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Neonatal polycythemia with transient cyanosisand cardiorespiratory abnormalities
T h e Journal o[ P E D I A T R I C S
1063
Neonatal polycythemia with transient cyanosis and cardiorespiratory abnormalities Ten in[ants with transient plethora and cyanosis in the newborn period are presented, with findings suggestive o[ transient cardiovascular strain. A search/or common etiologic [actors revealed considerable elevation in the hematocrit and hemoglobin levels consistent with neonatal polycythemia. The several sources o[ neonatal hypervolemia and polycythemia are discussed; it seems likely that an excessive trans[usion o[ placental blood at delivery is an important [actor. Spontaneous improvement generally occurs although phlebotomy has been therapeutically applied in two instances.
Richard A. Gatti, M.D., Alexander J. Muster, M.D., Roger B. Cole, M.D., and Milton H. Paul, M.D. * CHICAGO,
ILL.
T H I S R E P O R T c o n c e r n s 10 newborn infants referred to our cardiovascular center
during the past two years with the tentative diagnosis of cyanotic congenital heart disease. These infants had been noted to be cyanotic by the third day of life, but were in little or no cardiorespiratory distress. The early clinical findings, electrocardiograms, or chest roentgenograms were suggestive of heart disease, but these abnormal findings, as well as the clinical symptoms, were transient. A search for common factors revealed that all 10 infants were cyanotic and polycythemic with significantly high hematocrit and hemoglobin levels. The findings in these infants suggested From the Division o[ Cardiology (Willis ]. Ports Children's Heart Center), The Children's Memorial Hospital, and the Department o[ Pediatrics, Northwestern University Medical School. "~Address, Division o[ Cardiology, Children's Memorial Hospital, 707 Fullerton Ave., Chicago, Ill. 60614.
that transient cardiorespiratory distress can occur in the neonate in association with a high hematocrit level. In an extensive review of the literature, 17 similar cases of cyanosis and polycythemia and varying degrees of respiratory distress were foundl-a; in several infants the respiratory distress responded dramatically to phlebotomy. Phlebotomy was performed on 2 infants in our group; the symptoms subsided spontaneously by the age of 2 weeks in the remaining 8 patients. Such cases may be misdiagnosed as cyanotic congenital heart disease upon first observation; hence the importance of recognizing this clinical pattern. CLINICAL MANIFESTATIONS The prenatal histories, except for Case 3 (T. N.), were unremarkable. The maternal ages ranged from 19 to 33 years, and their gravidity from 1 to 7. The birth weights of the infants ranged from 5 pounds, 7 ounces,
1 064
December 1966
Gatti et al.
to 7 pounds, 14 ounces; all were delivered vaginally in encephalic presentation. Low forceps were used for all but one infant, who was delivered spontaneously. The delivery of Case 3 (T. N.) was induced at 27 weeks because of an equivocal maternal glucose tolerance test during pregnancy. All patients were referred to The Children's Memorial Hospital after birth, and, consequently, no accurate statements regarding the time of cord clamping after birth can be made. The clinical manifestations of the 10 infants are summarized in Table I. A plethoric and cyanotic appearance, the most consistent finding, was present in all infants and was first noted on the third day of life in most of them. The respiratory rate exceeded 50 per minute in only one infant, and the pulse rates ranged from 120 to 160 per minute. Subcostal retractions were noted in only one case, and the respirations were rapid (76 per minute) and shallow in another but without retractions. Systolic heart murmurs, considered to be possibly significant (Grade 2/6), were present in 4 infants, and the second heart sound was prominently split without respiratory variation in 3 of these 4. Myoclonic seizures were noted in 3 of the 10 infants. In Case 2, periods of myoclonic jerking continued until shortly after discharge at 3 weeks of age. The neurologic examination was normal at this time, and the electroencephalogram demonstrated cerebral dysrhythmia, Grade I. At 8 months of age, a left hemiparesis was discovered. In Case 3, "twitching" was observed on the first and second days of life, but subsided by the third day, when the blood glucose was 32 my. per cent and the serum calcium 7.6 mg. per cent. Treatment was not instituted in the absence of further twitching, and the serum calcium level returned to normal spontaneously. No neurologic symptoms or signs were found in this infant at 6 months of age. Another child (Case 6) began having myoclonic seizures shortly after birth; they have now been controlled with Mysoline.
HEMATOLOGIC
FINDINGS
In all 10 infants, a relatively high hematocrit or hemoglobin level was demonstrated (Fig. 1). All specimens for hematocrit and hemoglobin determinations were collected by heel puncture. In Cases 2, 4, 6, and 9, these levels actually increased after admission, even with an apparently adequate fluid intake and output. The increases in the hematocrit and hemoglobin values in Cases 2 and 9 were concurrent with the appearance of marked edema. This study was largely a retrospective analysis, and observations which might reveal the origin of the increased red cell mass in these infants are lacking. Nucleated erythrocyte counts, fetal hemoglobin levels, fi2A-globulin determinations and differential red cell agglutinations are available in only a few sporadic instances (Fig. 1), and their significance is considered in the discussion which follows. CARDIOVASCULAR
FINDINGS
Serial electrocardiograms and roentgenograms of the chest were obtained during the period of cardiorespiratory stress and during the recovery period. Though it is recognized that objective standards for borderline electrocardiographic abnormalities in the neonate are not yet completely established, Ziegler's criteria/s which were employed for interpretation in this study, have a wide range of normal values compared to other presently used symptoms, and, thus, rarely permit overinterpretation of the normal record. Using these criteria, 9 of the 10 infants had abnormal electrocardiograms. Careful review of the available serial electrocardiograms in these infants suggested only transient abnormalities, and the abnormal findings were not uniform within the group. The progression of the electrocardiograms during the first 6 weeks of life is summarized in Table II. Six infants (Cases 1, 2, 3, 7, 9, and 10) showed right atrial hypertrophy. Patients 2, 7, 8, and 9 showed right ventricular hypertrophy; patients 4 and 10 suggestive right ventricular hypertrophy. Three infants (Cases 1, 3, and 6) had left ventricular hypertrophy with possible combined yen-
Volume 69
Number 6
Neonatal polycythernia with transient cyanosis
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December 1966
G a t t i et al.
