Recent advances in medicine for newborn infants

MEDICAL PROGRESS

Recent advances in medicine for newborn infants Frederick C. Battaglia, M.D. DENVER~ COLO.

A n v A N C E S in medicine for newborn infants have been made in the recognition of new clinical entities, in general supportive care, and in the clarification of the relationship between obstetrical problems and neonatal diseases. Some of the clinical entities recognized in the last few years in the newborn infant include transient tachypnea of full-term infants, 1 the Wilson-Mikity syndrome, 2 neonatal hypoglycemia with somatic gigantism,3, 4 and the association of massive pulmonary hemorrhage ~ and symptomatic hypoglycemia 6, 7 in infants whose intrauterine growth has been retarded. Among the advances in supportive care are the vast improvements in technology facilitating accurate microchemical determinations, particularly in acid-base balance and oxygenation, in disposable plastic equipment for intravenous infusions and exchange transfusions, and in the wide variety of equipment for resuscitation and incubator care, including "servo" contro.1 equipment for the regulation of body temperature. The role of these technical improvements in nursery care should no.t be minimized, particularly since From the Departments o[ Pediatrics and Obstetrics-Gynecology, University of Colorado Medical Center. Supported by Public Health Service Grants l i d 01632-02 and HD 0078-03 Present address, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colo. 80220.

Vol. 71, No. 5, pp. 748-758

recent studies have shown the effectiveness of intravenous infusions as an adjunct to therapy for transient, symptomatic hypoglycemia, s for respiratory distress of the newborn, 9 and for early supplementation of markedly preterm infants, 1~ and have led to an enormous increase in the use of intravenous therapy in newborn nurseries. Furthermore, there has been an encouraging trend towards the use of specialized equipment such as cardioscopes, oximeters, and recording equipment for continuous monitoring of pulse, electrocardiogram, and body temperature in a nursery for "high-risk" or "intensive-care" infants rather than one for "premature" infants, which is segregated from the rest of the hospital in not-so-splendid isolation. This implies much more than a change in terminology; the present trend is toward a unit similar to a postoperative recovery room, with freer movement of physicians into and out of the unit. When the wide scope of neonatal medicine is considered, it is clear that its review must be confined to discussion of a few topics, especially since this is a division of pediatrics which cuts across arbitrary divisions by organ systems and more closely resembles a general practice confined to a narrow age group. Furthermore, like adolescent medicine, neonatal medicine is the connecting link between pediatrics and another medical specialty~in this case, obstetrics. As such, it requires con-

Volume 71 Number 5

Medical advances for newborns

749

2. The treatment of the idiopathic respiratory syndrome. 3. The recognition and management of infants with intrauterine-growth retardation. 4. Neonatal metabolic complications.

tinuous and detailed communication between obstetricians and pediatricians in caring for the newborn. While this may seem obvious, it is unfortunately usually missing, at the expense of optimal care of the infant. Frank and open discussion between members of two medical specialties can occur only in an atmosphere of mutual respect based upon an appreciation of the problems in each specialty that have prompted a particular course of action. With such collaboration in mind, I should like to discuss in some detail these 4 topics: 1. The association of obstetrical complications with neonatal problems (Table I).

OBSTETRICAL

COMPLICATIONS

R e s e a r c h in r e p r o d u c t i v e physiology has e x p a n d e d m a r k e d l y in the last f e w years a n d n e o n a t a l p e d i a t r i c s has g a i n e d f r o m this res e a r c h in a n u m b e r o.f i m p o r t a n t ways: m a n y obstetricM c o n d i t i o n s h a v e b e e n m o r e thoro u g h l y d e s c r i b e d in t e r m s of t h e i r p o t e n t i a l h a z a r d to the fetus a n d the n e w b o r n i n f a n t ; studies in n o r m a l physiology a n d b i o c h e m -

Table I. Association of obstetrical complications with variations in infant's birth weight and gestational age ~" Obstetrical complications Toxemia a. Pure pre-eclampsia in young primiparous patients b. Severe toxemia with albumlnuria and/or chronic hypertensive vascular disease

Diabetes

]

Newborn problems a. AGA,t preterm b. SGA, preterm LGA, term--owing to high mortality rate near term, these mothers are electively induced; thus infants are delivered as LGA, preterm infants.

Bleeding during pregnancy a. First trimester bleeding b. Placenta praevia c. Abruptio

a. ? LGA, preterm b. AGA, preterm c. AGA, preterm

Prolonged pregnancy Presence of any of following complications tends to increase the perinatal mortality rate Primiparity Advanced maternal age Large birth weight infant Hypertension Prolonged labor

a. Majority are AGA, postterm b. Smaller percentage are SGA, postterm

Cyanotic congenital heart disease

SGA, term or preterm

Smoking in pregnancy

SGA, term

Persistent asymptomatic bacteriuria in pregnancy

AGA, preterm

Placental Lesions a. Infarcts b. Tumors-chorioangiomas c. Single chorion in multiple pregnancies

a. SGA, term (generally in association with Toxemia b.) b. SGA, term c. Possibility of SGA/LGA infant pairs through arterlovenous anastomoses. d. Increased congenital anomaly rate, ? SGA

d. Single umbilical artery *For details of classification see Fig. 1. tSymbols, AGA ~-~ appropriate for gestational age; SGA z small for gestational age; LGA ~-~ large for gestational age.

