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Anencephaly: selected medical aspects.

Anencephaly: Selected Medical Aspects

Anencephaly is generally defined as the congenital absence of skull, scalp and forebrain (cerebral hemispheres). In most cases, the cause is unknown; whatever the teratogenic factor, it must operate very early in embryogenesis, around the time of closure of the cephalic end of the neural tube (3-1/2 weeks of gestation). [1]

Animal models and early human fetuses demonstrate that the exposed anterior position of the neural tube initially proliferates, as though attempting to form a forebrain, resulting in disorganized mass of primitive glial, neural, and vascular tissue arising from the upper end of the brainstem. This stage in the evolution of anencephaly is known as exencephaly. During gestation, this tissue typically degenerates, leaving by term only a remnant of varying amount called the cerebrovasculosa. Although the term "anencephaly" literally means "no brain," the actual amount of nervous system tissue compatible with that diagnosis can vary anywhere from only a few grams up to a normal full-term brain weight. [2] Anencephaly is classically subdivided into two forms: holo-anencephaly (complete absence of forebrain and cranium) and mero-anencephaly, in which "the cranium and the brain are present in rudimentary form." [3] Others employ the related terms "holoacrania" and "meroacrania," referring to the degree of bone absence.

The brainstem in anencephaly can display a spectrum of involvement anywhere from relatively normal to totally absent, with the congenital defect extending all the way into the spinal canal (craniorachischisis). There may also be associated malformations of other organ systems.

Differential Diagnosis

In the great majority of cases, the diagnosis of anencephaly is very obvious, and there is little, if any, chance of mistaking it for another condition. Nevertheless, not all cases are so straightforward. If anencephaly were clearly distinct from all other congenital brain malformations, it should be possible to give an operational definition of it that includes all cases of anencephaly and excludes all cases of everything else, yet such a definition has not been offered by anyone so far.

In their textbook on anencephaly, Lemire and colleagues stated: "An almost incomprehensible array of synonyms and classifications of anencephaly exists in the literature; many include entities now considered to be pathogenetically unrelated to the anencephaly spectrum." [4]

Another expert on congenital neuropathology, Josef Warkany, wrote:

As a congenital malformation that cannot be overlooked, [anencephaly] exemplifies the problems and difficulties of teratologic research in man. The terminology is confusing. I use the terms "anencephaly" for partial or total absence of the brain, "exencephaly" for exposure of the brain...and "pseudencephaly" for massive "area cerebrovasculosa" imitating the shape of the brain that it replaces. [5]

Although "exencephaly" is usually considered to be a mere stage in the evolution of anencephaly, his definition implies that what is exposed may be something more than mere cerebrovasculosa, and that exencephaly is not necessarily restricted to early fetuses.

Clearly, mutually exclusive operational definitions of anencephaly and exencephaly cannot be given, because the two conditions differ only in terms of the amount of exposed tissue, and therefore represent but two overlapping regions of a contiuous spectrum. On the other hand, if exencephaly is to be included within the general category of anencephaly, as most authors conceive it, we must either abandon the notion of anencephaly as "brain absence" (even "forebrain absence") or provide mutually exclusive operational definitions for "brain" and "exencephalic tissue." The latter distinction is based on the degree of neural organization present, and is difficult, if not impossible, to determine by gross visual inspection.

This leads directly to the problem of overlap with another spectrum of congenital malformations called "encephaloceles," defined by Warkany as "hernias of the brain protruding through a congenital opening of the skull." He remarks that:

Encephaloceles are closely related to exencephaly and anencephaly. If the protruding brain of an exencephaly deteriorates, anencephaly results. If it is covered by skin or epithelium, and persists, encephaloceles are formed. [6]

A major problem arises, however, if the covering of encephaloceles may, by definition, be merely "epithelium" (a thin membrane composed of surface-lining cells), because the cerebrovasculosa of anencephaly and exencephaly is also typically covered by an epithelial membrane continuous with the skin at the edge of the cranial defect. [7] Rendering the distinction even more obscure, he states: "In experimental teratology exencephalies are encountered frequently. Sometimes they are covered by skin or thin epithelium (Fig. 24-1) corresponding to encephaloceles in man." [8] Although this passage describes his Fig. 24-1 as illustrating an experimental exencephaly, the corresponding figure legend refers to the lesion as an "encephalocele."

Other investigators distinguish the conditions more on the basis of the degree of neural organization than on the thickness of covering. But the cerebrovasculosa in anencephaly/exencephaly may contain rudimentary cerebral ventricles and/or patches of laminated cortex, leading some investigators to reject "the widely accepted view that the area cerebrovasculosa is totally disorganized, and that anencephaly is characterized by absence of the forebrain." [9] Conversely, the tissue in some encephaloceles is so abnormal that it is probably devoid of neurophysiologic function. The parameter "degree of neural organization" is therefore hopelessly vague for the purpose of unambiguously distinguishing anencephaly/exencephaly from encephalocele.

In particular, mero-anencephaly (meroacrania), which involves only a partial absence of brain and calvarium, by definition admits of degrees to which both these structures may be present. The least severe forms of mero-anencephaly may involve relativel small skull and scalp defects, thereby forming a continuum with the most extreme forms of microcephaly with encephalocele.

A more explicit acknowledgment of the ambiguity inherent in these terms is provided by Lemire and colleagues in describing the picture of an infant with a partial skull defect, through which a round nubbin of brain tissue protrudes, the diameter of which is about half the length of the face (Fig. 4-12). [10] The figure legend states:

Lateral view of an infant with meroacrania who lived for several weeks. Since there is no skin covering, the basic lesion is that of anencephaly rather than of encephalocele (which is skin covered)... Because there is a significant protrusion of dysplastic cerebral cortex, it can be also be classified as exencephaly.

If the "skin" covering of encephaloceles is understood in Warkany's sense of any sort of surface membrane of unspecified thickness, and if the lesion had happened to be covered by an epithelial membrane, then it could legitimately have been classified as any of the three entities.