CASE I
Age(d) 3 Hcl 75
CASE 4
34
22. 21/8 18.9 11.-7
RBC
7.0 4.7
5.3
4 74
10 69
12
25
27 23,8 17.g 17.2 10.5
Hct
CASE 3
5 2 yrs 02
H(lb
Age (d) CASE 2
4
Hgb Mist
9
19 23 3m0 57!53 36.5
@
| 22 nucleated RBC/ 100 WBC o 24~, fetal hemoglobin 9 5.2 million RBC/mm 3
9
FAge(d) 5 8 16~k 6 mc Hct 71 61 41 34 i 120.2 19 14 10 Hgb Misc
9
|
Age (d)
5
l
Hct
61
65
Hgb
21
23.2 19 18
9 19 nucleated RBC/100 WBC | i
nucleated RBC/100 WBC
11 lmll3m( 58
52
9.4
CASE 5
Age (d) 3 5 7 Hct 84 85 72 28.7 128.2 25 Hgb Phlebot All Misc
CASE 6
Age (d) 2 3 7 12 19 Hct 13 76 70 71 57 Hgb 23.4 25,6 23.2 -~2A 18.9 Phlebot Misc
9 3 nucleated RBC/100 WBC o 6Y~ fetal hemoglobin 9 B-2A globulin absent 59. 7'~ fetal hemoglobin 9 karyotype -- normal
IAge (d)
9 5 reticulocytes / 100 RBC * B-2A globulin -- present o 12~ fetal hemoglobin 9 5.95 million RBC/mm 3
CASE 7
2 65
Hgb "
?4.2 23 19.1 16
Age (d) i Hct
i Hgb Misc Age (d) Hct
CASE 9
3 6 3wk 62 59 49
'Hct Misc
CASE 8
8 11 6m010m~ 68 69 35 32 23 24 12.3 11,2
Hgb
9 21 nucleated RBC/100 W B C
9 o 9 *
6.9 million RBC/mm 3 12. 5~ fetal hemoglobin 2. 4 reticulocytesl 100 RBC differential agglutination -- equivocal
9
1 69
5
9 56
52
13 53
9 B-2A globulin -- present
~, 6 ~ fetal hemoglobin 9 5. 7 million RBC /mm 3 9 ] reticulocyte/100 RBC
25.4 21.4 18.7 17 ,It
O
2 65
4 82
9
5 7 70 63
I i ~mo 55 33
20.6 23.2 21.2 20.& 18.3
* B-2A globulin -- present 9 1.6 reticulocytes / 100 RBC ,:, 774 fetal hemoglobin
Misc
CASE 10
Age (d)
2
Hot
75
Hgb
25
2mo I
(d) age in days
Fig'. l. Hematologic data.
20
Volume 69
Number 6
Neonatal polycythernia with transient cyanosis
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December 1966
G a t t i et al.
tricular hypertrophy. The electrocardiographic and roentgenographic abnormalities tended to correlate well with the peak of clinical polycythemia. Serial electrocardiograms in 2 infants (Nos. 2 and 3) demonstrate particularly well the dynamic nature of these cardiovascular changes (Fig.
genograms of several infants. A roentgenogram taken of Infant 5 at 17 hours of age revealed a normal thymus, but 3 days later the shadow was absent, and it did not reappear until the third week of life (Fig. 3).
2).
The diagnosis of polycythemia rests upon the demonstration of increased red cell volume by direct measurement, or indirectly by plasma volume determination. Because this was largely a retrospective study, these determinations were not available in our patients; however, the use of the term "neonatal polycythemia" seems justified by the work of Usher and associates, ~2 who have shown that an elevated hematocrit value is a reliable manifestation of increased red cell mass in the newborn, as well as of increased blood volume. Neonatal polycythemia has been discussed little in the pediatric literature, and in this regard it is of some impor-
Six infants (Nos. 1, 2, 3, 5, 7, and 10) had abnormal cardiac enlargement by x-ray examination during their illness, and 2 of these (Cases 2 and 3) had increased vascularity as well (Table I I I ) . The early disappearance of the thymic outline on the chest roentgenogram was an interesting observation in these infants. The mediastinum appeared unusually narrow, with an absent or minimal thymic outline during and immediately after the period of cardiorespiratory stress. The thymus returned to normal appearance, and continued to enlarge to an unusual prominence as evidenced in the follow-up roent-
DISCUSSION
Fig. 2. Rapidly changing electrocardiograms of Cases 2 and 3 at 5 and 9 days of age and 3 and 7 days of age, respectively. (For interpretations, see Table II.)