750

BattagIia

istry of the developing fetus have helped to clarify many of the changes occurring in the neonatat period; and the role of various drugs taken during pregnancy in producing newborn problems has been clarified. In addition to the thalidomide disaster, the association of other drugs with specific problems has been defined; these include a Parkinsonian-like syndrome caused by phenothiazine derivatives, ~ central nervous system depression by carbocaine, 12 thrombocytopenia and leukopenia by the thiazides, and possibly neonatal hemorrhage by various anticonvulsant drugs. Reference to these hematological problems of the newborn infant can be found in the review by Oski and Naiman? a For convenience, obstetrical factors that affect the fetus or newborn infant can be divided into (1) those which are not associated with any specific maternal disease and yet produce various disorders in the infant, and (2) those in which a specific maternal complication produces a related disease in the infant. Maternal age and perinatal outcome. Perinatal mortality rates are increased at both extremes of the child-bearing-age range. Studies of early teen-age pregnancies have shown an increased incidence of premature onset of labor and thus delivery of preterm infants of appropriate weight for their gestational age. *~' 15 Toxemia in the form of pure pre-eclampsia is a complication of approximately one fourth of all teen-age pregnancies, but is not an important factor in the poor perinatal outcome in this maternal age group. 14 Thus, though toxemia is a common complication of pregnancy in the 16 to 19 year age group, the perinatal-mortality rate in this maternal age group is the lowest of all. At least by this criterion, the years from 16 to 19 are prime ones for reproduction. 15 Advanced maternal age, that is, maternal age of 40 years and over, is associated with increased perinatal mortality, z~ with increased fetal distress in postterm pregnancies, :~ with increased incidence of certain congenital anoma.lies such as hydrocephalus and con-

The Journal o[ Pediatrics November 1967

genital heart diseasey and, more specifically, with an increased incidence of G, is D, and E trisomies, TM 2o and of Klinefelter's syndrome, 2~ although not of Turner's. 22 Other maternal factors not associated with specific metabolic problems in the infant. Heavy smoking during pregnancy is associated with a slight reduction in infant birth weight at any gestational age. 23 Cyanotic congenital heart disease in the mother, just as chronic hypertensive vascular disease with superimposed toxemia, is associated with both the early onset of labor and intrauterine, growth retardation of the infant leading to the production of preterm infants of low birth weight for gestational age. Persistent asymptomatic bacteriuria in pregnancy appears to be related to preterm births, 24 although there remains some controversy over the extent to which this is true. While it is not actually a maternal complication, the presence of a single umbilical artery is recognized as a particularly important prognostic aid to the pediatrician; this has been brought out most thoroughly in the largest prospective study to dateY 5 The incidence of a single umbilical artery is 0.76 per cent of all deliveries. If one omits fetal deaths, the incidence of major congenital anomalies in infants with a single umbilical artery is 26 per cent, with anomalies having been described in virtually every organ system of the body. Thus, single umbilical artery must be added to a list of factors, such as severe oligo- or polyhydramnios, which can be determined at birth and whose presence must alert the pediatrician to the possibility of major congenital anomalies in the newborn. Single umbilical artery differs from these, however, in the wide distribution of the associated anomalies. Metabolic complications of pregnancy affecting the newborn. Maternal diabetes has continued to be the subject of a large number of recent studies. Some years ago it was shown that infants born to mothers with overt diabetes had increased total body fat and decreased total body water, z~, ~7 There have been no recent studies, however, that have defined the metabolic consequences of

Volume 71 Number 5

this obesity. Several reports have described the increased incidence of congenital anomalies2s and of hypoglycemias in these infants. One of the clinical maternal-fetal relationships described recently is that between maternal hyperparathyroidism and neonatal tetany._Og, 30 Certainly all mothers whose infants deveIop severe hypocalcemia in the neonatal period should have determinations of their plasma calcium and phosphorus concentrations. Though comparatively few cases of neonatal hypocalcemia will prove to be caused by maternal parathyroid disease, this should always be considered because of its value both in the recognition of the asymptomatic mother and in the management of infants from subsequent pregnancies. Fetal distress. Most research in perinatal physiology has centered around the more precise definition of those factors which determine optimal fetal oxygenation in utero, especially during labor and delivery. This emphasis is understandable, since the majority of infants who have varying degrees of central nervous system or neuromuscular damage at birth do not have chromosomal abnormalities nor inborn errors of metabolism, but rather are presumed to have had hypoxic brain damage in utero. Though clear-cut evidence of in utero hypoxia is still difficult to come by, certain general clinical features can be recognized. Certain infants close to term are at high risk of fetal distress, especially at the time of labor and delivery. The infant of an elderly primigravida born after a longer than full-term pregnancy is in particular dangera6; such an infant may be stillborn or badly damaged. Since the fetus often has developed normally up to the time of distress, and since fetal distress often occurs close to term, a fairly mature infant would face lesser chances of mortality and morbidity if the pregnancy were interrupted once unequivocal evidence of fetal distress were obtained. Hence, it is not surprising that a great deal of recent work is aimed at detecting fetal distress as soon as a problem develops in utero. Methods for the early diagnosis of fetal distress make possible the selection of patients re-

