Viewpoint on the Brain Disorder in Autism

  (based on a review of research papers in the medical literature)

Viewpoint on the brain disorder(2003) (View in 2000)

The auditory system The inferior colliculus Hemoglobin & the brain

Concepts of autism Autism spectrum Social responsibility

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Conrad Simon Memorial Research Initiative
Date posted: 
© Copyright 2003
Eileen Nicole Simon
Introduction | I. Brain damage at birth | II. Auditory system | III. Language
IV.  Childhood handicaps | V. Brainstem Damage | VI.  References | Summaries
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Topics (section links):

Introduction

Preface

I. BRAIN DAMAGE AT BIRTH
1 - Asphyxia at Birth
2 - Hypoxic Birth
3 - Asphyxia Versus Hypoxia
4 - Human Conditions
5 - Stages of Asphyxia
6 - The Umbilical Cord Lifeline
7 - Developmental Delay
8 - Poor Manual Dexterity
9 - Progressive Degeneration
10 - Autism and Complications at Birth
11 - Mercury, and Other Toxic Factors

II. THE AUDITORY SYSTEM
12 - Metabolic Rank Order
13 - The Auditory System
14 - Auditory Dysfunction

III. LANGUAGE
15 - Language by Ear
16 - Verbal Auditory Agnosia
17 - Echolalic Speech
18 - Echolalic Speech is Pragmatic

IV. CHILDHOOD HANDICAPS
19 - Auditory and Motor Handicaps
20 - Increased Incidence of Autism
21 - Fetal to Postnatal Adaptation
22 - Forgotten History
23 - Worth Remembering
24 - Hemoglobin
25 - Infant Anemia
26 - Autism in Twins
27 - Male-Female Differences

V. BRAINSTEM DAMAGE
28 - Variable Vulnerability
29 - Patterns of Damage
30 - Wernicke's Encephalopathy
31 - Suffocation at the Molecular Level
32 - Thiamine Deficiency
33 - Brain-Gut Relationship

VI. REFERENCES (for all sections)
34 - Bibliography (for section I)
35 - Autism and Complications at Birth
36 - Umbilical Cord Clamping

Summaries (for all sections)
    Summaries (for section I)

[Site Links]


Overview (Brain Damage at Birth):

Complications at birth have been acknowledged as common among children with autism, but then most often dismissed as part of a genetic predisposition rather than as cause of developmental problems. However, research done long ago with monkeys provides evidence that a few minutes of asphyxia at birth damages brainstem auditory nuclei. Such damage could underlie failure to learn language by ear. Early brainstem damage also disrupts later development of wider areas of the brain. The effects of oxygen insufficiency at birth merit as much attention as the search for genetic causes of autism.


. . . .


Blood flow is highest in the inferior colliculus
Figure 1: Experiments on cerebral circulation in cats showed greatest perfusion of a radioactive tracer after 60 seconds, thus greatest blood flow, in nuclei of the brainstem auditory pathway. These auditory nuclei are therefore vulnerable during a brief period of circulatory arrest or asphyxia, and also to metabolic disturbances caused by all other etiologic conditions associated with autism.
(from Kety, 1962, with permission from Columbia University Press)

Preface
Auditory system impairment is the focus of the viewpoint paper posted on this website in April 2000, and that all "co-morbid" conditions associated with autism can compromise auditory function. In this update I reiterate this view but urge consideration that perinatal complications may be the most important cause of autism; further that the now standard procedure of immediate clamping of the umbilical cord could explain the increased incidence (or prevalence) of autism. Asphyxia and hypoxia damage cell membranes and disrupt the normal blood-brain barrier to substances in the blood like bilirubin. Likewise the mercury preservative (thimerosol) in vaccines may enter and damage the brain in infants compromised by oxygen insufficiency during birth.


. . . .

I. BRAIN DAMAGE AT BIRTH

1 - Asphyxia at Birth
I first learned of the vulnerability of the auditory system to asphyxia at birth when the October 1969 issue of Scientific American arrived in my mailbox [1]. My son Conrad was then five years old and spoke only in parroted phrases. He loved music and sang all his favorite songs played on the radio. But his hearing was not normal. He became confused and upset in noisy environments and was terrified to enter a room where he saw a telephone. Trying to get him to listen to someone on the phone could also be upsetting.


On the other hand Conrad was often unresponsive to sounds that would attract the attention of most people – like something crashing down behind his back or being called by name from across the room.

When I saw the picture of damage to the inferior colliculus in the Scientific American article "Asphyxia at Birth" by William Windle, I gasped; to me damage in this pair of midbrain auditory nuclei could very well explain Conrad's auditory problems and especially why he wasn't learning to speak normally!

The experiments with monkeys on asphyxia at birth were undertaken to investigate cerebral palsy [1, 2]. However, the asphyxiated monkeys did not develop cerebral palsy, and at first no brain damage could be found. Seymour Kety in extensive studies on cerebral circulation had found a few years earlier that the highest blood flow in the brain is to the inferior colliculus [3,4], and suggested to Windle that he look there for damage – and there it was found!




Damage by asphyxia at birth
Figure 2: Damage to the inferior colliculus in a monkey subjected to a brief period of asphyxia at birth and sacrificed at five years of age (from Windle, 1969).

Normal appearance of the inferior colliculus
Figure 3: Appearance of the inferior colliculus in the brain of a normal monkey of the same age (from Windle, 1969).

Figure 1 (up top) is an autoradiogram from Kety's research (in cats) that shows the greatest amount of a radioactive tracer in the inferior colliculus one minute after injection – thus indicating greatest circulation in this small nucleus of the brainstem auditory pathway. Results of the first experiments on blood flow were confirmed using different radioactive tracers [5, 6]. Methods for glucose uptake and measurement of aerobic enzymes later revealed that aerobic metabolism is highest in the inferior colliculus and other brain areas of high circulatory rate [7-14]. Methods for both blood flow and glucose uptake have been widely used in research on neurochemistry [15-25]

Figure 2 (above) shows damage in the inferior colliculi of the brain of a monkey subjected to asphyxia at birth. The inferior colliculi are pitted by cavities (bilaterally) left by cells that disintegrated over the five year lifespan of the monkey. Figure 3 shows by way of contrast the appearance of the inferior colliculus in the brain of a normal monkey of the same age in which the densely packed neurons are intact.
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2 - Hypoxic Birth
In their initial experiments Windle and co-workers pulled a saline-filled rubber sac over the head of infant monkeys at birth and then clamped the umbilical cord [26, 27]. The lungs were thus prevented from taking in air, and blood flow from the placenta was abruptly blocked. The result was a sudden catastrophic cutoff of respiratory gas exchange (asphyxia). That this did not cause cerebral palsy came as a complete surprise!

Still looking for causes of cerebral palsy, Ronald Myers (a member of Windle's team) employed a technique to produce intermittent obstruction of umbilical blood flow late in gestation [2]. This somewhat less catastrophic disruption more closely mimics what happens during a difficult birth, in which a state of partial oxygen insufficiency develops (hypoxia). Even partial interference with oxygen delivery is not healthy, and cerebral palsy and the pattern of cortical damage long associated with cerebral palsy were observed in monkeys subjected to hypoxia in this way.

However, figure 4 is from Myers' 1972 paper, "Two patterns of perinatal brain damage and their conditions of occurrence," and confirms that damage to the inferior colliculus results when oxygen delivery is totally obstructed at birth.


Most vulnerable in Myers' monotonous rank order of brainstem nuclei
Figure 4: Damage to the inferior colliculi in a newborn monkey subjected to 12 minutes of total asphyxia (from Myers, 1972).

