43
(1992) 43-50 Elsevier Scientific Publishers Ireland Ltd. Early
Human
Development,
29
EHD 01249
A 50-year overview of perinatal medicine Mary Ellen Avery Harvard
Medical
School
221, Longwood
Avenw,
Boston,
MA,
02115
(USA)
summary Infant mortality in 1990 was approximately one-tenth that of 1950 in most of the industrialized countries of the world. The forces of change included the socialpolitical climate, advent of neonatal intensive care, better insight into nutritional requirements of preterm infants and application of basic science to the study of events around the time of birth, and illnesses of the neonate. Attention has been paid to the advantages of human milk for the newborn infant, the importance of maternal bonding and involvement of both parents in care of the infant. Prenatal diagnosis, with option of abortion, has reduced the prevalence of some serious disorders of the fetus. Key words: infant mortality;
neonatal intensive care; history of neonatology
Introduction I have had the privilege of nearly 40 years as an observer of changes in obstetrics and neonatology as a medical student, house officer and later one engaged in a career of thinking about adaptations to extrauterine life. I welcome the opportunity to share these reflections, with apologies to those whose major contributions I may not specifically mention. Social-political environment The stage was set for increasing concern for the health of mothers and children by our predecessors, particularly Drs. Martha Eliot and Ethel Dunham. They, with the help of the Roosevelts (both Franklin and Eleanor) were instrumental in including Title V under the Social Security Act of 1935. This legislation enabled Correspondence
to:
Mary Ellen Avery, Harvard Medical School 221, Longwood Avenue, Boston, MA,
02115, USA. 037%3782/92/SO5.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
44
federal funding to the states for maternal and child health units and crippled children’s services. In 1965 the establishment maternal and infant care programs and children and youth clinics reached approximately 70% of all children and provided comprehensive services. Although it is not possible to have an objective measure of the impact of these services, I think it is fair to say that much of the decline in infant mortality from 1938 through the 1960s was facilitated by improved access to care. At the same time the social agenda was expanding, the National Institutes of Health were born and flourished, with ever-increasing support for medical research that has reached $9 billion a year. The societal mandate for improved services and augmented research and training was a signal that a reduction in maternal and infant mortalities were national goals and that those in obstetrics and pediatrics carried a major responsibility to produce the new knowledge and the training that would save lives. The legalizing of abortion in the United States, by way of the landmark Supreme Court decision, ‘Roe vs. Wade’ also contributed to the major reduction in maternal mortality and associated infant mortality. Indeed it must be underscored that the outlook for infants and children is tightly coupled to the concern for the status of women. Origins of neonatal intensive care I turn now to recall what I knew about the care of infants firsthand in the nurseries of the Johns Hopkins Hospital from 1952 to 1969. There were no such things as intensive care units, blood gases, ventilators, or even much intravenous therapy. Not only that, it was difficult to get any measurements of blood chemistries because micromethodologies were not available. Also, parents were not allowed to visit their infants in this physician-controlled setting. Infant nutrition In the 1950s much of the concern focused around what to feed infants and the use of half skimmed milk with added carbohydrate, followed the balance studies carried out by Levine and Gordon, principally at Cornell, in New York City. Their measurements constituted one of the first serious attempts to establish a scientific basis for infant feeding. This was in the setting of discouraging mothers from providing breast milk for their infants because it was felt to be nutritionally inadequate. We can only say in retrospect that it was soon discovered that infants of low birth weight did not thrive on half-skimmed milk and with further studies of serum amino acids and the like, it was evident that the metabolism of protein derived from cow’s milk did not lead to optimal blood levels of essential nutrients. Over the years, with major support from pharmaceutical companies, cow’s milk, modified to be closer in comparison to human milk, was made available and avoided some of the hyperphenylalanemia that had been associated with the high protein intake. Meanwhile, of course, it became evident that human milk had many desirable attributes for premature infants, not the least of which were the presence of irnmunoglobulins in the colostrum and the enhanced bioavailability of calcium that meant that tetany became a thing of the past.