Medical advances for newborns

75 1

quiring immediate delivery, vaginally when feasible, by emergency cesarean section when not. These include techniques such as amniocentesis, amnioscopy, and fetal scalp vein samples. None of these should be considered routine, nor is their clinical usefulness yet adequately established for the detection of hypoxia in utero. This is particularly true of fetal scalp vein sampling, which has been greeted with the same initial fervor as was the early work with intrauterine transfusions for erythroblastosis. 31 These comments do not apply to the use of amniocentesis in Rhsensitized pregnancies where its clinical value is firmly established, al While this is primarily an obstetrical problem, pediatricians can deal more effectively with those infants who have had fetal hypoxia in late pregnancy: (1) by knowing that the infants of certain mothers are susceptible to fetal distress during labor and delivery and (2) by anticipating some of the problems that these infants are likely to develop shortly after birth. Mothers whose infants are in particular danger of fetal distress include those with: postterm pregnancies, especially in those of advanced maternal age; primiparity; hypertension~; abruptio placentae; multiple pregnancy; or with chronic hypertensive vascular disease associated with toxemia, chronic renal disease, collagen vascular disease, or diabetes. Whether they were born preterm, full-term, or postterm by gestational age, these infants have often had intrauterine growth retardation as evidenced by disproportionately low birth weights for their gestational ages. They are, of course, prone to aspiration pneumonitis following the episodes of in utero distress, as well as to transient symptomatic hypoglycemia, and massive pulmonary hemorrhage. For all of these reasons, then, these are infants who often need extensive supportive care at the time of delivery. This care may take the form of any or all of the following: thorough suctioning of the oral and nasal pharynx and occasionally of the trachea as well; assisted ventilation by the technique most familiar to the pediatrician involved so that, when required, this can be carried out

7 5 2 Battaglia

The ]ournal of Pediatrics November 1967

promptly and safely; maintenance of the infant's body temperature (a difficult goal to attain, particularly in today's refrigerated delivery rooms). It is helpful to obtain a sample of umbilical cord blood for determination of hemogIobin, hematocrit, total protein, and sodium concentrations. These determinations can be carried out later, should the clinical course of the infant warrant it. TREATMENT

OF T H E

IDIOPATHIC RESPIRATORY DISTRESS SYNDROME

There has been and will continue to be a great deal written about the treatment of idiopathic respiratory distress syndrome, which in itself indicates that a mode of treatment which is consistently successful has not yet been established. In general, the extent to which good supportive care can be provided today has been greatly enhanced by advances in technology. The careful regulation of body temperature, the provision of adequate concentrations of oxygen in the inspired air to correct cyanosis (or preferably, to maintain adequate arterial oxygen tensions), the maintenance of adequate hydration, and the correction of severe acidosis by the intravenous administration of sodium bicarbonate are steps in the clinical management of idiopathic respiratory distress syndrome which have become generally accepted, though some are based on more carefully controlled studies than others. The place for assisted ventilation and of tracheobronchial lavage with mucolytic or surface-active agents have been and are still being investigated, but at this time no clear-cut recommendations can be made. A more controversial area, and possibly one with greater clinical potential, involves the use of compounds designed to lower pulmonary vascular resistance and thus increase pulmonary blood flow. The initial study by Chu and associates a2 reported a favorable clinical response to the infusion of acetylcholine in an uncontrolled series of observations of infants with idiopathic respiratory distress syndrome. Subsequently, there have

been several reports in the form of "letters to the editor," all characterized by insufficient data, advocating and/or discouraging the use of such pulmonary vasodilators as priscoline and acetytcholine. One subse.. quent report by Moss and associates 33 on the use of acetylcholine in 5 critically ill infants with idiopathic respiratory distress syndrome reported no clinical improvement with acetylcholine, and, in fact, the authors suggested that in those particular patients it may ha~e been harmful. In summation, one can say that the studies to date have shown that reduced pulmonary blood flow is a frequent, if not invariable accompaniment to idiopathic respiratory distress syndrome. It has not been shown, however, that ace@choline or p~iscoline can significantly reduce the morbidity or mortality of idiopathic respiratory distress syndrome. These drugs cannot therefore be recommended as routine adjuncts in its treatment. There is a second aspect to the possible relationship between pulmonary perfusion and idopathic respiratory distress syndrome. This concerns the role of a lowered blood pH in producing pulmonary vasoconstriction; it is possible that there is a vicious cycle established in which pulmonary vasoconstriction leads to increased hypoxia; this leads to increased lactic acidosis, which in turn leads to further vasoconstriction. This hypothesis is attractive, and it is unfortunate that sufficient evidence is not available to support it or, more particularly, to establish that the correction of acidosis in idiopathic respiratory distress syndrome improves pulmonary perfusion. It does seem likely to this writer, however, that such data wilI soon be forthcoming and will lend further support to the earlier work of Usher" on the clinical value of the correction of acidosis in idiopathic respiratory distress syndrome by the intravenous administration o.f sodium bicarbonate. It remains to be demonstrated, however, whether the reduction in the case fatality rate repo.rted by Usher was caused solely by a reversal of the sequence of events described above. This seems unlikely when one considers the general cellular effects of

