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Vol. 42. Núm. 90.
Páginas 9044-9048 (Mayo 1999)
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Vol. 42. Núm. 90.
Páginas 9044-9048 (Mayo 1999)
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Cerebral palsy and its relationship with hypoxic ischemia
T KAB Eskes
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Cerebral palsy and its relationship with hypoxic ischemia


XXV Congreso Español de Ginecología y Obstetricia

June 7-12, 1999. Zaragoza, Spain


Tom K.A.B. Eskes MD PhD FRCOG FACOG (hon)

Departament of Obstetrics and Gynaecology

University Hospital Nijmegen

6500 HB Nijmegen (NL)


In contrast to the general belief general palsy has to be attributed to fetal hypoxia during pregnancy (70%) more than during labor or the neonatal period (30%). Terms like fetal distress or asphyxia have to be replaced by acidosis and hypoxia. Proper use of Doppler flow techniques, fetal heart rate patterns, the fetal biophysical scoring, and fetal behavioural states will allows to detect fetal hypoxia and/or acidosis at an early stage.

The main topics to concentrate upon for further progress are inborn malformations, multiple births, low birth weight, maternal infection and vaginal bleeding.

Cerebral palsy is a «time marker». The study of congenital malformations can contribute to this timing. In this regard the observation that children with cerebral palsy have a disturbance of tooth enamel is interesting and opens the possibility of time-marking in relation to the embryonic-fetal period of tooth development. Prevention of multiple births has to have high priority as well as the early recognition of low birth weight. Maternal infection is a potential hazard for fetal brain infection.

For placental abruption, due to hyperhomocysteinemia and (gene-) enzyme deficiency in folate metabolism folic acid supplementation might cause a preventive break through.

The orthopaedic surgeon William Little from London in the UK described in 1862 for the first time a puzzling disorder of children who were or became spastic in their legs and to a lesser degree in their arms(1). Little wrote «... in 1853, I showed that premature birth, difficult labours, mechanical injuries during parturition..., convulsions following the act of birth, were apt to succeeded by a determinate affection of the limbs of the child, which I designated spastic rigidity of the limbs of the child...». Little witnessed two hundred cases and considered the subject worthy the notice of the obstetrical society.

In 1897 however the famous psychiatrist Sigmund Freud disagreed strongly with Little''s view: «Difficult birth, in certain cases is merely a symptom of deeper effects that influence the fetus»(2). Both docters set the scene for the years to come: cerebral palsy an extrinsic or intrinsic disease? or maybe both?

Is labour the main cause (Little) of cerebral palsy or was the fetal brain already damaged before labour started (Freud)?

General palsy cannot be attributed to fetal hypoxia during labour alone

Oxygen supply to the human fetus and its oxygenation was and still is one of the most interesting topics in obstetrics and studied since the end of the nineteenth century. Research findings could demonstrate the unique situation of the fetus as «Mount Everest in utero»(3). This concept leaded to the idea of fetal vulnerability especially for oxygen lack cerebral damage and cerebral palsy acquired during labor.

It is now recognized that only 3-13 percent of cases with cerebral palsy can be attributed to birth events. About 10-20 percent of children who have cerebral palsy acquired the disorder after birth.

The neuroanatomic and neurophysiologic basic factors in cerebral palsy are now described as damage to deep structures in the cerebrum (basal ganglia). Cerebral palsy does not usually occur as a result of hypoxia at term but the hypoxic event has taken place prior to 35 weeks gestation(4).

The dynamics of fetal circulatory responses to hypoxia is a rapid centralization of blood flow in favor of the brain, heart, and adrenals at the expense of all other systems. At the nadir of severe anoxia circulatory decentralization occurs and the fetus will experience severe brain damage or expire unless immediate resuscitation occurs(5).

Essential criteria for hypoxic damage are acidemia, low Apgar score and multi-organ failure

For the obstetrician it is important to know the essential criteria before an hypoxic cause of cerebral palsy can be considered. First of all the terms fetal distress or birth asphyxia have to be avoided because of inappropriate use.

A neonate who has had hypoxia severe enough to result in hypoxic encephalopathy will show: profound metabolic or mixed acidemia (pH < 7.00, Base deficit > 12 mmol/l, a persistent Apgar score of 0 - 3 longer than 5 minutes and evidence of multi-organ failure(6).

