PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1212-e1216 (doi:10.1542/peds.2007-0681)
ARTICLE |
Cerebrospinal Fluid Xanthochromia in Newborns Is Related to Maternal Labor Before Delivery
a Division of Emergency Medicine, Children's Hospital Boston, Boston, Massachusetts
c University of Massachusetts Medical School, Worcester, Massachusetts
d Division of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
b Harvard Medical School, Boston, Massachusetts
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ABSTRACT |
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OBJECTIVE. The purpose of this work was to investigate whether xanthochromia in newborns is related to maternal labor before delivery.
METHODS. We reviewed the medical charts of all of the infants 
30 days of age who had a lumbar puncture performed in a single pediatric emergency department between 2003 and 2005. Xanthochromia was detected by the hospital laboratory using the qualitative visual inspection method. We used logistic regression to determine the relationship between maternal labor before birth and the presence of cerebrospinal fluid xanthochromia, adjusting for factors known to be associated with xanthochromia.
RESULTS. Of the 478 newborns who had a lumbar puncture performed during the study period, 134 (28%) had xanthochromia. Of the 449 infants with delivery method recorded in the medical chart, 332 (74%) were born via vaginal delivery, 24 (5%) via cesarean section after maternal labor, and 93 (21%) via cesarean section without maternal labor. After excluding patients with hyperbilirubinemia (total bilirubin 
15 mg/dL) and adjusting for factors known to be associated with xanthochromia (cerebrospinal fluid red blood cells 20000 cells per mL and cerebrospinal fluid protein 150 mg/dL), infants born after maternal labor had a higher rate of cerebrospinal fluid xanthochromia than infants born without any labor.
CONCLUSIONS. Xanthochromia is a common finding in the cerebrospinal fluid of newborns and is associated with maternal labor preceding delivery.
Key Words: xanthochromia • cerebrospinal fluid • delivery method
Abbreviations: CSF—cerebrospinal fluid • LP—lumbar puncture • RBC—red blood cell • HSV—herpes simplex virus • PCR—polymerase chain reaction
Xanthochromia is the yellow discoloration of cerebrospinal fluid (CSF) that results from the presence of pigmented products of hemoglobin catabolism. When red blood cells enter the subarachnoid space, they are gradually lysed, and the released hemoglobin is then metabolized to the pigmented molecules oxyhemoglobin, methemoglobin, and bilirubin.1,2 This enzyme-dependent breakdown process begins after several hours3 but may take up to 12 hours after the onset of bleeding to develop.4,5 Xanthochromia is detected by either visual inspection or by spectrophotometry of the CSF.1 Xanthochromia has been observed in patients with an elevated serum bilirubin (15 mg/dL),6 elevated CSF protein (150 mg/dL),7 and in infants in whom the lumbar puncture (LP) is traumatic or yields a grossly bloody result.7,8 In an in vitro study, 70% of CSF specimens with 20000 red blood cells (RBCs) per mL had xanthochromia when samples were analyzed immediately compared with 100% if analysis was delayed by 1 hour.8
In adults presenting with acute-onset headaches, xanthochromia has been used as a marker for subarachnoid hemorrhage,5 a diagnosis that is an unusual consideration for young infants.9 The presence of xanthochromia in the CSF has also been observed among neonates with herpes simplex virus (HSV) meningoencephalitis.10 Although based on a single case series of Japanese children, the presence of xanthochromia alone often leads to the consideration of HSV infection in the youngest infants. The clinical significance of xanthochromia in newborn CSF is not well understood.
Maternal labor preceding birth has been associated with occult intracranial hemorrhage in asymptomatic newborns.11 We hypothesize that RBCs that enter the CSF during labor may later be catabolized, thus resulting in xanthochromia. To investigate the relationship between xanthochromia in the CSF of infants and maternal labor, we reviewed the medical charts of 
500 infants who underwent a LP in the emergency department during the first month of life.
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METHODS |
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Study Design
We performed a retrospective cohort study of all of the infants (
30 days of age) who had an LP performed in the emergency department of the study institution during a 3-year period (January 2003 to December 2005). Eligible patients were identified by query of a laboratory database and were included if they had CSF obtained in the emergency department. We included all of the patients with an available CSF cell count. As part of standard laboratory protocol, all of these patients had CSF color examined. The emergency department and inpatient medical charts of all of the study patients were retrospectively reviewed to determine patient demographics, mode of infant delivery (vaginal delivery, cesarean section after maternal labor, or cesarean section without maternal labor), clinical indication for LP, and patient disposition (discharged from the emergency department or admitted to the hospital). Laboratory databases were reviewed for serum bilirubin and CSF results (RBCs, white blood cells, protein, glucose, and color). Xanthochromia was determined at the time of specimen collection by laboratory personnel using centrifuged CSF specimen and qualitative visual inspection methods.1 Data were abstracted about neuroimaging and HSV testing, when either was performed.