These are not the only examples of such diagnostic ambiguity. A Dallas woman told the American Medical News "that her child, a daughter, lived fourteen months after being diagnosed--initially by the obstetrician--as having microcephaly with encephalocele, and later by a pediatric neurologist as having anencephaly." [11] This overlap between mero-anencephaly and microcephaly with encephalocele is important to acknowledge, because the latter constitutes a continuous spectrum of its own, at the other end of which are encountered quite functional individuals. [12]

Amniotic band syndrome, which encompasses a broad continuum of severity, can mimic anencephaly, as occurred in one large epidemiologic survey. [13] Other investigators would consider amniotic bands not so much a misdiagnosis, as an actual cause of anencephaly, constituting yet another blurred boundary between anencephaly and some other condition. [14]

These examples are not intended to exaggerate the potential for diagnostic confusion surrounding anencephaly: it is still quite true that in the vast majority of cases the diagnosis can be made easily and without risk of error. Nevertheless, the commonly encountered contention that "anencephaly" is so well defined and so distinct from all other congenital brain malformations that misdiagnoses cannot occur and that organ-harvesting policies limited to "anencephalics" cannot possibly extend to other conditions, is simply false.

Prevalence and Prenatal Screening

The prevalence of anencephaly varies widely around the world, ranging in previous decades from as high as 6.7 per 1,000 births in parts of Ireland to as low as 0.29 in Denmark. [15] There is a declining gradient from Europe to the Far East, with intermediate prevalences in the western hemisphere. [16] Ethnic differences also obtain; for blacks and Jews the prevalence rates are some three to seven times lower than for other races. For unknown reasons, the sex ratio is quite skewed toward females, who constitute around 70 percent of anencephalic births. [17] Of great interest is the worldwide steady decline of the prevalence of anencephaly over the past several decades. [18]

In the United States, various studies reported rates of anencephaly ranging from 1.93 per 1,000 births in the early 1950s to 0.45 to 1.39 in the '60s and early '70s. [19] Rates from the late 1970s were lower, between 0.35 and 0.48. [20] The most recent data indicate still lower prevalence rates. In California between 1983 and 1984, just prior to the institution of a statewide prenatal screening program for neural tube defects, it was 0.3. [21] The Birth Defects Monitoring Program database, a nationwide source, gives an average rate of 0.26 between 1984 and 1986, and the Metropolitan Atlanta Congenital Defects Program reports an average rate of 0.35 during the same period, figures believed to be relatively unaffected by prenatal screening. [22] Taking into account all of the above, a reasonable estimate of the natural prevalence rate of anencephaly in the United States in 1988 is around 0.3 per 1,000 births. With some 3.75 million births per year during the latter half of the 1980s, [23] that makes the estimated number of anencephalic infants potentially born yearly in this country to be around 1,125.

This incidence is, of course, drastically reduced in areas with active prenatal screening programs. Either ultrasound or maternal serum alphafetoprotein (MSAFP) measurements will identify nearly all anencephalic fetuses tested during the second trimester. Experience here, as in other countries with well-developed screening programs, indicates that the vast majority of detected anencephalic fetuses are electively aborted. [24]

In California, where mandatory offering of MSAFP screening has been in effect since the spring of 1986, or about 50 percent of all pregnancies have actually been screened during the second trimester. About 95 percent of all anencephalics screened have been detected in this way, and around 95 percent of the detected anencephalics have been electively aborted. [25] This does not include those diagnosed by ultrasound alone and electively aborted. It is probably fair to estimate that overall around 50 percent of the anencephalic fetuses in the state are being aborted. An educated guess as to the proportion of pregnancies nationwide that are being prenatally screened might be around 20 percent, and this is likely to increase over the next few years to a realistic maximum of around 50 percent, if the California experience turns out to be representative. [26]

The number of anencephalic aborted would probably diminish somewhat if their use as organ sources were to become widely accepted and routinely practiced, given that a fair amount of the impetus toward this in the last year seems to have come as much from parents of anencephalics as from transplant surgeons. It is the impression of the genetics counselors at the University of California, Los Angeles, however, that this would still have a relatively small impact on the total number of second trimester terminations for the condition. The diagnosis is so emotionally devastating to parents, and so many more months of pregnancy still lie ahead, that the vast majority of women want to get it over with and return to normal life as soon as possible.

Moreover, many obstetricians consider it improper to encourage a woman to carry a seond trimester anencephalic fetus to term, given the increased risk of complications to the pregnancy. [27] For these reasons, the possibility of organ donation would be expected to have much more of an impact on parental decisions to terminate pregnancy following a diagnosis in the third trimester than in the second.

Thus, taking 20 percent as a very rough estimate of the nationwide proportion of pregnancies prenatally screened for neural tube defects during the second trimester, and 95 percent as the proportion of detected anencephalic fetuses that are electively terminated, the theoretically projected 1,125 anencephalic births per year in the U.S. (which is based on trends from earlier years, relatively unaffected by prenatal screening) reduces to 911.

Prenatal diagnosis, although it permits improved obstetrical planning for high-risk cases, is unlikely to lower significantly the high rate of stillbirths associated with anencephaly. These infants' predisposition to stillbirth is probably due to their inability to withstand the pressures on and mechanical distortion of the exposed brain during its passage through the birth canal. Thus, the only effective way to lower the stillbirth rate would be by performing elective cesarean sections prior to the onset of labor, a maternal risk that virtually everyone agrees would be unwarranted in this setting. The proportion of anencephalics who are stillborn is difficult to determine from the literature, with estimates ranging from around half to as high as 90 percent. [28] A middle figure of around two-thirds is therefore not unreasonable, making the estimated annual number of live anencephalic births in the country 304.

Neurologic Functioning

Little has been published concerning the neurologic functioning of anencephalic infants. Given that the structural anomalies of the brainstem can range from severe to relatively mild, it goes without saying that a corresponding spectrum of neurologic dysfunction can occur. Abnormal fetal movements have been observed by means of real-time ultrasound. [29] Apart from absence of the visual cortex, many anencephalic infants would be peripherally blind on the basis of associated maldevelopment of the eyes, with small optic nerves that end blindly without connection to the brain. [30] Similarly, the middle and inner ears may be anomalous. [31] Thus, the pupillary light reflex, vestibulo-ocular and oculocephalic reflexes, and response to sound could all be absent on a peripheral basis, providing an occasion for the potential misdiagnosis of brain death.