In addition to the inferior colliculi, Myers noted a predictable involvement of what he referred to as a "monotonous rank order" of brainstem structures. These included:

  • Superior olives
    (acoustic processing & relay)
  • Trigeminal nerve sensory nuclei
    (5th cranial nerve from face & jaw)
  • Gracile and cuneate nuclei
    (lower & upper body sensory)
  • Vestibular nuclei
    (equilibrium & reflexive orientation)
  • Ventral thalamic nuclei
    (sensory processing & relay from brainstem & cerebellum to cortex)


Miller and Myers (1970, 1972) found the same pattern of brainstem damage also in adult monkeys subjected to cardiac arrest; and, as in the case of infant monkeys, found damage in the cerebral cortex in adult monkeys subjected to partial disruption of circulation [28, 29]. The infant heart withstands asphyxia longer, but the infant brain is no less vulnerable to damage than that of the adult [2]. Furthermore, the difficult to detect pattern of brainstem lesions in newborn monkeys resulted in a disruption of brain development; monkeys kept alive to maturity were found to have neuropathological changes in additional subcortical areas and the cerebral cortex [30].
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3 – Asphyxia Versus Hypoxia
Asphyxia is not just a more severe degree of hypoxia. Asphyxia is a different kind of insult. In situations of reduced blood flow or oxygen insufficiency (hypoxia), protective mechanisms go into effect. For example, respiratory gas exchange (oxygen for carbon dioxide) is a biochemical process that provides immediate adjustment during any hypoxic episode: Except in the lungs, hemoglobin releases oxygen in exchange for carbon dioxide; this mechanism (the Bohr effect) has been understood for nearly a century [31-36]. Organs of highest metabolic rate produce the greatest amount of carbon dioxide end-product; and these organs are first to obtain oxygen from hemoglobin, especially during any episode of oxygen (or circulatory) insufficiency.

The brain is a collection of separate sensory, motor, and association circuits with differing metabolic needs; nuclei within the auditory system have the greatest need for respiratory gas exchange. Thus during chronic compromise of circulation, hemoglobin will give up the oxygen needed by the inferior colliculus first, and then reach the so-called "watershed" areas of the cerebral cortex depleted of what oxygen it carried from the lungs or placenta. Cortical damage is the expected and most usual consequence of this kind of prolonged hypoxia [2].

Kusumoto et al. (1995) used an autoradiographic method to investigate cerebral blood flow in immature gerbils after bilateral occlusion of the carotid arteries [21]. In 2-week old gerbils 5 minutes of bilateral carotid occlusion produced severe forebrain ischemia. By way of contrast, blood flow in the inferior colliculus and nuclei of the pons increased dramatically (in the inferior colliculus from 91 to 124 ml per minute and in the pons from 61 to 90 ml).

Occlusion of the carotid arteries produced a severe but partial blockage of blood flow; otherwise measurement of residual circulation would not have been possible. The forebrain became severely ischemic at the expense of whatever protective mechanism went into effect to increase circulation to the inferior colliculus and nuclei of the pons. The effects of this change in circulation can be compared with the prolonged partial hypoxia Myers (1972) found caused damage to motor areas of the cortex in monkeys [2].

Asphyxia is catastrophic and most often fatal if it persists to the point of cardiac failure. Newborn monkeys could in most cases be resuscitated after up to 20 to 25 minutes of asphyxia [1, 2], but visible damage was evident in the brain if asphyxia lasted for eight to ten minutes. Later developing neuropathological changes were found throughout the brain in monkeys kept alive for several years, even in animals subjected to asphyxia of duration too short to produce visible brainstem lesions [30]. The commonly held assumption that infants withstand asphyxia and hypoxia better than mature individuals would appear to be a dangerous misconception, especially in view of the impact of early impairment on maturation of the brain.
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4 - Human Conditions
Myers rejected the idea that the brainstem pattern of damage had any relevance to what happens in human cases of hypoxic birth. But, figure 5 (below) shows damage of the inferior colliculi found in a human infant who died from accidental suffocation; and symmetric bilateral involvement of brainstem nuclei (including the inferior colliculi) has been noted in at least seven other reports of damage found following death in infancy related to injury at birth [37-43].


Windle proposed that the brainstem pattern of damage might lead to what at that time was called "minimal cerebral dysfunction" [44-46]. But can any damage within the brain be considered minimal? Is brainstem damage any less serious than damage within the cerebral cortex?

Cerebral palsy and mental retardation have always been feared as possible outcomes of a difficult birth. The purpose of fetal monitoring during labor is to avoid or minimize hypoxic episodes. Hypoxia (partial oxygen insufficiency) is surely more common than total asphyxia as inflicted in Windle's initial experiments.

But a few minutes of asphyxia (total cutoff of oxygen) can occur during labor or at birth. For example, if the umbilical cord wraps tightly around the neck, blood flow and oxygen are cutoff until the baby's head is born and the cord can be unwound.

A baby born with the cord around the neck may be depressed from lack of blood supply from the placenta. In such cases the cord should be allowed to refill with blood and not be cut at least until the baby starts breathing.

But, immediate clamping of the umbilical cord has become a standard practice [47-53]. A paper by Saigal and Usher (1977) is often cited as the rationale for immediate clamping of the cord.


Inferior colliculus damage (bottom) in a human infant
Figure 5: Visible damage in the inferior colliculi (bottom) in the brain of a human infant (from Leech & Alvord 1977 [39], with permission from the American Medical Association).

Saigal and Usher expressed the opinion that too large a transfusion of placental blood could put an infant at risk for polycythemia and jaundice [47]. Research by Windle and coworkers was apparently already part of forgotten history; Lucey et al. (1964) had demonstrated that even very high levels of bilirubin did not cross the blood brain barrier except in monkeys whose brains were already damaged by asphyxia [54].
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5 - Stages of Asphyxia
Myers believed that hypoxia during gestation was a more likely cause of brain impairment than asphyxia at birth, but he nevertheless thoroughly investigated what happens during asphyxia. His data can now be viewed as relevant to what must happen when the umbilical cord is clamped before a newborn infant's lungs are functional – and bring to mind the stages of drowning described by Sebastian Junger in The Perfect Storm [55].

Myers monitored heart rate, blood pressure, oxygen, carbon dioxide, pH, and respiratory efforts during asphyxia and resuscitation. He noted that envelopment of the fetal head and clamping of the umbilical cord led to an immediate increase in blood pressure followed within 20 seconds by a rapid decrease associated with a rapid fall in blood oxygen. Aerobic metabolism is completely halted by a minute and a half.

Myers commented that the early fall in blood oxygen is the most precipitous and dramatic of any of the changes during asphyxia and leads to deterioration of the heart and other organs of the body. Neurons then become dependent on glycogen stores within their surrounding astrocytes. Gasping began six minutes after cord clamping and continued to the fourteenth minute of asphyxia after which the animal entered a terminal state of apnea, becoming pulseless, pale, and flaccid. Windle noted minimal damage in two monkeys asphyxiated for only six minutes [1].

Visible lesions of brainstem nuclei were always seen in monkeys subjected to asphyxia of ten minutes duration in Myers' experiments. But microscopic examination revealed that damage to mitochondria and cell membranes preceded development of visible damage [2]. Damage of cell membranes is the basis for breakdown of the blood-brain barrier that protects against entry of substances like bilirubin from the blood stream. Compromise of brain and other organs clearly precedes the occurrence of visible damage.

Progressive long-term signs of damage throughout the brain were found by Faro and Windle (1969) in monkeys kept alive for several months or years following asphyxia [30]. Respiratory distress due to lung damage from asphyxia also led to more widespread damage. Damage from oxygen insufficiency is not ordinarily as "monotonously" predictable as found in the early experiments on asphyxia.

Respect for animal rights would prevent doing further experimentation of this kind with monkeys. But the data obtained deserves renewed attention. Myers demonstrated that prolonged partial disruption of circulation in utero leads to damage of the cerebral cortex and cerebral palsy, and he adamantly rejected the idea that brainstem damage caused by catastrophic asphyxia could be relevant to any human condition. But we are suddenly living in a time of increased developmental disorders, autism, childhood asthma, early gastrointestinal problems, and infant anemia. Immediate clamping of the umbilical cord at birth has become a standard procedure in the past 20 years and should be investigated as possibly contributory to rising rates of these childhood disorders.
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6 – The Umbilical Cord Lifeline
Clamping the umbilical cord at birth is a human invention. The umbilical cord is an infant's lifeline throughout gestation; it should go without saying that it remains the newborn's lifeline until lung function is established. Clamping the cord before a baby breathes can be expected to result in at least a brief period of oxygen deprivation. Seven to ten minutes of asphyxia resulted in visible damage in the brainstem in newborn monkeys, but Myers (1972) described microscopic changes following asphyxia of lesser duration. In human infants a low Apgar score at five minutes is ominous, and associated with autism [56, 57]. Even the briefest lapse of respiration should be avoided.