Statistical Analysis
We performed univariate testing with 
2 analysis. We performed multiple logistic regression to determine the association between maternal labor and CSF xanthochromia. We excluded all of the patients with serum bilirubin levels of 15 mg/dL, because xanthochromia may be because of an elevated serum bilirubin, independent of other factors.6 We did not exclude patients with intracranial hemorrhage identified on neuroimaging performed after the LP.
In the multivariate analysis, we adjusted both for patient age (in days) and for factors known to be associated with xanthochromia (elevated CSF RBC and CSF protein).7,8 We dichotomized CSF RBCs (20000 cells per mL)8 and CSF protein (150 mg/dL)7 based on published thresholds associated with xanthochromia. Only patients with complete data on all of the candidate predictors were included in the multivariable analysis.
For all of the analyses, we used SPSS (SPSS Inc, Chicago, IL).12 The study was approved by the institutional review board of the study institution.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We identified 478 infants
30 days of age who had a CSF obtained for analysis from an LP performed in the emergency department during the study period. No patient had >1 LP performed within the first 30 days of life during the study period. Table 1 provides the clinical and laboratory characteristics of the patients included in the study. LPs were obtained for the following clinical reasons: 89% for fever in a neonate, 9% for seizure, and 2% for other reasons. Of the 449 study patients with birth method recorded in the medical chart, 332 (74%) were born after vaginal delivery, 24 (5%) by cesarean section after maternal labor, and 93 (21%) by cesarean section without maternal labor. A total of 134 infants (28%) had xanthochromia noted in the CSF.
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In the univariate analysis, CSF xanthochromia varied by birth method: it was most common in infants born by vaginal delivery and least common in infants born by cesarean section with no trial of labor (Table 2). Consistent with published data,7,8 we observed that xanthochromia was associated with both high CSF protein and high CSF RBCs (Table 2).
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Figure 1 depicts the frequency of CSF xanthochromia based on patient age in days. The frequency of CSF xanthochromia decreased with increasing age (P < .001). This decrease was significant only among infants born after any labor.
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A serum bilirubin level was obtained from 92 infants (19%) who had an LP performed. Of which, 15 patients (3% of total) had a serum bilirubin level of
15 mg/dL and, thus, were excluded from the multivariate analysis. Eleven (73%) of these 15 patients had xanthochromia noted in the CSF. After adjusting for patient age, elevated CSF protein (150 mg/dL), and bloody CSF (CSF RBCs 20000 cells per mL), we found that maternal history of labor before infant delivery was independently associated with the presence of xanthochromia (adjusted odds ratio: 2.4; 95% confidence interval: 1.2–5.0; Table 3).
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Of the 478 study patients, 71 patients (15%) had neuroimaging performed (computed tomography, MRI, or ultrasound examinations of the head). Four of these patients had intracranial hemorrhage identified (3 with subdural hematomas and 1 with intraparenchymal blood). Xanthochromia was observed in the 1 infant with an intraparenchymal bleed; none of the 3 infants with subdural hematomas had xanthochromia noted in the CSF.
Sixty-one (13%) of patients had HSV polymerase chain reaction (PCR) sent from the CSF, of which, 1 infant tested positive. This infant was 11 days of age and presented with a vesicular rash suggestive of disseminated herpes infection. The CSF from this infant was xanthochromic and had a CSF RBC of 385 cells per mL.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In reviewing the CSF results for all of the infants undergoing LP in the first month of life, we found CSF xanthochromia to be relatively common among neonates (28% of all infants
30 days of life). First, we observed an inverse relationship between patient age and the presence of xanthochromia. Second, we found an independent association between history of maternal labor before delivery and CSF xanthochromia after excluding those infants with hyperbilirubinemia and adjusting for other factors reported to be associated with xanthochromia, including grossly bloody CSF and elevated CSF protein.6,8 We hypothesized that maternal labor may cause subclinical intracranial hemorrhage in some neonates. The hemoglobin from these RBCs that enter the subarachnoid spaces is later to be enzymatically degraded to the pigmented products (oxyhemoglobin, methemoglobin, and bilirubin), which may persist for several weeks.4,7 For those infants who later undergo LP, the resulting CSF may be xanthochromic.
