 |
<0.0001 |
Tone |
17.02±4.43 |
21.71±0.73 |
<0.0001 |
11.72±2.14 |
19.50±2.68 |
<0.0001 |
Reflexes and Reaction |
10.92±2.73 |
13.73±0.86 |
<0.0001 |
8.00±1.61 |
12.53±1.72 |
<0.0001 |
Global score |
57.36±12.04 |
71.15±1.68 |
<0.0001 |
42.36±4.20 |
64.57±6.41 |
<0.0001 |
It was revealed that infants who had lactate peak had significantly lower mean weight gain, lower head circumference and lower Hammersmith Global scores as compared to those not having lactate peak on 1st MRS. This was also true for neonates having lactate peak on 2nd MRS compared to not having lactate peak on 2nd MRS (performed in those who had lactate peak on 1st MRS) (p value <0.0001).
Hypoxic ischemic encephalopathy (HIE), secondary to perinatal asphyxia, is a primary cause of pediatric mortality and morbidity and results in neurologic outcomes, such as cerebral palsy mental retardation and epilepsy. Timely prognostic information is important in counseling parents and in determining the appropriate level of treatment.
In the current study, there was no significant difference in the APGAR scores at 1 minute and 5 minutes in asphyxiated neonates having a lactate peak as compared to those not having a lactate peak on 1st MRS. In a study by Amritanshu K it was reported that APGAR score does not exactly predict the neurodevelopmental outcome, but is still the most feasible and practical to perform parameter 46. In a study conducted by M H haidary the incidence of moderate and severe perinatal asphyxia was 21% and 60%,5 respectively which was similar to the incidence of moderate and severe asphyxia in intramural asphyxiated neonates in our study.
Sarnat & Sarnat HIE staging1 at birth could be obtained in all intramural neonates. In extramural neonates at the time of admission and during hospitalization HIE stage II was significantly higher as compared to HIE stage I and III. In our study, 6.74% (6) neonates had HIE stage I, 66.29% (59) neonates had HIE stage II and 26.97% (24) neonates had HIE stage III as the severest HIE staging during hospitalization. In a study done by Memon S neurological evaluation of asphyxiated neonates was done within 24 hour of admission and it was seen that clinical sign of HIE were present in 85% of cases. At this time 30% neonates were in stage I, 35% in stage II and 20% in stage III of HIE 6. In another study it was observed that during hospitalization maximum neonates had signs of HIE stage II (54%), 31% had HIE stage I and 14% had HIE stage III 7. Bhawana Tiwari in their study observed that at birth 20% neonates were in HIE stage I, 30% were in stage II and 16.6% were in stage III 8. The proportion of severest HIE staging was different from the observations of other researchers and may be because HIE staging is a dynamic process and the staging may differ at different time of examination. Also in the current study majority of the asphyxiated neonates were born extramurally and referred from a primary/peripheral health centre and was referred when the baby was very critical.
In our study, on 2nd MRS, amongst 38 neonates, 31.5% (12) had a lactate peak persisting even at a mean age of 67.41±7.91 days. Mean age of asphyxiated neonates at the time of 1st MRS in neonates having lactate was 12.61±6.84 (in days) and in neonates not having lactate was 8.90±3.62 (in days); the difference being statically significant (p value=.0.002). In a study done by A.J. Barkovich SP and Miller et al in 2006 at San Francisco, it was seen that several asphyxiated neonates had abnormal metabolite ratios on MR Spectroscopy 9. Thomas Alderliesten, MD Linda S in 2011 in their study observed that combination of MR imaging score with ADCs or Lac/ NAA ratios in the basal ganglia has a better association with neurodevelopmental outcome at 18 to 46 months of age of asphyxiated term neonates than does MR imaging alone. Poor outcome was associated with (a) lower ADCs in the basal ganglia (P < .001) and thalamus (P = .001) of neonates examined within 7 days of birth and (b) a higher lactate (Lac)-N-acetylaspartate (NAA) ratio in the basal ganglia (P < .001) 10. In the current study choline lactate peak ratio on 1st MRS were calculated in all asphyxiated neonates and did not observed >1 in any study neonates. It might be possible due to lactate level on MRS high at the time of asphyxia insult (observed in previous study), and in our study 1st MRS was done only after cardiovascular stabilization (lactate peak on MRS may be reduced after stabilization).
