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Technical Briefs |
Departments of1 Obstetrics & Gynaecology and 4 Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong;2 Department of Neonatology, Perinatal Medicine Center, Medical College of Jinan University, Guangzhou, China;3 Department of Neonatology, The 2nd Affiliated Hospital of Guangzhou Medical College, Guangzhou, China;5 Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, University Eye Centre, Hong Kong Eye Hospital, Kowloon, Hong Kong;
aaddress correspondence to this author at: 1st Floor, Block E, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; fax 852-2636-0008, e-mail msrogers{at}cuhk.edu.hk
When a fetus is subjected to a massive perinatal hypoxic-ischemic insult, it may suffer sufficient damage to cause intrauterine death and stillbirth (1)(2)(3)(4)(5). In less severe, nonfatal cases, prolonged or severe intrauterine hypoxia may lead to serious neonatal complications such as hypoxic-ischemic encephalopathy (HIE), cerebral palsy, and impaired myocardial function (6)(7)(8). Hypoxia during labor leads to anaerobic respiration in the fetus and an accumulation of lactic acid in the tissues, producing metabolic acidosis. Damage to the brain and heart in asphyxia neonatorum is not a direct result of hypoxia, but rather of the toxic effects of reactive oxygen species generated after reperfusion of ischemic tissues. We have demonstrated that lipid peroxidation in the fetus increases during normal labor (9) and that umbilical cord plasma lipid peroxide concentrations are higher in situations known to lead to intrapartum hypoxia (10)(11)(12) and much lower after elective cesarean delivery (13). Reperfusion of damaged organs with oxygenated blood after delivery may also be detrimental to the infant’s long-term survival.
Prediction of long-term neurodevelopmental outcomes in infants with birth asphyxia remains challenging. Unfortunately, previous studies have shown that clinical and biochemical variables, such as umbilical artery blood gases or Apgar scores, are of limited value in predicting morbid neonatal outcome. We have proposed the use of lipid peroxidation products, acting as footprints of oxidative stress, as alternative measures of perinatal outcome (14). Increased concentrations of lipid peroxidation products in cord arterial blood are associated with clinical situations known to cause fetal distress, but they have not been shown to be associated with significant morbid outcomes such as HIE. This study aims to demonstrate an association between increased umbilical cord blood lipid peroxide concentrations and morbid neonatal outcomes. The study hypotheses are (a) that cord arterial plasma isoprostane (15) concentrations are higher in neonates who require immediate admission to the neonatal intensive care unit (NICU) for respiratory support than in healthy neonates, and (b) that cord arterial plasma isoprostane concentrations are higher in infants who will ultimately develop HIE than in those who will recover without neurologic sequelae.
In total, 301 neonates had cord blood 8-isoprostane measured, and 297 cord blood samples were confirmed as arterial in origin (see the Materials and Methods section of the Data Supplement that accompanies the online version of this Technical Brief at http://www.clinchem.org/content/vol51/issue7/). Of the infants for whom arterial cord blood samples were available, 13.1% (39 of 297) required immediate postdelivery admission to a NICU for respiratory support, and another neonate (1 of 297; 0.3%) died immediately after birth and was classified as a fresh stillbirth. Of these 40 (39 + 1) cases, 24 (60%) were originally classified as having asphyxia neonatorum, with 11 of the 24 (45.8%) ultimately classified as having poor outcome [8 with HIE and 3 with postnatal death (PND)]; the remaining 13 cases (54.2%) were classified as having a good outcome. Another 25% of infants (10 of 40) showed no evidence of asphyxia at birth but were treated in a NICU because of pneumonia (9 with bacterial sepsis and 1 with meconium aspiration syndrome), and 15% (6 of 40) were admitted solely because of prematurity. The maternal, obstetric, and neonatal characteristics for all 297 neonates who had cord blood samples available, grouped according to outcome, are shown in Table 1 of the online Data Supplement. Statistical significance was achieved (P <0.01) in a group sequential analysis comparing cord arterial 8-isoprostane concentrations in the 40 sick neonates requiring immediate NICU admission for respiratory support (including the 1 fresh stillbirth) and the 257 healthy control infants (Fig. 1
of the online Data Supplement), and in the post hoc analysis comparing cord isoprostane in NICU cases that developed HIE with those that did not.
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Shown in Fig. 1
is a scatter plot of cord arterial blood 8-isoprostane plotted against cord arterial base excess according to actual neonatal outcome group for all cases. Lowess regression suggested a linear relationship between 8-isoprostane concentrations and base excess when base excess was below –10. Linear regression analysis of this group (n = 23) gave a correlation coefficient (r) of –0.673 (P = 0.002).
The results of ROC curve analysis for predictions of poor outcome (HIE/PND) on the basis of 1- and 5-min Apgar score, cord arterial blood isoprostane concentration, cord arterial pH, and cord arterial base excess are shown in Table 1
. The values for the 40 cases admitted to a NICU for respiratory support are listed first, followed by the values for all 297 cases. All infants who survived with evidence of significant brain damage (HIE) had severe metabolic acidosis (base excess –12 or lower), as did one of the infants who subsequently died. The pattern of oxidative stress was similar, with 6 of these 9 cases (66.7%) having increased 8-isoprostane concentrations. The 8-isoprostane concentration was also increased in 25 nonasphyxiated cases (9.2%); 17 (68%) of these had nuchal cord entanglement detected at birth, with 12 (48%) having tight nuchal entanglement.