A pre-requisite for the diagnosis of acidemia is that the obstetrician has to have the equipment for determining the acid-base balance either in umbilical cord or heel blood of fetus or neonate. Also the interpretation of these values has to be learned.

In regard to the Apgar score we have to use the score as meant by Virginia Apgar(7) indicating the effectiveness of resuscitation and not a prediction of outcome.

Multi-organ failure includes bowel necrosis, renal failure, hepatic injury, cardiac damage, respiratory complications or hematological abnormalities. Occasionally only the brain may be affected. The cerebral palsy is of the spastic quadriplegic or dyskinetic type.

There is a sequence of evens when the fetus deteriorates

The sequence of events when progressive fetal deterioration occurs is as follows(8):

* Pathologic Doppler flow patterns of the umbilical arteries,

* abnormal fetal behaviour states,

* change in the quality of fetal movements,

* heart rate decelerations,

* decreased heart rate variability,

* decreased fetal body movements,

* decreased respiratory movements and

* terminal fetal heart rate patterns.

Between the start of fetal deterioration and fetal death is a (small) window of neurologic morbidity.

Doppler flow techniques offer early diagnostics of fetal and placental vasoconstriction

Doppler flow diagnostic techniques are available also for the fetus. When the pulsatile index of the umbilical arteries is rising, the wide and dilated peripheral vascular bed in the placenta is changed into a constricted one. The fetus has to adapt to this higher peripheral resistance. Preferential flow or absence of flow can be than demonstrated in the fetal brain or umbilical arteries. When the end-diastolic flow is absent, or even reserved, placental insufficiency will lead to fetal death(9).

Fetal heart rate patterns offer only a diagnostic tool

The scarce randomized controlled evidence available for the use of electronic fetal monitoring states that this technique does not prevent cerebral palsy(10,11). Standardized definitions of some characteristics of FHR patterns have been reached (Task Force NIH). A base line heart rate of 110-160 bpm and a variability of 6-25 bpm and absent decelerations indicates that the fetus is not at risk of acidemia. The other extremes are absent FHR variability and persistent late or variable decelerations or bradycardia which can lead to damaging acidemia.

The timing of the hypoxic event occurring before or during labour is not easy to trace, but a sudden, rapid and sustained deteriotiation of the fetal heart rate pattern usually follows the hypoxic event where the pattern was previously normal. Other variants of the normal pattern have to wait for further research on the variability, validity for adverse outcome prompting obstetric intervention.

We also have to realize that FHR patterns can point to a diagnosis like suspicious for hypoxia, acidemia or umbilical cord compression and that electronic fetal monitoring is not a panacee for everything.

Ultrasound provides a fetal «biophysical score»

With ultrasound imaging techniques important studies were made on the assessment of fetal biophysical variables. Five biophysical variables were introduced: fetal breathing and body movements, fetal tone, amniotic fluid volume and fetal heart rate activity. In analogy with the Apgar socre 0-2 points were allocated to each variable. The so-called biophysical score correlated strongly with the perinatal mortality rate(12).

Antepartum assessment by fetal biophysical profile scoring was also associated with a significant reduction in the incidence of cerebral palsy compared with untested patients.

The relationship between the last test score and the incidence of cerebral palsy was inverse and exponential suggesting that antenatal asphyxia is an important and potentially avoidable cause of cerebral palsy(13).

Fetal biophysical assessment demonstrates a sequence of events in the «asphyxiation process».

The fetal biophysical assessment demonstrated a certain order of disapperance of biophysical activities in the «asphyxiation process»(14).

Those activities that became active first in fetal development, for example the fetal tone center in the cortical-subcortical area which is functioning at 7-9 weeks'' gestation, is the last to disappear during asphyxia. The presence of poor or absent fetal tone was associated with the highest perinatal death rate (42.8%).

The fetal movement center, starting at about 9 weeks of development, is more sensitive to hypoxia than the fetal tone center. The fetal heart rate activity center in the posterior hypothalamus and medulla is functional by the end of the second trimester and is the most sensitive to hypoxia.

Fetal behavioural states

Fetal behavioural states, using fetal body movements, fetal eye movements and fetal heart rate patterns as criteria, offered a further diagnostic tool for fetal neurologic assessment(15).

Doppler flow techniques, fetal heart rate patterns, fetal biophysical scoring and the assessment of fetal behavioural states now open a new possibility to study fetal neurology creating possibilities to trace a fetal neurological event in time, with the possibilities of prevention.