Looking back at historical textbooks on obstetrics, waiting at least for the infant to breathe on its own was traditionally always required before cutting the cord [58-65].

For example from 1850 to 1930:
"A strong healthy child, as soon as it is born, will begin to breathe freely, and in most cases cry vigorously. As soon as it has thus given satisfactory proof of its respiratory power, you may at once proceed to separate it from its mother by tying and dividing the umbilical cord." (Swayne 1856, p20)

"As soon as the child cries we may proceed to tie and separate the cord." (Playfair 1880, p283)

"The cord should not be tied until the child has breathed vigorously a few times. When there is no occasion for haste, it is safer to wait until the pulsations of the cord have ceased altogether."
(Lusk 1882, pp214)


"Immediately after its birth the child usually makes an inspiratory movement and then begins to cry. In such circumstances it should be placed between the patient's legs in such a manner to have the cord lax, and thus avoid traction upon it… Normally the cord should not be ligated until it has ceased to pulsate…"
(Williams 4th ed 1917, p342)


"As soon as the lungs begin to function, the circulation through the umbilical arteries normally ceases in from five to fifteen minutes after birth." (Williams 6th ed 1931, p418)

By the 1940s a change of opinion is evident:
"We have adopted an intermediate course, feeling that to always wait for complete cessation of pulsation frequently interferes with the proper conduct of the third stage of labor, and at the same time, that most of the available blood in the cord had been incorporated in the fetal circulation during the few minutes immediately following delivery." (Stander [Williams 8th ed] 1941, p429)

"Whenever possible, clamping or ligating the umbilical cord should be deferred until its pulsations wane or, at least, for one or two minutes…There has been a tendency of late, for a number of reasons, to ignore this precept. In the first place the widespread use of analgesic drugs in labor has resulted in a number of infants whose respiratory efforts are sluggish at birth and whom the obstetrician wishes to turn over immediately to an assistant for aspiration of mucus, and if necessary, resuscitation. This readily leads to the habit of clamping all cords promptly." (Eastman [Williams 10th ed] 1950, p397)

Would Williams recognize the 20th edition of his textbook?
"Although the theoretical risk of circulatory overloading from gross hypervolemia is formidable, especially in preterm and growth-retarded infants, addition of placental blood to the otherwise normal infant's circulation ordinarily does not cause difficulty… Our policy is to clamp the cord after first thoroughly clearing the infant's airway, all of which usually takes about 30 seconds."
(Cunningham et al. [Williams 20th ed] 1997, p336)

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7 - Developmental Delay
Monkeys subjected to asphyxia did not develop cerebral palsy as had been expected. However, monkeys asphyxiated at birth displayed transient difficulties with motor control.


Normal monkey
Figure 6: A normal monkey assumes an alert crouching stance soon after birth (from Windle, 1969).

Asphyxiated monkey
Figure 7: A monkey subjected to asphyxia at birth is hypotonic and unable to control its arms and legs normally
(from Windle, 1969).

Figure 6 illustrates the ability of a normal infant monkey to rise and bear weight on its arms and legs. Figure 7 by way of contrast shows the early motor impairment of a monkey asphyxiated at birth.

Monkeys asphyxiated at birth appeared to "outgrow" this initial hypotonia, but deficits in manual dexterity and memory remained [1, 44-46.]

Human children with early deficits and delay in motor control may be diagnosed as having "hypotonic" cerebral palsy. More often parents are told their child is just a little slow and will outgrow such early problems.

But poor manual dexterity and lack of fine-motor control have been reported as part of "soft neurological signs" in children with autism. Handwriting that is poorly formed, overly large, and often laboriously produced has been noted, even in high-functioning children with Asperger's syndrome (see figure 8 below).

The asphyxiated monkeys were not deaf despite the severe damage in the inferior colliculi.



The loss of neurons evident in figures 2 and 4 above would suggest that sound transmission to the temporal lobes might be totally blocked. However, the monkeys with damage in the inferior colliculi startled at the sound of buzzers, but they did not localize the sound as normal infant monkeys did [45, 46]. Sound localization has been shown to be a major function of the inferior colliculus [66-68]. The startle reaction may be a reflex response mediated by nuclei in the lower brainstem auditory pathway.
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8 – Poor Manual Dexterity
Figure 8 is a letter home from my son Ralf when he was sixteen and at a school for children with learning disabilities (or what Windle referred to as minimal cerebral dysfunction). The handwriting illustrates his limitation in manual dexterity – compared for example with that of a college-bound teenager. Large handwriting (macrographia) has been described in individuals with high-functioning autism [69].

Ralf suffered a traumatic birth and his development, including speech, was alarmingly delayed. We were told not to worry, "He's a boy. Boys are often slow," etc.


My grandmother (living in Florida) arranged an appointment for Ralf to be evaluated by a neurologist when he was still not walking at eighteen months – she planned to come to Boston and take him herself if I would not. Concerns of family members I came to realize are often far more important than the advice of professional experts.

The neurologist told me Ralf had a "mild" form of cerebral palsy, hypotonic cerebral palsy. Then he added the phrase that echoes in my mind still to this day, "He'll never be quite the person he would have been."

Ralf did finally begin walking two months later, and like the asphyxiated monkeys outgrew his early motor problems. I am eternally grateful that he did not have spastic cerebral palsy. Ralf became quite athletic; running, swimming, basketball, and bicycling have given him a great deal of pleasure. But into adulthood his handwriting and other fine motor skills remain deficient.


Letter home from Ralf

Figure 8: Handwriting sample of a 16-year-old with what Windle would have termed "Minimal Cerebral Dysfunction," and residual deficits in manual dexterity.
[Top]

The rest of the world could care less about Ralf's "minimal" handicaps. I am painfully aware that he is not quite the person he would have been. Mostly he is not highly motivated or ambitious, but I know few people as sensitive to others, cheerful, and intent upon enjoying life. A few years ago I saw his "minimal cerebral dysfunction" recorded as PDD NOS. I dislike this label because of the pernicious implication that he and our family carry genes for "autism spectrum" disorder. Monkeys subjected to asphyxia at birth carried no such genes.

Ralf was crying at birth before anyone could answer my question whether the baby was a boy or a girl. A minute or so later the doctor held him up by his feet and announced, "It's a boy!" Ralf was howling and totally pink except for his feet, which were very blue. I suspect that oxygen deficiency occurred during my long difficult labor, and during which he incurred a prominent cephalhematoma. Because Ralf had a large head and forceps were required, I am sure a few minutes of total asphyxia occurred.

Conrad suffered a much more severe asphyxia; he was flaccid and ashen white at birth, and required resuscitation. I am sure Ralf suffered some impairment of function in the inferior colliculi, and that the same long-term progressive damage found in monkeys is the reason he is, as the neurologist told me many years ago, "not quite the person he would have been."

9 - Progressive Degeneration
Signs of on-going progressive neuropathologic changes were observed in monkeys kept alive for months or years following asphyxia at birth, even in monkeys without the characteristic lesions of the inferior colliculi [30]. Asphyxia had to be of seven to eight minutes duration before visible damage of the inferior colliculi was seen. Impairment of function within the inferior colliculus could reasonably be expected in cases where asphyxia was not of long enough duration to produce visible lesions.