Volume 71 Number 5

severe acidosis, and it seems reasonable to anticipate that future studies will demonstrate reduced function of many organ systems in association with the profound acidosis of severe idiopathic respiratory distress syndrome. In short, evidence is accumulating in a variety of ways which supports the clinical usefulness of the prompt and vigorous correction of the metabolic acidosis which develops in idiopathic respiratory distress syndrome, with intravenous sodium bicarbonate. It is necessary, however, that the plasma concentration of sodium be followed closely whenever sodium bicarbonate is used in newborn infants for the treatment o.f metabolic acidosis. Occasionally, in severe idiopathic respiratory distress syndrome, the quantity of bicarbonate required for the correction of acidosis will entail the administration of a sodium load too great for the infant to handle, and severe hypernatremia will develop. One is then forced to choose between the correction of a continuing acidosis (e.g., pH 7.20 and lower), and the aggravation of an already hyperosmolar state (e.g., [Na+] 165 mEq. per liter). Since both the severe acidosis and the hyperosmolarity may produce widespread cellular damage, the choice is not a simple one. It has been my impression that, when a situation develops in which a newborn infant has required sufficient sodium bicarbonate to produce a marked elevation in the plasma concentration of sodium without complete correction of the acidosis, the prognosis is uniformly bad. I believe that it is in this group of patients that the use of T H A M for the further correction of acidosis may possibly have some advantage over the continued use of sodium bicarbonate in the face of existing hypernatremia. Unfortunately, the few reported studies on the use of T H A M for the treatment of the metabolic acidosis accompanying idiopathic respiratory distress syndrome have been based on observations in which T H A M was used from the beginning rather than as a replacement for sodium bicarbonate. The only conclusion that can be drawn at this time is that there appears to be no advantage in the use of

Medical advances for newborns

75 3

T H A M rather than sodium bicarbonate in the initial management of the acidosis. INTRAUTERINE RETARDATION

GROWTH

In the past few years we have become more aware of a group of infants whose common feature is abnormally low birth weight for their gestational age, particularly those infants of low birth weight born at or near full term. A more precise recognition of these infants has been made possible by the publication of a number of graphs or tables giving the frequency distribution of birth weights at various gestational ages. The reports by Lubchenco, a4 Butler, 35 Gruenwald, 36 and Battaglia a7 have made it quite clear that, despite differences in the populations studied, there is remarkable agreement among these studies on the tenth percentile distribution of birth weights at varying gestational ages. The report by Yerushalmy 3s also points out some of the differences between infants with intrauterine growth retardation on the one hand and true prematurity on the other. It provides still another method of classifying newborn infants by birth weight and gestational age. Any of these birth weight/gestational age distributions can be equally useful clinically. The important thing is that some single set of standards be used on all nursery services, because the clinical usefulness of comparing each newbm~n infant by birth weight and gestational age with a population as a whole has become more and more firmly established. For convenience in illustrating some of the clinical features of infants with intrauterine growth retardation, I should like to refer to the classification illustrated in Fig. 1a9 by which infants are divided into 9 groups: 3 by gestational age, preterm, fullterm, and postterm; and each of those groups divided by weight into 3 subgroups, those greater than the ninetieth percentile (largefor-gestational age), those less than the tenth percentile (small-for-gestational age), and those between the tenth and ninetieth percentiles (appropriate-for-gestational age). In several reports the striking differences in

754

Battaglia

The ]ournal o/ Pediatrics November 1967

GRAMS 5000

,

4~50 =500 4~0

I ?

4~00 ~7#0 ~500 3250

~750

Fig. 1

~500 ~0 ~000 17~0 ,~OC ~Z~O I00C

500

? WEEKS OF GESTATION . . . . TERM

I

TERM'

I POST-TER~ j

NEONATAL MORTALITYRATE/ 100 4.0 3.6 ~ 3,2 ~ 2.8 r~

Fig. 2

I

3

~

'

90%

2,4 2.0 1.6 .8 ,4

60

24 27 30 83 36 39 42 WEEKSOF GESTATION

Fig. 1. University of Colorado Medical Center classification of newborn infants by birth weight and gestational age. Fig. 2. Birth weight given in kilograms; percentile curves taken from Fig. 1; neonatal mortality rate per 100 is shown for infants of the same birth weight but different gestational ages, taken from the study of Erhardt and associates.'~9

neonatal mortality rates between infants of the same birth weights but different gestational ages have been pointed out. These differences are illustrated in Fig. 2 which shows neonatal mortality rates for infants of comparable weight but different gestational ages. Furthermore, all infants who are small for their gestational ages do not share common clinical features such as long, thin trunk, meconium-stained skin and nails, which in the past have been associated with postmature infants and interpreted as the result of placental insufficiency. It is true that a variety