Volume
69
Number 6
Neonatal polycytheraia with transient cyanosis
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Fig. 3. Roentgenograms of the chest of Patient 5, taken at 17 hours (left) and 5 days of age
(right), show the absence of the thymic outline concurrent with clinical distress. tance to define the normal range of hemoglobin and hematocrit values during the first 2 weeks of life. Moe 9 recently reported normal hemoglobin and hematocrit levels to be 19.8 Gm. per cent (S.D. = 2.4) and 65.9 per cent (S.D. = 7.5), respectively, from 2 to 6 days of age. We have obtained similarly high hematocrit values in a larger group of apparently normal newborn infants. ~ Although such high normal values for hematocrit and hemoglobin may cast doubt on the etiologic significance of polycythemia in the syndrome of neonatal polycythemia with cyanosis and cardiorespiratory abnormalities, reports by Bergstedt s and Sacks s on twins with parabiotic placental circulation offer convincing similarities between the polycythemic member of each twin pair and the cases in this study. Cases in the literature which resemble those in this study are reported as maternal-fetal transfusions, 4 intrauterine parabiotic syndrome, 1~ neonatal respiratory distress associated with a high hematocrit, Gplacental transfusion syndrome, 8 and acute heart failure in babies of diabetic mothers, r *Capillary hematocrlt (629 infants), at the age of I day (62.9 +_ S.D. 3.2) to the age of 10 days (53.7 + S.D.
2.5).
The following observations strongly suggest that polycythemia is at least partially responsible for the clinical picture described in the infants reported here: (1) A moderate cyanotic appearance is a uniform finding. (2) The cardiovascular changes are transient and subside concurrently with the "abnormal" hematologic findings. (3) Cardiac catheterization measurements in one infant (Case 10) demonstrated elevated right and left ventricular and diastolic pressures. (4) Walther, ~ and Danks and Stevens 6 have reported a dramatic response of this respiratory distress to phlebotomy. On the other hand, in our study of hematocrit values in 629 newborn infants, neither cyanosis nor cardiorespiratory stress was noted in 25 neonates with hematocrit values of 75 per cent or greater. It would appear that only a small number of infants appeared to have hypervolemic strain with significant cardiorespiratory abnormality. I t is of additional interest and importance that in our experience patients under the age of 1 month with cyanotic heart disease rarely have hematocrit values over 65 per cent. Of 54 patients reviewed, in whom cardiac catheterization studies under the age of 1 month confirmed the diagnosis of cyanotic congen-
Volume 69 Number 6
Neonatal polycythemia with transient cyanosis
ital heart disease with marked peripheral unsaturation, only 3 had hematocrit values over 65 per cent, and none tested over 70 per cent. The findings in monochorial, diaminotic twin pregnancies with parabiotic circulation have some relevance to the possible role of polycythemia and hypervolemia. In such twin pregnancies, the plethoric twin grows at the expense of the anemic twin. Naeye 1~ reported postmortem findings of dehydration in oligohydramnios in the anemic twin. All were born prematurely, and cardiorespiratory stress was equally prominent in the plethoric twin and the anemic one. If hypervolemia, resulting from an absolute increase in the total circulating red cell volume, is a significant factor in the pathogenesis of transient cardiorespiratory strain in these neonates, the origin of the excessive blood volume must be sought. Three possible sources are: (1) an excessive transfusion of placental blood into t h e infant at the time of delivery; (2) an arteriovenous placental anastomosis with constant maternofetal transfusion in utero; and (3) increased erythropoiesis secondary to chronic hypoxia in utero. DeMarsh, Windle, and Alt 1~ and Usher and co-workers12' 13 have demonstrated that late cIamping of the umbilical cord will raise the mean hematocrit value in newborn infants. The placental vessels contain approximately 150 ram. of whole blood; the range is 50 to 200 ml. According to Usher, Shepard, and. Lind, ~ one half of this volume enters the infant during the first 60 seconds following birth, and, if clamping of the cord is delayed for 5 minutes, the infant receives almost the entire volume, which increases the total blood volume of the infant approximately 61 per cent. The time of cord clamping in our cases was unknown with the exception of Patient 6, whose cord was clamped approximately 2 minutes after delivery. The diagnosis of maternofetal transfusion is based on (Fig. 1) : (1) high hematocrit and hemoglobin values, (2) a low proportion of fetal hemoglobin, (3) demonstration of maternal erythrocytes in the infant's blood by differential aggIutination, and (4) the
107l
presence of fi2A-globulin (IgA) in the infant's serum. Previous investigators have used the presence of /?2M-globulin (IgM) as a criterion for maternofetal transfusion, a We have tested 20 normal newborn infants from 2 to 7 days of age, using the Ouchterlony agar diffusion technique, and have found /?2M to be present in 18 of these infants, whereas p2A-globulin was absent in all. Similar findings were recently reported by Allensmith and Buell, 1~ using immunoelectrophoresis. /?2A-globulin is neither synthesized by the neonate nor does it cross the placenta; thus, in order to detect maternal serum in the infant's blood, the presence of fi~A-globulin rather than fi2M-globulin should be identified in the infant. The third possible source of hypervolemia, increased fetal erythropoiesis secondary to chronic hypoxia and pIacental insufficiency, is difficult to support by direct evidence. Wood 2 noted marked dryness and peeling of the skin in one infant, and a second infant was born after a 44 week gestation period. She postulated that "the clinical syndrome presented may be a manifestation of the placental dysfunction syndrome." None of our patients were postmature by history or by clinical findings, and the placentas were not available for study. Primary erythrocytosis (benign familial polycythemia) has apparently not been described in the newborn or young child? 7 Other investigators have reported an increased amount of erythropoietin in fetal and cord blood; this factor stimulates intrauterine erythropoiesis.~ Such a mechanism would partially explain the elevated nucleated erythrocyte counts observed in Cases 2, 3, and 5. Of the 3 patients in our group with myoclonic seizures, 2 had neurologic sequelae (Table I). Chaptal and associates ~ reported 5 neonates with polycythemia and convulsions, and Wood described 2 infants who had convulsions associated with cyanosis and Plethorm Wood's first patient developed grand real seizures with episodes of transient blindness 7 years later. Such neurologic deficits may be related to capillary stasis and sludging of blood, since viscosity of the blood
10 72
Gatti et al.