Because the neural structures that mediate typical newborn behaviors are located mainly in the brainstem, those anencephalic infants with relatively intact brainstems exhibit many such behaviors, for example, purposeless back-and-forth movements of the extremities, sucking and swallowing, normal orofacial expressions to gustatory stimuli, crying, withdrawal from noxious stimuli, and wake/sleep cycles. The main behavioral difference described between normal newborns and those without cerebral hemispheres, whether due to anencephaly or hydranencephaly (in utero destruction of both cerebral hemispheres, with intact skull and scalp), is increased irritability and lack of habituation to repeated stimuli, [32] although even these differences are not universally observed among infants lacking forebrains. [33] Some hydranencephalic infants have even demonstrated a capacity for paired associative learning [34] and visual tracking. [35] Of particular interest is the occasional high performance of these infants on measures of state-regulatory behaviors, such as self-quieting and hand-to-mouth facility, and of social behaviors, such as responsiveness to cuddling, consolability, and distinguishing mother from other adults by nonvisual cues. [36] Thus, it is hardly surprising that parents of hydranencephalic infants often mistake their child for normal during the first month or two of life. Similarly, though on a milder scale, newborns who have suffered a massive hemispheric stroke, which would produce a profound hemiplegia in an adult, often manifest only a subtle, if any, abnormality in muscle tone or movement.

These behavioral similarities between decerebrate and normal newborns are consistent with current knowledge of developmental neuroanatomy: even though cerebral hemispheres are present in gross structure in normal newborns, they are very immature microscopically compared to the brainstem. [37] In addition, patterns of regional cerebral energy metabolism, revealed by positron emission tomography, also suggest a relative lack of cerebral cortical function in normal human newborns. n38 In an older child or adult, such a metabolic pattern would constitute strong evidence for a persistent vegetative state (PVS). Nevertheless, newborns are able to carry out complex behaviors and sensory discriminations that would never be attributed to PVS patients. [39] Only gradually does the human cortex assume its adult-type primacy in the functional hierarchy of the brain--a developmental process known as "encephalization."

Animal experiments and comparative neuroanatomy also reveal that the brainstem is potentially capable of much more complex integrative activity than is usually attributed to it, incuding some functions generally considered to be "cortical" even in animals. [40] Both the clinical and experimental evidence strongly suggest that this is also the case with the human brainstem (at least in the newborn). This is not to say that the newborn cortex is physiologically irrelevant or that decerebrate infants manifest all the complex (and probably cortical) sensory and cognitive abilities that specialized testing can reveal in normal newborns. But neither should one falsely minimize the functional capacity of those anencephalic infants with relatively intact brainstems.

Consciousness in Anencephalics

All this has obvious bearing on the issue of anencephalic consciousness. Whether or not an anencephalic infant, or even a normal infant, is "conscious" or capable of "suffering" is a philosophical question that is empirically unanswerable, if by these terms one means a subjective self-awareness associated with the respective behavioral reaction to environmental stimuli.

It seems established beyond doubt that in the mature human brain, the content of consciousness is processed in the cerebral cortex, while behavioral arousal and receptivity of the cortex is governed by the reticular activating system of the brainstem. [41] Children and adults with bilateral destruction of the cerebral cortex remain in a vegetative state, characterized by wake/sleep cycles, yet without evidence of any content of consciousness or voluntary movement during the periods of alert facial expression. [42]

Based on such considerations, there has been a traditional (usually unspoken) assumption that newborn infants, particularly prematures, because of their relative lack of cortical function, are not "consious" even though they may be awake, and that their crying following painful stimuli does not necessarily reflect any subjective experience of unpleasantness or pain, any more than the reflex facial grimacing of patients in persistent vegetative state does. A practical consequence is that circumcisions and other types of surgery have traditionally been performed on newborns in the absence of anesthesia or analgesia. Needless to say, if this theory is true, it would apply all the more to infants born without cerebral hemispheres.

For this inference to follow logically from established principles of "adult" neurophysiology, however, a second (usually unspoken) premise must be accepted, namely, that the newborn brain is like a miniature adult brain with respect to the physiology of consciousness, and therefore, a newborn operating from a mere brainstem is equivalent to an adult operating from a mere brainstem. Although this may yet prove to be the case, discoveries in developmental neurobiology over the past several decades indicate that this is an extremely hazardous assumption, because the newborn brain does function quite differently from a "miniature adult brain" in many other (and relevant) ways.

The fact that decerebrate newborns behave much more similarly to normal newborns than to decerebrate adults is already an important distinction that cannot be overemphasized. This is no longer the case by around 2 months of age, when decerebrate infants begin to exhibit the rigidity typical of PVS patients. But at the newborn stage, the essential difference between normal and decerebrate infants is in the area of potential for future development, with only subtle differences in actual, present functioning. Also, associative learning and conditioning, which can occur in some decerebrate newborns, have, to my knowledge, never been reported in older PVS patients.

Secondly, it is a great fallacy to assume that the functional deficit associated with congenital absence of a certain part of the brain is the same as that associated with destruction of that part in a fully formed brain. The literature on developmental neuroplasticity is overwhelming on this point. [43] As a general rule in both animals and humans, the earlier the neurologic lesion, the greater the capacity of other parts of the brain to reorganize in a functionally compensatory way. [44]

The most relevant question with respect to neuroplasticity in anencephalic infants is whether subcortical structures are capable of taking over certain "cortical" functions, if the cortical lesion occurs early enough in fetal development. Unfortunately, the evidence on this point is both meager and conflicting. In rats and rabbits, no evidence has been found for such compensation. [45] In higher species, however, it has been clearly shown to occur to a limited extent. For example, cats rendered decorticate neonatally are capable of complex social behaviors and of learning stimulus discrimination coupled to an adaptive motor performance, in contrast to the more severe deficits of adult-lesioned animals. [46] Subcortical assumption of otherwise "cortical" visual and motor functions has also been implicated in other experiments involving neonatally lesioned cats and monkeys. [47]

Th point is not, of course, to imply that plasticity can permit a brainstem to substitute for a cerebral cortex; clearly the extent to which it can assume lost cortical function in higher newborn animals and man is very limited. The point is, however, that decerebrate newborns are not merely miniature PVS patients, and that brainstem plasticity might possibly suffice to provide a decerebrate newborn with some primitive form of awareness. Just as we are now beginning to recognize that the brainstem is capable of more complex functioning than was previously realized, and as clinical practice is beginning to take into account the apparent reality of newborn pain, [48] so should we remain open-minded about the possibility that the subjective experimences of anencephalic infants, like their external behaviors, may resemble more those of normal newborns than of older PVS patients. The inherent uncertainties about infant consciousness are an important yet overlooked factual premise for various ethical analyses.

