Nucleated red blood cells: An update on the marker for fetal asphyxia

doi:10.1016/S0002-9378(96)80010-X

American Journal of Obstetrics and Gynecology

Volume 175, Issue 4, Part 1, October 1996, Pages 843-846

Presented at the Sixteenth Annual Meeting of the Society of Perinatal Obstetricians, Kamuela, Hawaii, February 4-10, 1996.

https://doi.org/10.1016/S0002-9378(96)80010-X Get rights and content

Abstract

OBJECTIVE: Our goal was to update our experience with nucleated red blood cells as a marker for fetal asphyxia and to determine whether a relationship exists between the presence of nucleated red blood cells and long-term neurologic impairment. STUDY DESIGN: Nucleated red blood cell data from 153 singleton term neurologically impaired neonates were compared with cord blood nucleated red blood cells of 83 term nonasphyxiated newborns. Newborns with anemia, intrauterine growth restriction, and maternal diabetes were excluded. The group of neurologically impaired neonates was separated into the following subgroups: group I, persistent nonreactive fetal heart rate pattern from admission to delivery (n = 69); group II, reactive fetal heart rate on admission followed by tachycardia with decelerations and absent variability (n = 47); group III, reactive fetal heart rate on admission followed by an acute prolonged deceleration (n = 37). The first and highest nucleated red blood cell value and the time of nucleated red blood cell disappearance were assessed. RESULTS: The mean number of initial nucleated red blood cells was significantly higher in the group of neurologically impaired neonates (30.3 ± 77.5, range 0 to 732 per 100 white blood cells) than in the control group (3.4 ± 3.0, range 0 to 12 per 100 white blood cells) (p < 0.000001). When the group of neurologically impaired neonates was separated on the basis of timing of the neurologic impairment, distinct nucleated red blood cell patterns were observed. Significant differences were obtained between each of the three groups of neurologically impaired neonates and the normal group, with respect to initial nucleated red blood cells (group I, 48.6 ± 106.9; group II, 11.4 ± 9.8; group III, 12.6 ± 13.4; p≤ 0.000002). Maximum nucleated red blood cell values were higher in group I (mean 51.5 ± 108.9) than in groups II and III combined (mean 12.7 ± 11.9) (p = 0.0005). Group I also had a longer clearance time (119 ± 123 hours) than groups II and III combined (mean 59 ± 64 hours) (p < 0.001). CONCLUSION: Our ongoing study indicates that nucleated red blood cells identify the presence of fetal asphyxia. When fetal asphyxia is present, distinct nucleated red blood cell patterns are observed that relate to the timing of fetal injury. In general, intrapartum injuries are associated with lower nucleated red blood cell values. Thus our data continue to support the concept that nucleated red blood cell levels may assist in determining the timing of fetal neurologic injury. (Am J Obstet Gynecol 1996;175:843-6.)

Section snippets

MATERIAL AND METHODS

We used a case-control study design to compare normal nonasphyxiated newborns⁶ with neurologically impaired neonates in whom hypoxic ischemic encephalopathy had been diagnosed in the neonatal period.⁸ Mixed umbilical cord blood samples obtained at birth were analyzed from normal newborns who were delivered at a community hospital and met the following entry criteria: appropriate-for-gestational-age neonate at ≥37 weeks' gestation, birth weight >2800 gm, Apgar score ≥7 at both 1 and 5 minutes,

RESULTS

During the course of the investigation, 83 normal, nonasphyxiated newborns underwent umbilical cord blood analysis to determine the nucleated red blood cell count at birth.⁶ Of 269 term live-born neurologically impaired neonates in the registry, 153 (57%) met selection criteria for the study. The reasons for exclusion are illustrated in Table I.

The distribution of nucleated red blood cells for the normal and asphyxial injury population is illustrated in Fig. 1. There the normal nonasphyxiated

COMMENT

The current investigation supports our prior work on the role of nucleated red blood cells as a potential marker for fetal asphyxia.⁶ Regardless of the fetal pathophysiologic mechanism responsible for fetal injury, the nucleated red blood cell counts were significantly higher among asphyxiated neonates than for a group of normal nonasphyxiated newborns. The time required to produce an elevation in nucleated red blood cell count remains unknown but appears to be relatively short in the light of

References (10)

DW Green et al.
Nucleated erythrocytes in healthy infants and in infants of diabetic mothers
J Pediatr
(1990)
GW. Anderson
Studies on the nucleated red blood cell count in the chorionic capillaries and the cord blood of various ages of pregnancy
Am J Obstet Gynecol
(1941)
JP Phelan et al.
Nucleated red blood cells: a marker for fetal asphyxia?
Am J Obstet Gynecol
(1995)
JP Phelan et al.
Perinatal observations in forty-eight neurologically impaired term infants
Am J Obstet Gynecol
(1994)
CS Ryerson et al.
The age of pregnancy - histologic diagnosis from percentage of erythroblasts in chorionic capillaries
Arch Pathol
(1934)

There are more references available in the full text version of this article.