In the current study, the mean age of asphyxiated neonates at the time of the first MRS in those with a lactate peak was 12.61±6.84 days, which was significantly higher than 8.90±3.62 days in neonates without a lactate peak (p-value = 0.002). Since the first MRS was performed immediately after the neonates were stabilized, this suggests that asphyxiated neonates with a lactate peak required more time to achieve hemodynamic and neurologic stabilization compared to those without a lactate peak. The mean age of asphyxiated neonates at the time of the second MRS in infants with a lactate peak was 67.41±7.91 days, compared to 79.5±13.00 days in those without a lactate peak on the second MRS. This variation may be due to the flexible timing of the second MRI, which was planned for between 2-3 months of age and dependent on infant follow-up. The precise age of complete lactate peak disappearance could not be determined due to ethical and logistical limitations on repeat MRS. In 26 (68.42%) of asphyxiated neonates who initially had a lactate peak on the first MRS, no lactate peak was observed on the second MRS, suggesting that in the majority of infants, it resolves over time, usually by three months of age. No similar studies were found upon an extensive literature review, highlighting the need for future well-designed studies to determine the timing of lactate disappearance in asphyxiated neonates.
Figure 11: Short term outcome (expired/discharged) and Hammersmith Global score at 6 to 7 months of age in asphyxiated neonates with or without lactate peak on 1st MRS
In the current study out of 89 asphyxiated neonates, 55.1% (49) neonates were having a lactate peak on 1st MR spectroscopy. Out of these 45 neonates, 8.25% (4) expired and 91.75% (41) survived. These 41 survived neonates who had a lactate peak on 1st MRS had a mean Hammersmith global score (HINE) of 57.36±12.04 at 6-7 months of age. 40 asphyxiated neonates had no lactate peak on 1st MR spectroscopy and out of these 2.5% (1) neonates expired and 97.5% (39) survived neonates had a mean Hammersmith global score (HINE) of 71.15±1.68 which was significantly higher as compared to the 41 neonates having lactate peak on 1st MRS. 80% (4 out of 5) expired asphyxiated neonates had lactate peak on 1st MRS as compared to 20% (1 out of 5) who did not have a lactate peak. It is therefore very clear that expired neonates have a higher chance of having presence of lactate on MRS.
In a pioneer study conducted in 1998 by Hanrahan I D and Cox I J etal at Hammersmith Hospital, United Kingdom using 1H proton magnetic resonance spectroscopy (1H MRS) was used to test the hypothesis that lactate can be detected later than 1 mo after birth in the brains of infants who display severe neurodevelopmental impairment 1 yr after transient perinatal hypoxia-ischemia 11. Although the sample size was small, the study concluded that lactate is detected later than the 1st month after birth in 87.5% infants having abnormal neurodevelopmental outcome [maximum detected lactate/Cr was median (range) 0.44 (0.24-0.67)]. In this study lactate was not detected later than the 1st month after birth in infants with normal neurodevelopmental outcome, nor in 83% control subjects, although a small amount of lactate was detected in one control infant (lactate/Cr = 0.04) 11. This study looked at persistence of lactate peak until 1 month of post-natal age, but the results suggested that the pathologic postasphyxial process, indicated by persistent cerebral lactate, may not be confined to the period immediately after injury.
In a preliminary study lactate was detected by 1H MRS in the brains of two severely affected infants some weeks after birth asphyxia, and others have reported the detection of lactate in the brain of one infant 3 months after a focal cerebral lesion. The present study thus tested the hypothesis that lactate can be detected later than 1 month after birth in the brains of infants who display severe neurodevelopmental impairment 1 year after transient perinatal hypoxia-ischemia.
The findings of the current study become important in the context of the observations made by Hanrahan I D and Cox I J et al as early as 1998 because in the current study there is a larger sample size of 89 asphyxiated neonates as compared to 18 asphyxiated neonates in the Hanrahan study. Also, the first MRS was done within 2 weeks mean age of 10.94±5.89 (days) and a second MRS was performed between 2-3 months (mean 75±5.89 days) of age.