Main topics for further progress in the prevention of cerebral palsy are:

Inborn malformations, multiple birth, low birthweight and (pre-) term birth, maternal infection and vaginal bleeding during pregnancy.

Embryonic and fetal malformations represent the timing event of «cerebral palsy»

Infants with cerebral palsy are described who had major multiple congenital or metabolic abnormalities. Because cerebral palsy can be seen as a «timing event» it is important to recognize the various stages of embryonic and fetal development.

Recently it has been observed that children with cerebral palsy also have missing of enamel on certain teeth(16).

This tooth defect can be traced to specific time events in early development. The tooth and enamel development takes place between the 9th and 28th week of pregnancy. Enamel is derived from the ectoderm (as well as the brain). In the sixth week the ectodermal dental lamina give rise to the enamel organ, which secretes the enamel of the tooth. The neural crest cells that initially form the dental papilla (8 weeks) differentiate into the odontoblasts, which secrete the dentin.

This so-called bell stage of enamel development (17) offers the possibility to trace back the hypoxic event in utero in time.

Multiple pregnancy can be prevented

In case of multiple pregnancy the prevalence of cerebral palsy is higher than in single pregnancies. Retrospective studies demonstrate an excess of twins among children with cerebral palsy (5-10%). Population-bases studies report pravalence rates of 6.7 per 1.000 for twins and 32.0/1.000 for triplets. Monozygotic twins are more likely for seizure disorder than dizygotic twins(18). In recent years most multiple pregnancies occur due to overstimulation of the ovaries during infertility treatment.

The obstetrician has to communicate with those colleagues who are specialized in infertility treatment about prevention of overstimulation of Graafian follicles and too numerous conceptions.

Low birth weight and (pre)-term births are high-risk factors for cerebral palsy

Low birth weight babies are 100 times more likely to develop cerebral palsy than normal birth weight infants(19).

The obstetrician nowadays has more tools than 40 years ago when only abdominal palpation was available, The ultrasound technique makes it possible to measure fetal size. Percentiles of weight and statistical judgement of weight and growth are now available.

When there is a growth retardation of two to seven days of the embryo or fetus in the first trimester a immature /premature delivery a birth weight of less than 2500 gram between 24 and 32 weeks can be expected(20). This knowledge is important in avoiding hypoxia in low birth weigh and/or pre-term children.

Maternal infection contributes significantly towards cerebral palsy

Cerebral palsy can be caused by inflammation of the brain. Grether y cols. (1997)(21) analyzed neonatal blood between the first and 18th day of life from 31 children with cerebral palsy. Most of these children were full-term infants without known malformations or syndromes at birth. All of the children with cerebral palsy had higher concentration of chemokines in their blood than any of the controls. This information raises the possibility that fetal inflammation can damage the neonatal brain (Odds ratio 9.3 with a 95% confidence interval of 2.7-31.0). Cytokines can constrict the placental vasculature causing brain lesions through fetal hypertension. The obstetrician than has to be vigilant for early detection and treatment of an intra-uterine infection.

Vaginal bleeding due to placental abruption can possibly be prevented with folic acid

Vaginal bleeding accompanied by excessive uterine activity points towards the possibility of the syndrome of placental abruption. This syndrome is feared because of its high perinatal mortality and neuro- morbidity including cerebral palsy together with a risk for maternal morbidity (multi-organ failure) and even mortality. The fetus is usually growth retarded and the placenta can show numerous infarcts caused by maternal vascular disease especially in the uterine (spiral) arteries in which the normal pregnancy changes are absent(22).

The task of the obstetrician is here timely delivery to prevent further sequellae either vaginally or abdominally.

For primary prevention of placental abruption only a few risk factors are known like smoking, the use of cocaine and hypertension.

It was known that folic acid played some role in the pathogenesis of placental abrpution. Studies on folic acid levels however clearly failed to recognize women at risk until it was recognized that homocysteine, a prime parameter for folate status, had to be the target of interest. Indeed it was found that a substantial percentage of women who experienced placental abruption had a derangement of homocysteine metabolism(23,24) expressed as hyperhomocysteinaemia. A mutation of the methylenetetrahydrofolate reductase (MTHFR) gene is responsible for this «inborn error of metabolism»(25). Hyperhomocysteinaemia as well as the metabolic consequences of the gene mutation can be corrected with folic acid. It is to be expected that clinical trials will demonstrate the possibility that folic acid will prevent placental abruption to occur or recur like it did in neural tube defects(26).


