NRBC Concentrations Over Time in Neonates with Moderate to Severe NE with and without Sentinel Events

doi:10.21203/rs.3.rs-3238335/v1

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NRBC Concentrations Over Time in Neonates with Moderate to Severe NE with and without Sentinel Events

https://doi.org/10.21203/rs.3.rs-3238335/v1

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published 29 Jan, 2024

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Objective: To study the serum concentrations of NRBC over time in neonates with moderate to severe NE.

Study Design: A retrospective cohort study with subjects subdivided into three groups based on definite sentinel events (n=52), probable sentinel events (n=20) and no history of sentinel events (n=63). Peak absolute NRBC concentration and NRBC/100 WBC were compared between groups and compared with MRI Injury score, cord and admission pH/base deficit.

Results: Absolute NRBC concentration peaked at 24.05 hours after birth (CI: 15.30- 32.79), 17.56 hours after birth (CI: 7.35-27.77), and 39.81 hours after birth (CI: 28.73-50.89) in each respective group. The peak in absolute NRBC correlated with the severity of injury in the grey matter in group 2 and white matter in groups 1 and 2. Higher peak absolute NRBC value correlated to a lower admission ABG pH (p<0.05).

Conclusion: NRBC peak at 24 hours after birth in neonates with sentinel events.

Health sciences/Biomarkers

Health sciences/Diseases/Neurological disorders

Neonatal encephalopathy

Nucleated red blood cells

Nucleated red blood cells (NRBC) are red blood cells in the circulation that contain a nucleus. They are produced in the fetal bone marrow in response to erythropoietin and are stored in the bone marrow as precursors to reticulocytes and mature erythrocytes (1). NRBC are also referred to as erythroblasts, normoblasts or normocytes in the bone marrow (1). Although NRBC are rarely found circulating in older children, they are commonly found in the blood of newborns (1, 2). Lipman, in 1924, reported NRBC in the blood of 41 of 42 newborns in the first day of life and NRBC are found in low concentrations in healthy newborns during the first days of life, usually at concentrations less than 10 NRBC/100 White Blood Cells (1, 3–7). Conditions with states of relative hypoxia that may increase the numbers of circulating NRBC at birth in term neonates include intrauterine growth restriction, maternal diabetes and preeclampsia (8). NRBC have been shown to be elevated in neonates with fetal acidemia and neonatal encephalopathy (NE) in multiple studies (4, 5, 7). NRBC have been found to be higher in the circulation of neonates with moderate to severe NE compared with mild NE and are increased in neonates with NE who have poor neurodevelopmental outcomes at 24 months of age (4). The rise in NRBC following hypoxia-ischemia is thought to be mediated by erythropoietin (9–11). Recently it has been proposed that it takes 28–29 hours to observe an increase in NRBC in response to a hypoxic event (12).

Only a small fraction of neonates with NE (15–29%) have a documented sentinel event such as a placental abruption, uterine rupture, cord prolapse, or shoulder dystocia (13, 14). Therefore, in most neonates, the exact timing of the hypoxic-ischemic injury is unknown. This may confound interpretation of the NRBC count at birth since the hypoxic-ischemic event may have occurred prior to birth.

The purpose of this study was to understand the time interval from an acute hypoxic-ischemic event to the peak concentration of NRBC in neonates with moderate to severe NE who underwent hypothermia treatment. Neonates who had undergone hypothermia were divided into three groups using a retrospective chart review. Group 1 consisted of neonates with a definite sentinel event like cord prolapse, uterine rupture, abruptio placenta, placenta previa, maternal hypotension following trauma or epidural analgesia and shoulder dystocia. Group 2 was composed of neonates who had a probable sentinel event like prolonged deceleration without clear etiology, cord compression, or a true cord knot. Finally, group 3 was composed of neonates with no history of a sentinel event and therefore the timing of the hypoxic-ischemic event was unknown. We hypothesized that NRBC would reach a maximum concentration at 28–29 hours after a well-defined perinatal sentinel event in neonates who underwent therapeutic hypothermia for moderate-severe NE. A series of secondary questions were also examined. NRBC trends over time were assessed to understand if they differ in NE neonates among those who have well- defined sentinel events versus those who do not have sentinel events. The association between peak NRBC and severity of MRI brain injury was assessed.