In another study performed in Boston, USA by Maria K Zarifi and their group in 2002 a higher lactate-choline ratios (L/C ratio in MRS of 1) measured between 1-10 days in basal ganglia and thalami of 26 asphyxiated neonates were predictive of worse clinical outcomes. They also looked at absolute ADC in the same brain regions but did not find any statistically significant relationship with clinical outcome. They concluded that cerebral lactate level is useful in identifying infants who would benefit from early therapeutic intervention 12. However, in this study the relationship between presence of higher lactate/choline ratio, therapeutic intervention and outcome was not studied in detail. In the current study the sample size was almost 2.5 times than the Boston study. However, first MRS could be performed only at a mean age of 10.94±5.89 (days) which was the age when the neonate was hemodynamically stable and MRI could be performed without any logistic difficulties. This was in contrast to the Boston study where MRS was performed within first 10 days. In the current study a standard treatment protocol was used in all asphyxiated neonates. Because of ethical reasons, it is not possible to find out effect of various therapeutic regimens on presence and/or persistence of lactate peak in asphyxiated neonates. However, it is possible that Therapeutic hypothermia may definitely have an impact on presence and/or persistence of lactate in brain and thereby influence outcome. Based on the observation of Boston study regarding the correlation between Apparent diffusion coefficient (ADC) and neurologic outcome, we did not look at ADC in the current study. A similar study was not found in the extensive review of world literature to compare the brain lactate peak on MRS with adverse outcome of asphyxiated neonates.
In the current study, on comparing the percentage of asphyxiated neonates having presence or absence of lactate peak on 1st MRS in different HIE stages did not reveal any significant difference indicating that presence or absence of a lactate peak is equally distributed in different HIE stages and may not be determined by the severity of HIE. In all the asphyxiated babies having HIE stage I at admission and having presence of lactate peak on 1st MRS, no lactate peak was seen on 2nd MRS. However, in babies with HIE stage II and III at admission and having a lactate peak on 1st MRS, lactate peak continued to persist in 28.57% of HIE stage II babies and 9 % of HIE stage III babies. It is clear from the observations of the current study that asphyxiated neonates with HIE stage II and III had more severe asphyxial insult and encephalopathy with persistence of lactate for a longer duration (67.41±7.91 in days). In the study by Hanrahan et al and the Boston study, relationship between HIE severity and presence or absence of lactate peak was not seen 21. However, in another study by Tai-Wei Wu conducted in Los Angeles, CA, United States on 52 asphyxiated neonates, it was observed that serum lactate concentration decreased over time. Cerebral lactate concentration remained low for less severe injury and slowly decreased over time for more severe injury. In this study it was observed that cerebral lactate remained detectable even after therapeutic hypothermia (TH) 13.
Table 8: MANCOVA – Lactate peak with others variable
Multivariate Tests |
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value |
F |
df1 |
df2 |
p |
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Lactate Peak |
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Pillai's Trace |
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0.582 |
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19.0 |
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6 |
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82 |
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< .001 |
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Wilks' Lambda |
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0.418 |
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19.0 |
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6 |
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82 |
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< .001 |
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Univariate Tests |
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Dependent Variable |
Sum of Squares |
df |
Mean Square |
F |
p |
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Lactate Peak |
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sex |
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0.7933 |
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1 |
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0.79330 |
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3.3431 |
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0.071 |
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GDM |
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0.1239 |
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1 |
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0.12388 |
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3.8837 |
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0.052 |
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PIH |
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0.1716 |
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1 |
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0.17157 |
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1.5764 |
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0.213 |
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Mode of delivery |
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0.0132 |
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1 |
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0.01321 |
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0.0770 |
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0.782 |
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pH |
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0.0337 |
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1 |
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0.03365 |
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5.4420 |
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0.022 |
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Base deficit |
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478.4721 |
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1 |
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478.47208 |
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104.9925 |
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< .001 |
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Residuals |
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sex |
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20.6449 |
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87 |
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0.23730 |
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GDM |
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2.7750 |
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87 |
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0.03190 |
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PIH |
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9.4689 |
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87 |
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0.10884 |
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Mode Of Delivery |
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14.9306 |
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87 |
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0.17162 |
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pH |
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0.5380 |
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87 |
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0.00618 |
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Base Deficit |
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396.4767 |
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87 |
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4.55720 |
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Lactate Peak Present =1, Absent = 0
In the current study there was no statistically significant relationship between presence or absence of lactate peak on 1st MRS and gender, weight, mode of delivery, maternal GDM and PIH. However, it was interesting to note that 66.66% of neonates born to mothers with PIH had lactate peak on 1st MRS. We recommend more studies to be performed to investigate the impact of PIH and other causes of uteroplacental insufficiency on presence or absence of lactate peak in both asphyxiated and non-asphyxiated babies.