Cited by (128)

Haematological issues in neonates with neonatal encephalopathy treated with hypothermia
2021, Seminars in Fetal and Neonatal Medicine
Citation Excerpt :
nRBCs in cord blood are predictive of NE in case-control studies with both acute and chronic antepartum fetal hypoxia and ischemia [11]. Korst et al. suggested that the nRBCs could be indicative of the timing of the hypoxic-ischemic event with higher levels of nRBCs reported in neonates who had abnormal fetal heart rate tracings prior to labour (n = 153), compared to those neonates who had intrapartum changes in fetal heart rate tracing (n = 83) [12]. Ghosh et al. found elevated nRBCs in umbilical blood also correlated with poor early neonatal outcome [11].
Neonatal encephalopathy (NE) is associated with abnormality of neurological function and involves multiorgan dysfunction. There are long-term complications such as cerebral palsy and developmental delay. Cardiac, renal, neurological and other organ dysfunctions are well described. Haematological dysfunction is relatively common and includes anaemia, thrombocytopenia, monocyte and neutrophil activation, hypofibrinogenemia and coagulopathy. There is a lack of consensus definitions of hematological parameters and optimal levels for intervention due to the lack of interventional studies in term neonates and the lack of knowledge of the optimal values during therapeutic hypothermia. However, derangements in hematological values are also associated with neurodevelopmental outcomes. This article outlines the different hematological complications associated with NE and therapeutic hypothermia and suggests a framework for management.
FIRS: Neonatal considerations
2020, Seminars in Fetal and Neonatal Medicine
Fetal Inflammatory Response Syndrome (FIRS) is the fetal counterpart of systemic inflammatory response syndrome (SIRS) described in adults. When the fetus is directly exposed to inflammation of the fetal membranes or the placental-fetal circulation, and organs are adversely affected, the disorder is known as FIRS. This syndrome can significantly affect multiple organs with significant short and long term implications for the newborn. In cases of neonatal encephalopathy when no obvious etiology is identified, FIRS needs to be considered. Based on the significant incidence of chorioamnionitis and its potential effects on the newborn, any evidence of maternal, fetal, or neonatal infection should mandate further evaluation of the placenta and membrane histopathology.
Nucleated red blood cell counts: An early predictor of brain injury and 2-year outcome in neonates with hypoxic-ischemic encephalopathy in the era of cooling-based treatment
2014, Brain and Development
Citation Excerpt :
However, there has been no reliable method to differentiate poor neurological prognosis in the first 6 hours after birth [2,3]. Factors such as pH, base deficit, and lactate levels at birth are markers for acute asphyxia, but they do not provide a good estimate of the chronicity of the acid-base disturbance, which is an important antecedent of irreversible brain damage [9,21]. In contrast, because of the time taken for the process of NRBC elevation after hypoxia, an increased umbilical/peripheral NRBC count reflects both the chronicity and severity of the acid-base disturbance and may be an important early predictor of poor neurodevelopment [12,16,21].
Background: Raised nucleated red blood cell (NRBC) counts in neonates may indicate in utero hypoxia and brain damage. Objective: The study aimed to examine the use of NRBC counts as a predictor of brain injury and neurodevelopmental outcomes in neonates with hypoxic–ischemic encephalopathy (HIE) treated under current cooling-based strategy. Methods: Forty-three neonates with asphyxia between 2004 and 2010 were retrospectively investigated. Twenty neonates with moderate/severe HIE underwent hypothermia (HT), and 23 with mild HIE were treated in normothermia (NT). Neonates were divided into groups according to the presence of cerebral parenchymal lesions on magnetic resonance imaging (MRI) at 2 weeks after birth. All patients were followed-up neurologically for ⩾24 months. NRBC counts during the first 3 days were compared between groups. Results: Eleven HT (HT-N) and 21 NT (NT-N) neonates had normal MRI, and 9 HT (HT-L) and 2 NT (NT-L) neonates had parenchymal lesions. NRBC counts, both absolute and /100 white blood cells (WBC) counts, during the first 3 days in HT-L and NT-L were significantly higher than those in HT-N and NT-N, particularly within 6 hours after birth (HT-N: 502 [0–3060]/mm³ vs HT-L: 2765 [496–6192]; 0 [0–3417] vs NT-L: 4384 [3978–4789], median [range]). Neonates with /100 white blood cells ⩾6/mm³ and absolute NRBC counts ⩾1324/mm³ within 6 hours of birth had high risks of abnormal MRIs and 2-year outcomes. Conclusions: NRBC counts can predict brain injury and neurological outcomes in cooled and non-cooled asphyxiated neonates.