45
Retinopathy of prematurity In the 1950s an epidemic of retrolental fibroplasia reached its peak and by the mid-1950s an association with high inspired oxygen concentrations was made. The timing of that epidemic was shortly after World War II, when new hospitals were being built and better incubators were available. It is to the great credit of Patz in Baltimore and Ashton in London that the kitten, whose immature retina at term resembles that of the premature infant, was studied in high oxygen environments and the natural evolution of retrolental fibroplasia became clear. The problem was that the consequences of that new knowledge was to limit oxygen so severely that we had devices on incubators that would not permit it to go over 40%. It was not until Ashton did the critical experiment that demonstrated that it was the oxygen tension in the blood, not the environment, that was crucial in the pathogenesis of the lesion, that it became clear that many of these small babies were dying from hypoxemia when oxygen intake was restricted to 40%. Respiratory distress syndrome The next major focus of interest was on the nature or cause of the respiratory distress that seemed to worsen in the hours after birth in many premature infants. Named hyaline membrane disease by the pathologists, the clinical description of the infants with that disorder was not really clear until the early 1950s when Miller made the observation that infants with elevated respiratory rates and retractions had a serious prognosis. In fact, hyaline membrane disease was for many years the leading cause of death of live-born premature infants. It no longer is, having been reduced substantially by the advent of ventilators, application of positive end-expiratory pressure to prevent the atelectasis and use of prenatal glucocorticoids to accelerate lung maturation and since 1990 the licensing of pulmonary surfactants for replacement therapy. That in one sentence describes nearly 30 years of effort that was progressing through studies on lung maturation and its regulation as well as clinical evaluation. The nurseries of the 1950s It is interesting to reflect on what was happening in the nurseries of the world when ventilators were beginning to be used, but before we had the availability to monitor blood gases, and before we appreciated the importance of end-expiratory pressure. The results were not impressive. At the same time, concentration on the clinical description of hyaline membrane disease led to theories of pathogenesis, such as aspiration. It was in the early 1960s that some of these babies were kept on nothing by mouth for 3 days for fear that they would aspirate any liquid and that could make things worse. It did make things worse in as much as they developed severe acidosis and dehydration, but aspiration was not the cause of hyaline membrane disease. Other good intentions were to flood the incubators with mist, sometimes of such density that it was hard to see the baby. In the process, this very humid environment led to flourishing of opportunistic organisms, such as Pseudomonas, and infection became a significant problem.
46
One of the major advances of the 1950s was the recognition that much of what was done for these babies with respiratory distress, was empirical, extrapolated sometimes from experience in older individuals. In other words, the widespread use of mist was never evaluated as to its efficacy until Silverman, Sinclair and others recognized the importance of controlled clinical trials. They are responsible for getting the mist generators out of the incubators. Temperature regulation It was also of interest to note that the routine orders for the care of infants in the 1950s dictated that the incubator temperature remain between 88” and 90°C. When that was the case with very-low-birth-weight infants, their body temperatures could be between 88” and 90°C which it was subsequently shown did not do them any good. In fact, again, it was controlled clinical trials that made it clear that infants needed to be in a thermal neutral zone, which was dependent on their birth weight and postnatal age. Interactions with basic scientists Looking back on these years, I feel that a major stimulus to my own interest in the study of physiology came in part from the opportunity to meet basic scientists in several kinds of settings, one of which was CIBA Symposia sponsored by the CIBA Foundation in London and another, Ross Conferences, sponsored by Ross Laboratories in this country. Although I never had the privilege of meeting Sir Joseph Barcroft, the English physiologist who had such an influence on the field of fetal physiology, I certainly have had the pleasure of working with a number of his former colleagues and others, in the great schools of English physiology at Oxford and Cambridge. Barcroft’s classic work, Researches on Pre-natal Life, is as valid today as it was 46 years ago when first published. Much of what we know about infant nutrition came from the studies of McCance and Widdowson, who presented their work frequently at symposia with clinicians as well as biochemists. It was also Maureen Young, a former colleague of Sir Joseph Barcroft, who taught us much of placental transport of amino acids and fetal growth, and Dawes, Mott and their many colleagues, who illuminated the fetal circulation, fetal breathing and transitions at birth. Through the 196Os, 1970s and 198Os, many of us had the pleasure of frequent interactions with our colleagues in England and elsewhere in the United States, so that the form of communication of new ideas through publication was augmented significantly by the opportunity to build friendships with those colleagues pursuing answers to similar questions and sharing in the delight of new news, no matter what its source. Much of the new knowledge of the 1940s and early 1950s was brought to the attention of pediatricians by Clement Smith in his text, The Physiology of the Newborn Infant (1945). Certainly one of the forces that is driving the advancement of knowledge at an ever-increasing rate has been enhanced communications, not only with periodic symposia, but the ability now to work with scientists around the world, by the many forms of communication.
