Neonatal encephalopathy – the ACOG and AAP criteria

Radek Bukowski MD, PhD

and

Gary D. V. Hankins, M.D.

Division of Maternal Fetal Medicine

The University of Texas Medical Branch

Galveston, Texas

Introduction

The American College of Obstetricians and Gynecologists created a multidisciplinary Task Force to review and consider the current state of scientific knowledge about the mechanisms, timing, and etiologies of neonatal encephalopathy and cerebral palsy. Jointly sponsored by both the American College of Obstetricians and Gynecologists (ACOG) and by the American Academy of Pediatrics (AAP), a consensus document was developed and circulated to many other professional societies and governmental agencies for their critique, input, and endorsement.

Ultimately four criteria were identified, all of which were felt to be required to accurately define an acute intrapartum hypoxic event as sufficient to cause cerebral palsy. (Table I) Additionally, it was recognized that there are other criteria that suggest an intrapartum timing for the occurrence of the injury, but which by themselves are not sufficiently specific. (Table II)

Many nonspecific markers have been used to represent intrapartum asphyxia or birth asphyxia. Included among these have been such markers as meconium stained amniotic fluid, abnormalities of the electronic fetal monitor strip, or condition of the baby as described by Apgar scores or time to spontaneous respirations at birth. Given the lack of equivalence of any of these criteria, in addition to their lack of specificity, the potential for diagnostic misclassification has been enormous. 1 As one illustration, in the very recent past the International Classification for Disease Manual used the Apgar score to define not only birth asphyxia, but the degree of birth asphyxia. Unfortunately, once this diagnosis was entered onto the newborn’s chart, it tended to be perpetuated until it artificially achieved a status of reality. In contrast, epidemiological studies have suggested that in only 6-10% of cases of neonatal encephalopathy of a moderate to severe degree was the cause in fact isolated intrapartum hypoxia. 2-6 Some studies suggested that hypoxia may be superimposed upon other antepartum risk factors in as many as another 25% of cases of moderate to severe newborn encephalopathy. Ultimately, however, about 70% of moderate to severe newborn encephalopathy would appear to have no relationship whatsoever with intrapartum hypoxia or asphyxia. Among the host of variables that account for the at least 70% that are not intrapartum hypoxia or asphyxia are intrauterine growth restriction, intrauterine infection, maternal or fetal coagulation disorders, multiple pregnancies, antepartum hemorrhage, abnormal presentations, and chromosomal or congenital abnormalities. 4;7-36 Infections and inflammations along with thromboses and coagulopathies are recognized as being associated with white matter damage and cerebral palsy. Research in animals and humans has shown an association between inflammatory markers, elevated fetal cytokines in both amniotic fluid and fetal blood. 21-24 and periventricular leukomalacia and neonatal encephalopathy. 20 Coagulation disorders such as antithrombin III and protein C or protein S deficiencies, and prothrombin gene and factor V Leiden mutation can lead to stroke. 17;25-27 Occlusion of either arterial supply or venous return can also cause permanent focal damage. Such damage may rarely be secondary to trauma in pregnancy, especially if in conjunction with an existing coagulation disorder.

Early imaging studies may be useful in identifying and evaluating a specific etiology. Additionally, numerous genetic and metabolic disorders can present clinically as neonatal encephalopathy. Although there exists an ever expanding list of genetic causes, in most infants with neonatal encephalopathy the condition does not result from an identifiable genetic cause. Diagnosis of a genetic cause is unlikely unless there is heightened clinical suspicion based on specific findings or based upon family history. The provider should nonetheless attempt to identify such disorders by taking a detailed family history, performing a thorough examination of the infant for dysmorphic features consistent with a genetic etiology, and ordering appropriate laboratory studies if warranted. Additionally, the obstetric provider should remain in close contact with the pediatrician or neonatologist providing care to the child. Sharing of accurate information is of utmost importance to all concerned. Knowledge has certainly advanced to the point that today it is not plausible to hypothesize that cerebral palsy can be the result of intrapartum asphyxia absent the development of neonatal encephalopathy. Pathophysiologically it simply is not possible for intrapartum asphyxia to result in brain injury yet have an infant with a normal newborn course! 6;36

What then does this mean for the practicing obstetrician? First and foremost, there is a need for all of us to use precision in terminology. In those instances where one has delivered a baby that is significantly depressed, it is recommended that umbilical arterial and umbilical venous cord blood be analyzed for pH, blood gases, and buffering capacity and levels. Similarly, histopathologic examination of the placenta and placental membranes and umbilical cord may be enlightening as regards the cause of the newborn’s condition. The importance of early neuroimaging studies and collection of appropriate specimens to look for multiple organ system injuries to include the liver, coagulation system, and kidneys should be discussed with the infant’s caregiver. In regards to providing care to the severely growth restricted infant, Badawi and associates have shown that if the fetus is at less than the third percentile it will carry a 38-fold increase in risk of manifesting moderate to severe encephalopathy. Such growth restricted fetuses are also usually intolerant of labor. Accordingly, we discuss the delivery options with the parents in advance and encourage them to accept a cesarean section delivery timed such that the neonatal team can be available to receive and treat the infant. This concept is not original inasmuch as Sigmund Freud hypothesized long ago that the previously injured fetus is unable to adapt to the usual stresses of labor. In the instance of such a severely growth restricted fetus, one can almost be guaranteed of abnormal fetal heart rate tracings which will then be blamed as causal of injury, when in fact most often they have absolutely nothing to do with the injury. This practice recommendation has certainly not been tested in an interventional randomized trial, however, when the product of the pregnancy has a demonstrated risk of moderate to severe encephalopathy of above 10% it seems prudent to optimize the outcome for all concerned – fetus as well as obstetrician.