Neurotransmitters are produced in the inferior and superior colliculi of immature laboratory animals, which are thought to guide formation of synapses and promote growth of later developing areas of the cerebral cortex [70, 71]. Submicroscopic as well as visible damage within the inferior colliculi might then disable the biochemical mechanisms required for normal maturation of the cerebral cortex. Failure to fully develop frontal lobe cognitive abilities becomes more and more painfully evident as a child with autism or "minimal cerebral dysfunction" matures. [Top]

Neuropathology found following long-term survival after asphyxia at birth involved:


Brainstem

periaqueductal gray

oculomotor nuclei

inferior olives

reticular formation

Cerebellum

diminished Purkinje cells

Subcortical

mammillary bodies

hippocampus

amygdala

Cortical

frontal and parietal cortex

corpus callosum (left-right hemisphere connection)

ventricular enlargement

Anomalies in many of these areas have been reported as part of the neuropathology of autism or its behavioral handicaps [72-82]. Functional impairment of the amygdala, cerebellum, hippocampus, and frontal lobe connections are at the forefront of theories of autistic disorder. Long-term brain changes following asphyxia at birth provide a mechanism by which impairment of these brain areas might come about, without having to hunt for gene loci on chromosomes.
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10 - Autism and complications at birth
Autism is not generally acknowledged as having anything to do with difficulties at birth. Perinatal problems have been discussed in several papers, but then usually dismissed as minimal or non-specific [57, 83-95]. As Juul-Dam et al. (2001) noted "No presently apparent unifying feature" can be identified as a unique predisposition for autism.

But oxygen insufficiency is the major "unifying feature" of all complications at birth. Respiration is the most immediate and essential need of all life forms dependent upon oxygen. Asphyxia at birth results in selective damage within the brainstem auditory pathway, and auditory dysfunction is a characteristic of autistic disorder. Failure to learn language by ear, as normal children all do, is the most serious obstacle to further development for children with autism. Asphyxia at birth warrants investigation as a cause of autism as much as if not before consideration of genetics, infections, or exposure to toxic substances.

Some researchers have argued that complications at birth are due to a pre-existing problem with the infant or mother. But damage to the inferior colliculi had nothing to do with any pre-existing problem of monkeys subjected to asphyxia at birth.


Cephalhematoma
Figure 9: Cephalhematoma, bruising of head caused by dystocia or difficult passage through the maternal pelvis
(from Towbin, 1970).

One monkey followed by Faro and Windle (1969) had been a breech birth and suffered asphyxia, and damage to the inferior colliculi, because of difficulty extracting the head [30]. Birth can be a hazardous experience, but malpresentation and dystocia should not be viewed as unpreventable pre-existing (genetic) causes of brain damage.

The inferior colliculi are small nuclei in the tectum (roof) of the midbrain, and although prominent these lesions were overlooked in the search for anticipated involvement of the cerebral cortex in the asphyxiated monkeys.

Neuropathology is not easily detected in autism. Pathology has been reported in brains from some autistic individuals, which included some of the rank-order of brainstem nuclei Myers found damaged by asphyxia [72-82], as well as the brain structures affected by progressive "trans-neuronal" degeneration [30].

Only Williams et al. (1980) reported looking for damage in the inferior colliculi in one case of autism in which asphyxia at birth had been suspected as a possible cause [72].


But the article by Willams et al. is a prime example of the difficulty finding visible signs of brain impairment: Reduced Purkinje cell density was noted in the cerebellum of a male patient who had a chronic seizure disorder and died at age twelve. This patient also had reduced pyramidal cell dendrites in the midfrontal gyrus. The same pyramidal cell abnormality was seen in the brain of a 27-year old autistic subject who belatedly was found to have phenylketonuria (PKU), and this was the only abnormality found!

Figure 9 is a drawing from an article by Towbin (1970) in a textbook of neuropathology [96]. The drawing bears such a striking resemblance to my son Ralf that I contacted Dr. Towbin, who told me the drawing was made in September 1962 in the newborn nursery at the Boston Lying-In Hospital. That is when and where Ralf was born, and if figure 9 is not a drawing of him, it looks just like him, even today in adulthood. His eyes were swollen shut right after birth (more so than shown in the picture), and he still bears a scar under his right eye from use of forceps.

I was told my difficult delivery with Ralf was because he was a "brow presentation." The article by Towbin and many chapters in textbooks of obstetrics describe the dangers of malpresentation at birth.
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11 - Mercury and Other Toxic Factors
Windle and coworkers found that bilirubin levels (from jaundice) can be very high and not cross the blood brain barrier (BBB), and therefore not damage the brain. In experiments with newborn monkeys, bilirubin was found to enter brain tissue only in those animals also subjected to asphyxia [54]. Compromise of the BBB by asphyxia may be part of a protective response to increase blood flow and help get oxygen into neurons.


But compromise of the BBB by asphyxia also allows bilirubin or any other toxic substance in the blood to get into brain tissue and damage it further. Thus administration of hepatitis B (or any other) vaccine in the newborn nursery may likewise compound the effects of asphyxia incurred during complications at birth.

Many parents are convinced that the mercury preservative in vaccines caused their child to develop autism [97-101]. The auditory system is damaged by mercury poisoning in Minamata disease [102]. Loss of BBB integrity could allow the small amounts of mercury preservative in vaccines to get into brain tissue just as happens with bilirubin, especially vaccines given in the first hours or days after birth.


Kernicterus
Figure 10: Kernicterus (bilirubin staining of subcortical nuclei) found only in monkeys subjected to asphyxia (from Windle, 1969).

Figure 10 shows staining by bilirubin of nuclei in the basal ganglia (subcortical motor nuclei) in a monkey subjected to asphyxia at birth. How can it be safe to assume that the immature brain is more resistant to oxygen insufficiency? Changes in the blood-brain barrier caused by asphyxia are not visible, and disruption of metabolic systems that precede the appearance of visible damage may still lead to serious impairment of function.


. . . .

[Top]
VI. REFERENCES

34 - Bibliography

Asphyxia and Hypoxia at Birth
  1. Windle, W. F. (1969). Brain damage by asphyxia at birth. Scientific American, 221(#4), 76-84.
  2. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276.
    Back to: Asphyxia at birth, Hypoxic birth, Asphyxia vs hypoxia, Umbilical cord lifeline,
    Developmental delay, [Top]

    Cerebral Blood Flow
  3. Landau WM, Freygang WH, Rowland LP, Sokoloff L, Kety SS (1955) The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Transactions of the American Neurological Association 80:125-129.
  4. Kety SS (1962) Regional neurochemistry and its application to brain function. In French, JD, ed, Frontiers in Brain Research. New York: Columbia University Press, pp 97-120.
  5. Reivich M, Jehle J, Sokoloff L, Kety SS (1969) Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. Journal Of Applied Physiology 27:296-300.
  6. Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo-14-C-antipyrine. American Journal of Physiology, 234, H59-H66.
    Back to: Figure 1, Asphyxia at Birth, [Top]

    Measures of Aerobic Metabolism (Deoxyglucose Uptake)
  7. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. Journal of Neurochemistry 28:897-916.
  8. Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Gallagher B, Hoffman E, Alavi A, Sokoloff L (1977) Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose. Acta Neurologica Scandinavica. Supplementum 64:190-1
    Back to: Asphyxia at Birth, Metabolic Rank Order, [Top]

    Correlates of High Deoxyglucose Uptake
  9. Gross PM, Sposito NM, Pettersen SE, Panton DG, Fenstermacher JD. Topography of capillary density, glucose metabolism, and microvascular function within the rat inferior colliculus. J Cereb Blood Flow Metab. 1987 Apr;7(2):154-60.
  10. Rahner-Welsch S, Vogel J, Kuschinsky, W (1995) Regional congruence and divergence of glucose transporters (GLUT1) and capillaries in rat brains. Journal of Cerebral Blood Flow and Metabolism 15:681-686.
  11. Zeller K, Rahner-Welsch S, Kuschinsky W (1997) Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism 17:204-209.
  12. Calingasan NY, Baker H, Sheu KF, Gibson GE (1994) Distribution of the alpha-ketoglutarate dehydrogenase complex in rat brain. Journal Of Comparative Neurology 346:461-479.
  13. Hovda DA, Chugani HT, Villablanca JR, Badie B, Sutton RL (1992) Maturation of cerebral oxidative metabolism in the cat: a cytochrome oxidase histochemistry study. Journal of Cerebral Blood Flow and Metabolism 12:1039-1048
  14. Gonzalez-Lima F, Valla J, Matos-Collazo S (1997) Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. Brain Research 752:117-126.
    Back to: Asphyxia at Birth, [Top]