To be sure, anencephalic infants with complete craniorachischisis or severe brainstem maldevelopment cannot experience consciousness or suffering. But these are not the ones of interest as organ sources, because they are almost invariably stillborn. Concerning those with more intact brainstems, it simply begs the question to state categorically that they lack conscious awareness because they lack cerebral hemispheres. Much less is there any logical or physiological basis for the claim of some that an anencephalic infant can neither feel nor experience pain "by definition." [49] For practical purposes, one should presume, at the very least, that anencephalic infants are no less aware or capable of suffering than some laboratory animals with even smaller brains, which everyone seems to feel obliged to treat "humanely."

Life Span and Cause of Death

The life span of an individual anencephalic infant depends on both the severity of dysgenesis of the brainstem and the intensity of medical and nursing care provided. Although it is commonly stated that these infants invariably die within a few days of birth, various large studies and a number of anecdotal reports of longer survivals cast serious doubt on this contention. According to one study of 181 such infants, 42 percent of those born alive survived longer than twenty-four hours, 15 percent survived longer than three days, and 5 percent longer than seven days. [50] The longest survivor died on the fourteenth day. A review of the California Birth Cohort File between 1978 and 1982 revealed that of the 205 liveborn anencephalic infants with birthweight greater than 2,500 grams (and therefore of greatest interest vis a vis organs), 47 percent died within one day, an additional 44 percent between one day and one week, 8 percent between one week and one month, and 1 percent around three months of age. [51] There are also documented cases of anencephalic infants living five and a half months, [52] seven months, [53] and fourteen months. [54]

The cause of death in anencephaly has never been systematically studied and remains essentially unknown. It undoubtedly varies from case to case, depending upon the severity of the anomalies of the brain and other organ systems. If the brainstem respiratory and/or vasomotor centers are abnormally developed, then one would expect hypoventilation and/or blood pressure instabilities to set in within a short period of time. Trauma to the exposed brain during the birth process, less severe than to cause stillbirth, could also result in hypoventilation during the first several hours. These are the most likely explanations for the many deaths within the first day.

The infants whose brainstems are intact enough to maintain respiratory drive and regulate blood pressure may succumb over the next few days to endocrine abnormalities. Common findings in anencephaly are absent or hypofunctioning pituitary glands, as well as hypoplastic, poorly functioning adrenal glands. [55] These could result in ultimately fatal electrolyte imbalances and inability to handle various physiologic stresses, eventually leading to either hypoventilation or a cardiac arrhythmia as the immediate cause of death.

Although the brain is exposed, infection is rarely, if ever, cited as a cause of death, probably because these infants tend to die before infection can set in. Those who live longer tend to have less extensive cranial defects, which are also more likely to be covered by an epithelial membrane, protecting the brain not only from infection but also from damage by direct contact with air. The cause of death of the rare infants who survive several months or more is probably aspiration, to which they would be highly prone.

From what we know of the anatomy and pathophysiology of anencephaly, therefore, it is unlikely that the primary cause of death of these infants is progressive brainstem destruction or degeneration. The final apnea may result from a developmental lack of chemoreceptormediated respiratory drive, from systemic disorders, or from potentially transient trauma-induced brainstem dysfunction; in any case, it does not necessarily indicate progressive and irreversible structural damage to the brainstem, as occurs in brain death. Theoretically, therefore, artificial ventilation and intensive care should help to preserve the integrity of the brainstem just as much as that of the other organs, and the only accomplishment would be to postpone the moment of death until some systemic complication were to supervene.

Utility of Organs for


Anencephalic infants tend to be born prematurely (53 to 58 percent of cases) , with a mean gestational age of thirty-three to thirty-six weeks. [56] In addition, most have intrauterine growth retardation, with 33 percent having weight below the mean by greater than two standard deviations. [57] According to various series, 50 to 80 percent have birth weights less than 2,500 grams. [58] It is reasonable to assume, therefore, for purposes of calculation, that around 60 percent of liveborn anencephalics will be too small to provide useful organs for transplantation, reducing the above-estimated yearly 304 liveborn anencephalics to 122 potentially useful ones.

Although there is no hard data on the proportion of brain-dead children whose parents are willing to donate their organs, the experience in UCLA's pediatric intensive care unit approximates 75 percent. In the case of anencephalics, there will be a need either to prolong the infant's dying process (by means of a ventilator and intensive care, while awaiting "brain death") or to remove the organs while the infant is still alive (if the laws change). Neither of these alternatives will be acceptable to some parents, so it is safe to assume that a somewhat lower proportion, say two-thirds at best, will be willing to donate. This brings the annual number of useful, donated anencephalic infants down to eighty-one.

One-third to one-half of anencephalic infants have associated gross malformations of at least one other organ system. [59] Around one-third have urinary tract malformations, most of which are nevertheless compatible with transplantable kidneys. Even though the kidneys tend to be hypoplastic, once transplanted they can grow and function normally. [60] Nevertheless, the overall experience with long-term graft survival from infant kidney donors in general has been poor. [61] Furthermore, the ability to support infants in renal failure by means of chronic peritoneal dialysis has improved enough that pediatric nephrologists prefer to maintain infants this way until several years of age, when the likelihood of a successful transplant is much higher. Typically, the kidneys from infant liver or heart donors go unclaimed, as was the case with the famous baby Gabrielle, Loma Linda University Medical Center's first anencephalic heart donor.