A. Patient Population

1. Neonates with moderate to severe NE

This was a single center, retrospective, observational cohort study approved by the University of Florida Institutional Review Board (IRB) prior to the collection of any data. Following IRB approval, an integrated data repository (IDR) of all neonates who underwent therapeutic hypothermia at UF Health, level IV NICU between 1/2012 and 1/2020 was created. All clinical data in the electronic health record were extracted and used for this work.

Entry criteria for hypothermia included a gestational age of 35 weeks or greater, a birth weight of 1.8 kg or greater, and less than or equal to 6 h of age. Enrolled neonates had evidence of encephalopathy as defined by seizures or abnormalities on a modified Sarnat exam (level of consciousness, spontaneous activity, posture, tone, primitive reflexes including suck and Moro, and autonomic system findings including pupils, heart rate, and respirations) (6). Evidence of hypoxic–ischemic injury was defined by 1) a pH of 7.0 or less and/or a base deficit of greater than 16, or 2) a pH between 7.01 and 7.15 and/or a base deficit between 10 and 15.9, or 3) no blood gas available and neonate had an acute perinatal event (cord prolapsed, heart rate decelerations, uterine rupture) (6).

B. Determination of timing of Hypoxic-Ischemic Event

Maternal and neonatal dyad chart review was done to segregate neonates into 3 groups. The definition for each of the 3 groups were as follows:

Group 1: Neonates with history of definite sentinel events like cord prolapse, uterine rupture, abruptio placenta, placenta previa, maternal hypotension following trauma or epidural analgesia and shoulder dystocia. History of these events during peripartum period would indicate that hypoxic-ischemic injury occurred at time of birth.

Group 2: Neonates with history of probable sentinel events like prolonged deceleration without clear etiology, cord compression and true knot indicating that hypoxic-ischemic injury to neonate occurred within few hours of time of birth.

Group 3: Neonates with no known history of sentinel events who suffered hypoxia-ischemia and underwent hypothermia treatment. Hence, these neonates could have chronic or acute on chronic hypoxia-ischemia.

Two physicians were involved in the chart review to classify neonates into each of the above 3 groups. When prenatal monitoring strips were available, the strips were analyzed by a Board Certified Obstetrician to confirm the timing of injury. Fetal monitoring strips were available only for inborn neonates (n = 13). Time of onset of abnormal fetal heart rate tracing was used as time of hypoxic-ischemic insult.

C. Nucleated Red Blood Cells

Neonates admitted for moderate-severe NE undergo serial labs for monitoring during therapeutic hypothermia process. Complete blood cell count (CBC) with differential is monitored every 12 hours during hypothermia treatment up to 24 hours after rewarming in our center’s hypothermia management protocol. NRBC are one of the components of this test. The CBC provides White Blood Cell (WBC) count per mm³ of blood and manual differential provides percentage of NRBC or NRBC/100WBC using wright stain of blood smear. For calculation of absolute NRBC, first a corrected WBC count was obtained, followed by absolute NRBC count using the following formula (15):

Absolute NRBC count (/mm3) = corrected WBC count* NRBC%(NRBC/100WBC)/100

NRBC per 100 WBCs and absolute NRBC counts were obtained from the time of admission, then every 12 hours up to 120 hours of life and trends were compared among the 3 groups as described above.