Comparison of the umbilical artery blood gas, nucleated red blood cell, C-reactive protein, and white blood cell differential counts between neonates of diabetic and nondiabetic mothers
2011, Taiwanese Journal of Obstetrics and Gynecology
The aim of this study was to compare the neonatal umbilical artery blood gas values, C-reactive protein (CRP) levels, nucleated red blood cells (NRBCs), and white blood cells (WBCs) differential counts between offspring’s of the diabetic mothers who needed insulin during pregnancy and normal mothers after cesarean delivery.
A prospective study was performed involving 68 pregnant diabetic women who needed insulin during pregnancy and 410 healthy pregnant women and their neonates with gestational ages between 35 weeks and 41 weeks. Arterial blood was analyzed for pH and blood gas values and venous blood was analyzed for CRP level, NRBC, and WBC differential counts.
The mean NRBC count in the neonates of diabetic mothers and healthy mothers was 560 ± 985/μL and 202 ± 281/μL, respectively (p < 0.001). The umbilical arterial blood gas showed a lower pH (7.22 ± 0.07 vs. 7.24 ± 0.04, p = 0.004) and a higher pCO₂ (49.33 ± 10.08 vs. 47 ± 8.67, p = 0.045) in neonates of diabetic mothers compared with the controls. Values of pO₂, HCO₃⁻, base excess, WBC differential counts, and CRP levels were almost similar in the two groups.
Lower pH, higher pCO₂, and elevated NRBC counts were found in the neonates of diabetic mothers that may be suggestive of chronic intrauterine acidosis.
Cerebral palsy and perinatal asphyxia (II - Medicolegal implications and prevention)
2011, Gynecologie Obstetrique et Fertilite
La constante augmentation de la pression médicolégale en obstétrique constitue un problème préoccupant dans les pays développés, du fait des indemnisations croissantes des paralysies cérébrales, avec comme conséquence une flambée des primes d’assurance professionnelle conduisant de nombreux obstétriciens à abandonner la pratique des accouchements. Cinquante-quatre à 74 % des plaintes en responsabilité concernent des anomalies des tracés cardiotocographiques (CTG), mal interprétées ou suivies de réactions inadéquates ou trop tardives. Une revue critique des neuf critères retenus par le Collège des obstétriciens et gynécologues américains et par l’Académie américaine de pédiatrie pour caractériser l’encéphalopathie néonatale et la paralysie cérébrale, est effectuée à propos des quatre paramètres essentiels définissant l’asphyxie chez le nouveau-né à terme et des cinq critères mineurs évoquant une atteinte intrapartum. La nécessité d’un examen anatomopathologique du placenta est soulignée afin de pouvoir rattacher une paralysie cérébrale à une asphyxie fœtale, grâce à la confirmation d’événements « sentinelles » survenus avant ou pendant le travail ou bien grâce à la découverte de lésions thrombotiques affectant la circulation fœtale, d’aspects évoquant une insuffisance placentaire ou de réponses circulatoires d’adaptation à une hypoxie chronique dans les villosités. L’histologie placentaire doit aussi permettre d’exclure l’origine asphyxique d’une paralysie cérébrale en révélant des réactions inflammatoires aiguës de chorioamniotite avec dissémination au fœtus ou des aspects compatibles avec une maladie métabolique. L’imagerie cérébrale par résonance magnétique (IRM) nucléaire est fondamentale pour élucider le mécanisme et la chronologie des atteintes tissulaires hypoxiques, en localisant préférentiellement les lésions sur la substance blanche ou sur la substance grise du cerveau. Certaines asphyxies intrapartum peuvent être prévenues en effectuant une césarienne programmée pour un fœtus fragile, en évitant la survenue de certains événements « sentinelles » et surtout en répondant de façon appropriée aux anomalies CTG et en procédant avec compétence à la réanimation néonatale. Au cours de la réunion d’expertise contradictoire, il est indispensable de disposer d’un CTG lisible, d’un partogramme bien documenté, d’une analyse des gaz du sang au cordon ombilical, d’un examen anatomopathologique du placenta et d’une évaluation complète du nouveau-né incluant une IRM cérébrale. Le risque médicolégal peut être réduit par une formation continue en CTG, en respectant les recommandations nationales concernant le rythme cardiaque fœtal (RCF), en utilisant des