In the current study, 79 Out of 89 enrolled asphyxiated neonates were followed up at 6 to 7 months of age for their neurodevelopmental outcome using Hammersmith infant neurological score (HINE). The mean global score was 57.36±12.04 and 71.15±1.68 respectively in asphyxiated neonates with or without lactate peak on 1st MRS. L Haataja, E Mercuri et al in 2001 studied a cohort of 53 term HIE neonates and observed that HINE scores were always optimal in the infants with normal or minor neonatal magnetic resonance imaging findings (abnormal signal intensities) in basal ganglia and white matter lesions. The lowest scores were associated with severe basal ganglia and white matter lesions. All the infants who had a global score between 67 and 78 at 1 year were able to walk independently at 2 years and without restrictions at 4 years. Scores between 40 and 67 were associated with restricted mobility and scores <40 with severely limited self-mobility at 2 and 4 years 14.
Even on extensive review of literature we did not find a similar study where brain lactate peak on MRS was correlated with Hammersmith infant neurological score in asphyxiated neonates. However, in the current study it was very clear that presence of brain lactate peak on MRS during neonatal period was associated with a lower global score at 6-7 months of age as compared to babies who did not have a brain lactate peak on MRS during neonatal period. Infants who continued to have persistence of a lactate peak on 2nd MRS between 2 to 3 months of age continued to have a lower global score at 6-7 months as compared to infants who did not have persistence of lactate peak in 2nd MRS performed between 2-3 months of age. This indicates that presence of lactate peak in neonatal period and its persistence during infancy has a poor neurodevelopmental outcome.
Figure12: Lactate peak on 1st MRS and neurodevelopmental status at 6-7 months of age
Figure13: Lactate peak on MRS and neurodevelopmental status at 6-7 months of age
In the current study, 79 out of 89 enrolled asphyxiated neonates were followed up at 6 to 7 months of age for their neurodevelopmental outcome using Hammersmith infant neurological score (HINE). In asphyxiated neonates who did not have a lactate peak on 1st MRS, no neurodevelopmental abnormalities were seen with a mean global score of 71.15±1.68 (p-value <0.0001). This indicates that neurodevelopmental scores at 6 to 7 months of age are better in asphyxiated babies who do not have a lactate peak on MR spectroscopy in the neonatal period. 2nd MR spectroscopy was performed in all infants who had a lactate peak on 1st MRS after 1 month of 1st MRS and within 3 months of age. 2nd MRS could be done in 77.5% (38) out of 49 asphyxiated infants who had lactate peak on 1st MRS and out of these 31.57% (12) neonates had persistence of lactate peak while 68.42% (26) did not have lactate peak on 2nd MRS. 91.66% (11/12) asphyxiated neonates who had persistence of lactate peak on 2nd MRS had developmental delay with mean global score of 42.36±4.00 and 8.44% (1/12) of these neonates expire. 31.03% (9/26) asphyxiated neonates who did not have lactate peak on 2nd MRS had development delay with mean global score of 59.47±7.18 and 46.15% (12) had no development delay with mean global score of 67.47±2. None of these babies expired.
In the study performed by Hanrahan et al at Hammersmith Hospital, United Kingdom, cerebral lactate was examined by 1H MRS and it was observed that lactate in the basal ganglia persisted beyond 1 month after birth and these babies had a poor neurodevelopmental outcome, while lactate did not persist/detected in infants with normal development or in normal controls 11. We observed a similar pattern in the current study and could demonstrate persistence of lactate peak until mean age of 67.41±7.91 days in 31.75% infants who had lactate peak during the neonatal period and 91.66% of these infants had neurodevelopmental abnormalities.