of clinical signs have been shown to correlate rather closely with gestational age, features such as development of flexor control, size of breast nodule, and development of skin creases. These clinical signs, described in a number of recent reports/~ ~, ~ are useful in making a clinical estimate of gestational age from physical findings in the infant when the menstrual history is inadequate or unavailable, as it is in 10 to 20 per cent of all pregnancies. A recent article by Robinson 4~ is especially useful in this respect, since it is the first real attempt to sort through a myriad of clinical neurological signs to a few that are consistently useful. In some infants the estimate of gestational age based upon the last menstrual period is in rather striking disagreement with the clinical estimate based upon the physical findings. Today, we have no explanation for this discrepancy nor any clear information upon which to choose between the two estimations of chronological age. The use of both gestational age and birth weight in the categorization of newborn infants has helped in their care in several ways. First, by recognizing the differences in neonatal mortality rates among infants of the same size but very different gestational ages (including the high-birth-weight, low-gestational-age group), a more appropriate selection of high-risk infants can be made for observation in an intensive care nursery and thus, better utilize the highly trained personnel and specialized facilities of the hospital. In the past, the initial assignment of an infant to a low-risk (fullterm) nursery or a high-risk (premature) nursery was made on the basis of the infant's birth weight alone, in the absence of any early clinical problem. It is not surprising that the use of 2 pieces of information about the infant, its birth weight and gestational age, should better enable one to select those infants likely to have a stormy course in the first few weeks of life. Second, certain neonatal problems are becoming recognized as peculiar to one group of infants such as idiopathic respiratory distress syndrome with preterm infants, or massive pulmonary hemorrhage with infants who are small for their

Volume 71 Number 5

gestational ages. Some of the neonatal problems which develop in infants with intrauterine growth retardation have been reported recently. These include transient, symptomatic hypoglycemia and massive pulmonary hemorrhage. It is interesting that many of the clinical features that have been described in massive pulmonary hemorrhage are the same as those described in symptomatic hypoglycemia or congenital polycythemia2, 8 Two recent reports have shown an association between an abnormal concentration of a normally occurring hemoglobin and a chromosomal anomaly. The first report concerned the persistence of Gower 2 hemoglobin in infants with D-Trisomy 4a and the second, the precocious synthesis of adult hemoglobin with a normal chromosomal complement, but with an abnormally long chromosome in the D group. 44 These reports are of in, terest for several reasons. First, D-Trisomy, like Down's syndrome, is associated with intrauterine growth retardation, although not nearly as marked as in E-Trisomy. 45 Second, both reports 4a' ~4 presented a chromosomal anomaly in the D group with some alteration in the sequential appearance of the various normal hemoglobins (Hb-Gower 1, Hb-Gower 2, Hb-F, Hb-A), in the one case representing a delay, and in the other case, an acceleration in the normal sequence of their appearance. There is a number of clinical syndromes characterized by multiple congenital anomalies that have been associated with intrauterine-growth retardation. 46 In most instances, the number of reported cases for each syndrome have been insufficient to arrive at any conclusions as to birth weight versus gestational age relationships. It is interesting, though, that in most of the clinical conditions in which short stature in later childhood has been associated with congenital malformations, intrauterine growth retardation has been noted at birth2 ~ Hurler's syndrome is one of the notable exceptions to this general association of short stature, congenital malformations, and intrauterine growth retardation. The association of congenital malformations with intrauterine growth retardation has been especially strik-

Medical advances /or newborns

75 5

ing in the de Lange syndrome 47 and in the Silver-Russell syndrome. 4s Finally, there are some problems in infants who are small for their gestational ages that are fairly recognized even though they are not yet adequately substantiated in pediatric literature. The infant is often delivered after a complicated pregnancy, that is, a high-risk pregnancy, as for example in the elderly primigravida, the woman with chronic hypertensive vascular disease with superimposed toxemia, the patient with chronic renal disease, or the one with cyanotic congenital heart disease. It is not surprising, therefore, that many of the infants who are small for gestational age are born after periods of fetal distress. Such infants have many of the neonatal complications associated with fetal distress, such as central nervous system depression at birth, which presents a resuscitation problem in the delivery room, and which may be further complicated by pneumonitis due to aspiration of meconium and other debris. NEONATAL

METABOLIC

COMPLICATIONS In general, the metabolic problems that have been described in the neonatal period have been measured by marked changes from the normal concentrations of various solutes such as glucose, calcium, sodium, total protein, tyrosine, and not in variation in the total quantities of these or other compounds in the body, except for studies on oxygen consumptions of newborn infants. In great part, the reason for this focus on solute concentration changes is a technical one, it is much easier to carry out a study based on serial determinations of the concentration of a compound in a body fluid, particularly when an adequate micro method is available, than it is to carry out valid metabolic balance studies in the newborn infant. The oxygen consumption studies in newborn infants have attempted to correlate oxygen consumption to the infant's body temperature, size, and degree of maturity. Such studies have established, for instance, that a ininimum oxygen consumption is one of the advantages of maintaining a notarial body temperature in healthy newborn infants (for