is k n o w n to increase m a r k e d l y as the h e m a t o crit rises above 70 to 75 p e r cent. 15 Oxygen, digitalis, a n d p h l e b o t o m y m a y be considered with r e g a r d to therapy. Recently, the administration of continuous oxygen thera p y has been a d v o c a t e d in the t r e a t m e n t of p o l y c y t h e m i a secondary to chronic lung disease? ~ Continuous oxygen t h e r a p y decreases the red cell volume a n d the h e m a t o c r i t value by depressing bone m a r r o w activity, a n d thus lowers the viscosity of the blood. This m e c h a n i s m m i g h t be helpful in avoiding capillary stasis a n d neurologic complications of p o l y c y t h e m i a in the neonate. I n view of the a p p a r e n t benign n a t u r e of polycythemia, overly vigorous t r e a t m e n t does not seem necessary, but cautious p h l e b o t o m y has been useful in some infants w i t h persistent cardiorespiratory distress. T w o of our infants h a d phlebotomies totaling 45 c.c. each over a 4 day period. But they were not in m a r k e d distress, and, hence, i m p r o v e m e n t was difficult to quantitate. T h e p e r i p h e r a l e d e m a in 5 of 10 infants m a y not be on a cardiac basis, and, though significant cardiomegaly seemed to justify the use of digitalis at the time, there appears to be little indication for its use in these patients. SUMMARY
T e n infants with the tentative diagnosis of cyanotic congenital h e a r t disease were noted to be plethoric a n d cyanotic, b u t in little or no cardiorespiratory distress. T h e associated auscultatory, electrocardiographic, and roentgenographic findings of cardiovascular strain were transient. A search for c o m m o n etiologic factors in these infants revealed considerable elevation in the h e m a t o c r i t a n d hemoglobin values consistent with n e o n a t a l polycythemia. Several possible etiologic factors in neonatal polycythemia have been discussed. T h e r a p y for this m a y include the administration of oxygen, with or without digitalis, and, when spontaneous improvem e n t does not occur a n d the respiratory distress remains excessive, the p e r f o r m a n c e of phlebotomy. T h e prognosis appears to be excellent, although neurologie sequelae have been observed in 2 of 3 infants with myoelonic seizures.
December 1966
We wish to express our gratitude to Drs. Judith Wood and Burton Fink for contributing information regarding two of the patients discussed in this paper. REFERENCES
1. Chaptal, J., Jean, R., Izarn, P., Campo, C., and Menard, P.: La polyglobulie pathologique n6o-natale, P6diatrie 13: 515, 1958. 2. Wood, J. L,: Plethora in the newborn infant associated with cyanosis and convulsions, J. P~DIAT. 54: 143, 1959. 3. Sacks, M. O.: Occurrence of anemia and polycythemia in phenotypicaIIy dissimilar single-ovum human twins, Pediatrics 24: 604, 1959. 4. Michael, A. F., and Mauer, A. M.: Maternalfetal transfusion as a cause of plethora in the neonatal period, Pediatrics 28: 458, 1961. 5. Bergstedt, J.: Monozygotic twins, one with high erythrocyte values and jaundice, the other with anemia neonatorum and no jaundice, Acta paediat. 46: 201, 1957. 6. Danks, D. M., and Stevens, L. H.: Neonatal respiratory distress associated with a high hematocrit reading, Lancet 2: 499, 1964. 7. Walther, T.: Is acute heart failure the cause of the neonatal syndrome in children born of diabetic mothers? Ann. pgdiat. 189: 26, 1957. 8. Kresky, B.: Transplacental transfusion syndrome, Clin. Pediat. 3: 600, 1964. 9. Moe, P. J.: Normal red blood picture during the first three years of life, Acta paediat. 54: 69, 1965. 10. Naeye, R. L.: Human intrauterine parabiotic syndrome and its complications, New England J. Med. 268: 804, 1963. 11. DeMarsh, Q. B., Windle, W. F., and Alt, H. L.: Blood volume of newborn infant in relation to early and late clamping of the umbilical cord, Am. J. Dis. Child. 63: 1123, 1942. 12. Usher, R_, Shepard, M., and Lind, J.: The blood volume of the newborn infant and placental transfusion, Acta paediat. 52: 497, 1963, 13. Buckcls, L. J., and Usher, R.: Cardiopulmonary effects of placental transfusion, J. PEDIAT. 67: 239, 1965. 14. Allensmith, M., and Buell, D. N.: The relationship of gamma-lA globulin and reagin in cord sera, J. Allergy 35: 339, 1964. 15. Rudolph, A. M., Nadas, A., and Borges, W. H.: Hematologic adjustments to cyanotic congenital heart disease, Pediatrics 11: 454, 1953. 16. Chamberlain, D. A.: and Millard, F. J. C.: The treatment of polycythemia secondary to hypoxie lung disease by continuous oxygen administration, Quart. J. Med. 32: 341, 1963. 17. Abildgaard, C. F., Cornet, J., and Schulman, I.: Primary erythrocytosis, J. Prmav. 63: 1072, 1963. 18. Ziegler, R. F.: Electrocardiographic studies in normal infants and children, Springfield, Ill., 1951, Charles C Thomas, Publisher.