    Research on Blood Flow and Glucose Uptake
  15. Sokoloff L (1981) Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. Journal of Cerebral Blood Flow and Metabolism 1:7-36.
  16. Hakim AM and Pappius HM (1981) The effect of thiamine deficiency on local cerebral glucose utilization. Annals of Neurology 9:334-339.
  17. Vingan RD, Dow-Edwards ML, Riley EP (1986) Cerebral metabolic alterations in rats following prenatal alcohol exposure: a deoxyglucose study. Alcoholism, Clinical and Experimental Research 10:22-26.
  18. Bertoni JM and Sprenkle PM (1989) Lead acutely reduces glucose utilization in the rat brain especially in higher auditory centers. Neurotoxicology 9:235-242.
  19. Nehlig A, Pereira de Vasconcelos A, Boyet S (1989) Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [14C]iodoantipyrine technique in freely moving rats. Journal of Cerebral Blood Flow and Metabolism 9:579-588.
  20. Dow-Edwards DL, Freed LA, Fico TA (1990) Structural and functional effects of prenatal cocaine exposure in adult rat brain. Brain Research Developmental Brain Research 57:263-268.
  21. Kusumoto, M., Arai, H., Mori, K., & Sato, K. (1995). Resistance to cerebral ischemia in developing gerbils. Journal of Cerebral Blood Flow and Metabolism, 15, 886-891.
    Back to: Asphyxia Vs Hypoxia, [Top]

  22. Chugani HT, Hovda DA, Villablanca JR, Phelps ME, Xu, W-F (1991) Metabolic maturation of the brain: a study of local cerebral glucose utilization in the developing cat. Journal of Cerebral Blood Flow and Metabolism 11:35-47.
  23. Burchfield DJ, Abrams RM (1993). Cocaine depresses cerebral glucose utilization in fetal sheep. Developmental Brain Research 73:283-288.
  24. Grünwald F, Schröck H, Biersack HJ, Kuschinsky W (1993) Changes in local cerebral glucose utilization in the awake rat during acute and chronic administration of ethanol. Journal of Nuclear Medicine 34:793-798.
  25. Antonelli PJ, Gerhardt KJ, Abrams RM, Huang X. Fetal central auditory system metabolic response to cochlear implant stimulation. Otolaryngol Head Neck Surg. 2002 Sep;127(3):131-7.
    Back to: Asphyxia at birth, [Top]

    Early Research of Windle and Coworkers
  26. Ranck JB, Windle WF (1959). Brain damage in the monkey, Macaca mulatta, by asphyxia neonatorum. Experimental Neurology 1: 130-154.
  27. Jacobson HN & Windle WF (1960) Responses of foetal and new-born monkeys to asphyxia. The Journal of Physiology (London) 153:447-456.
    Back to: Hypoxic Birth, [Top]

    Circulatory Arrest in Adult Monkeyts
  28. Miller JR, Myers RE (1970) Neurological effects of systemic circulatory arrest in the monkey. Neurology 20:715-724.
  29. Miller JR, Myers RE (1972) Neuropathology of systemic circulatory arrest in adult monkeys. Neurology 22:888-904.
    Back to: Hypoxic Birth, [Top]

    Developmental Degeneration Following Asphyxia
  30. Faro MD & Windle WF (1969) Transneuronal degeneration in brains of monkeys asphyxiated at birth. Experimental Neurology 24:38-53.
    Back to: Hypoxic Birth, Asphyxia vs Hypoxia, Stages of Asphyxia,
    Progressive Degeneration, Complications At Birth, [Top]

    Biochemistry of Respiration
  31. Bohr C, Hasselbalch K, Krogh A (1904) Ueber einen in biologischer Beziehung wichtigen Einfluss, den die Kohlensaurespannung des Blutes auf dessen Sauerstoffbindung ubt. Skandinavishes Archiv fur Physiologie 16:402-412.
  32. Tigerstedt R (1911) Christian Bohr: Ein Nachruf. Skandinavishes Archiv fur Physiologie 25:v-xviii.
  33. Edsall JT (1980) Hemoglobin and the origins of the concept of allosterism. Federation Proceedings 39:226-35
  34. Dickerson RE, Geis I (1983) Hemoglobin: structure, function, evolution, and pathology. Menlo Park, California: Benjamin Cummings.
  35. Schaffartzik W, Spies C (1996) Christian Bohr -- ein vergessener Wegbereiter der Atemphysiologie. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie 31:239-243
  36. Simon N (1998) Hemoglobin and the brain: a piece of the autism puzzle? Journal of Autism and Developmental Disorders 28:579-80.
    Back to: Asphyxia Versus Hypoxia , [Top]

    Brainstem Lesions in Human Infants
  37. Norman MG (1972) Antenatal neuronal loss and gliosis of the reticular formation, thalamus, and hypothalamus. A report of three cases. Neurology (Minneapolis) 22:910-916.
  38. Griffiths AD, Laurence KM (1974) The effect of hypoxia and hypoglycemia on the brain of the newborn human infant. Developmental Medicine and Child Neurology 16:308-319.
  39. Grunnet ML, Curless RG, Bray PF, Jung AL (1974) Brain changes in newborns from an intensive care unit. Developmental Medicine and Child Neurology 16:320-328.
  40. Schneider H, Ballowitz L, Schachinger H, Hanefield F, Droeszus J-U (1975) Anoxic encephalopathy with predominant involvement of basal ganglia, brain stem, and spinal cord in the perinatal period. Acta Neuropathologica (Berlin) 32:287-298.
  41. Leech RW, Alvord EC (1977) Anoxic-ischemic encephalopathy in the human neonatal period, the significance of brain stem involvement. Archives of Neurology 34:109-113.
  42. Roland EH, Hill A, Norman MG, Flodmark O, MacNab AJ (1988) Selective brainstem injury in an asphyxiated newborn. Annals of Neurology 23:89-92.
  43. Natsume J, Watanabe K, Kuno K, Hayakawa F, Hashizume Y (1995) Clinical, neurophysiologic, and neuropathological features of an infant with brain damage of total asphyxia type (Myers). Pediatric Neurology 13:61-64.
    Back to: Human Conditions, [Top]

    Minimal Cerebral Dysfunction?
  44. Windle WF (1969) Asphyxial brain damage at birth, with reference to the minimally affected child. In Perinatal Factors Affecting Humn Development. Pan American Health Organization, proc. spec. session, 8th meeting, pp. 215-221
  45. Sechzer JA, Faro MD, Barker JN, Barsky D, Gutierrez S, Windle WF. Development behaviors: delayed appearance in monkeys asphyxiated at birth. Science. 1971 Mar 19;171(976):1173-5.
  46. Sechzer JA, Faro MD, Windle WF. Studies of monkeys asphyxiated at birth: implications for minimal cerebral dysfunction. Semin Psychiatry. 1973 Feb;5(1):19-34.
    Back to: Human Conditions, Developmental Delay, [Top]