41
Evolution of training in neonatology In the 195Os, The Hospital for Women of Maryland did not have a full-time neonatologist. Alexander Schaffer was their pediatrician-in-chief, while he was engaged in private practice in Baltimore. He found that some individuals from overseas were glad to have the opportunity to work with him in looking after newborns and this is my first recollection of neonatal fellows. I cannot overestimate the importance of the role of fellows, who began to address the needs of the newborn at a time when there were few tools, but there was an appalling mortality rate. Perhaps that was the main reason for the motivation of young pediatricians to focus on newborn infants. Because the tools soon became available, the new knowledge led to ever-better outcomes, and even more interest in infants in an almost continuous pattern from the 1930s to the present time. The 1950s and 1960s were notable too for many important clinical observations, such as Clifford’s postmaturity syndrome which alerted obstetricians to the harm to the fetus of prolonged pregnancy. Similarly, Lubchenco’s recognition of intrauterine growth retardation coupled with Widdowson’s observations on the ‘runt of the litter’ stimulated clinicians to consider gestational age as well as birth weight in assessment of the newborn. Regiooalizatioa Referrals to centers did not become common during the era when little was available in these centers to facilitate the care of the infant. In the mid-1950s sometimes babies were brought in in little doggie boxes by ambulance, mainly because there were no nursing personnel in some small hospitals to take care of the babies and the only special care that was provided in centers was in essence gavage feeding. Once ventilators were used successfully, (and that depended on the availability of micro blood gas analyses), by the late 1960s there was a drive for regionalization, given significant momentum by the perinatal mortality studies sponsored by the Province of Quebec. This Province-wide survey of the outcome by birth weight and place of birth, with or without transport to centers, made it clear that infant mortality could be reduced when there was a suitable mechanism to transfer babies to centers. The forces that drove regionalization included the availability of the capacity to do something for the babies when they were sent to a center, but also from some malpractice suits that emerged with penalties to those who did not transfer babies to centers. Regionalization depended in part on appropriate reimbursement for the very expensive care that was available. When that reimbursement took effect, there were a number of nurseries that simply put a sign on the door calling themselves ‘intensive care nurseries’, later, ‘neonatal intensive care units’, when in fact the pediatricians often had no formal training in management of ventilators and other aspects of intensive care. The need for more well-trained individuals, in turn led to the establishment of standards for training of individuals who administered intensive care and the evolution of Board certification in neonatology and perinatology.
48
Involvement of parents The involvement of parents in relating to their infants in the high-tech and sometimes, emotionally sterile environments of intensive care nurseries is a remarkable and important aspect of neonatal intensive care. In the 1950s mothers were denied the opportunity to visit their infants or to hold them, as it was thought they might spread infection. In the irrationality of the era, student nurses were allowed rotations in the premature nurseries but mothers were not allowed to enter. From our perspective in the 199Os, we welcome the presence of parents, of other caretakers and students of psychology in our ‘neonatal intensive care units’ to help us understand how best to foster the well-being of our small patients. Follow-up As ever more low-birth-weight infants survive, we appreciate that we are the caretakers of a new group of humans who have never been with us before the lowering of neonatal mortality. The obligation to learn of their outcomes after hospital discharge is obvious in order to evaluate the long-term effects of some of our interventions. On balance, we know that infants over 1.5 kg birth weight do about as well as those born at term and the same is true for some, but by no means all, of the very-low-birth-weight infants. Future directions If past lessons are also beacons for future progress, let us turn to ‘Where do we go from here?’ I think we can ask the question about what led to the transition of new knowledge from preliminary observations to changes of practice and when were they too slow and when were they too precipitous? Delays in application in new knowledge One might use hyperbilirubinemia as an example. When Cremer made his observation in 1958 in a nursery in England that showed babies near the window had less physiologic jaundice, than those not in such a bright light, it was taken with considerable skepticism. By 1968 Lucey had demonstrated conclusively in a controlled trial that phototherapy worked. Nonetheless, there was a decade of uncertainty on the part of some individuals as to whether exposure to blue light may have adverse side effects that might not show up for years and hence a reluctance to use it. Gradually, as time went by, the efficacy of phototherapy was unequivocal, the toxicity minimal and it is used routinely around the world. This has led to a great reduction in the need for exchange transfusion and hence, has been life-saving. Another illustration in a delay,in acceptance of new knowledge has been the long and continuing interval to acknowledge the conclusive demonstration by Liggins and Howie in New Zealand in the late 1960s that prenatal glucocorticoids could accelerate lung maturation. Subsequently, the beneficial effects of glucocorticoids on closure of the ductus, on maturation of the intestine, on excretion of bile salts, on
49
