7 - William Windle on the embryology of blood and fetal circulation

Windle (1940) presented a paper at the Round Table Discussion on Anemias of Infancy as part of the tenth annual American Academy of Pediatrics.  In his talk Windle began by summarizing research on development of red blood cells, which begins in the wall of the embryonic yolk sac.  Blood vessels begin to form during the fifth week, and after sufficient development of the liver, blood cell formation becomes one of its primary functions for the fetus until the spleen and bone marrow mature and are able to produce blood cells.  How essential oxygen delivery is, that red cells, blood vessels, and circulation powered by the fetal heart (the earliest functioning organ) follow such an elegant plan. Windle continued with a detailed description of how oxygen is transferred across the placenta, and how fetal hemoglobin is designed to readily take up oxygen at low partial pressures on the maternal side of the placenta, again emphasizing the importance of maintaining full aerobic activity. Placental blood is fully part of the fetal circulatory system, and found by many investigators to contain one-fifth to one-fourth of the total fetal blood at birth.   Windle pointed out that this placental blood does not pass into the infant at birth until uterine contractions have a chance to compress the placenta, and he stated:

"... The rather common practice of promptly clamping the cord at birth should be condemned.  Of course, this will make it imposible to salvage placental blood for 'blood banks.'  However, the collection of usable quantities of placental blood robs the newborn infant of blood which belongs to him and which he retrieves under natural conditions...  Immediate clamping of the cord is comparable to submitting the infant to a rather severe hemorrhage." Windle 1940, p546.

Ethical or unethical research?

Windle with DeMarsh, Wilson, and Alt (1941, 1942, 1948), and like many before and since, did research with human infants using immediate or delayed clamping of the cord.  I am not sure I understand why any more  "randomized controlled trials" needs to be done.  Windle would during the 1950s begin doing research with monkeys, which many now would find unethical.  If it's unethical to do experiment with animals, how can use of human subjects be ethical?

In any case, Windle and his colleagues found increased erythropoiesis (more active blood formation) in infants when the cord was clamped early that when it was clamped late.  Early clamping of the umbilical cord leaves the infant in an anemic state.  The main reason immediate clamping of the cord has gained favor, is that fewer red cells leads to less likelihood of developing jaundice, with the aim of preventing kernicterus (yellow staining of nuclei in the subcortical motor system.  This goal has not been accomplished.  Sadly, kernicterus is still prevalent.

Meaningful research

In their first paper on the effects of asphyxia at birth in monkeys, Ranck and Windle (1959) noted that the pattern of ischemic brainstem lesions caused by asphyxia resembled the pattern of damage seen in kernicterus, but without the bilirubin staining.  Others had already noted that bilirubin staining is not uniform throughout the brain, but only enters subcortical nuclei in which the blood-brain barrier had been compromised by anoxia or an infectious process (Orth 1875, Schmorl 1904,.Zimmerman & Yannet 1933).

Bilirubin levels are normally high in newborn infants.  This is not a recent development.  Physiological jaundice of the newborn was recognized long before becoming viewed as pathological, and in need of eradication.   Meaningful research into causes of kernicterus should be to focus on factors that cause break-down of the blood-brain barrier, and allow bilirubin to get into neurons.  Further, why is bilirubin staining selective for certain subcortical nuclei?  The finding of Ranck and Windle (1959) has anwered this question.

The rank order of brainstem nuclei damaged by asphyxia at birth follow the same rank order of sites in the brain with highest blood flow and aerobic metabolism.  Brainstem nuclei in the sensory pathways are metabolically more active that the memory system of the cerebral cortex.  This does not make intuitive sense, but consider the activity of the auditory system.  Fisch (1970) noted that the auditory system is always active, even during sleep.  This is why alarm clocks were invented.  The auditory system is the vigilance system of the brain, and in need of continuous high blood flow and metabolism.

Oxygen deprivation, not bilirubin, causes kernicterus

Asphyxia, as inflicted by Ranck and Windle, prevented the lungs from functioning and cutoff circulation from the placenta.  This caused a catastrophic ischemia of the brain.  The immediate reaction would appear to be breach of the blood-brain barrier, especially in the brainstem nuclei of high metabolic rate, a desperate response to open any channel that might overcome the lack of oxygen.

Oxygen insufficiency, not bilirubin, is the root cause of kernicterus.  How to avoid even a brief lapse in respiration at birth should be the first priority.  Immediate clamping of the umbilical cord runs the risk of producing a lapse in respiration, especially if it is clamped before the first breath.  Ischemic damage of brainstem nuclei as found in the experiments of Ranck and Windle produces kernicterus, with or without bilirubin.  Infiltration of bilirubin into these brainstem nuclei simply highlights where the primary damage has occurred.

Future directions for research should begin in the past

In his commentary on the Cochrane Review, Dr. Morley stated that it was unethical for any more  studies to have been done subsequent to one conducted in 1993, which clearly showed the benefits of delayed clamping of the umbilical cord in premature infants.  Randomized controlled studies imply that informed consent is not part of the procedure - tough luck for the parents who may then spend the rest of their lives struggling to help a handicapped child.  My sense is that the results of myriad studies made it clear that waiting for pulsations of the cord to cease is the safest course - beginning with those of Budin in 1875, Schucking in 1877, and certainly those of Haselhorst (1929), Allmeling (1930), Frischkorn & Rucker (1939), Windle (1940, 1941, 1942, 1948), Ballentine (1947), Colozzi (1954), Gunther (1957), and Redmond et al. (1965). My grief is great.  I was a "clinic patient" in 1963, before medical insurance covered childbirth.  My husband was a graduate student, and in those days everyone told us he should quit his graduate studies and get a job so that I would not have to work after having the baby.  I was part of the "Collaborative Perinatal Study," which I thought would provide more attention and better care.  Now I realize, and wouldn't know how to find out, if I was assigned to some randomized control group. I gave consent, but was not fully informed.  When Dr. Morley read my story on the internet, he asked me if I knew when my son's umbilical cord was cut.  It certainly was before he was breathing, and I remember the panic I felt that he was on the other side of the delivery room, taken away from me, and asking, "Why isn't he crying?" My son and I were victims of very unethical research procedures, and all along the answers were and still are in medical journals predating the start of the Cochrane Review period.  My hope is that I can in some small way help inform other parents-to-be by pointing out what has been known for a long time, but is totally neglected by present-day "experts."

From:

http://placentalrespiration.net/ sprepu

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