756

BattagIia

a review of this area see reference Nos. 49 and 50). Of all solute concentrations, glucose levels have been most intensively investigated. The changes in glucose concentrations in the first few days after birth have been adequately described in full-term and preterm infants, as well as in infants of diabetic mothers; these studies have recently been reviewed, s After birth, all infants have a transient fall in the plasma concentration of gluco.se from that of umbilical cord blood, which is followed by a slow rise over some days. The clinical problem resolves itself into selecting the comparatively small percentage of all newborn infants who will require treatment specifically directed at a low plasma concentration of glucose. The decision is a clear one in those infants with both a low plasma glucose concentration and one or more clinical signs? The decision is more difficult in those infants with no clinical signs despite rather striking hypoglycemia. The treatment of infants with transient symptomatic hypoglycemia has been described in several recent reports. Hyperglycemia in the neonatal period is rare but has been reported in infants with a transient diabetic syndrome and in those with persistent diabetes mellitus. 8, 5~ Of interest in this regard is the recent report by Geefhuysen 52 questioning the reliability of the presence of or absence of intrauterine growth retardation, insulin requirement, and acetonuria in distinguishing persistent diabetes mellitus from this transient clinical syndrome. The current interest in recognition and management of hypoglycemia in the neonatal period has brought home to us the surprisingly large percentage of infants, particularly p reterm and small-for-gestationalage infants, who have clinical signs compatible with hypoglycemia, but upon investigation turn out to have other problems responsibIe for the jitteriness and hypotonia. The recent report by Pildes and associates 5'~ is especially interesting in this regard since they found that only 14 of the 182 infants having clinical signs compatible with hypoglycemia actually were hypoglycemie.

The Journal of Pediatrics November 1967

Another possible cause of clinical respiratory or neurological problems in newborn infants is marked polycythemia. The number of cases reported is sufficiently large to warrant our regarding marked polycythemia (capillary hematocrit > 75 venous hematocrit > 70) with suspicion in those newborns with respiratory or neurological problems without other obvious cause. Of course, the physiology of the microcirculation and the rheology of blood in the newborn are badly in need of exploration, particularly in light of the frequency of unexplained ptdmonary or central nervous system hemorrhage in the newborn infant. Unfortunately, adequate data on the normal range of plasma concentrations for many solutes such as calcium and magnesium for infants of varying gestational ages are not available. In addition, the methods of analysis for these compounds are not as standardized as those for the determination of glucose. The role of atomic absorption spectrophotometry versus fluorometric or colorimettic methods for the clinical determination of true total calcium or magnesium concentrations remains to be studied. Furthermore, it is likely that, with the availability of electrodes responsive to varying calcium or magnesium activities, we shall see clinical studies correlating different degrees of motor excitability of the infant with their chemical activities rather than with their total concentrations. In generaI, hypocalcemia represents the next most common problem after hypoglycemia in this group of infants, followed by hypo- and hypernatremia. The role of hypomagnesemia in producing clinically significant neurological problems in newborn infants remains to be demonstrated. However, in the last 2 years, 5 infants have been reported,~4, 5.~,s~, ~7, ~s all with convulsions, hypocalcemia, and hypomagnesemia. In each case, there was both a clinical and biochemical response to the administration of magnesium salts. In some cases, magnesium supplementation had to be continued for a prolonged period of timeP s Hypomagnesemia as a cause of neonatal convulsions in the absence of hypocalcemia has not been reported.

Volume 71 Number 5

F u r t h e r m o r e , just as in clinical studies in adults, h y p o m a g n e s e m i a has been associated w i t h seizures, b u t not w i t h clinical tetany. I t is clear f r o m the above reports t h a t p l a s m a m a g n e s i u m concentrations should be determ i n e d in an infant w i t h seizures a n d hypoc a l c e m i a in w h o m there has been a p o o r clinical response to the intravenous a d m i n istration of calcium salts. I n summation, it is evident t h a t the newb o r n infant w i t h a n y of a wide s p e c t r u m of nervous system signs should have a fairly extensive w o r k u p , t a k i n g cognizance t h a t the m a j o r i t y of such infants will have p r o b lems o t h e r t h a n hypoglycemia. T h e m o r e t h o r o u g h the w o r k u p , the l e s s often a n ubiquitous diagnosis of central nervous system d a m a g e from in utero hypoxia will have to be m a d e as an e x p l a n a t i o n for n e o n a t a l seizures. This diagnosis should be m a d e after exclusion of o t h e r possibilities, m a n y of which are correctable with a p p r o p r i a t e therapy. REFERENCES 1. Avery, M. E., Gatewood, O. B., and Brumley, O.: Transient tachypnea of newborn, Am. J. Dis. Child. 3: 380, 1966. 2. Wilson, M. G., and Mikity, V. G.: A new form of respiratory disease in premature infants, Am. J. Dis. Child. 99: 489, 1960. 3. Beckwith, J. B., Wang, C. I., Donnell, G. N., and Gwinn, J. L.: Hyperplastic fetal visceromegaly with macroglossia, omphalocele, cytomegaly of adrenal fetal cortex, postnatal somatic gigantism, and other abnormalities: Newly recognized syndrome, Proc. Am. Pediat. Soc. Seattle, Wash., June, 1964 (Abst. No. 4I). 4. Combs, J. T., Grunt, J. A., and Brandt, I. K.: New Syndrome of neonatal hypoglycemia, New England J. Med. 275" 236, 1966. 5. Butler, N.: Perinatal death, in Dawkins, M., and MacGregor, B., editors: Gestational age, size, and maturity, Clinics in developmental medicine, London, England, 1965, The Spastics Society Medical Education and Information Unit in Association with William Heinemann, Ltd., No. 19, pp. 74-82. 6. Neligan, G. A., Robson, E., and Watson, J.: Hypoglycaemia in newborn: A sequel of intrauterine malnutrition, Lancet 1: 1282, 1963. 7. Cornblath, M., Wybregt, S. H., Baens, G. S., and Klein, R. I.: Symptomatic neonatal hypoglycemia, Pediatrics 33: 388, 1964. 8. Cornblath, M., and Schwartz, R.: Disorder of carbohydrate metabolism in infancy. Major problems in clinical pediatrics, Philadelphia, 1966, W. B. Saunders Company, vol. III. 9. Usher, R. H.: Reduction of mortality from respiratory distress syndrome of prematurity