    Umbilical Cord Clamping
  47. Saigal S, Usher RH. Symptomatic neonatal plethora. Biol Neonate. 1977;32(1-2):62-72.
  48. American College of Obstetricians and Gynecologists Obstetric Practice Committee (1994) Utility of umbilical cord blood acid-base assessment. ACOG Committee Opinion: Committee on Obstetric Practice. Number 138--April 1994. International Journal of Gynaecology and Obstetrics 45:303-304.
  49. Wardrop CA, Holland BM. The roles and vital importance of placental blood to the newborn infant. J Perinat Med. 1995;23(1-2):139-43.
  50. Morley GM (1998) Cord Closure: Can Hasty Clamping Injure the Newborn? OBG MANAGEMENT July 1998; 29-36.
  51. Papagno L. Umbilical cord clamping. An analysis of a usual neonatological conduct. Acta Physiol Pharmacol Ther Latinoam. 1998;48(4):224-7.
  52. Rabe H, Wacker A, Hulskamp G, Hornig-Franz I, Schulze-Everding A, Harms E, Cirkel U, Louwen F, Witteler R, Schneider HP. A randomised controlled trial of delayed cord clamping in very low birth weight preterm infants. Eur J Pediatr. 2000 Oct;159(10):775-7.
  53. Mercer JS. Current best evidence: a review of the literature on umbilical cord clamping. J Midwifery Womens Health. 2001 Nov-Dec;46(6):402-14.
    Back to: Human Conditions, Umbilical Cord Lifeline, Complications At Birth, [Top]

    Bilirubin Only Gets into Oxygen-Deprived Tissues
  54. Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF (1964) Kernicterus in asphyxiated newborn monkeys. Experimental Neurology 9:43-58.
    Back to: Human Conditions, Mercury and other toxic factors, [Top]

    Stages of Drowning
  55. Junger S (1998) The Perfect Storm. New York: HarperTorch/ HarperCollins, pp 179-185 (in the chapter: The Zero-Moment Point).
    Back to: Stages of Asphyxia, [Top]

    Low 5-minute Apgar Score
  56. Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: a population-based register study of 1 million term births. Obstet Gynecol. 2001 Jul;98(1):65-70.
  57. Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002 Jul;13(4):417-23.
    Back to: Umbilical Cord Lifeline, Complications At Birth, [Top]

    Historical Textbooks on Obstetrics
  58. Swayne JG (1856) Obstetric Aphorisms: For the use of students commencing midwifery practice. London: John Churchill.
  59. Playfair WS (1880) A Treatise on the Science and Practice of Midwifery. Philadelphia: Henry C. Lea, p 283
  60. Lusk WT (1882) The Science and Art of Midwifery. New York: D Appleton and Company, pp 214-215
  61. Williams JW (1917) Obstetrics: A Text-Book for the Use of Students and Practicioners, Fourth Edition. New York & London: D. Appleton and Company, pp 342-343
  62. Williams JD (1930) Obstetrics: A Text-Book for the Use of Students and Practicioners, Sixth Edition. New York: D. Appleton-Century, pp 418-419
  63. Stander HJ (1941) Williams Obstetrics, Eighth Edition. New York, London: D. Appleton-Century company, pp 429-430.
  64. Eastman HJ (1950) Williams Obstetrics, Tenth Edition. New York: Appleton-Century-Crofts , pp 397-398
  65. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC, Hankins GDV, Clark SL, Williams JW, (1997) Williams Obstetrics, Twentieth Edition. Stamford, Conn: Appleton & Lange, pp 336-337.
    Back to: Umbilical Cord Lifeline, [Top]

    Sound Localization
  66. Rose JE, Gross NB, Geisler CD, Hind JE (1966) Some neural mechanisms in the inferior colliculus of the cat which may be relevant to localization of a sound source. Journal of Neurophysiology 29:288-314.
  67. Brainard MS (1994) Neural substrates of sound localization. Current Opinion In Neurobiology 4:557-562
  68. Litovsky RY, Delgutte B. Neural correlates of the precedence effect in the inferior colliculus: effect of localization cues. J Neurophysiol. 2002 Feb;87(2):976-94.
    Back to: Developmental Delay, [Top]

    Large Handwriting (Macrographia)
  69. Beversdorf DQ et al. (2001) Macrographia in high functioning autism. Journal of Autism and Developmental Disorders 31:97-101.
    Back to: Poor Manual Dexterity, [Top]

    Neurotrophic Influences on Maturation
  70. VonHungen K, Roberts S, Hill DF (1974) Developmental and regional variations in neurotransmitter-sensitive adenylate cyclase systems in cell-free preparations from rat brain. Journal of Neurochemistry 22:811-819.
  71. Kungel M and Friauf E (1995). Somatostatin and leu-enkephalin in the rat auditory brainstem during fetal and postnatal development. Anatomy and Embryology, 191, 425-443.
    Back to: Progressive Degeneration, [Top]

    Brain Abnormalities in Autism
  72. Williams RS, Hauser S, Purpura DP, deLong GR, Swisher CN (1980) Autism and mental retardation: Neuropathologic studies performed in four retarded persons with autistic behavior. Archives of Neurology 37:748-753.
  73. Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, Ritvo A (1986) Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report. American Journal of Psychiatry 143:862-6
  74. Jacobson R, LeCouteur A, Howlin P, Rutter M (1988) Selective subcortical abnormalities in autism. Psychological Medicine 18:39-48.
  75. Gaffney GR, Kuperman S, Tsai LY, Minchin S (1988) Morphological evidence for brainstem involvement in infantile autism. Biological Psychiatry 24:578-586.
  76. Egaas B, Courchesne E, Saitoh O (1995) Reduced size of corpus callosum in autism. Archives of Neurology 52:794-801.
  77. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL (1988) Hypoplasia of cerebellar vermal lobules VI and VII in autism. New England Journal of Medicine 318:1349-1354.
  78. Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, Kuroda Y (1995) Development of the brainstem and cerebellum in autistic patients. Journal of Autism and Developmental Disorders 25:1-18.
  79. Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology 370:247-261.
  80. Piven J, Bailey J, Ranson BJ, Arndt S (1997) An MRI study of the corpus callosum in autism. American Journal of Psychiatry 154:1051-1056
  81. Kemper TL, Bauman M (1998). Neuropathology of infantile autism. Journal of Neuropathology and Experimental Neurology 57:645-652 .
  82. Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, Rutter M, Lantos P (1998) A clinicopathological study of autism. Brain 121:889-905.
    Back to: Progressive Degeneration, Complications At Birth, [Top]

    Autism and Complications at Birth
  83. Lobascher ME, Kingerlee PE, Gubbay SS. Childhood autism: an investigation of aetiological factors in twenty-five cases. Br J Psychiatry. 1970;117:525-529.
  84. Finegan J-A, Quarrington B. Pre-, peri- and neonatal factors and infantile autism. J Child Psychol Psychiatry. 1979;20:119-128
  85. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989 May;30(3):405-16.
  86. Lord C, Mulloy C, Wendelboe M, Schopler E. Pre- and perinatal factors in high-functioning females and males with autism. J Autism Dev Disord. 1991 Jun;21(2):197-209.
  87. Ghaziuddin M, Shakal J, Tsai L. Obstetric factors in Asperger syndrome: comparison with high-functioning autism. J Intellect Disabil Res. 1995 Dec;39 ( Pt 6):538-43.
  88. Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997 Feb;36(2):272-81
  89. Burd L, Severud R, Kerbeshian J, Klug MG. Prenatal and perinatal risk factors for autism. J Perinat Med. 1999;27(6):441-50.
  90. Matsuishi T, Yamashita Y, Ohtani Y, Ornitz E, Kuriya N, Murakami Y, Fukuda S, Hashimoto T, Yamashita F. Brief report: incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. J Autism Dev Disord. 1999 Apr;29(2):161-6
  91. Juul-Dam N, Townsend J, Courchesne E. Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics. 2001 Apr;107(4):E63.
  92. Bodier C, Lenoir P, Malvy J, Barthélemy C, Wiss M, Sauvage D. (2001) Autisme et pathologies associées. Étude clinique de 295 cas de troubles envahissants du developpment. [Autism and associated pathologies. Clinical study of 295 cases involving development disorders] Presse Médicale 2001 Sep 1; 30(24 Pt 1):1199-203. French.
  93. Greenberg DA, Hodge SE, Sowinski J, Nicoll D. Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet 2001 Nov;69(5):1062-7
  94. Zwaigenbaum L, Szatmari P, Jones MB, Bryson SE, MacLean JE, Mahoney WJ, Bartolucci G, Tuff L. Pregnancy and birth complications in autism and liability to the broader autism phenotype. J Am Acad Child Adolesc Psychiatry 2002 May;41(5):572-9
  95. Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci. 2002 Sep;112(9):1085-98.
    Back to: Complications At Birth, [Top]