Cardiovascular malformations occur in some 8 to 41 percent of anencephalics, including a 5 to 10 percent rate of "major" malformations. [62] A large proportion of the hearts are hypoplastic, and some may be unsuitable for transplantation merely on the basis of their size. Around one-fourth of anencephalics have gross gastrointestinal anomalies, [63] and their livers tend to contain decreased glycogen (energy stores), [64] which may compromise organ viability during a transplant procedure. Although in one series, the liver weights of anencephalics born at term were near normal (92 percent of controls), [65] in another series, of the infants with birth weight over 2,500 grams, 55 percent had livers smaller than one standard deviation below the mean. [66] Size is much more crucial for liver transplants than for heart, and selection criteria generally require that donor and recipient livers be similar in size (ordinarily judged preoperatively on the basis of body weight). [65] Thus, say around 15 percent of the hearts and 25 percent of the livers will be unusable on the basis of malformation or size, reducing the estimated annual number of usable kidneys, hearts and livers available from anencephalics to zero, sixty-nine, and sixty-one, respectively.

Not every potentially transplantable organ finds its way into a recipient, however. For various reasons, around 25 percent of all organ referrals (all ages combined) are found acceptable by established organ sharing networks. [68] The figure is lower for hearts, usually because an excessive amount of medication is required to maintain the potential donors' blood pressure before referral, disqualifying them under most protocols. At present infants with biliary atresia almost always receive a palliative surgical procedure (Kasai procedure) first and then are placed on the national transplant waiting list at age four or five months. [69] Nevertheless, there are still some at this age who have failed to gain weight and are therefore small enough to be size-compatible with a newborn donor. For both hearts and livers, blood type compatibility between potential donor and recipient is preferred, unless the latter is listed as having less than twenty-four hours to live. If there is no potential recipient in geographic proximity, some parents would be reluctant to allow the body of their child to be flown to a distant city for organ harvesting. In spite of national computerized organ sharing networks, the need for temporal coincidence of potential donors and compatible potential recipients remains a major reason for the nonuse of transplantable organs.

Some of these problems have already been illustrated by the experience with Loma Linda's anencephalic protocol, which went into effect in mid-December 1987. Out of thirteen anencephalic infants donated as of August 9, 1988 (including the first case, referred from Canada prior to the formal establishment of their protocol), only three were declared "braid dead" within the specified seven-day limit, and from those only a single vital organ, a heart, made its way into another child. [70]

Based on the meager experience so far, it is difficult to estimate the proportion of organs that would actually be used from potentially suitable and donated anencephalic infants, if similar protocols were to become widespread or laws changed to relax the requirement that anencephalic "donors" be dead. Even if the latter were to come about, it is highly doubtful that any more than 25 and 15 percent of otherwise suitable hearts and lives, respectively, would ever be used, reducing the yearly number of used anencephalic kidneys, hearts, and livers to zero, seventeen, and nine, respectively, at most.

Finally, the proportion of infant recipients actually benefitted is not entirely clear, as there has been so little experience to date with transplantation in such a young age group. Few institutions perform heart transplantation in newborns. To date, of the seventeen heart transplants in infants under six months of age performed by Dr. Leonard Bailey at Loma Linda, thirteen are alive, with follow-up periods ranging from a few days to two-and-a-half years. [71] The eventual proportion of long-term survivors will undoubtedly be somewhat less than 13/17, with the current state of the art. Dr. Constantine Mavroudis, at the University of Louisville, has performed seven heart transplants in infants, six of whom were newborns. Four of the seven are alive at eight months to two years at follow-up. [72] Based on the experience at these two centers, a 50 percent long-term survival is optimistically reasonable. Liver transplantation in newborns is in a much more preliminary stage of development. Even some of the most active liver transplant teams in the country, for example at UCLA and the University of Pittsburgh, usually reject offers of newborn livers on account of the high incidence of complications, preferring instead those from somewhat older infants. [73]

If we use estimates of 50 and 20 percent long-term survival for recipients of newborn hearts and livers, respectively, the yearly number of patients in the country actually benefitting from anencephalic kidneys, hearts, and livers optimistically projects to zero, nine, and two, respectively.

It is interesting to try to project these figures into the near future, say ten years from now. Based on present trends, there will probably be around 4,000,000 births annually. The natural anencephaly prevalence rate of 0.3 per 1,000 births will probably have fallen by, say, 3 percent per year, which over 10 years will bring the rate to 0.22. Prenatal screening will have become more widespread, resulting in, say, termination of 50 percent of anencephalic fetuses nationwide. Let us assume that the proportion of stillbirths, the mean gestational age, organ malformation rate, and the proportion of parents willing to donate, remain about the same. For the sake of argument, let us suppose that the use of neonatal kidney donors were to become standard (with, say, 15 percent of kidneys unusable). The logistics of matching donors and recipients will have improved somewhat, so that, say, 25 percent of otherwise suitable kidneys, hearts, and livers would be used (a high estimate of the current salvage rate across all ages). The outcomes of neonatal transplantation will also have improved, so let us assume that the proportion of long-term survivors receiving neonatal kidneys, hearts, and livers will be optimistically 75, 75 and 50 percent, respectively. Combining all these figures, and assuming two kidney recipients for each anencephalic "donor," the annual number of infants in the country who will benefit from anencephalic organs ten years from now projects to at most twenty-five, twelve, and seven, for kidneys, hearts, and livers, respectively.

Such present and future projections ought to be borne in mind in discussions of the impact of anencephalic organ harvesting upon the many hundreds of children who die each year from congenital kidney, heart, and liver disease, before we expend great effort in modifying diagnostic criteria for brain death, changing statutory definitions of death, or relaxing fundamental principles of transplantation ethics in order to obtain anencephalic organs.


[1] Ronald J. Lemire, "Neural Tube Defects," Journal of the American Medical Association 259:4 (January 22/29, 1988), 558-62.

[2] Michael Melnick and Ntinos C. Myrianthopoulos, "Studies in Neural Tube Defects II. Pathologic Findings in a Prospectively Collected Series of Anencephalics," American Journal of Medical Genetics 26:4 (April 1987), 797-810.