Medical advances for newborns

10.

11.

12.

13.

14.

15. 16. 17. 18.

19.

20.

21.

22.

23.

24. 25. 26.

75 7

with early administration of intravenous glucose and sodium bicarbonate, Pediatrics 32: 966, 1963. Cornblath, M., Forbes, A. E., Pildes, R. S., Luebben, G., and Greengard, J.: A controlled study of early fluid administration on survival of low-birth-weight infants, Pediatrics 38: 547, 1966. Hill, R. M., Desmond, M. M., and Kay, J. L.: Extrapyramidal dysfunction in an infant of a schizophrenic mother, J. PEmAT. 69: 589, 1966. Sinclair, J. C., Fox, H. A., Lentz, J. F., Fuld, G. L., and Murphy, J.: Intoxication of the fetus by a local anesthetic, New England J. Med. 273: 1173, 1965. Oski, F. A., and Naiman, J. L.: Hematologic problems in the newborn. Major problems in clinical pediatrics, Philadelphia, Pennsylvania, 1966, W. B. Saunders Company, vol. IV, pp. 38-39. Battaglia, F. C., Frazier, T. M., and Hellegers, A. E.: Obstetric and pediatric complications of juvenile pregnancy, Pediatrics 32: 902, 1963. Marchetti, A. A., and Menaker, J. S.: Pregnancy and the adolescent, Am. J. Obst. & Gynec. 59: 1013, 1950. Lucas, W. E., Anctil, A. O., and Callagan, D. A.: The problem of postterm pregnancy, Am. J. Obst. & Gynec. 91: 241, 1965. Milham, S., Jr., and Gittelsohn, A. M.: Parental age and malformations, Human Biol. 37: 12, 1965. Penrose, L. S.: The causes of Down's syndrome, in Woollam, D. H. M., editor: Advances in teratology, New York, 1966, Academic Press, Inc., pp. 17-21. Rosenfield, R. L., Breibart, S., Isaacs, H., Jr., Klevit, H. D., and Mellman, W. J.: Trisomy of chromosomes 13-15 and 17-18: Its association with infantile arteriosclerosis, Am. J. M. Sc. 244: 763, 1962. Conen, P. E., and Erkman, B.: Frequency and occurrence of chromosomal syndromes II. E-trisomy, Am. J. Human Genet. 18: 387, 1966. Ferguson-Smith, M. A., Mack, W. S., Ellis, P. M., Dickson, M., Sanger, R., and Race, R. R.: Parental age and the source of the X chromosome in XXY Klinefelter's syndrome, Lancet 1: 46, 1964. Ferguson-Smith, M. A.: Karyotype pheno correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations, J. M. Genet. 2: 142, 1965. Goldstein, H., Goldberg, I. D., Frazier, T. M., and Davis, G. E.: Cigarette smoking and prematurity, Public Health Rep. 79: 553, 1964. Henderson, M.: Significant bacteriuria and duration of pregnancy, Arch. Environmental Health 8: 527, 1964. Froehlich, L. A., Fujikura, T.: Significance of a single umbilical artery, Am. J. Obst. & Gynec. 94: 274, 1966. Osler, M., and Pedersen, J.: The body corn-

758

27.

28.

29. 30.

31.

32.

33.

34.

35.

36. 37.

38. 39. 40. 41. 42.

43.

