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Thrombosis in the newborn: Comparison between infants of diabetic and nondiabetic mothers
JOURNAL OF
THE
PEDIATRICS OCTOBER
1965
Volume
67
Number
4
Thrombosis in the newborn: Comparison betveen infants of diabetic and nondiabetic mothers Venous thrombosis was present in 45 newborn in[ants in a series o[ 4,000 cases reviewed. The incidence in in[ants o[ diabetic mothers was 15.8 per cent (13 o[ 82 cases), compared to an incidence o[ less than 1 per cent in the remaining cases. The adrenal and renal veins were most [requently involved, each comprising one third o[ the cases. Thrombosis was associated with hydramnios, toxemia, birth trauma, sepsis, and recent surgery. Injection and surgery were contributing [actors in in[ants o[ nondiabetic mothers, whereas a history o[ hydramnios and toxemia occurred more [requently in in[ants born to diabetic women. T h e latter survived [or shorter periods, and the thrombus in these cases showed more [requent organization and calcification, suggesting intrauterine [ormation.
Ella H. Oppenheimer, M.D., and John R. Esterly, M.D.* BALTIMORE, MD.
VENOUS T H R O M B O S I S in the newborn infant is an infrequent finding and has been described primarily in renal and intracranial veins? Because of successful treatment of unilateral renal vein occlusion, the clinical diagnosis of this condition may be lifesaving.2 Since the first report of the occurrence of renal vein thrombosis in infants of diabetic
mothers a ( I D M ) , the association has been confirmed and extended to include infants of prediabetic mothersr Thrombosis of dural sinuses and cerebral veins occurs in infants with infection and dehydration, but when seen in the newborn is usually associated with birth t r a u m a ? Adrenal hemorrhage is also seen in eases of perinatal distress, but thrombosis of the adrenal or other visceral veins is considered decidedly uncommon. 6 This report reviews our experience with
From the Department o[ Pathology, The Johns Hopkins University School o[ Medicine and Hospital. *Address, Department o] Pathology, The Johns Hopkins Hospital, Baltimore 5, Md.
549
5 50
Oppenheimer and Esterly
October 1965
thrombosis in the newborn and contrasts the findings in the infants of diabetic mothers with infants of nondiabetic mothers (IN-DM). OBSERVATIONS
The records of 4,000 infants under 2 weeks of age who were autopsied consecutively between 1933 and 1964 were reviewed. All stillborn infants weighing more than 400 grams were included. In 82 cases there was a documented history of maternal diabetes mellitus; in these cases hyperplasia of the islets of Langerhans was a consistent finding. Thrombosis was found at autopsy in 45 babies. Of these, 13 were offspring of diabetic mothers. The sites of thrombosis are listed in Table I. The renal and adrenal vein each represent approximately one third of the total. In 3 cases (1 IDM, 2 IN-DM) there were thrombi in both the renal and adrenal veins. Renal vein thrombosis was bilateral in 5 of the 11 infants of nondiabetic mothers. Similarly both adrenal veins were affected in 4 of the 10 cases of adrenal vein thrombosis in the I N - D M group. There were 4 cases (1 IDM, 3 I N - D M ) of puhnonary embolization, source unknown, making a total of 45 cases with thrombosis. In addition, pulmonary emboli were present in 13 instances of known venous thrombosis (4 IDM, 9 INDM). In 14 cases (2 IDM, 12 I N - D M ) ,
thrombi were present in multiple vessels, either as isolated thrombi, or as extensions into adjacent venous branches. The incidence of thrombosis in the 4,000 cases reviewed was 15.8 per cent in the 82 offspring of diabetic mothers in contrast to 0.8 per cent in the 3,918 infants of nondiabetic mothers, and 1.1 per cent over-all. The duration of life in the 45 cases with thrombosis is listed in Table II. Death occurred in utero, at birth, or within the first 24 hours in over half the infants of diabetic mothers. In infants of nondiabetic mothers, 80 per cent survived more than one day and 50 per cent survived more than 4 days. A majority (80 per cent) of the thromboses was recent or terminal in the absence of maternal diabetes, whereas almost half of the thrombi in infants born to diabetic mothers showed organization or calcification. Some of the factors which have been thought to predispose to neonatal thrombosis are listed in Table III. A difficult or prolonged labor was present in 11 cases, and with no difference in proportion in the two groups. Of the 13 cases of thrombosis in infants with sepsis, 10 were infants of nondiabetic mothers. Dehydration could not be documented with certainty from the case records and is not tabulated. All 5 postoperative thromboses occurred in infants of nondiabetic mothers. Polycythemia (hemato-
Table I. Distribution and incidence of venous thrombosis in infants of diabetic mothers (IDM) and infants of nondiabetic mothers (IN-DM) In 82 in[ants of diabetic mothers
In 3,918 in[ants of nondiabetic mothers
R e n a l vein 5 (1 bilateral) 9 (4 A d r e n a l vein 4 9 (3 A d r e n a l a n d renal veins 1 2 (1 I n t r a c r a n i a l veins 0 3 U m b i l i c a l vein 1 2 L i v e r ( p o r t a l veins, d u c t u s venosus) 1 1 Splenic veins (/ 1 M e s e n t e r i c veins I) 1 Iliac a n d v e n a c a v a 0 1 P u l m o n a r y e m b o l i : Source u n k n o w n ~ 1 3 Totalst 13 32 Incidence (%) 15.8 0.8 *Pulmonary emboli from venous thromboses were present in 4 II)M and 9 IN-DM. tThe totals include 14 cases (2 IDM and 12 IN-DM) with multiple sites of venous
bilateral) bilateral) bilateral)
thrombosis.