1063
Neonatal polycythemia with transient cyanosis and cardiorespiratory abnormalities Ten in[ants with transient plethora and cyanosis in the newborn period are presented, with findings suggestive o[ transient cardiovascular strain. A search/or common etiologic [actors revealed considerable elevation in the hematocrit and hemoglobin levels consistent with neonatal polycythemia. The several sources o[ neonatal hypervolemia and polycythemia are discussed; it seems likely that an excessive trans[usion o[ placental blood at delivery is an important [actor. Spontaneous improvement generally occurs although phlebotomy has been therapeutically applied in two instances.
Richard A. Gatti, M.D., Alexander J. Muster, M.D., Roger B. Cole, M.D., and Milton H. Paul, M.D. * CHICAGO,
ILL.
T H I S R E P O R T c o n c e r n s 10 newborn infants referred to our cardiovascular center
during the past two years with the tentative diagnosis of cyanotic congenital heart disease. These infants had been noted to be cyanotic by the third day of life, but were in little or no cardiorespiratory distress. The early clinical findings, electrocardiograms, or chest roentgenograms were suggestive of heart disease, but these abnormal findings, as well as the clinical symptoms, were transient. A search for common factors revealed that all 10 infants were cyanotic and polycythemic with significantly high hematocrit and hemoglobin levels. The findings in these infants suggested From the Division o[ Cardiology (Willis ]. Ports Children's Heart Center), The Children's Memorial Hospital, and the Department o[ Pediatrics, Northwestern University Medical School. "~Address, Division o[ Cardiology, Children's Memorial Hospital, 707 Fullerton Ave., Chicago, Ill. 60614.
that transient cardiorespiratory distress can occur in the neonate in association with a high hematocrit level. In an extensive review of the literature, 17 similar cases of cyanosis and polycythemia and varying degrees of respiratory distress were foundl-a; in several infants the respiratory distress responded dramatically to phlebotomy. Phlebotomy was performed on 2 infants in our group; the symptoms subsided spontaneously by the age of 2 weeks in the remaining 8 patients. Such cases may be misdiagnosed as cyanotic congenital heart disease upon first observation; hence the importance of recognizing this clinical pattern. CLINICAL MANIFESTATIONS The prenatal histories, except for Case 3 (T. N.), were unremarkable. The maternal ages ranged from 19 to 33 years, and their gravidity from 1 to 7. The birth weights of the infants ranged from 5 pounds, 7 ounces,
1 064
December 1966
Gatti et al.
to 7 pounds, 14 ounces; all were delivered vaginally in encephalic presentation. Low forceps were used for all but one infant, who was delivered spontaneously. The delivery of Case 3 (T. N.) was induced at 27 weeks because of an equivocal maternal glucose tolerance test during pregnancy. All patients were referred to The Children's Memorial Hospital after birth, and, consequently, no accurate statements regarding the time of cord clamping after birth can be made. The clinical manifestations of the 10 infants are summarized in Table I. A plethoric and cyanotic appearance, the most consistent finding, was present in all infants and was first noted on the third day of life in most of them. The respiratory rate exceeded 50 per minute in only one infant, and the pulse rates ranged from 120 to 160 per minute. Subcostal retractions were noted in only one case, and the respirations were rapid (76 per minute) and shallow in another but without retractions. Systolic heart murmurs, considered to be possibly significant (Grade 2/6), were present in 4 infants, and the second heart sound was prominently split without respiratory variation in 3 of these 4. Myoclonic seizures were noted in 3 of the 10 infants. In Case 2, periods of myoclonic jerking continued until shortly after discharge at 3 weeks of age. The neurologic examination was normal at this time, and the electroencephalogram demonstrated cerebral dysrhythmia, Grade I. At 8 months of age, a left hemiparesis was discovered. In Case 3, "twitching" was observed on the first and second days of life, but subsided by the third day, when the blood glucose was 32 my. per cent and the serum calcium 7.6 mg. per cent. Treatment was not instituted in the absence of further twitching, and the serum calcium level returned to normal spontaneously. No neurologic symptoms or signs were found in this infant at 6 months of age. Another child (Case 6) began having myoclonic seizures shortly after birth; they have now been controlled with Mysoline.
HEMATOLOGIC
FINDINGS
In all 10 infants, a relatively high hematocrit or hemoglobin level was demonstrated (Fig. 1). All specimens for hematocrit and hemoglobin determinations were collected by heel puncture. In Cases 2, 4, 6, and 9, these levels actually increased after admission, even with an apparently adequate fluid intake and output. The increases in the hematocrit and hemoglobin values in Cases 2 and 9 were concurrent with the appearance of marked edema. This study was largely a retrospective analysis, and observations which might reveal the origin of the increased red cell mass in these infants are lacking. Nucleated erythrocyte counts, fetal hemoglobin levels, fi2A-globulin determinations and differential red cell agglutinations are available in only a few sporadic instances (Fig. 1), and their significance is considered in the discussion which follows. CARDIOVASCULAR
FINDINGS
Serial electrocardiograms and roentgenograms of the chest were obtained during the period of cardiorespiratory stress and during the recovery period. Though it is recognized that objective standards for borderline electrocardiographic abnormalities in the neonate are not yet completely established, Ziegler's criteria/s which were employed for interpretation in this study, have a wide range of normal values compared to other presently used symptoms, and, thus, rarely permit overinterpretation of the normal record. Using these criteria, 9 of the 10 infants had abnormal electrocardiograms. Careful review of the available serial electrocardiograms in these infants suggested only transient abnormalities, and the abnormal findings were not uniform within the group. The progression of the electrocardiograms during the first 6 weeks of life is summarized in Table II. Six infants (Cases 1, 2, 3, 7, 9, and 10) showed right atrial hypertrophy. Patients 2, 7, 8, and 9 showed right ventricular hypertrophy; patients 4 and 10 suggestive right ventricular hypertrophy. Three infants (Cases 1, 3, and 6) had left ventricular hypertrophy with possible combined yen-
Volume 69
Number 6
Neonatal polycythernia with transient cyanosis
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December 1966
G a t t i et al.