In a meta-analysis done in 2020 by Zhang S in China and Sweden 8 randomized controlled trials and 2 observational studies in asphyxiated neonates were analysed. According to a random effects model, the pooled rate of cerebral palsy in the randomized controlled trials was 20.3% (95% CI: 16.0–24.5) and the incidence of cerebral palsy in the observational studies was 22.2% (95% CI: 8.5–35.8) 15. In another study done by Nazeer S in a cohort of 50 asphyxiated neonates it was reported that 14% had abnormal neurological outcome (assessed by CDC grading of motor milestones, Trivandrum development screening chart, Amiel Tison angles, head circumference and weight measured) 16. However, it is clear from the current study that there is 4 times increase in neurodevelopmental abnormalities with approximately 92% of asphyxiated neonates having an abnormal outcome if there is persistence of lactate peak on MRS between 2-3 months of age.
It is also very clear from the current study that presence of lactate peak had poor outcome and failure to thrive. It means brain lactate peak (Mean age at the time of 1st MRS 10.94±5.84 days) clearly associated with asphyxia brain insult. Tai-Wei Wu in their study in 48 cohort of HIE observed the Cerebral lactate concentrations were also higher in accordance to the radiographic scoring of injury, which was determined by a paediatric neuroradiologist blinded to both MRS findings and clinical characteristics. Cerebral lactate concentrations were significantly higher in the Basal Ganglia and Thalamus regions of infants with moderate–severe injury compared to normal–mild injury 13.
Asphyxiated neonates were following up at 6-7 months of age in the current study and it was revealed that mean head circumference was 38.18±1.01 cm who had lactate peak on 1st MRS as compared to 39.63±0.93 cm who did not have lactate peak on 1st MRS (p-value <0.0001). A study was done in 2019 by S Preeti, A Kadam et al in Pune, Maharastra observed that all anthropometric parameters were significantly lower with the presence of death or disability in 76 asphyxiated neonates followed up at 1 year of age 17. In another study done by S Adhikari it was observed that infants with Perinatal HIE have developmental delay in all sectors of milestone 18.
Hypoxic ischemic injury during perinatal period is significant cause of morbidity and mortality during neonatal period and survivors are left with neurodevelopmental sequele. At present there are no markers which can predict their neurodevelopmental abnormalities at later age. The current study clearly establishes that lactate detected on MR spectroscopy persists until at least 2-3 months of age in a significant proportion of asphyxiated neonates. Presence of lactate peak on MR spectroscopy during neonatal period and its persistence beyond 3 months of age correlates with a poor neurodevelopmental outcome and also poor weight gain & head growth during infancy. From the conclusions of the current study, it is recommended that lactate peak demonstrated on MRS in asphyxiated neonates can be a useful tool to predict neurodevelopmental sequelae in asphyxiated neonates. Therefore, we recommend MRS to be performed routinely with MRI in all asphyxiated neonates and to perform an intensive neurodevelopmental follow up in any asphyxiated infant where lactate peak is demonstrated in MRS.
Lactate detected on neonatal MRS often persists until 2-3 months in asphyxiated neonates, correlating with poor neurodevelopmental outcomes, growth, and head circumference. Routine MRS alongside MRI is recommended for all asphyxiated neonates to assess and monitor lactate levels.
Limitation and future recommendations:
Our study included 89 asphyxiated neonates as a study cohort. The sample size was appropriate as per study design as it was a single centre study. In the current study, brain lactate on MRS was performed only after cardiovascular stabilization and therefore we were unable to perform MRS immediately at the time of acute injury and when the baby had severest form of HIE. Similarly, because of logistic and technical reasons ABG could not be performed at the time of birth or in cord blood which correlates more appropriately with severity of asphyxiated insult. In the current study, we could not find out the maximum age up to which lactate peak on MRS persists in asphyxiated neonates. Also, it will be very interesting to find out whether presence/persistence of lactate peak beyond 3 months of age correlated with abnormal outcome even during later childhood. There is a need for multicentric studies performed with a larger multi-ethnic and genetically diverse population to increase the validity and applicability of these data and observations.