D. MRI scoring

MRI were performed at either 3–5 days of age following rewarming (n = 97) or 7–12 days of age (n = 32, not clinically stable for imaging at 3–5 days of age). Six neonates had MRIs at greater than 12 days of life (range 14–41 days) due to comorbidities and clinical instability. Neonates were imaged on a Siemens Magnetom Verio 3T scanner (n = 82) or 1.5 T Siemens Avanto (n = 50) (Siemens, Malvern, PA) at UF Health Gainesville. Analysis focused on the T1-weighted, T2-weighted, and diffusion-weighted imaging (DWI) abnormalities. A single blinded subspecialty board-certified neuroradiologist with over 10 years of experience in neonatal imaging interpreted all the MRI images using the Weeke scoring system (16). The Weeke scoring system scores injury in different brain regions using a scale with increasing values representing worsening injury. Individual brain regions scored included the total grey matter injury, total white matter injury, total cerebellar injury, and a total brain injury score. Each individual score was compared to both the absolute and corrected NRBC in each of the three groups to examine for correlations to the extent of injury to each of the scored brain regions.

E. Statistical analysis:

For each subject, peak NRBC values (absolute and normalized) were obtained, as well as the corresponding hours of life (i.e., hours of life of peak absolute NRBC and peak normalized NRBC values). A major hypothesis of whether the hours of life for each peak was within the 28–29 hours following birth was investigated using normal-theory (approximate) confidence intervals that were computed both for the entire sample, as well as for each of the 3 groups. Lack of significance of the group effect on the hours of life of the peak NRBC was ascertained using conventional normal theory one-way ANOVA model and Welch test (when the group variance homogeneity was violated) and validated nonparametrically using Kruskal-Wallis test (17).

Nonlinear associations between the NRBC values (response/outcome) and the corresponding hours of life were investigated using generalized additive (mixed) models (18). Likelihood ratio test (chi-squared) was used to test the full model with group-specific nonlinear temporal trends versus the null model that has the same nonlinear trend shared by the three sentinel event groups.

Model search approach emphasizing well-formulated linear model selection (19) was used to explore the associations between peak NRBC (response) and each individual explanatory variable that included age, severity of MRI brain injury as measured by Weeke scores of brain regions, Sarnat score, cord pH, cord base deficit, arterial blood gas (ABG) pH and ABG base deficit, while controlling for any potential group effects. Specifically, let Y denote the response and X denote one of the above covariates; for each choice of X, we fitted a sequence of nested models that included the interaction between X and the group, additive model with X and the group (no interaction) and the simple linear regression of Y on X. For each covariate, the model with the interaction term statistically significant (p-value < 0.05) or (else) the model with statistically significant main effects was used for inference. Additionally, we explored the group-specific regressions of Y on X. These analyses were carried out for peak absolute and peak normalized NRBC as the response variable.

A. Patient population

A total of 135 neonates with moderate-severe NE were studied with 52 neonates in group 1, 20 neonates in group 2 and 63 neonates in group 3. Mean birthweight in the 3 groups was similar with a mean weight of 3171 ± 731grams in group 1, 3251 ± 589 grams in group 2 and 3200 ± 699 grams in group 3. Gestational age (GA) was similar among the 3 groups with a mean GA of 38.22 ± 2.55 weeks, 38.7 ± 1.99 weeks and 38.6 ± 1.78 weeks respectively in group 1, 2 and 3. Almost 2/3 of patients were outborn in all groups. 66.7% of neonates were born via Cesarean section in group 1 with definite sentinel events, 35% were born via Cesarean section in group 2 with probable sentinel events and 59% were born via Cesarean section in group 3 with no evidence of sentinel events. In group 1, 50% of neonates had information on cord pH and base deficit with mean cord pH of 6.91 ± 0.21 and base deficit of 19.1 ± 9.5, 60% of neonates in group 2 had information on cord pH and base deficit with mean cord pH 6.8 ± 0.16 and base deficit of 18.4 ± 5.16, and 51% of neonates in group 3 had information on cord gas and base deficit with mean pH 6.98 ± 0.18 and mean base deficit of 15.4 ± 6.27. The first neonatal arterial blood pH was comparable in all 3 groups with pH of 7.16 ± 0.17, 7.14 ± 0.16 and 7.13 ± 0.17 respectively in group 1, 2 and 3. Arterial base deficit was also similar with base deficit of 14.7 ± 6.49, 15.2 ± 6.02 and 18.82 ± 6.27 respectively in group 1, 2 and 3. Apgar scores at 1, 5 and 10 minutes were similar in the 3 groups. A higher death rate of 11.7% was noted in group 1 compared to death rates of 5% and 3% in group 2 and 3 (Table 1).