    Cephalhematoma
  96. Towbin A (1970) Neonatal damage of the central nervous system. In Tedeschi CG (ed) Neuropathology: Methods and Diagnosis. Boston, Little, Brown & Co., pp 609-653.
    Back to: Complications At Birth, [Top]

    Controversy Over Mercury Preservatives in Vaccinge
  97. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry. 2002;7 Suppl 2:S42-3.
  98. Blaxill MF. Any changes in prevalence of autism must be determined. BMJ. 2002 Feb 2;324(7332):296.
  99. Borchers AT, Keen CL, Shoenfeld Y, Silva J Jr, Gershwin ME. Vaccines, viruses, and voodoo. J Investig Allergol Clin Immunol. 2002;12(3):155-68.
  100. Kimmel SR. Vaccine adverse events: separating myth from reality. Am Fam Physician. 2002 Dec 1;66(11):2113-20.
  101. Wakefield AJ. Measles, mumps, and rubella vaccination and autism. N Engl J Med. 2003 Mar 6;348(10):951-4; author reply 951-4.
    Back to: Mercury and other toxic factors, [Top]

    Mercury Damages the Auditory System
  102. Oyanagi K, Ohama E, & Ikuta F. (1989). The auditory system in methyl mercurial intoxication: a neuropathological investigation on 14 autopsy cases in Niigata, Japan. Acta Neuropathologica (Berlin), 77, 561-568.
    Back to: Mercury and other toxic factors, [Top]

. . . .

35 – Autism and Complications at Birth


  • "… 5 items were found to significantly predict group membership (prescriptions taken during pregnancy, length of labor, viral infection, abnormal presentation at delivery, and low birth weight)."
    Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci. 2002 Sep;112(9):1085-98.

  • "Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results:The risk of autism was associated with daily smoking in early pregnancy (OR = 1.4; CI = 1.1-1.8), maternal birth outside Europe and North America (OR = 3.0; CI = 1.7-5.2), cesarean delivery (OR = 1.6; CI = 1.1-2.3), being small for gestational age (SGA; OR = 2.1; CI = 1.1-3.9), a 5-minute Apgar score below 7 (OR = 3.2, CI = 1.2-8.2), and congenital malformations (OR = 1.8, CI = 1.1-3.1)." Note: The OR and CI were both greatest for 5-min Apgar score below 7.
    Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002 Jul;13(4):417-23.

  • "Children with autism spectrum disorders have lower optimality (higher rates of complications) than unaffected siblings…"
    Zwaigenbaum L, Szatmari P, Jones MB, Bryson SE, MacLean JE, Mahoney WJ, Bartolucci G, Tuff L. Pregnancy and birth complications in autism and liability to the broader autism phenotype. J Am Acad Child Adolesc Psychiatry 2002 May;41(5):572-9

  • "In a sample of families selected because each had exactly two affected sibs, we observed a remarkably high proportion of affected twin pairs, both MZ and DZ…"
    Greenberg DA, Hodge SE, Sowinski J, Nicoll D. Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet 2001 Nov;69(5):1062-7

  • "The highest OR [odds ratio] was found for vaginal breech delivery (OR 6.7), birth weights above 5 kg (OR 6.3), and second born twins (OR 4.1)."
    Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: A population-based register study of 1 million term births. Obstet Gynecol 2001;98:65-70

  • "Among the children with a serious medical condition, 34.4% also had ante- or perinatal antecedents. Among the 33% without any medical factor, 77% also had ante- or perinatal antecedents."
    Bodier C, Lenoir P, Malvy J, Barthélemy C, Wiss M, Sauvage D. (2001) Autisme et pathologies associées. Étude clinique de 295 cas de troubles envahissants du developpment. [Autism and associated pathologies. Clinical study of 295 cases involving development disorders] Presse Médicale 2001 Sep 1; 30(24 Pt 1):1199-203.

  • "… specific complications that carried the highest risk of autism and PDD-NOS represented various forms of pathologic processes with no presently apparent unifying feature."
    Juul-Dam N, Townsend J, Courchesne E. Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics. 2001 Apr;107(4):E63.

  • "AD was identified in 18 of the 5,271 children and the incidence was 34 per 10,000 (0.34%). This value was more than twice the highest prevalence value previously reported in Japan. Children with AD had a significantly higher history of the meconium aspiration syndrome (p = .0010) than the controls. Autistic patients had different risk factors than CP." Note: CP (cerebral palsy) occurred in 57 of the 5,271 children.
    Matsuishi T, Yamashita Y, Ohtani Y, Ornitz E, Kuriya N, Murakami Y, Fukuda S, Hashimoto T, Yamashita F. Brief report: incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. J Autism Dev Disord. 1999 Apr;29(2):161-6

  • "…[obstetric] optimality score (OS), were compared in two groups: 78 families containing an autistic proband (ICD-10 criteria) and 27 families containing a down syndrome (DS) proband… RESULTS: Autistic and DS probands had a significantly elevated OS compared with unaffected siblings, regardless of birth order position. The elevation was mainly due to an increase in mild as opposed to severe obstetric adversities."
    Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997 Feb;36(2):272-81

  • "Males with AS showed a trend toward lower Apgar scores at one minute …"
    Ghaziuddin M, Shakal J, Tsai L. Obstetric factors in Asperger syndrome: comparison with high-functioning autism. J Intellect Disabil Res. 1995 Dec;39 ( Pt 6):538-43.

  • "These data provide slight support for the contribution of nonspecific pre- and perinatal factors to other etiological bases of autism."
    Lord C, Mulloy C, Wendelboe M, Schopler E. Pre- and perinatal factors in high-functioning females and males with autism. J Autism Dev Disord. 1991 Jun;21(2):197-209.

  • In most of the pairs discordant for autism, the autistic twin had more perinatal stress.
    Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989 May;30(3):405-16.

  • "Abnormal presentation at birth is the only factor that occurred more frequently for the autistic sample…"
    Levy S, Zoltak B, Saelens T. A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations. J Autism Dev Disord. 1988 Dec;18(4):573-81.

Back to: Complications At Birth, [Top]



. . . .

36 - Umbilical Cord Clamping

Clamping the umbilical cord at birth is a human invention. The umbilical cord is an infant's lifeline throughout gestation; it should go without saying that it remains the newborn's lifeline until lung function is established. Clamping the cord before a baby breathes can be expected to result in at least a brief period of oxygen deprivation.

Looking back at historical textbooks on obstetrics, waiting at least for the infant to breathe on its own was traditionally always required before cutting the cord [58-65].

From 1850 to 1930:
  • "A strong healthy child, as soon as it is born, will begin to breathe freely, and in most cases cry vigorously. As soon as it has thus given satisfactory proof of its respiratory power, you may at once proceed to separate it from its mother by tying and dividing the umbilical cord."
    Swayne JG (1856) Obstetric Aphorisms: For the use of students commencing midwifery practice. London: John Churchill, p 20.
  • "As soon as the child cries we may proceed to tie and separate the cord."
    Playfair WS (1880) A Treatise on the Science and Practice of Midwifery. Philadelphia: Henry C. Lea, p 283
  • "The cord should not be tied until the child has breathed vigorously a few times. When there is no occasion for haste, it is safer to wait until the pulsations of the cord have ceased altogether."
    Lusk WT (1882) The Science and Art of Midwifery. New York: D Appleton and Company, pp 214-215
  • "Immediately after its birth the child usually makes an inspiratory movement and then begins to cry. In such circumstances it should be placed between the patient's legs in such a manner to have the cord lax, and thus avoid traction upon it… Normally the cord should not be ligated until it has ceased to pulsate…"
    Williams JW (1917) Obstetrics: A Text-Book for the Use of Students and Practicioners, Fourth Edition. New York & London: D. Appleton and Company, pp 342-343
  • "As soon as the lungs begin to function, the circulation through the umbilical arteries normally ceases in from five to fifteen minutes after birth."
    Williams JW (1930) Obstetrics: A Text-Book for the Use of Students and Practicioners, Sixth Edition. New York: D. Appleton-Century, pp 418-419

By the 1940s a change of opinion is evident:

  • "We have adopted an intermediate course, feeling that to always wait for complete cessation of pulsation frequently interferes with the proper conduct of the third stage of labor, and at the same time, that most of the available blood in the cord had been incorporated in the fetal circulation during the few minutes immediately following delivery."
    Stander HJ (1941) Williams Obstetrics, Eighth Edition. New York, London: D. Appleton-Century company, pp 429-430.