[3] Josef Warkany, Congenital Malformations (Chicago: Year Book Medical Publishers, 1971), 195.

[4] Ronald J. Lemire, J. Bruce Beckwith, and Josef Warkany, Anencephaly (New York: Raven Press, 1978), 5.

[5] Warkany, Congenital Malformations, 189 (note 3).

[6] Warkany, Congenital Malformations, 211 (note 3).

[7] Warkany, Congenital Malformations, 192 (note 3); Jeanne E. Bell and Robert J.L. Green, "Studies on the Area Cerebrovasculosa of Anencephalic Fetuses," Journal of Pathology 137:4 (August 1982), 315-28.

[8] Warkany, Congenital Malformations, 212 (note 3).

[9] Bell and Green, "Studies on the Area Cerebrovasculosa" at 315 (note 7); see also Toshihiko Terao et al., "Neurological Control of Fetal Heart Rate in 20 Cases of Anencephalic Fetuses," American Journal of Obstetrics and Gynecology 149:2 (May 15, 1984), 201-208.

[10] Ronald J. Lemire et al., Normal and Abnormal Development of the Human Nervous System (Hagerstown, MD: Harper & Row, 1975), 62.

[11] Diane M. Gianelli, "Anencephalic Heart Donor Creates New Ethics Debate," American Medical News (November 6, 1987), 3, 47-49, at 49.

[12] Pictures of cephalic lesions further exemplifying this diagnostic ambiguity are found in Warkany, Congenital Malformations, Fig. 22-11 at 198, 24-4 at 213 (note 3); Yvonne Brackbill, "The Role of the Cortex in Orienting: Orienting Reflex in an Anencephalic Human Infant," Developmental Psychology 5:2 (September 1971), 195-201; J.M. Nielsen and R.P. Sedgwick, "Instincts and Emotions in an Anencephalic Monster," Journal of Nervous and Mental Disease 110:4 (October 1949), 387-94.

[13] Patricia A. Baird and Adele D. Sadovnick, "Survival in Infants with Anencephaly," Clinical Pediatrics 23:5 (May 1984), 268-71.

[14] H. Urich and M. Kaarsoo Herrick, "The Amniotic Band Syndrome as a Cause of Anencephaly. Report of a Case," Acta Neuropathologica (Berlin) 67:3-4 (August 1985), 190-94.

[15] J. Mark Elwood and J. Harold Elwood, Epidemiology of Anencephalus and Spina Bifida (Oxford: Oxford University Press, 1980), 87-90; J. Haase et al., "A Cohort Study of Neural Tube Defects (NTD) in Denmark Covering the First Seven Years of Life," Child's Nervous System 3 (1987), 117-20.

[16] Ntinos C. Myrianthopoulos and Michael Melnick, "Studies in Neural Tube Defects I. Epidemiologic and Etiologic Aspects," American Journal of Medical Genetics 26 (1987), 783-96.

[17] Mary J. Seller, "Neural Tube Defects and Sex Ratios," American Journal of Medical Genetics 26:3 (March 1987), 699-707; Elwood and Elwood, Epidemiology 130-38 (note 15).

[18] Lechaim Naggan, "The Recent Decline in Prevalence of Anencephaly and Spina Bifida," American Journal of Epidemiology 89:2 (February 1969), 154-60; Ian Leck, "Spina Bifida and Anencephaly: Fewer Patients, More Problems," British Medical Journal 286 (May 28, 1983), 1679-80; David H. Stone, "The Declining Prevalence of Anencephalus and Spina Bifida: Its Nature, Causes and Implications," Developmental Medicine and Child Neurology 29:4 (August 1987), 541-49; Elwood and Elwood, Epidemiology, 107-19 (note 15).

[19] Elwood and Elwood, Epidemiology, 89 (note 15); Myrainthopoulos and Melnick, "Studies, I" (note 16); Roberta H. Raven et al., "Geographic Distribution of Anencephaly in the United States," Neurology 33:9 (September 1983), 1243-46.

[20] Sherman C. Stein et al., "Is Myelomeningocele a Disappearing Disease?" Pediatrics 69:5 (May 1982), 511-14; Gayle C. Windham and Larry D. Edmonds, "Current Trends in the Incidence of Neural Tube Defects," Pediatrics 70:3 (September 1982), 333-37. (Prevalence rates for each sex are shown separately on their graphs; the total prevalence rate of 0.48 cited here was provided through the courtesy of Mr. Edmonds.)

[21] Personal communication, Linda Lustig, M.S., Chief, Neural Tube Defect Section, Genetic Disease Branch, California Department of Health Services, Berkeley, CA.

[22] Data made available through the courtesy of Larry D. Edmonds, M.S.P.H., Birth Defects Branch, Centers for Disease Control, U.S. Department of Health and Human Services, Atlanta, GA.

[23] U.S. Bureau of the Census, Statistical Abstract of the United States: 1988 108th edition (Washington, DC: U.S. Government Printing Office, 1987), Tables 81 and 83 at 59-60.

[24] See, for example, H. Thom et al., "The Impact of Maternal Serum Alpha Fetoprotein Screening on Open Neural Tube Defect Births in North-East Scotland," Prenatal Diagnosis 5:1 (January 1985), 15-19.

[25] Personal communications, Linda Dobbs, R.N., Southern California Regional Coordinator for the AFP Screening Program, UCLA Medical Center, Los Angeles, CA, and Linda Lustig (note 21).

[26] Personal communication, Linda Doobs (note 25).

[27] Jack A. Pritchard, Paul C. MacDonald, and Norman F. Gant, Williams Obstetrics (New York: Appleton-Century-Crofts, 1985), 17th ed., 462, 802-803.

[28] Elwood and Elwood, Epidemiology, 58, 75-76, 84, 109 (note 15); Windham and Edmonds, "Current Trends" (note 20).

[29] G.H.A. Visser et al., "Abnormal Motor Behavior in Anencephalic Fetuses," Early Human Development 12:2 (November 1985), 173-82.

[30] Lemire, Beckwith, and Warkany, Anencephaly, 52-53 (note 4).