CASE I
Age(d) 3 Hcl 75
CASE 4
34
22. 21/8 18.9 11.-7
RBC
7.0 4.7
5.3
4 74
10 69
12
25
27 23,8 17.g 17.2 10.5
Hct
CASE 3
5 2 yrs 02
H(lb
Age (d) CASE 2
4
Hgb Mist
9
19 23 3m0 57!53 36.5
@
| 22 nucleated RBC/ 100 WBC o 24~, fetal hemoglobin 9 5.2 million RBC/mm 3
9
FAge(d) 5 8 16~k 6 mc Hct 71 61 41 34 i 120.2 19 14 10 Hgb Misc
9
|
Age (d)
5
l
Hct
61
65
Hgb
21
23.2 19 18
9 19 nucleated RBC/100 WBC | i
nucleated RBC/100 WBC
11 lmll3m( 58
52
9.4
CASE 5
Age (d) 3 5 7 Hct 84 85 72 28.7 128.2 25 Hgb Phlebot All Misc
CASE 6
Age (d) 2 3 7 12 19 Hct 13 76 70 71 57 Hgb 23.4 25,6 23.2 -~2A 18.9 Phlebot Misc
9 3 nucleated RBC/100 WBC o 6Y~ fetal hemoglobin 9 B-2A globulin absent 59. 7'~ fetal hemoglobin 9 karyotype -- normal
IAge (d)
9 5 reticulocytes / 100 RBC * B-2A globulin -- present o 12~ fetal hemoglobin 9 5.95 million RBC/mm 3
CASE 7
2 65
Hgb "
?4.2 23 19.1 16
Age (d) i Hct
i Hgb Misc Age (d) Hct
CASE 9
3 6 3wk 62 59 49
'Hct Misc
CASE 8
8 11 6m010m~ 68 69 35 32 23 24 12.3 11,2
Hgb
9 21 nucleated RBC/100 W B C
9 o 9 *
6.9 million RBC/mm 3 12. 5~ fetal hemoglobin 2. 4 reticulocytesl 100 RBC differential agglutination -- equivocal
9
1 69
5
9 56
52
13 53
9 B-2A globulin -- present
~, 6 ~ fetal hemoglobin 9 5. 7 million RBC /mm 3 9 ] reticulocyte/100 RBC
25.4 21.4 18.7 17 ,It
O
2 65
4 82
9
5 7 70 63
I i ~mo 55 33
20.6 23.2 21.2 20.& 18.3
* B-2A globulin -- present 9 1.6 reticulocytes / 100 RBC ,:, 774 fetal hemoglobin
Misc
CASE 10
Age (d)
2
Hot
75
Hgb
25
2mo I
(d) age in days
Fig'. l. Hematologic data.
20
Volume 69
Number 6
Neonatal polycythernia with transient cyanosis
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December 1966
G a t t i et al.
tricular hypertrophy. The electrocardiographic and roentgenographic abnormalities tended to correlate well with the peak of clinical polycythemia. Serial electrocardiograms in 2 infants (Nos. 2 and 3) demonstrate particularly well the dynamic nature of these cardiovascular changes (Fig.
genograms of several infants. A roentgenogram taken of Infant 5 at 17 hours of age revealed a normal thymus, but 3 days later the shadow was absent, and it did not reappear until the third week of life (Fig. 3).
2).
The diagnosis of polycythemia rests upon the demonstration of increased red cell volume by direct measurement, or indirectly by plasma volume determination. Because this was largely a retrospective study, these determinations were not available in our patients; however, the use of the term "neonatal polycythemia" seems justified by the work of Usher and associates, ~2 who have shown that an elevated hematocrit value is a reliable manifestation of increased red cell mass in the newborn, as well as of increased blood volume. Neonatal polycythemia has been discussed little in the pediatric literature, and in this regard it is of some impor-
Six infants (Nos. 1, 2, 3, 5, 7, and 10) had abnormal cardiac enlargement by x-ray examination during their illness, and 2 of these (Cases 2 and 3) had increased vascularity as well (Table I I I ) . The early disappearance of the thymic outline on the chest roentgenogram was an interesting observation in these infants. The mediastinum appeared unusually narrow, with an absent or minimal thymic outline during and immediately after the period of cardiorespiratory stress. The thymus returned to normal appearance, and continued to enlarge to an unusual prominence as evidenced in the follow-up roent-
DISCUSSION
Fig. 2. Rapidly changing electrocardiograms of Cases 2 and 3 at 5 and 9 days of age and 3 and 7 days of age, respectively. (For interpretations, see Table II.)
Volume
69
Number 6
Neonatal polycytheraia with transient cyanosis
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December 1966
Gatti et al.