méthodes complémentaires comme le pH ou les lactates au scalp, en réalisant de régulières revues de mortalité et morbidité (RMM) des dossiers litigieux et en instaurant la pratique périodique d’audits ou d’évaluations de la pratique professionnelle (EPP) à propos des acidoses néonatales sévères, des transferts en réanimation néonatale, des ventilations assistées et des délais observés entre la décision et la réalisation des accouchements opératoires. Compte tenu de la rapidité d’installation des lésions cérébrales fœtales en cas d’asphyxie aiguë, il reste de nombreux dossiers où aucune faute ne peut être retenue contre l’accoucheur. Inversement, un épisode hypoxique anténatal bien documenté au niveau cérébral n’exclut pas automatiquement une aggravation par une prise en charge défaillante pendant l’accouchement.
Obstetric litigation is a growing problem in developed countries and its escalating cost together with increasing medical insurance premiums is a major concern for maternity service providers, leading to obstetric practice cessation by many practitioners. Fifty-four to 74 % of claims are based on cardiotocographic (CTG) abnormalities and their interpretation followed by inappropriate or delayed reactions. A critical analysis is performed about the nine criteria identified by the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics in their task force on Neonatal Encephalopathy and Cerebral Palsy: four essential criteria defining neonatal asphyxia and five other suggesting an acute intrapartum event sufficient to cause cerebral palsy in term newborns. The importance of placental histologic examination is emphasized in order to confirm sudden catastrophic events occurring before or during labor or to detect occult thrombotic processes affecting the fetal circulation, patterns of decreased placenta reserve and adaptative responses to chronic hypoxia. It may also exclude intrapartum hypoxia by revealing some histologic patterns typical of acute chorioamnionitis and fetal inflammatory response or compatible with metabolic diseases. Magnetic resonance imaging (MRI) of the infant's damaged brain is very contributive to elucidate the mechanism and timing of asphyxia in conjunction with the clinical picture, by locating cerebral injuries predominantly in white or grey matter. Intrapartum asphyxia is sometimes preventable by delivering weak fetuses by cesarean sections before birth, by avoiding some “sentinel” events, and essentially by responding appropriately to CTG anomalies and performing an efficient neonatal resuscitation. During litigation procedures, it is necessary to have access to a readable CTG, a well-documented partogram, a complete analysis of umbilical cord gases, a placental pathology and an extensive clinical work-up of the newborn infant including cerebral MRI. Malpractice litigation in obstetric care can be reduced by permanent CTG education, respect of national CTG guidelines, use of adjuncts such as fetal blood sampling for pH or lactates, regular review of adverse events in Clinical Risk Management (CRM) groups and periodic audits about low arterial cord pH in newborns, admission to neonatal unit, the need for assisted ventilation and the decision-to-delivery interval for emergency operative deliveries. Considering the fast occurrence of fetal cerebral hypoxic injuries, and thus despite an adequate management, many intrapartum asphyxias will not be preventable. Conversely, well-documented hypoxic-ischemic brain insults during the antenatal period do not automatically exclude intrapartum suboptimal obstetric care.
Nucleated red blood cells in neonates with hypoxic ischaemic encephalopathy treated with hypothermia: A worthwhile prognostic biomarker for clinicians in LMIC?
2023, SAJCH South African Journal of Child Health

View all citing articles on Scopus

^☆: From the Department of Obstetrics and Gynecology, The Perinatal Center, Pomona Valley Hospital Medical Center; the Department of Obstetrics and Gynecology, Cha Women's Hospital of Seoul; the Department of Neonatology, Queen of the Valley Hospital; and the Department of Pediatrics, University of California, Irvine, School of Medicine.

^☆☆: Reprint requests: Jeffrey P. Phelan, MD, Suite 200, 1030 S. Arroyo Parkway, Pasadena, CA 91105.

^★: 0002-9378/96 $5.00 + 0 6/6/75614

View full text

Nucleated red blood cells: An update on the marker for fetal asphyxia☆,☆☆,★

Abstract

Section snippets

MATERIAL AND METHODS

RESULTS

COMMENT

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

The age of pregnancy - histologic diagnosis from percentage of erythroblasts in chorionic capillaries

Arch Pathol