Battaglia

position of newborn infants of diabetic mothers, Pediatrics 26: 985, 1960. Fee, B. A., and Well, W. B., Jr.: Body composition of infants of diabetic mothers by direct analysis, Ann. New York Acad. Sc. If0: 869, 1963. Pedersen, L. M., Tygstrup, I., and Pedersen, J.: Congenital malformations in newborn infants of diabetic women, Lancet 1" 1124, 1964. Mizrahi, A., and Gold, A. P.: Neonatal tetany secondary to maternal hyperparathyroidism, J. A. M. A. 190: 155, 1964. Hutchin, P., and Kessner, D. M.: Neonatal tetany: Diagnostic lead to hyperparathyroidism in the mother, Ann. Intern. Med. 61" 1109, 1964. Lucey, J. F., and Butterfield, L. J., editors: Intrauterine transfusion and erythroblastosis fetalis. Report of the fifty-third Ross Conference on pediatric research, Columbus, Ohio, 1966, Ross Laboratories. Chu, J., Clements, J. A., Cotton, E., Klaus, M. H., Sweet, A. Y., Thomas, M. R., and Tooley, W. H.: Preliminary report. The pulmonary hypoperfusion syndrome, Pediatrics 35: 733, 1965. Moss, A. J., Emmanouilides, G. C., Rettori, O., and Adams, F. H.: Acetylcholine in the treatment of idiopathic respiratory distress syndrome, J. PEDIAT. 69: 817, 1966. Lubchenco, L. O., Hansman, C., Dressier, M., and Boyd, E.: Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation, Pediatrics 32: 793, 1963. Butler, N. R., and Bonham, D. G., editors: Perinatal mortality. The first report of the British perinatal mortality survey, London, 1963, E. & S. Livingstone, Ltd. Gruenwald, P.: Growth of the human fetus. I. Normal growth and its variation, Am. J. Obst. & Gynec. 94: 1112, 1966. Battaglia, F. C., Frazier, T. M., and Hellegers, A. E.: Birth weight, gestational age, and pregnancy outcome, with special reference to high birth-weight, low-gestational-age infant, Pediatrics 37: 417, 1966. Yerushalmy, J.: The classification of newborn infants by birth weight and gestational age, J. PEDIAT. 71: 164, 1967. Battaglia, F. C., and Lubchenco, L. O.: A practical classification of newborns by weight and gestational age, J. PEDrAT. 71: 159, 1967. Saint-Anne Dargassies, S.: Le nouveau-nil 5. terme: Aspect neurologique, Biol. Neonat. 4: 174, 1962. Robinson, R. J.: Assessment of gestational age by neurological examination, Arch. Dis. Childhood 41: 437, 1966. Usher, R., McLean, F., and Scott, K. E.: Judgment of fetal age. II. Clinical significance of gestational age and an objective method for its assessment, Pediat, Clin. North America 13: 835, 1966. Huehns, E. R., Hecht, F., Keil~ J. V., and

The ]ournal o[ Pediatrics November t967

44.

45.

46. 47. 48. 49. 50~ 51. 52. 53.

54. 55,

56.

57.

58. 59.

60.

Motulsky, A. G.: Developmental hemoglobin anomalies in a chromosomal triplication: D1trisomy syndrome, Proc. Nat. Acad. Sc. USA 51: 89, 1964. Weller, S. D. V., Apley, J. and Raper, A. B.: Malformations associated with precocious synthesis of adult hemoglobin, Lancet I: 7441, 1966. Schutt, W.: Foetal factors in intrauterinegrowth retardation, in Dawkins, M., and MacGregor, B., editors: GestationaI age, size, and maturity. Clinics in developmental medicine, London, England, 1965, The Spastics Society Medical Education and Information unit in Association with William Heinemann, Ltd., No. 19, pp. 1-9. Smith, D. W.: Compendium on shortness of stature, J. PEDIAT. 70: 463, 1967. Silver, H. K.: The de Lange syndrome, Am. J. Dis. Child. 108: 523, 1964. Silver, H. K.: Asymmetry, short stature, and variations in sexual development, Am. J.. Dis. Child. 107: 495, 1964. Scopes, J. W.: Metabolic rate and temperature control in the human baby, Brit. M. BulI. 22: 88, 1966. Adamsons, K.: The role of thermal factors in fetal and neonatal life, Pedlar. Clin. North America 13: 599, 1966. Lewis, S. R., and Mortimer, P. E.: Idiopathic neonatal hyperglycaemia, Arch. Dis. Childhood 39: 618, 1964. Geefhuysen, J.: Temporary idiopathic neonatal hyperglycemia, Pediatrics 38: 1009, 1966. Pildes, R., Forbes, A. E.: O'Connor, S. M., and Cornblath, M.: The incidence of neonatal hypoglycemia--a completed survey, J. PEDIAT. 70: 76, 1967. Davis, J. A., Harvey, D. R., and Yu, J. S.: Neonatal fits associated with hypomagnesaemia, Arch. Dis. Childhood 40: 286, 1965. Paunier, L., Radde, I. C., Kooh, S. W., and Fraser, D.: Primary hypomagnesemia with secondary hypocalcemia (Abst. No. 67), J. PEDIAT. 67: 945, 1965. Salet, J., Polonovski, C., de Gouyon, F., Pean, G., Melekian, B., Fournet, J-P.: Recurrent hypocalcaemic tetany due to a congenital deficiency of the Mg in the blood; A new metabolic disease, Arch. Franc. Pediat. 23: 749, 1966. Friedman, M., Hatcher, G. and Watson, L.: Primary hypomagnesaemia with secondary hypocalcaemia in an infant, Lancet 1: 703, 1967. Clarke, P. C. N., and Carre, 2. J.: Hypocalcemic hypomagnesemic convulsions, J. PEDIAT. 70: 806, 1967. Erhardt, C. L., Joshi, G. B., Nelson, F. G., Kroll, B. H., and Weiner, L.: Influence of weight and gestation on perinatal and neonatal mortality by ethnic group, Am. J. Public Health 54: 1841, 1964. Benlrschke, K., and Driscoll, S. G.: The pathology of the human placenta, New York and Berlin, 1967, Springer-Verlag, Inc.