Fig. 3. Roentgenograms of the chest of Patient 5, taken at 17 hours (left) and 5 days of age
(right), show the absence of the thymic outline concurrent with clinical distress. tance to define the normal range of hemoglobin and hematocrit values during the first 2 weeks of life. Moe 9 recently reported normal hemoglobin and hematocrit levels to be 19.8 Gm. per cent (S.D. = 2.4) and 65.9 per cent (S.D. = 7.5), respectively, from 2 to 6 days of age. We have obtained similarly high hematocrit values in a larger group of apparently normal newborn infants. ~ Although such high normal values for hematocrit and hemoglobin may cast doubt on the etiologic significance of polycythemia in the syndrome of neonatal polycythemia with cyanosis and cardiorespiratory abnormalities, reports by Bergstedt s and Sacks s on twins with parabiotic placental circulation offer convincing similarities between the polycythemic member of each twin pair and the cases in this study. Cases in the literature which resemble those in this study are reported as maternal-fetal transfusions, 4 intrauterine parabiotic syndrome, 1~ neonatal respiratory distress associated with a high hematocrit, Gplacental transfusion syndrome, 8 and acute heart failure in babies of diabetic mothers, r *Capillary hematocrlt (629 infants), at the age of I day (62.9 +_ S.D. 3.2) to the age of 10 days (53.7 + S.D.
2.5).
The following observations strongly suggest that polycythemia is at least partially responsible for the clinical picture described in the infants reported here: (1) A moderate cyanotic appearance is a uniform finding. (2) The cardiovascular changes are transient and subside concurrently with the "abnormal" hematologic findings. (3) Cardiac catheterization measurements in one infant (Case 10) demonstrated elevated right and left ventricular and diastolic pressures. (4) Walther, ~ and Danks and Stevens 6 have reported a dramatic response of this respiratory distress to phlebotomy. On the other hand, in our study of hematocrit values in 629 newborn infants, neither cyanosis nor cardiorespiratory stress was noted in 25 neonates with hematocrit values of 75 per cent or greater. It would appear that only a small number of infants appeared to have hypervolemic strain with significant cardiorespiratory abnormality. I t is of additional interest and importance that in our experience patients under the age of 1 month with cyanotic heart disease rarely have hematocrit values over 65 per cent. Of 54 patients reviewed, in whom cardiac catheterization studies under the age of 1 month confirmed the diagnosis of cyanotic congen-
Volume 69 Number 6
Neonatal polycythemia with transient cyanosis
ital heart disease with marked peripheral unsaturation, only 3 had hematocrit values over 65 per cent, and none tested over 70 per cent. The findings in monochorial, diaminotic twin pregnancies with parabiotic circulation have some relevance to the possible role of polycythemia and hypervolemia. In such twin pregnancies, the plethoric twin grows at the expense of the anemic twin. Naeye 1~ reported postmortem findings of dehydration in oligohydramnios in the anemic twin. All were born prematurely, and cardiorespiratory stress was equally prominent in the plethoric twin and the anemic one. If hypervolemia, resulting from an absolute increase in the total circulating red cell volume, is a significant factor in the pathogenesis of transient cardiorespiratory strain in these neonates, the origin of the excessive blood volume must be sought. Three possible sources are: (1) an excessive transfusion of placental blood into t h e infant at the time of delivery; (2) an arteriovenous placental anastomosis with constant maternofetal transfusion in utero; and (3) increased erythropoiesis secondary to chronic hypoxia in utero. DeMarsh, Windle, and Alt 1~ and Usher and co-workers12' 13 have demonstrated that late cIamping of the umbilical cord will raise the mean hematocrit value in newborn infants. The placental vessels contain approximately 150 ram. of whole blood; the range is 50 to 200 ml. According to Usher, Shepard, and. Lind, ~ one half of this volume enters the infant during the first 60 seconds following birth, and, if clamping of the cord is delayed for 5 minutes, the infant receives almost the entire volume, which increases the total blood volume of the infant approximately 61 per cent. The time of cord clamping in our cases was unknown with the exception of Patient 6, whose cord was clamped approximately 2 minutes after delivery. The diagnosis of maternofetal transfusion is based on (Fig. 1) : (1) high hematocrit and hemoglobin values, (2) a low proportion of fetal hemoglobin, (3) demonstration of maternal erythrocytes in the infant's blood by differential aggIutination, and (4) the
107l
presence of fi2A-globulin (IgA) in the infant's serum. Previous investigators have used the presence of /?2M-globulin (IgM) as a criterion for maternofetal transfusion, a We have tested 20 normal newborn infants from 2 to 7 days of age, using the Ouchterlony agar diffusion technique, and have found /?2M to be present in 18 of these infants, whereas p2A-globulin was absent in all. Similar findings were recently reported by Allensmith and Buell, 1~ using immunoelectrophoresis. /?2A-globulin is neither synthesized by the neonate nor does it cross the placenta; thus, in order to detect maternal serum in the infant's blood, the presence of fi~A-globulin rather than fi2M-globulin should be identified in the infant. The third possible source of hypervolemia, increased fetal erythropoiesis secondary to chronic hypoxia and pIacental insufficiency, is difficult to support by direct evidence. Wood 2 noted marked dryness and peeling of the skin in one infant, and a second infant was born after a 44 week gestation period. She postulated that "the clinical syndrome presented may be a manifestation of the placental dysfunction syndrome." None of our patients were postmature by history or by clinical findings, and the placentas were not available for study. Primary erythrocytosis (benign familial polycythemia) has apparently not been described in the newborn or young child? 7 Other investigators have reported an increased amount of erythropoietin in fetal and cord blood; this factor stimulates intrauterine erythropoiesis.~ Such a mechanism would partially explain the elevated nucleated erythrocyte counts observed in Cases 2, 3, and 5. Of the 3 patients in our group with myoclonic seizures, 2 had neurologic sequelae (Table I). Chaptal and associates ~ reported 5 neonates with polycythemia and convulsions, and Wood described 2 infants who had convulsions associated with cyanosis and Plethorm Wood's first patient developed grand real seizures with episodes of transient blindness 7 years later. Such neurologic deficits may be related to capillary stasis and sludging of blood, since viscosity of the blood
10 72
Gatti et al.