1. Little, W.J, 1862. On the influence of abnormal parturition, difficult labours, premature birth, and asphyxia neonatorum, on the mental and physical condition of the child, especially in relation to deformities. Trans Obstet Soc London 1862;3:293-344.

2. Longo, LD, Ashwall S, William Osler. Sigmund Freud and the evolution of ideas concerning cerebral palsy. J Hist Neurosci 1993;2:255-82.

3. Eastman NJ. «Mount Everest in utero». Am J Obstet Gynecol 1954;67:701-11.

4. Towbin A. Brain damage in the newborn and its neurological sequels. PRM Publishing Company, Inc. Danvers, Massuchusetts, 1998.

5. Jensen A, Garnier Y, Berger R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur J Obstet Gynecol Reprod Biol 1999 to be published.

6. ACOG committee opinion: inappropriate use of the terms fetal distress and birth asphyxia. Int J Obstet Gynecol 1998;61:309-10.

7. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 1953;32:260-7.

8. Bekedam DJ, Visser GHA, Van der Zee AGJ, Snijders RJM, Poelman-Weesjes J. Abnormal velocity waveform of the umbilical artery in growth retarded fetuses: relationship to antepartum late heart rate decelerations and outcome. Early Hum Dev 1990;24:79- 90.

9. Reuwer PJHM, Symons EA, Bruinse HW. Intrauterine growth retardation: prediction of perinatal distress by Doppler ultrasound, Lancet 1987;2:415-8.

10. MacDonald D. Cerebral palsy and intrapartum fetal monitoring, N Engl J Med 1996;334:659-60.

11. Nelson KB, Dambrosia JM, Ting TY, Grether JK. Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N Engl J Med 1996;334:613-8.

12. Manning FA, Platt LD, Sipos L. Antepartum fetal evaluation: development of a fetal biophysical profile. Am J Obstet Gynecol 1980;136;787-95.

13. Manning FA, Bondaji N, Harman CR, Casiro O, Menticoglou S, Morriosn I, Berck DJ. Fetal assessment based on fetal biophysical profile scoring VIII the incidence of cerebral palsy. Am J Obstet Gynecol 1998;178:697-706.

14. Vintzileos AM, Campbell WA, Ingardia CJ, Nochimson DJ. The fetal biophysical profile and its predictive value. Obstet Gynecol 1983;62:271-8.

15. Nijhuis JG, Prechtl HFR, Martin CB Jr, Bots RSGM. Are there behavioural states in the human fetus? Early Hum Dev 1982;6: 177-95.

16. National Institute of Neurological disorders and stroke. Bethesda, Maryland USA. Cerebral Palsy Internet, 1999.

17. Larson WJ. Human Embryology. Churchill Livingstone New York, 1993.

18. Keith LG, Papiernik E, Keith DM, Luke B. Editors: Multiple pregnancy, epidemiology, gestation and perinatal outcome. The Parthenon Publishing Group New York, London, 1995.

19. Kuban KCK, Leviton A. Cerebral palsy. N Engl J Med 1994;330: 188-95.

20. Smith GCS, Smith MFS, McNay MB, Fleming JEE. First trimester growth and the risk of low birth weight. N Engl J Med 1998;339:1817-22.

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

22. Eskes TKAB. Abruptio placentae. A «classic» dedicated to Elizabeth Ramsey. Eur J Obstet Gynecol Biol 1997;75:63-70.

23. Goddijn-Wessel TA, Wouters MG, Van de Molen EF, Spuijbroek MD, Steegers-Theunissen RFM, Blom HJ, Boers GH. Eskes TK. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Biol 1996;66(1):23-9.

24. Van der Molen EF, Verbruggen B, Novákova·I, Monnens LAH, Blom HJ. Hyperhomocysteinemia and other thrombolic risk factors in women with placental vasculopathy (a case-control study). Lanceta to be published.

25. Van der Molen EF, Arends GE, Nelen WDLM, Van der Put NJM, Heil SG, Eskes TKAB, Blom HJ. A common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene as a new risk factor for placental vasculopathy. Amer J Obstet Gynaecol 1999b to be published.

26. Eskes TKAB. Open or closed. Eur J Obstet Gynecol Reprod Biol 1998;78:169-77.

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