[31] I. Friedmann, J.L.W. Wright, and P.D. Phelps, "Temporal Bone Studies in Anencephaly," The Journal of Laryngology and Otology 94:8 (August 1980), 929-44.

[32] Brackbill, "The Role of the Cortex" (note 12); Patricia L. Francis, Patricia A. Self, and Mary Anne McCaffree, "Behavioral Assessment of a Hydranencephalic Neonate," Child Development 55:1 (February 1984), 262-66. (Judging from the authors' description, this infant probably suffered from maximal hydrocephalus rather than hydranencephaly.)

[33] Gary G. Berntson et al., "The Decerebrate Human: Associative Learning," Experimental Neurology 81:1 (July 1983), 77-88; Frances K. Graham et al., "Precocious Cardiac Orienting in a Human Anencephalic Infant," Science 199 (Jan. 20, 1978), 322-24.

[34] David S. Tuber et al., "Associative Learning in Premature Hydranencephalic and Normal Twins," Science 210 (November 28, 1980), 1035-37; Thomas Deiker and Ralph D. Bruno, "Sensory Reinforcement of Eyeblink Rate in a Decorticate Human," American Journal of Mental Deficiency 80:6 (May 1976), 665-67; Berntson et al., "The Decerebrate Human: Associative Learning" (note 33).

[35] Glen P. Aylward, Anthony Lazzara, and John Meyer, "Behavioral and Neurological Characteristics of a Hydranencephalic Infant," Developmental Medicine and Child Neurology 20:2 (April 1978), 211-17. (One cannot entirely exclude the possibility, however, that the visual tracking reported in this case was mediated by a shrunken remnant of occipital lobe.)

[36] Julius Hoffman and Leopold Liss, "'Hydranencephaly.' A Case Report with Autopsy Findings in a 7-Year-Old Girl," Acta Paediatrica Scandinavia 58:3 (May 1969), 297-300; James H. Halsey, Jr., Norman Allen, and Harrie R. Chamberlin, "Chronic Decerebrate State in Infancy. Neurologic Observations in Long Surviving Cases of Hydranencephaly," Archives of Neurology 19:3 (September 1968), 339-46; Francis et al., "Behavioral Assessment of a Hydranencephalic Neonate" (note 32); Nielsen and Sedgwick, "Instincts and Emotions" (note 12).

[37] Lemire et al., Normal and Abnormal Development, 40-52, 231-39, 260-65 (note 10).

[38] Harry T. Chugani, Michael E. Phelps, and John C. Mazziotta, "Positron Emission Tomography Study of Human Brain Functional Development," Annals of Neurology 22:4 (October 1987), 487-97.

[39] Marshall M. Haith and Joseph J. Campos (volume editors), "Infancy and Developmental Psychobiology," in Paul H. Mussen, ed., Handbook of Child Psychology 4th edition, Vol. II (New York: John Wiley & Sons, 1983).

[40] Robert J. Norman et al., "Classical Eyeblink Conditioning in the Bilaterally Hemispherectomized Cat," Experimental Neurology 44:3 (September 1974), 363-80; Ann M. Travis and Clinton N. Woolsey, "Motor Performance of Monkeys After Bilateral Partial and Total Cerebral Decortications," American Journal of Physical Medicine 35:5 (October 1956), 273-310; Stanley Finger and Donald G. Stein, Brain Damage and Recovery. Research and Clinical Perspectives (New York: Academic Press, 1982), 245-50; David A. Hovda, Richard L. Sutton, and Dennis M. Feeney, "Amphetamine-Induced Recovery of Visual Cliff Performance After Bilateral Visual Cortex Ablation in Cat: Measurements of Depth Perception Thresholds," Behavioral Neuroscience (1988), in press; Dennis M. Feeney and David A. Hovda, "Reinstatement of Binocular Depth Perception by Amphetamine and Visual Experience After Visual Cortex Ablation," Brain Research 342:2 (September 9, 1985), 352-56.

[41] Fred Plum and Jerome B. Posner, The Diagnosis of Stupor and Coma 3rd Edition (Philadelphia: F.A. Davis, 1980), 1-30.

[42] Ronald E. Cranford, "The Persistent Vegetative State: The Medical Reality (Getting the Facts Straight)," Hastings Center Report 18:1 (February/March 1988), 27-32.

[43] See, for example, Hans Flohr and Wolfgang Precht, eds., Lesion-Induced Neuronal Plasticity in Sensorimotor Systems (Berlin: Springer-Verlag, 1981); Carl W. Cotman, ed., Synaptic Plasticity (New York: Guilford Press, 1985); Jaime R. Villablanca, J. Wesley Burgess, and Charles E. Olmstead, "Recovery of Function After Neonatal or Adult Hemispherectomy in Cats: I. Time Course, Movement, Posture and Sensorimotor Tests," Behavioural Brain Research 19:3 (March 1986), 205-26, and sequels II and III in 20 (1986), 1-18, 217-30; Finger and Stein, "Brain Damage and Recovery," 63-81, 103-52, 287-302 (note 40).

[44] See, for example, M.A. Jeeves, "Age Related Effects of Agenesis and Partial Sectioning of the Neocortical Commissures," in Functional Recovery from Brain Damage, Marius W. van Hof and Gesine Mohn, eds. (Amsterdam: Elsevier/North-Holland, 1981), 31-52; Sid Gilman, James R. Bloedel, and Richard Lechtenberg, Disorders of the Cerebellum (Philadelphia: F.A. Davis, 1981), 263.

[45] Brian Kolb, Ian Q. Whishaw, and Derek van der Kooy, "Brain Development in the Neonatally Decorticated Rat," Brain Research 397:2 (November 12, 1986), 315-26; P.M. Stuurman, M.W. Van Hof, and J. Hobbelen, "Behavioural Effects of Early and Late Unilateral Ablation of the Occipital Lobe in the Rabbit," in van Hof and Mohn, Functional Recovery, 121-29 (note 44).

[46] L.-M. Bjursten, K. Norrsell, and U. Norrsell, "Behavioural Repertory of Cats without Cerebral Cortex from Infancy," Experimental Brain Research 25:2 (May 28, 1976), 115-30.