Table 1

Demographic data of 3 cohort
	Group 1(N = 52)	Group 2(N = 20)	Group 3(N = 63)
Birth weight (gms)	3171 ± 731	3251 ± 589	3200 ± 699
Sex (Male)	47%	55%	54%
Gestational age (GA)	38.22 ± 2.55	38.7 ± 1.99	38.6 ± 1.78
Maternal Preeclampsia	11(21%)	3(15%)	11(17%)
Infant of gestational diabetes	5(10%)	3(15%)	13(20%)
IUGR	6(11%)	1(5%)	1(1.5%)
Out born	60.7%	65%	59%
Method of delivery C section	66.7%	35%	59%
APGAR 1, 5, 10	1.78 3.56 4.66	1.95 4.2 4.28	2.03 4.16 5.24
Cord pH	6.91 ± 0.21	6.8 ± 0.16	6.98 ± 0.18
Cord Base Deficit	19.1+/- 9.5	18.4 ± 5.16	15.4 ± 6.27
First neonatal arterial pH	7.16+/-0.17	7.14 ± 0.16	7.13 ± 0.17
First neonatal arterial BD	14.7 ± 6.49	15.2 ± 6.02	18.82 ± 6.27
Death	6 (11.7%)	1 (5%)	2 (3%)

B. Time to reach peak absolute NRBC and NRBC/100WBC from time of birth among 3 cohorts

Absolute NRBC count reached a mean peak value of 3014.73 (CI: 2159.52- 3869.950) across patients at a mean peak of 24.05 hours after birth (CI: 15.30- 32.79) in group 1 with definite sentinel events. Neonates in group 2 with probable sentinel events had an absolute NRBC peak value of 3865.78 (CI: 1665.64-6065.91) across patients at 17.56 hours after birth (CI: 7.35–27.77), and neonates in group 3 with no history of sentinel events had an absolute NRBC value of 4163.84 (CI: 2803.341- 5524.339) at 39.81 hours after birth (CI: 28.73–50.89) (Fig. 1, Fig. 2A, B). The earliest mean peak in absolute NRBC occurred in group 2, however there was no difference in the time to reach mean peak NRBC concentration between groups 1 and 2. There was a difference in the time to reach a mean peak in absolute NRBC between groups 2 and 3 as well as groups 1 and 3 (p < 0.05).

Peak NRBC/100WBC mean values across patients occurred at mean peak of 38.93 (CI: 16.00-60.78) at 36.58 hours after birth (CI: 26.53–46.63) in group 1, a mean peak value of 31.98 (CI: 11.88–52.07) at 19.14 hours after birth (CI: 8.64–29.64) in group 2 and mean peak value of 110.58 (CI: 42.25–178.90) at 40.13 hours after birth (CI: 30.83–49.42) in group 3. There was a difference to the time to mean peak NRBC/100WBC between groups 2 and 3 as well as between groups 1 and 2 (p < 0.05) (Fig. 3A, 3B).

C: Trends over time

Absolute NRBC

The trends of the absolute NRBC over time were analyzed. Although marked subject variation was present, following the peak values, groups 2 and 3 demonstrated a trend of a rapid decline following the peak in the concentration of the absolute NRBC over the first 20 hours of life. Group 1 demonstrated a trend of a gradual decline in the concentration of absolute NRBC over time.

NRBC/100WBC

For the NRBC/100WBC, there was wide individual subject variation that made the interpretation of trends analysis difficult. For groups 1 and 2 no appreciable trend was identified. Group 3 demonstrated an increase from 0–40 hours of life then a decrease after peaking (p < 0.05).