renal tubular function have made it clear that glucocorticoids accelerate maturation, which greatly facilitates the neonatal adaptation of a number of organs. Even now, however, some obstetricians seem loathe to use prenatal glucocorticoids, even in a situation where there would be the requisite 24-48 h for their effect to take place. Only 8% of the infants in the a trial of surfactant replacement were born to mothers who had received prenatal glucocorticoids. When Jobe reviewed those data, however, he noted that among the mothers who had the full course of glucocorticoids and surfactant replacement, there were no deaths among the infants. Thus, the combined effects of these two interventions is powerful indeed, but to this date not widely appreciated. We can also call attention to the lag between Fujiwara’s first publication in 1980 that pulmonary surfactant instilled as a liquid in to the trachea greatly ameliorated the course of hyaline membrane disease and licensing of surfactant preparations in the United States in 1990. The topic remains lively and has been extensively reviewed, so I will leave it there, except to note that it took almost 20 years to go from the initial observation of surfactant deficiency to successful replacement and another decade before licensure of these materials by the FDA, made them widely available in the United States. Precipitous use of new knowledge
The evidence that sometimes new knowledge has been used precipitously or inappropriately applied is underscored by the overzealous restriction of oxygen in the 1950s that led to increased deaths from hyaline membrane disease, even though it spared the retina from libroplasia. The lesson is obvious; too little can be as dangerous as too much and with oxygen therapy there is indeed an optimal requirement. Another illustration was the excessive use of hexachlorophene to prevent staphylococcal disease, leading to absorption through the skin and in some instances, fatal neurotoxicity. The intravenous vitamin E-sepsis story, is another illustration of when a little might be good, too much might be dangerous. Evolution of perinatology
Although there is a long history of combined morbidity and mortality conferences where obstetricians and pediatricians were interactive, the consultation that can take place before delivery is a relatively more recent event and has been a major advance. Pediatricians have watched with interest the increasing use of cesarean section and have noted that it has effectively replaced the use of forceps. While section rates of 20% or 30% are very surprising to those who grew up with the belief that 5% was appropriate, there is no question that babies who are delivered today are spared much of the trauma that they endured during the ‘trials’ of labor, or difficult versions or forceps deliveries. Continued vigilance is appropriate, however and most revealing when obstetricians and pediatricians realize their interdependence. Lessons learned
If there is a comment to all of this, I would think it would be that we must build our interventions on the relevant basic science. Where that does not exist, we must make every effort with animal models and tissue culture methodology to unearth
50
understanding of the appropriate regulatory mechanisms that may need to be stimulated. Another lesson is that we need to work with epidemiologists and statisticians to construct studies that will give us clean answers and not further confuse the situation by type II errors, or inability to know enough to control for confounding factors in clinical trials. We need to recognize the power of prospective, randomized, controlled, clinical trials, but also to realize that there are other equally valid ways of gaining information about efficacy of interventions, such as having a given infant serve as its own control, or sequential comparisons of interventions in some situations. The great need is to know ‘what works’ in intensive care. In the future, I hope we continue to receive the societal support that has been so very important. I hope that advances in reproductive technologies will make the abortion debate moot, because there will be widely available abortifacients, such as RU 486 and better methods of contraception, so that it can be a fact that every baby is a wanted baby. In the future I hope that with the help of the basic scientists we can learn more about the causes of congenital malformations that are now the number one cause of neonatal mortality. At least we have profited from prenatal diagnosis with ultrasound and the detection of the major lethal malformations that can be prevented by abortion. Insight into the risk factors for malformations has the potential effect of making possible measures to prevent injury to the fetus. When we reflect upon deaths in the first year of life, we realize they are greatly over-represented in under-privileged populations and that it is not uniquely the province of perinatology to address those issues. It is our responsibility to flag them and to work with our colleagues in the social sciences to improve the standard of living world-wide to avoid some of the preventable causes of premature onset of labor and potential toxicity to infants by way of substances of abuse, AIDS and even cigarette smoking. We have firm evidence of the capacity to reduce infant mortality by 50% in the United States. This is because reductions of that sort have taken place in other parts of the world. I hope those concerned with the perinatal period will enlist colleagues from many disciplines to discuss the complex social and ethical issues that relate to questions about reproductive technologies and the pediatric dilemma, how small is too small, when not to prolong an inevitable death and when to ‘fight for life’. The rules change as the knowledge base increases. My own hope is that we will recognize worldwide the compelling need to see that every child is a wanted child and every mother has the choice to decide when and how often to become pregnant.