is k n o w n to increase m a r k e d l y as the h e m a t o crit rises above 70 to 75 p e r cent. 15 Oxygen, digitalis, a n d p h l e b o t o m y m a y be considered with r e g a r d to therapy. Recently, the administration of continuous oxygen thera p y has been a d v o c a t e d in the t r e a t m e n t of p o l y c y t h e m i a secondary to chronic lung disease? ~ Continuous oxygen t h e r a p y decreases the red cell volume a n d the h e m a t o c r i t value by depressing bone m a r r o w activity, a n d thus lowers the viscosity of the blood. This m e c h a n i s m m i g h t be helpful in avoiding capillary stasis a n d neurologic complications of p o l y c y t h e m i a in the neonate. I n view of the a p p a r e n t benign n a t u r e of polycythemia, overly vigorous t r e a t m e n t does not seem necessary, but cautious p h l e b o t o m y has been useful in some infants w i t h persistent cardiorespiratory distress. T w o of our infants h a d phlebotomies totaling 45 c.c. each over a 4 day period. But they were not in m a r k e d distress, and, hence, i m p r o v e m e n t was difficult to quantitate. T h e p e r i p h e r a l e d e m a in 5 of 10 infants m a y not be on a cardiac basis, and, though significant cardiomegaly seemed to justify the use of digitalis at the time, there appears to be little indication for its use in these patients. SUMMARY
T e n infants with the tentative diagnosis of cyanotic congenital h e a r t disease were noted to be plethoric a n d cyanotic, b u t in little or no cardiorespiratory distress. T h e associated auscultatory, electrocardiographic, and roentgenographic findings of cardiovascular strain were transient. A search for c o m m o n etiologic factors in these infants revealed considerable elevation in the h e m a t o c r i t a n d hemoglobin values consistent with n e o n a t a l polycythemia. Several possible etiologic factors in neonatal polycythemia have been discussed. T h e r a p y for this m a y include the administration of oxygen, with or without digitalis, and, when spontaneous improvem e n t does not occur a n d the respiratory distress remains excessive, the p e r f o r m a n c e of phlebotomy. T h e prognosis appears to be excellent, although neurologie sequelae have been observed in 2 of 3 infants with myoelonic seizures.
December 1966
We wish to express our gratitude to Drs. Judith Wood and Burton Fink for contributing information regarding two of the patients discussed in this paper. REFERENCES
1. Chaptal, J., Jean, R., Izarn, P., Campo, C., and Menard, P.: La polyglobulie pathologique n6o-natale, P6diatrie 13: 515, 1958. 2. Wood, J. L,: Plethora in the newborn infant associated with cyanosis and convulsions, J. P~DIAT. 54: 143, 1959. 3. Sacks, M. O.: Occurrence of anemia and polycythemia in phenotypicaIIy dissimilar single-ovum human twins, Pediatrics 24: 604, 1959. 4. Michael, A. F., and Mauer, A. M.: Maternalfetal transfusion as a cause of plethora in the neonatal period, Pediatrics 28: 458, 1961. 5. Bergstedt, J.: Monozygotic twins, one with high erythrocyte values and jaundice, the other with anemia neonatorum and no jaundice, Acta paediat. 46: 201, 1957. 6. Danks, D. M., and Stevens, L. H.: Neonatal respiratory distress associated with a high hematocrit reading, Lancet 2: 499, 1964. 7. Walther, T.: Is acute heart failure the cause of the neonatal syndrome in children born of diabetic mothers? Ann. pgdiat. 189: 26, 1957. 8. Kresky, B.: Transplacental transfusion syndrome, Clin. Pediat. 3: 600, 1964. 9. Moe, P. J.: Normal red blood picture during the first three years of life, Acta paediat. 54: 69, 1965. 10. Naeye, R. L.: Human intrauterine parabiotic syndrome and its complications, New England J. Med. 268: 804, 1963. 11. DeMarsh, Q. B., Windle, W. F., and Alt, H. L.: Blood volume of newborn infant in relation to early and late clamping of the umbilical cord, Am. J. Dis. Child. 63: 1123, 1942. 12. Usher, R_, Shepard, M., and Lind, J.: The blood volume of the newborn infant and placental transfusion, Acta paediat. 52: 497, 1963, 13. Buckcls, L. J., and Usher, R.: Cardiopulmonary effects of placental transfusion, J. PEDIAT. 67: 239, 1965. 14. Allensmith, M., and Buell, D. N.: The relationship of gamma-lA globulin and reagin in cord sera, J. Allergy 35: 339, 1964. 15. Rudolph, A. M., Nadas, A., and Borges, W. H.: Hematologic adjustments to cyanotic congenital heart disease, Pediatrics 11: 454, 1953. 16. Chamberlain, D. A.: and Millard, F. J. C.: The treatment of polycythemia secondary to hypoxie lung disease by continuous oxygen administration, Quart. J. Med. 32: 341, 1963. 17. Abildgaard, C. F., Cornet, J., and Schulman, I.: Primary erythrocytosis, J. Prmav. 63: 1072, 1963. 18. Ziegler, R. F.: Electrocardiographic studies in normal infants and children, Springfield, Ill., 1951, Charles C Thomas, Publisher.