D: Relationship between peak NRBC and hypoxic-ischemic brain injury as measured on MRI

A linear regression model was used to study the relationship between peak absolute NRBC and the severity of both total brain injury and injury by brain regions as measured by the Weeke MRI score. Neonates in groups 1 and 2 with higher peak absolute NRBC were associated with higher total MRI brain injury score indicating more severe brain injury (p < 0.05). The peak in absolute NRBC correlated with the severity of injury in the grey matter in group 2 and the severity of injury in the white matter in groups 1 and 2, demonstrating higher absolute NRBC values correlating to higher injury scores.

When linear regression modeling was used to examine the peak NRBC/100WBC and the total brain injury score, only group 2 demonstrated a correlation with higher peak NRBC/100WBC correlating with higher total brain injury scores indicating a higher severity of injury. When individual brain regions were examined, higher peak NRBC/100WBC correlated with increasing injury severity scores in the grey matter in groups 2 and 3 and white matter in groups 1 and 2. In group 1, higher peak NRBC/100WBC demonstrated a correlation with the higher injury severity scores in the cerebellum.

E: Relationship between NRBC and blood gas variables

When linear regression was utilized to examine the association between peak absolute NRBC and the cord pH and base deficit, no relationship was found. The peak absolute NRBC did demonstrate a correlation with the initial neonatal ABG pH with higher peak absolute NRBC value correlating to a lower neonatal ABG pH (p < 0.05).

There was no correlation between the peak NRBC/100WBC and the cord and neonatal pH or base deficits.

F: Relationship between NRBC and Sarnat score

No correlation was noted between peak values of absolute NRBC and NRBC/100WBC with the initial Sarnat score.

The study demonstrated peak absolute NRBC concentration at 24 hours after birth in neonates with a definite sentinel event at the time of birth. We hypothesized that the peak absolute NRBC concentration would peak at 28–29 hours. Our hypothesis was based on the proposed mechanism of erythropoietin production increasing following a hypoxic-ischemic event and the emergence time of NRBC following administration of Darboietin proposed by Christensen et al (12). In the study by Christensen, serial values of NRBC were measured following Darboietin administration and the emergence time of NRBC in the circulation was greater than 24 hours, but accounting for erythropoietin synthesis an emergence time of 28–29 hours was proposed as the emergence time following a hypoxic event (12). Although our study looked at the peak of the absolute NRBC concentration and not time to emergence of NRBC, we used the hypothesis set forth by Christensen as a theoretical hypothesis for the peak concentration time following a hypoxic-ischemic event. Our data in the sentinel event group demonstrated a peak at 24 hours. The timing of the peak of absolute NRBCs was consistent with the hypothesis proposed by Christensen et al in a neonatal population with NE undergoing hypothermia. However, in this clinical cohort, there was great patient variation in the timing of the peak in the sentinel event group with some of the neonates having elevations in absolute NRBC concentrations at birth. This may be related to hypoxia occurring prior to birth and highlights the difficulty testing our proposed hypothesis due to multiple potential confounding variables in a clinical patient cohort.

The peak NRBC occurred earlier in cohort 2 with probable sentinel events (prolonged deceleration without clear etiology, cord compression and true knot) at 17.56 hours after birth. Again, as discussed above, the earlier peak in the absolute NRBC concentration may be due to the onset of hypoxia-ischemia hours prior to birth or may have a subacute hypoxia-ischemia or acute hypoxia-ischemia that led to peaking of absolute NRBC earlier. Cohort 3 with no evidence of sentinel events had a peak NRBC at 39.81 hours after birth. It is possible that due to lack of acute onset hypoxia-ischemia events, cohort 3 may have different pathophysiology other than erythropoietin mediated mechanism leading to rise in NRBC. Our finding also suggested that absolute NRBC values were more consistent with our hypothesis than NRBC/100WBC. Neonates have multiple other reasons for elevated WBC (sepsis, steroid use, stress) and using corrected NRBC per 100WBC may have skewed our data.