Finally, we would commend to all a thorough review of the document Neonatal Encephalopathy and Cerebral Palsy – Defining the Pathogenesis and Pathophysiology, co-published by the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics, and endorsed by a host of other organizations to include the Centers for Disease Control and Prevention, the March of Dimes Birth Defects Foundation, the National Institutes of Child Health and Human Development, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, the Society for Maternal Fetal Medicine, and the Society of Obstetricians and Gynaecologists of Canada. This has resulted in one of the most highly peer-reviewed and scientifically rigorous documents ever published on the topic.

References

1. Blair E. A research definition for 'birth asphyxia'? Dev Med Child Neurol 1993;35:449-52.

2. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998;317:1554-58.

3. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998;317:1549-53.

4. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr 1988;112:515-19.

5. MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054-59.

6. The American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy and Cerebral Palsy, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics. Neonatal encephalopathy and cerebral palsy: defining the pathogenesis and pathophysiology. Washington, DC: the American College of Obstetricians and Gynecologists, 2003:1-85.

7. Rosenbloom L. Dyskinetic cerebral palsy and birth asphyxia. Dev Med Child Neurol 1994;36:285-89.

8. Stanley FJ, Blair E, Hockey A, Petterson B, Watson L. Spastic quadriplegia in Western Australia: a genetic epidemiological study. I: Case population and perinatal risk factors. Dev Med Child Neurol 1993;35:191-201.

9. Michaelis R, Rooschuz B, Dopfer R. Prenatal origin of congenital spastic hemiparesis. Early Hum Dev 1980;4:243-55.

10. Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol 1998;179:507-13.

11. Govaert P, Matthys E, Zecic A, Roelens F, Oostra A, Vanzielegem B. Perinatal cortical infarction within middle cerebral artery trunks. Arch Dis Child Fetal Neonatal Ed 2000;82:F59-F63.

12. Miller V. Neonatal cerebral infarction. Semin Pediatr Neurol 2000;7:278-88.

13. Sreenan C, Bhargava R, Robertson CM. Cerebral infarction in the term newborn: clinical presentation and long-term outcome. J Pediatr 2000;137:351-55.

14. Harum KH, Hoon AH, Jr., Casella JF. Factor V Leiden: a risk factor for cerebral palsy. Dev Med Child Neurol 1999;41:781-85.

15. Chow G, Mellor D. Neonatal cerebral ischaemia with elevated maternal and infant anticardiolipin antibodies. Dev Med Child Neurol 2000;42:412-13.

16. Gunther G, Junker R, Strater R, Schobess K, Kurnik K, Heller C et al. Symptomatic ischemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors. Stroke 2000;31:2437-41.

17. Kraus FT, Acheen VI. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999;30:759-69.

18. Thorarensen O, Ryan S, Hunter J, Younkin DP. Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis. Ann Neurol 1997;42:372-75.

19. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278:207-11.

20. Kadhim H, Tabarki B, Verellen G, De Prez C, Rona AM, Sebire G. Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurology 2001;56:1278-84.

21. Martinez E, Figueroa R, Garry D, Visintainer P, Patel K, Verma U et al. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage. J Matern Fetal Investig 1998;8:101-07.

22. Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:1433-40.

23. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions and cerebral palsy. Am J Obstet Gynecol 1997;177:19-26.

24. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC et al. High expression of tumor necrosis factor-a and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997;177:406-11.

25. Kraus FT. Cerebral palsy and thrombi in placental vessels of the fetus: insights from litigation. Hum Pathol 1997;28:246-48.

26. Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 1998;44:665-75.

27. de Veber G, Andrew M. Cerebral sinovenous thrombosis in children. N Engl J Med 2001;345:417-23.

28. Barkovich AJ. MR and CT evaluation of profound neonatal and infantile asphyxia. AJNR Am J Neuroradiol 1992;13:959-72.

29. Barkovich AJ, Westmark K, Partridge C, Sola A, Ferriero DM. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol 1995;16:427-38.

30. Barkovich AJ. The encephalopathic neonate: choosing the proper imaging technique. AJNR Am J Neuroradiol 1997;18:1816-20.

31. Amess PN, Penrice J, Wylezinska M, Lorek A, Townsend J, Wyatt JS et al. Early brain proton magnetic resonance spectroscopy and neonatal neurology related to neurodevelopmental outcome at 1 year in term infants after presumed hypoxic-ischaemic brain injury. Dev Med Child Neurol 1999;41:436-45.

32. Hanrahan JD, Cox IJ, Azzopardi D, Cowan FM, Sargentoni J, Bell JD et al. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol 1999;41:76-82.

33. Cowan FM, Pennock JM, Hanrahan JD, Manji KP, Edwards AD. Early detection of cerebral infarction and hypoxic ischemic encephalopathy in neonates using diffusion-weighted magnetic resonance imaging. Neuropediatrics 1994;25:172-75.

34. Robertson RL, Ben-Sira L, Barnes PD, Mulkern RV, Robson CD, Maier SE et al. MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia. AJNR Am J Neuroradiol 1999;20:1658-70.

35. Blair E, Stanley FJ. When can cerebral palsy be prevented? The generation of causal hypotheses by multivariate analysis of a case-control study. Paediatr Perinat Epidemiol 1993;7:272-301.

36. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 1986;315:81-86.

37. Centers for Disease Control. Intrauterine West Nile Virus Infection - New York, 2002. MMWR 2002;51:1135-36.