(1992) 43-50 Elsevier Scientific Publishers Ireland Ltd. Early
Human
Development,
29
EHD 01249
A 50-year overview of perinatal medicine Mary Ellen Avery Harvard
Medical
School
221, Longwood
Avenw,
Boston,
MA,
02115
(USA)
summary Infant mortality in 1990 was approximately one-tenth that of 1950 in most of the industrialized countries of the world. The forces of change included the socialpolitical climate, advent of neonatal intensive care, better insight into nutritional requirements of preterm infants and application of basic science to the study of events around the time of birth, and illnesses of the neonate. Attention has been paid to the advantages of human milk for the newborn infant, the importance of maternal bonding and involvement of both parents in care of the infant. Prenatal diagnosis, with option of abortion, has reduced the prevalence of some serious disorders of the fetus. Key words: infant mortality;
neonatal intensive care; history of neonatology
Introduction I have had the privilege of nearly 40 years as an observer of changes in obstetrics and neonatology as a medical student, house officer and later one engaged in a career of thinking about adaptations to extrauterine life. I welcome the opportunity to share these reflections, with apologies to those whose major contributions I may not specifically mention. Social-political environment The stage was set for increasing concern for the health of mothers and children by our predecessors, particularly Drs. Martha Eliot and Ethel Dunham. They, with the help of the Roosevelts (both Franklin and Eleanor) were instrumental in including Title V under the Social Security Act of 1935. This legislation enabled Correspondence
to:
Mary Ellen Avery, Harvard Medical School 221, Longwood Avenue, Boston, MA,
02115, USA. 037%3782/92/SO5.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
44
federal funding to the states for maternal and child health units and crippled children’s services. In 1965 the establishment maternal and infant care programs and children and youth clinics reached approximately 70% of all children and provided comprehensive services. Although it is not possible to have an objective measure of the impact of these services, I think it is fair to say that much of the decline in infant mortality from 1938 through the 1960s was facilitated by improved access to care. At the same time the social agenda was expanding, the National Institutes of Health were born and flourished, with ever-increasing support for medical research that has reached $9 billion a year. The societal mandate for improved services and augmented research and training was a signal that a reduction in maternal and infant mortalities were national goals and that those in obstetrics and pediatrics carried a major responsibility to produce the new knowledge and the training that would save lives. The legalizing of abortion in the United States, by way of the landmark Supreme Court decision, ‘Roe vs. Wade’ also contributed to the major reduction in maternal mortality and associated infant mortality. Indeed it must be underscored that the outlook for infants and children is tightly coupled to the concern for the status of women. Origins of neonatal intensive care I turn now to recall what I knew about the care of infants firsthand in the nurseries of the Johns Hopkins Hospital from 1952 to 1969. There were no such things as intensive care units, blood gases, ventilators, or even much intravenous therapy. Not only that, it was difficult to get any measurements of blood chemistries because micromethodologies were not available. Also, parents were not allowed to visit their infants in this physician-controlled setting. Infant nutrition In the 1950s much of the concern focused around what to feed infants and the use of half skimmed milk with added carbohydrate, followed the balance studies carried out by Levine and Gordon, principally at Cornell, in New York City. Their measurements constituted one of the first serious attempts to establish a scientific basis for infant feeding. This was in the setting of discouraging mothers from providing breast milk for their infants because it was felt to be nutritionally inadequate. We can only say in retrospect that it was soon discovered that infants of low birth weight did not thrive on half-skimmed milk and with further studies of serum amino acids and the like, it was evident that the metabolism of protein derived from cow’s milk did not lead to optimal blood levels of essential nutrients. Over the years, with major support from pharmaceutical companies, cow’s milk, modified to be closer in comparison to human milk, was made available and avoided some of the hyperphenylalanemia that had been associated with the high protein intake. Meanwhile, of course, it became evident that human milk had many desirable attributes for premature infants, not the least of which were the presence of irnmunoglobulins in the colostrum and the enhanced bioavailability of calcium that meant that tetany became a thing of the past.