Only a few studies have been performed to examine the temporal relationship of peak NRBCs to timing of a hypoxic-ischemic insult. Shah et al examined the temporal relationship of NRBC among 2 cohorts (with and without sentinel event) and followed NRBC every 4 hours until 33 hours of life and found that NRBC peaked at 15–21 hours of life and remained elevated until day 2 in both cohorts. Based on their results, they concluded that peak NRBCs couldn’t be used to time a hypoxic insult (20). Due to the subject variability in our study, we conclude the same principle that NRBC alone at a single time point cannot be used to determine the exact time of a hypoxic-ischemic insult in utero. However, NRBC trends over time combined with other clinical, laboratory and MRI findings may provide data in determining the general timing of a hypoxic-ischemic insult.

Although NRBC alone may not be useful in determining the timing of injury, NRBC peaks do serve as a biomarker for MRI injury severity. All neonates with NE in our study with higher peak absolute NRBC had higher total MRI injury score, total grey matter injury score and total white matter injury score. Other studies have shown an association between abnormal MRI and cord NRBC/admission NRBC but identification of brain region injury on MRI hasn’t been previously reported. A study by Jingang et al showed neonates with more than 6 NRBC/100 WBCS at 6 hours of life had abnormal MRI (21). In our study peak NRBC/100WBC and the association with MRI injury severity was examined. Our results demonstrated an association with increasing peak NRBC/100WBC and increasing total brain injury severity scores in groups 2 in neonates with probable sentinel events. When individual brain regions were examined, higher peak NRBC/100WBC correlated with increasing injury severity scores in the grey matter in groups 2 and 3 and white matter in groups 1 and 2. In group 1, higher peak NRBC/100WBC demonstrated a correlation with the higher injury severity scores in the cerebellum. Overall, the data suggest that the NRBC/100WBC peaks may serve as promising biomarker of injury for specific brain regions and the peaks in the different groups may be related to different pathophysiologic mechanisms.

Our study revealed an association between lower ABG pH obtained on admission to the NICU and higher peak absolute NRBC. No association was noted between cord pH and base deficit to peak absolute NRBC. However, other studies have reported an association between cord pH/base deficit and cord NRBC (7, 22, 23). Our results may differ from these studies because our study analyzed NRBC concentrations that were obtained serially after birth instead of cord sample.

Several limitations were present in our study. The sampling of serial CBCs were performed every 12 hours, hence we may not have been able to capture the exact timing of peak NRBC as the peak may have occurred between sampling intervals.

In this study, we were unable to obtain fetal heart rate (FHR) monitoring for all patients to better allocate the exact timing of potential hypoxic-ischemic insult as 62% of the study population were outborn. Hence, a chart review was used to establish the time of the potential hypoxic-ischemic insult. For group1 this was established as around the time of birth. For outborn neonates in groups 2 and 3 the exact timing from a chart review was difficult to determine as definitively as in group 1. This is especially relevant for group 2 with probable sentinel events where the hypoxia-ischemia might have started hours prior to birth and analysis of the FHR would have allowed improved the ability to time insult prior to birth. Even in the group 1 with known sentinel events there also could have existed sub-acute or chronic hypoxia that contributed to early elevations of NRBC.

NRBC peak at 24 hours after birth in neonates with sentinel events consistent with mediation by erythropoietin after sentinel events. However, there may be other pathways especially in neonates without sentinel events that lead to elevation in NRBC.

NE- Neonatal Encephalopathy

NICU- Neonatal Care Unit

NRBC- Nucleated Red Blood Cells

Conflict of Interest: The authors had no conflicts related to work in this manuscript.

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There is NO conflict of interest to disclose.

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NRBC Concentrations Over Time in Neonates with Moderate to Severe NE with and without Sentinel Events

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I. Introduction

II. Materials and Methods

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