Other investigators have demonstrated occult intracranial hemorrhage in asymptomatic newborns.11,13 Whitby et al performed cranial MRIs on 111 normal asymptomatic newborns.11 Nine infants (8% of study patients) had subdural hemorrhages identified all by MRI performed at 48 hours of life. All of the hemorrhages had spontaneously resolved by the time of a repeat MRI performed at 4 weeks of life. The incidence of xanthochromia in infants with subdural hematoma is unknown; however, none of the 3 infants with subdural hematomas in our study had xanthochromia.
Investigators have previously identified an association between mode of infant delivery and intracranial hemorrhage. In a birth cohort of >500000 newborns, Towner et al13 found that forceful delivery (either use of forceps or vacuum extraction) was associated with an increased risk of clinically significant intracranial hemorrhage. In a second study, Looney et al14 performed MRIs on 97 neonates between 1 and 5 weeks of life. Seventeen neonates (18% of study patients) had intracranial hemorrhages identified; all of these infants were born vaginally. Although some of these infants likely had an LP performed in the neonatal period, neither study reported CSF findings.
CSF xanthochromia has been described in children with HSV encephalitis.10 Neonatal HSV infection is an important clinical concern among febrile neonates and may result in severe neurologic sequelae. In our study, only 13% of patients had CSF herpes PCR tests sent. The only infant who had a positive HSV PCR did have CSF xanthochromia but also had a classic whole-body vesicular rash. Given the rarity of HSV infections,10,15 our study was not powered to determine the sensitivity of CSF xanthochromia for HSV encephalitis. However, in almost 500 infant LPs, the presence of xanthochromia did not identify a single case of unsuspected HSV infection. Given the frequency with which CSF xanthochromia is observed in healthy neonates (28%) and the rarity of herpes meningoencephalitis in well-appearing infants without seizures or vesicular rash, we would argue that CSF xanthochromia alone should not prompt consideration of neonatal HSV infection. With that said, one must always have a low suspicion for testing and treatment for HSV among young febrile infants (<1 month of age), particularly if CSF pleocytosis is found.
Our study has the following limitations. First, our study was retrospective, and birth method was collected by medical chart review. However, only 6% of all of the charts reviewed were lacking information regarding birth method. In addition, for the 94% of patients who were admitted to the hospital, we noted perfect correlation between the emergency department and inpatient records for birth method. Second, CSF xanthochromia was determined by using visual inspection rather than spectrometry. Although visual inspection may be less sensitive test than spectrometry,16,17 this technique is used by almost all institutions (99.7% of US clinical laboratories in a recent survey).1 In addition, spectrophotometry has only moderate-to-low specificity,18 and the literature suggests that the discrepancy between visual detection methods and spectrophotometry is not as great as previous studies have claimed.19 Third, we do not know the length of time between the physician performing the LP and the analysis of the CSF by the clinical laboratory. Previous investigators have demonstrated that xanthochromia increases with a delay in specimen processing.8 However, after discussion with technicians in the clinical laboratory, these delays should have been minimal and certainly would be unrelated to the mode of infant delivery. Furthermore, only 19% of patients had serum bilirubin obtained at the time of their emergency department evaluation. However, patients with a serum bilirubin level of 15 mg/dL would likely appear jaundiced, and most clinicians would obtain a bilirubin measurement. Last, only a minority of study patients had neuroimaging performed. Therefore, we could not assess the correlation between CSF xanthochromia and radiographic intracranial hemorrhage in our study population. With that said, patients with clinical presentations concerning for significant hemorrhage would have had head imaging performed.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We found CSF xanthochromia to be common among young infants, and it is associated with a history of maternal labor. We hypothesize that maternal labor may be associated with subclinical hemorrhage in some newborns, with resulting CSF xanthochromia, which may persist throughout the first month of life. Therefore, the finding of CSF xanthochromia alone in an infant
30 days of age should not, in and of itself, prompt consideration of significant intracranial hemorrhage.
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ACKNOWLEDGMENTS |
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This work was supported by National Research Service Awards (grant T32 HD40128-01 Research Training in Pediatric Emergency Medicine and grant T32 HD043034-04 Research Training in Pediatrics [to Dr Nigrovic]).
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FOOTNOTES |
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Accepted Apr 12, 2007.
Address correspondence to Lise E. Nigrovic, MD, MPH, Division of Emergency Medicine, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail: lise.nigrovic{at}childrens.harvard.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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