[47] David A. Hovda, Jaime R. Villablanca, and B.L. Shook, "Sparing of the Visual Field Is Associated with Less Metabolic Depression in the Superior Colliculus of Neonatal versus Adult Hemispherectomized Cats," Society for Neuroscience Abstracts 13 (1987), 1692; Patricia S. Goldman and Thelma W. Galkin, "Prenatal Removal of Frontal Association Cortex in the Fetal Rhesus Monkey: Anatomical and Functional Consequences in Postnatal Life," Brain Research 152:3 (September 8, 1978), 451-58.

[48] K.J.S. Anand and P.R. Hickey, "Pain and its Effects in the Human Neonate and Fetus," New England Journal of Medicine 317:21 (November 19, 1987), 1321-29.

[49] John C. Fletcher, John A. Robertson, and Michael R. Harrison, "Primates and Anencephalics as Sources for Pediatric Organ Transplants. Medical, Legal, and Ethical Issues," Fetal Therapy 1:2-3 (1986), 150-64, at 155.

[50] Baird and Sadovnick, "Survival in Infants with Anencephaly" (note 13).

[51] Jeffrey Pomerance and Barry S. Schifrin, "Anencephaly and the 'Baby Doe' Regulations," Pediatric Research 21:4 (Part 2, April 1987), 373A; Jeffrey Pomerance et al., "Anencephalic Infants: Life Expectancy and Organ Donation," Journal of Perinatology (in press).

[52] Brackbill, "The Role of the Cortex in Orienting" (note 12).

[53] Personal experience, Warwick J. Peacock, MD, Associate Professor of Pediatric Neurosurgery, UCLA Medical Center, Los Angeles, CA.

[54] Gianelli, "Anencephalic Heart Donor Creates New Ethics Debate," at 49, col. 4 (note 11).

[55] L. Pajor, A. Nemeth, and T. Illes, "Functional Morphology of the Adrenal Cortex in Newborns. I. Morphometric Study," Acta Morphologica Hungarica 34:1-2 (1986), 31-37; L. Cavallo et al., "Endocrine Function in Four Anencephalic Infants," Hormone Research 15 (1981), 159-66; Bruce R. Carr et al., "Regulation of Steroid Secretion by Adrenal Tissue of a Human Anencephalic Fetus," Journal of Clinical Endocrinology and Metabolism 50:5 (1980), 870-73.

[56] Elwood and Elwood, Epidemiology, 55-56 (note 15); A. Giroud, "Anencephaly," in Handbook of Clinical Neurology, Vol. 30, P.J. Vinken and G.W. Bruyn, eds. (Amsterdam: North-Holland, 1977), 173-208 at 176.

[57] George Cassady, "Anencephaly. A 6 Year Study of 367 Cases," American Journal of Obstetrics and Gynecology 103:8 (April 15, 1969). 1154-59.

[58] Cassady, "Anencephaly" (note 57)); Pomerance et al., "Anencephalic Infants" (note 51).

[59] Melnick and Myrianthopoulos, "Studies, II" (note 2); Lemire, Beckwith, and Warkany, Anencephaly, 66-84 (note 4).

[60] P. Kinnaert et al., "Transplantation of Both Kidneys of an Anencephalic Newborn to a 23-Year-Old Patient," European Urology 7:6 (1981), 373-76.

[61] Robert B. Ettenger and Richard N. Fine, "Renal Transplantation," in Pediatric Nephrology, Malcolm A. Holliday, T. Martin Barratt, and Robert L. Vernier, eds. (Baltimore: Williams & Wilkins, 1987), 2nd ed., 828-46; Caliann T. Lum, Steven J. Wassner, and Donald E. Martin, "Current Thinking in Transplantation in Infants and Children," Pediatric Clinics of North America 32:5 (October 1985), 1203-30.

[62] Melnick and Myrianthopoulos, "Studies, II" (note 2); Lemire, Beckwith, and Warkany, Anencephaly, 73-74 (note 4).

[63] Melnick and Myrianthopoulos, "Studies, II" (note 2); Lemire, Beckwith, and Warkany, Anencephaly, 79-80 (note 4).

[64] Richard L. Naeye and William A. Blanc, "Organ and Body Growth in Anencephaly: A Quantitative, Morphological Study," Archives of Pathology 91: (February 1971), 140-47.

[65] Naeye and Blanc, "Organ and Body Growth" (note 64).

[66] Extrapolated from Lemire, Beckwith, and Warkany, Anencephaly, Fig. 3-6 at 80 (note 4).

[67] Lum, Wassner, and Martin, "Current Thinking in Transplantation" (note 61); Carlos O. Esquivel et al., "Liver Transplantation Before 1 Year of Age," Journal of Pediatrics 110:4 (April 1987), 545-48.

[68] Personal communication, Barbara L. Schulman, R.N., Transplant Coordinator, Regional Organ Procurement Agency of Southern California, UCLA Medical Center, Los Angeles, CA.

[69] John R. Lilly, Roberta J. Hall, and R. Peter Altman, "Liver Transplantation and Kasai Operation in the First Year of Life: Therapeutic Dilemma in Biliary Atresia," Journal of Pediatrics 110:4 (April 1987), 561-62.

[70] Robert Steinbrook, "Center Modifies Baby-Organ Harvesting," Los Angeles Times, April 16, 1988, Part I, 20; personal communication, Stephen Ashwal, MD, Division of Pediatric Neurology, Loma Linda University Medical Center, Loma Linda, CA.

[71] Personal communication, Anita Rockwell, assistant director of community relations, Loma Linda University Medical Center, Loma Linda, CA.

[72] Constantine Mavroudis et al., "Infant Orthotopic Cardiac Transplantation," Journal of Cardiovascular Surgery (in press).

[73] Esquivel et al., "Liver Transplantation" (note 67); Lum, Wassner, and Martin, "Current Thinking in Transplantation" (note 61).

D. Alan Shewmon is assistant professor of pediatrics and neurology at UCLA Medical Center, Los Angeles, CA.
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Author:Shewman, D. Alan
Publication:The Hastings Center Report
Date:Oct 1, 1988
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