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Although the significant difference in isoprostane concentrations between healthy infants and neonates requiring NICU admission for respiratory support is of interest, an ability to identify those infants who will ultimately develop HIE or PND from among sick infants requiring NICU admission would be of greater value. In a post hoc analysis of the 39 infants admitted to a NICU for respiratory support, cord arterial isoprostane concentrations were shown to be significantly higher (P <0.01) in neonates who subsequently were classified as having a poor outcome.
The 8-isoprostane concentration performed significantly better than chance (area under the curve, 0.74), roughly on a par with cord arterial pH and 5-min Apgar score, but it significantly underperformed compared with base excess (DeLong statistic, P <0.05). The 1-min Apgar score was not able to differentiate between infants who were later classified as HIE/PND and those with a good outcome. Isoprostane exhibited only a moderate ability to identify those infants with a poor outcome from among all neonates studied (area under the curve, 0.70), but it underperformed compared with the standard outcome measures (pH, base excess, and 1- and 5-min Apgar scores). This reflects the wider variance in 8-isoprostane concentrations among apparently healthy neonates, particularly when there has been evidence of cord compression during labor. Base excess appears to be a better predictor of HIE, suggesting that the duration of sublethal hypoxic insult, as well as its severity, plays an important role in the pathophysiology of HIE. The prediction of poor outcome cannot be improved by combining isoprostane with base excess because all 8 cases of HIE had base excess measurements between –12 and –20.
For those neonates with metabolic acidosis, cord arterial blood isoprostane concentrations and base excess showed a linear relationship, suggesting that oxidative stress plays a role in a significant proportion of cases with hypoxic-ischemic encephalopathy. Only 1 of the 3 perinatal deaths had a base excess in this range. This suggests that the other 2 perinatal deaths were unrelated to chronic intrapartum hypoxia. In fact, one was a fresh stillbirth associated with a massive placental abruption, and the other was a neonatal death attributable to chorioamnionitis but with no evidence of fetal distress or asphyxia at birth (Apgar scores of 9 at 1 min and 10 at 5 min). It is not surprising, therefore, to find that these 2 cases also had 8-isoprostane concentrations within the reference interval. Despite the presence of metabolic acidosis in the poor-outcome group, only 2 cases actually had a cord arterial blood pH <7.05 (1 stillbirth and 1 case with HIE). One healthy neonate also had a low pH and base excess of –12.
The links between obstetric complications, intrapartum fetal heart rate abnormalities, and perinatal outcome measures are tenuous, partly because of the therapeutic effect of intervention on outcome measurements (treatment paradox) (16). Obstetric intervention may remove the cause of fetal distress but does not necessarily represent an abrupt end to the pathologic processes. Unlike pH, which can be affected by intra- and postpartum resuscitation, lipid peroxide concentrations remain relatively stable immediately after delivery and may actually continue to increase after resuscitation if the hypoxic injury has been severe (17).
In the pathogenesis of perinatal HIE, variable degrees of hypoxia occur over a period of several hours, usually during labor. During this time, the fetus compensates for the production of excess lactic acid by producing buffering hydrogen ions, causing an increase in base deficit: the pH therefore remains within the reference interval until these buffering systems decompensate. Similarly, excess oxygen free radicals are removed by various circulating and tissue antioxidants, causing depletion of total antioxidant capacity; evidence of oxidative stress (increased lipid peroxidation) manifests only after these antioxidant systems decompensate. Whether these 2 systems are damaged by recurrent asphyxia to an equal extent and during the same time frame is beyond the scope of this observational study.
Our study highlights the fact that isoprostane concentrations have the same limitations as other measures of obstetric outcome, such as pH and Apgar score: i.e., they are increased in neonates with HIE, but may also be increased in apparently healthy infants and may be within reference values in infants who die from acute causes or in whom a pathology manifests after delivery.
Acknowledgments
We are grateful to all medical and nursing staffs in the labor wards and neonatal units at Prince of Wales Hospital, The First Affiliation Hospital of Medical College of Jinan University, and The Women’s & Children’s Hospital of Guangdong Province for case recruitment and sample collection. The study was supported by the Hong Kong Special Administration Region Research Grant Council (CUHK4329/99M). All contributors and guarantors in this study are independent from the funding agency, and the views expressed here are those of the authors. This report was partially awarded (Asian-Pacific Congress of Clinical Biochemistry Regional Service Award) and represented at the 10th Asian-Pacific Congress of Clinical Biochemistry and 42nd Annual Scientific Conference of the Australasian Association of Clinical Biochemists in Perth, Australia, during September 2004.
References
concentration. Am J Obstet Gynecol 2004;192:289-294.[CrossRef]
The following articles in journals at HighWire Press have cited this article:
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  K. S. Khaw, C. C. Wang, W. D. Ngan Kee, W. H. Tam, F. F. Ng, L. A. H. Critchley, and M. S. Rogers Supplementary oxygen for emergency Caesarean section under regional anaesthesia, Br. J. Anaesth., January 1, 2009; 102(1): 90 - 96. [Abstract] [Full Text] [PDF]
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, prematurity only; 
, perinatal death; 
, poor outcome (asphyxia at birth); 
, sepsis (no asphyxia at birth); 
, good outcome (asphyxia at birth); X, good outcome (no asphyxia); ——, lowess regression for the total sample.