45
Retinopathy of prematurity In the 1950s an epidemic of retrolental fibroplasia reached its peak and by the mid-1950s an association with high inspired oxygen concentrations was made. The timing of that epidemic was shortly after World War II, when new hospitals were being built and better incubators were available. It is to the great credit of Patz in Baltimore and Ashton in London that the kitten, whose immature retina at term resembles that of the premature infant, was studied in high oxygen environments and the natural evolution of retrolental fibroplasia became clear. The problem was that the consequences of that new knowledge was to limit oxygen so severely that we had devices on incubators that would not permit it to go over 40%. It was not until Ashton did the critical experiment that demonstrated that it was the oxygen tension in the blood, not the environment, that was crucial in the pathogenesis of the lesion, that it became clear that many of these small babies were dying from hypoxemia when oxygen intake was restricted to 40%. Respiratory distress syndrome The next major focus of interest was on the nature or cause of the respiratory distress that seemed to worsen in the hours after birth in many premature infants. Named hyaline membrane disease by the pathologists, the clinical description of the infants with that disorder was not really clear until the early 1950s when Miller made the observation that infants with elevated respiratory rates and retractions had a serious prognosis. In fact, hyaline membrane disease was for many years the leading cause of death of live-born premature infants. It no longer is, having been reduced substantially by the advent of ventilators, application of positive end-expiratory pressure to prevent the atelectasis and use of prenatal glucocorticoids to accelerate lung maturation and since 1990 the licensing of pulmonary surfactants for replacement therapy. That in one sentence describes nearly 30 years of effort that was progressing through studies on lung maturation and its regulation as well as clinical evaluation. The nurseries of the 1950s It is interesting to reflect on what was happening in the nurseries of the world when ventilators were beginning to be used, but before we had the availability to monitor blood gases, and before we appreciated the importance of end-expiratory pressure. The results were not impressive. At the same time, concentration on the clinical description of hyaline membrane disease led to theories of pathogenesis, such as aspiration. It was in the early 1960s that some of these babies were kept on nothing by mouth for 3 days for fear that they would aspirate any liquid and that could make things worse. It did make things worse in as much as they developed severe acidosis and dehydration, but aspiration was not the cause of hyaline membrane disease. Other good intentions were to flood the incubators with mist, sometimes of such density that it was hard to see the baby. In the process, this very humid environment led to flourishing of opportunistic organisms, such as Pseudomonas, and infection became a significant problem.
46
One of the major advances of the 1950s was the recognition that much of what was done for these babies with respiratory distress, was empirical, extrapolated sometimes from experience in older individuals. In other words, the widespread use of mist was never evaluated as to its efficacy until Silverman, Sinclair and others recognized the importance of controlled clinical trials. They are responsible for getting the mist generators out of the incubators. Temperature regulation It was also of interest to note that the routine orders for the care of infants in the 1950s dictated that the incubator temperature remain between 88” and 90°C. When that was the case with very-low-birth-weight infants, their body temperatures could be between 88” and 90°C which it was subsequently shown did not do them any good. In fact, again, it was controlled clinical trials that made it clear that infants needed to be in a thermal neutral zone, which was dependent on their birth weight and postnatal age. Interactions with basic scientists Looking back on these years, I feel that a major stimulus to my own interest in the study of physiology came in part from the opportunity to meet basic scientists in several kinds of settings, one of which was CIBA Symposia sponsored by the CIBA Foundation in London and another, Ross Conferences, sponsored by Ross Laboratories in this country. Although I never had the privilege of meeting Sir Joseph Barcroft, the English physiologist who had such an influence on the field of fetal physiology, I certainly have had the pleasure of working with a number of his former colleagues and others, in the great schools of English physiology at Oxford and Cambridge. Barcroft’s classic work, Researches on Pre-natal Life, is as valid today as it was 46 years ago when first published. Much of what we know about infant nutrition came from the studies of McCance and Widdowson, who presented their work frequently at symposia with clinicians as well as biochemists. It was also Maureen Young, a former colleague of Sir Joseph Barcroft, who taught us much of placental transport of amino acids and fetal growth, and Dawes, Mott and their many colleagues, who illuminated the fetal circulation, fetal breathing and transitions at birth. Through the 196Os, 1970s and 198Os, many of us had the pleasure of frequent interactions with our colleagues in England and elsewhere in the United States, so that the form of communication of new ideas through publication was augmented significantly by the opportunity to build friendships with those colleagues pursuing answers to similar questions and sharing in the delight of new news, no matter what its source. Much of the new knowledge of the 1940s and early 1950s was brought to the attention of pediatricians by Clement Smith in his text, The Physiology of the Newborn Infant (1945). Certainly one of the forces that is driving the advancement of knowledge at an ever-increasing rate has been enhanced communications, not only with periodic symposia, but the ability now to work with scientists around the world, by the many forms of communication.