  • "Whenever possible, clamping or ligating the umbilical cord should be deferred until its pulsations wane or, at least, for one or two minutes…
    There has been a tendency of late, for a number of reasons, to ignore this precept. In the first place the widespread use of analgesic drugs in labor has resulted in a number of infants whose respiratory efforts are sluggish at birth and whom the obstetrician wishes to turn over immediately to an assistant for aspiration of mucus, and if necessary, resuscitation. This readily leads to the habit of clamping all cords promptly."

    Eastman HJ (1950) Williams Obstetrics, Tenth Edition. New York: Appleton-Century-Crofts , pp 397-398

Would Williams recognize the 20th edition of his textbook?

  • "Although the theoretical risk of circulatory overloading from gross hypervolemia is formidable, especially in preterm and growth-retarded infants, addition of placental blood to the otherwise normal infant's circulation ordinarily does not cause difficulty… Our policy is to clamp the cord after first thoroughly clearing the infant's airway, all of which usually takes about 30 seconds."
    Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC, Hankins GDV, Clark SL, Williams JW, (1997) Williams Obstetrics, Twentieth Edition. Stamford, Conn: Appleton & Lange, pp 336-337.


Preventing jaundice

  • It appears that Saigal et al (1972) and Saigal & Usher (1977) may have initiated the fear that delayed clamping of the umbilical cord could result in circulatory overload, polycythemia (too many red blood cells) and jaundice. But polycythemia is more often a physiological response to abnormalities like methemoglobinemia, which results from a genetic or drug-induced abnormality of the hemoglobin molecule.

    Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics. 1972 Mar;49(3):406-19.

    Saigal S, Usher RH. Symptomatic neonatal plethora. Biol Neonate. 1977;32(1-2):62-72.

  • Jellett (1910) in a Manual of Midwifery discussed the issue of polycythemia after stating, "The old dispute as to when the cord should be tied possesses now little more than an academic interest, as it is conclusively settled that this should not be done until all pulsations in the cord have ceased."

    Jellett cited research apparently well known in 1910: White (1785, 1773) had written about the absurdity of supposing that it was possible for the change from placental to pulmonary circulation, with all that this implies, to take place in a moment, "that this wonderful alteration in the human machine should be brought about in one instant of time, and at the will of a bystander?"

    Jellett further cited research by Schmidt (1894) in which it was found that 72 percent of children in whom immediate ligation of the cord was done were jaundiced, while only 42 percent were jaundiced when the cord was not tied until ten minutes after birth. It may be time to consider whether postnatal anemia isn't a greater risk for more infants than polycythemia and jaundice.

    Jellett H (1910) A Manual of Midwifery for Students and Practitioners. New York: William Wood & Company.

    White C (1773) A Treatise on the Management of Pregnant and Lying-In Women. Science History Publications/ Watson Publishing International, Canton MA, 1987.


A Radical Change

Whatever its motivation, the now routine clamping of the umbilical cord within 30 seconds following birth is a radical change from traditional practice. If an infant is breathing on its own at the time of cord clamping, the most important transition from fetal to neonatal life has taken place (see Mercer & Skovgaard, 2002). This transition has not taken place in an infant in need of resuscitation. It may be only a small minority of infants who do not breathe immediately at birth, but might this minority account for the increased prevalence of autism or other developmental disabilities?

Mercer JS, Skovgaard RL. Neonatal transitional physiology: a new paradigm. J Perinat Neonatal Nurs. 2002 Mar;15(4):56-75.
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. . . .

Summaries

I. BRAIN DAMAGE AT BIRTH

1 - Asphyxia at Birth
Experiments with monkeys on asphyxia at birth were undertaken in the 1950s to investigate ways to prevent cerebral palsy. The outcome was not cerebral palsy, and damage to the brain was confined to the brainstem. The inferior colliculus in the midbrain auditory pathway was always most severely involved. The inferior colliculus had been found in earlier experiments on cerebral circulation to have the highest rate of blood flow in the brain.

2 - Hypoxic Birth
In the initial experiments asphyxia was inflicted by covering the newborn monkey's head and clamping the umbilical cord, producing a sudden catastrophic cutoff of respiratory gas exchange. Cerebral palsy was found in later experiments to result from partial blocking of umbilical blood flow late in gestation. Circulatory insufficiency induced in this way led to widespread damage throughout the brain. Hypoxia is a state of partial oxygen insufficiency. Asphyxia occurs when oxygen delivery is completely blocked and if not fatal results in a predictable pattern of brainstem damage.

3 - Asphyxia Versus Hypoxia
Asphyxia is different from hypoxia. Protective mechanisms go into effect to preserve oxygen delivery to the inferior colliculus during a period of hypoxia. High blood flow to the inferior colliculus supports a high rate of aerobic metabolism, generating high levels of carbon dioxide. Hemoglobin delivers oxygen in exchange for carbon dioxide, an immediate adjustment that ensures continuing support of aerobic metabolism in this nucleus of the auditory system. The rest of the brain then becomes deprived of oxygen, and over time widespread damage occurs.

4 - Human Conditions
Asphyxia causes a sudden and catastrophic cessation of aerobic metabolism that is often fatal. Damage to the inferior colliculus is evident in children and adults who survive for at least several days following resuscitation. In the 1960s damage involving only the brainstem was thought to underlie what was then referred to as "minimal cerebral dysfunction."

5 - Stages of Asphyxia
Monitoring what happens during the stages of asphyxia indicates that the heart, brain, and other organs incur compromise earlier than the time required for visible damage to be evident.

6 - The Umbilical Cord Lifeline
Clamping of the umbilical cord at birth is a human invention and a dangerous procedure if performed on an infant who is not yet breathing. Respiration is the most immediate and essential need of all life forms dependent upon oxygen. Placental respiration must be maintained until an infant's lungs and heart have completed the transition from pre- to postnatal adaptation.

7 - Developmental Delay
Monkeys subjected to asphyxia at birth exhibited muscle weakness and delay in developing motor control; they never overcame poor manual dexterity. The asphyxiated monkeys were not deaf, despite the conspicuous damage to the inferior colliculus, but they did not orient to sounds as normal monkeys did.

8 - Poor Manual Dexterity
Monkeys subjected to asphyxia at birth remained deficient in manual dexterity. Large and laboriously produced handwriting is characteristic of children with developmental delay and children with "high functioning" autism.

9 - Progressive Degeneration
Widespread degeneration was evident in the brains of monkeys who survived several months or years following asphyxia at birth. Anomalies of the same brain areas (cerebellum, amygdala, corpus callosum, etc.) are evident in the brains of individuals who were autistic in childhood.

10 - Autism and Complications at Birth
Many children with autism suffered complications at birth. Oxygen insufficiency is the greatest danger during a difficult birth. Problems during labor and delivery are frequently attributed to pre-existing genetic factors, but monkeys subjected to experimental asphyxia had no pre-existing problems.

11 - Mercury, and Other Toxic Factors
In the experiments with monkeys the effects of high levels of bilirubin (jaundice) were investigated. Bilirubin did not enter brain tissue except in monkeys that had been subjected to asphyxia. Mercury preservatives in vaccines and other substances may also only cross a blood-brain barrier compromised by asphyxia or hypoxia. Does the hepatitis-B vaccine need to be given in the newborn nursery?
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Revision: October 1, 2003

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