41
Evolution of training in neonatology In the 195Os, The Hospital for Women of Maryland did not have a full-time neonatologist. Alexander Schaffer was their pediatrician-in-chief, while he was engaged in private practice in Baltimore. He found that some individuals from overseas were glad to have the opportunity to work with him in looking after newborns and this is my first recollection of neonatal fellows. I cannot overestimate the importance of the role of fellows, who began to address the needs of the newborn at a time when there were few tools, but there was an appalling mortality rate. Perhaps that was the main reason for the motivation of young pediatricians to focus on newborn infants. Because the tools soon became available, the new knowledge led to ever-better outcomes, and even more interest in infants in an almost continuous pattern from the 1930s to the present time. The 1950s and 1960s were notable too for many important clinical observations, such as Clifford’s postmaturity syndrome which alerted obstetricians to the harm to the fetus of prolonged pregnancy. Similarly, Lubchenco’s recognition of intrauterine growth retardation coupled with Widdowson’s observations on the ‘runt of the litter’ stimulated clinicians to consider gestational age as well as birth weight in assessment of the newborn. Regiooalizatioa Referrals to centers did not become common during the era when little was available in these centers to facilitate the care of the infant. In the mid-1950s sometimes babies were brought in in little doggie boxes by ambulance, mainly because there were no nursing personnel in some small hospitals to take care of the babies and the only special care that was provided in centers was in essence gavage feeding. Once ventilators were used successfully, (and that depended on the availability of micro blood gas analyses), by the late 1960s there was a drive for regionalization, given significant momentum by the perinatal mortality studies sponsored by the Province of Quebec. This Province-wide survey of the outcome by birth weight and place of birth, with or without transport to centers, made it clear that infant mortality could be reduced when there was a suitable mechanism to transfer babies to centers. The forces that drove regionalization included the availability of the capacity to do something for the babies when they were sent to a center, but also from some malpractice suits that emerged with penalties to those who did not transfer babies to centers. Regionalization depended in part on appropriate reimbursement for the very expensive care that was available. When that reimbursement took effect, there were a number of nurseries that simply put a sign on the door calling themselves ‘intensive care nurseries’, later, ‘neonatal intensive care units’, when in fact the pediatricians often had no formal training in management of ventilators and other aspects of intensive care. The need for more well-trained individuals, in turn led to the establishment of standards for training of individuals who administered intensive care and the evolution of Board certification in neonatology and perinatology.
48
Involvement of parents The involvement of parents in relating to their infants in the high-tech and sometimes, emotionally sterile environments of intensive care nurseries is a remarkable and important aspect of neonatal intensive care. In the 1950s mothers were denied the opportunity to visit their infants or to hold them, as it was thought they might spread infection. In the irrationality of the era, student nurses were allowed rotations in the premature nurseries but mothers were not allowed to enter. From our perspective in the 199Os, we welcome the presence of parents, of other caretakers and students of psychology in our ‘neonatal intensive care units’ to help us understand how best to foster the well-being of our small patients. Follow-up As ever more low-birth-weight infants survive, we appreciate that we are the caretakers of a new group of humans who have never been with us before the lowering of neonatal mortality. The obligation to learn of their outcomes after hospital discharge is obvious in order to evaluate the long-term effects of some of our interventions. On balance, we know that infants over 1.5 kg birth weight do about as well as those born at term and the same is true for some, but by no means all, of the very-low-birth-weight infants. Future directions If past lessons are also beacons for future progress, let us turn to ‘Where do we go from here?’ I think we can ask the question about what led to the transition of new knowledge from preliminary observations to changes of practice and when were they too slow and when were they too precipitous? Delays in application in new knowledge One might use hyperbilirubinemia as an example. When Cremer made his observation in 1958 in a nursery in England that showed babies near the window had less physiologic jaundice, than those not in such a bright light, it was taken with considerable skepticism. By 1968 Lucey had demonstrated conclusively in a controlled trial that phototherapy worked. Nonetheless, there was a decade of uncertainty on the part of some individuals as to whether exposure to blue light may have adverse side effects that might not show up for years and hence a reluctance to use it. Gradually, as time went by, the efficacy of phototherapy was unequivocal, the toxicity minimal and it is used routinely around the world. This has led to a great reduction in the need for exchange transfusion and hence, has been life-saving. Another illustration in a delay,in acceptance of new knowledge has been the long and continuing interval to acknowledge the conclusive demonstration by Liggins and Howie in New Zealand in the late 1960s that prenatal glucocorticoids could accelerate lung maturation. Subsequently, the beneficial effects of glucocorticoids on closure of the ductus, on maturation of the intestine, on excretion of bile salts, on
49
renal tubular function have made it clear that glucocorticoids accelerate maturation, which greatly facilitates the neonatal adaptation of a number of organs. Even now, however, some obstetricians seem loathe to use prenatal glucocorticoids, even in a situation where there would be the requisite 24-48 h for their effect to take place. Only 8% of the infants in the a trial of surfactant replacement were born to mothers who had received prenatal glucocorticoids. When Jobe reviewed those data, however, he noted that among the mothers who had the full course of glucocorticoids and surfactant replacement, there were no deaths among the infants. Thus, the combined effects of these two interventions is powerful indeed, but to this date not widely appreciated. We can also call attention to the lag between Fujiwara’s first publication in 1980 that pulmonary surfactant instilled as a liquid in to the trachea greatly ameliorated the course of hyaline membrane disease and licensing of surfactant preparations in the United States in 1990. The topic remains lively and has been extensively reviewed, so I will leave it there, except to note that it took almost 20 years to go from the initial observation of surfactant deficiency to successful replacement and another decade before licensure of these materials by the FDA, made them widely available in the United States. Precipitous use of new knowledge
The evidence that sometimes new knowledge has been used precipitously or inappropriately applied is underscored by the overzealous restriction of oxygen in the 1950s that led to increased deaths from hyaline membrane disease, even though it spared the retina from libroplasia. The lesson is obvious; too little can be as dangerous as too much and with oxygen therapy there is indeed an optimal requirement. Another illustration was the excessive use of hexachlorophene to prevent staphylococcal disease, leading to absorption through the skin and in some instances, fatal neurotoxicity. The intravenous vitamin E-sepsis story, is another illustration of when a little might be good, too much might be dangerous. Evolution of perinatology
Although there is a long history of combined morbidity and mortality conferences where obstetricians and pediatricians were interactive, the consultation that can take place before delivery is a relatively more recent event and has been a major advance. Pediatricians have watched with interest the increasing use of cesarean section and have noted that it has effectively replaced the use of forceps. While section rates of 20% or 30% are very surprising to those who grew up with the belief that 5% was appropriate, there is no question that babies who are delivered today are spared much of the trauma that they endured during the ‘trials’ of labor, or difficult versions or forceps deliveries. Continued vigilance is appropriate, however and most revealing when obstetricians and pediatricians realize their interdependence. Lessons learned
If there is a comment to all of this, I would think it would be that we must build our interventions on the relevant basic science. Where that does not exist, we must make every effort with animal models and tissue culture methodology to unearth
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understanding of the appropriate regulatory mechanisms that may need to be stimulated. Another lesson is that we need to work with epidemiologists and statisticians to construct studies that will give us clean answers and not further confuse the situation by type II errors, or inability to know enough to control for confounding factors in clinical trials. We need to recognize the power of prospective, randomized, controlled, clinical trials, but also to realize that there are other equally valid ways of gaining information about efficacy of interventions, such as having a given infant serve as its own control, or sequential comparisons of interventions in some situations. The great need is to know ‘what works’ in intensive care. In the future, I hope we continue to receive the societal support that has been so very important. I hope that advances in reproductive technologies will make the abortion debate moot, because there will be widely available abortifacients, such as RU 486 and better methods of contraception, so that it can be a fact that every baby is a wanted baby. In the future I hope that with the help of the basic scientists we can learn more about the causes of congenital malformations that are now the number one cause of neonatal mortality. At least we have profited from prenatal diagnosis with ultrasound and the detection of the major lethal malformations that can be prevented by abortion. Insight into the risk factors for malformations has the potential effect of making possible measures to prevent injury to the fetus. When we reflect upon deaths in the first year of life, we realize they are greatly over-represented in under-privileged populations and that it is not uniquely the province of perinatology to address those issues. It is our responsibility to flag them and to work with our colleagues in the social sciences to improve the standard of living world-wide to avoid some of the preventable causes of premature onset of labor and potential toxicity to infants by way of substances of abuse, AIDS and even cigarette smoking. We have firm evidence of the capacity to reduce infant mortality by 50% in the United States. This is because reductions of that sort have taken place in other parts of the world. I hope those concerned with the perinatal period will enlist colleagues from many disciplines to discuss the complex social and ethical issues that relate to questions about reproductive technologies and the pediatric dilemma, how small is too small, when not to prolong an inevitable death and when to ‘fight for life’. The rules change as the knowledge base increases. My own hope is that we will recognize worldwide the compelling need to see that every child is a wanted child and every mother has the choice to decide when and how often to become pregnant.