In 4,000 neonates 14 13 3 3 3 2 1 I 1 4 45 1 1
Volume 67 Number 4
Thrombosis in the newborn
crit of 72) was considered a contributing factor in one case of a cyanotic congenital cardiac malformation in the absence of maternal diabetes. In this case as well as 2 of the postoperative deaths, arterial thrombi were also found. In only one offspring of a diabetic mother was arterial thrombosis found. This infant had thrombi in the innominate artery and aorta. These were interpreted as paradoxical emboli produced in utero from extensive thrombosis of the renal veins. Hydramnios was present in four mothers, all diabetic. The incidence of toxemia was higher in the diabetic group. The relationship to toxemia and the time of thrombosis are illustrated in the case recorded in detail in the appendix. In this 5,400 gram infant of a mother with diabetes and toxemia, adrenal thrombosis and infarction preserved the fetal adrenal architecture (Fig. 1). The other adrenal showed almost complete resolution of the fetal zone at death on the ninth day (Fig. 2). In 5 cases (1 IDM, 4 IN-DM) no ma-
Table II. Age at death and "age" of thrombi in[ants o[ diabetic mothers
In 32 in[ants o[ nondiabetic mothers
3 4 3 2 1
3 4 6 4 15
7 1 4
26 4 1
1
1
In 13
Age at death Stillborn ~24 Hours 24 to 48 Hours 2 to 4 Days > 4 Days Thrombus morphology Fresh Early organization Organization with calcification Calcification
55 1
ternal abnormalities which could be related to the thrombosis were found. DISCUSSION Venous thrombi were present in 15.8 per cent of the autopsied infants of diabetic mothers and in less than 1 per cent of the remaining newborn infants in this series. There was a sharp contrast in thrombus morphology and duration of life in these groups. The majority of infants of nondiabetic mothers in whom thrombosis was found, had survived the first day of life and only terminal thrombi were found at autopsy. Correlation with clinical factors, such as surgery or sepsis, was frequent. In contrast, the infants born to mothers with diabetes survived a shorter period, but showed more evidence of "age" in thrombus architecture. Hydramnios was present only in these cases, and toxemia was present in a higher proportion than in the infants of nondiabetic mothers (61 per cent compared to 21 per cent) (Table IV). It is generally agreed that much of the increased weight of the infants of diabetic mothers is fat. Total body water in these infants both by indirect 7, s and direct 9 measurement is decreased. There is evidence suggesting that further water loss occurs with the metabolism of glycogen stores so that in the first days of life this deficiency remains unchanged. 1~ Dehydration could not be evaluated in these cases, but its predisposing role in thrombosis is well known. Potential birth trauma indicated by a difficult or prolonged labor occurred in approximately one quarter of the cases in each group. In 4 of the 11 cases with this history (1 IDM, 3 I N - D M ) there was intracranial hemorrhage (Table V). Adrenal hemorrhage and thrombosis were present in all the
Table III. Factors associated with thrombosis
IDM (13 eases) IN-DM (32 cases) Total (45 cases)
Prolonged or di~cult labor
Sepsis
Postoperative complication
Maternal h~dramnios
Maternal toxemia
3 8 11
3 10 13
0 5 5
4 0 4
8 7 15
552
Oppenheimer and Est
October
Fig. 1. N o r m a l right adrenal. Note differentiated " a d u l t " cortex, with collapsed s t r o m a of previous provisional zone, A. A small g r o u p of m e d u l l a r y cells can be seen to the right of the venous channel, B. ( H e m a t o x y I i n a n d eosin, x65.)
Fig. 2. I n f a r c t e d portion of left adrenal, same magnification. I n contrast to width of n o r m a l adrenal, only a portion of the infarcted fetal zone can be included at this magnificati~m. Focal calcification c a n be seen at p e r i p h e r y of infarct, A, a n d in a small t h r o m b u s , B ( ) u t e r rim of viable cortex remains at, C. (•
1965
Volume 67 Number 4
Thrombosis in the newborn
553
Fig. 3. A portion of the infarcted fetal zone of left adrenal. Fetal zone cells can be recognized in spite of calcium precipitation. A small disintegrating thrombus is present at, A. (x170.) infants of diabetic mothers in this group. This m a y be more than a fortuitous association because of the high incidence of adrenal hemorrhage in infants with a history of intrauterine distress and birth trauma. 11' 12 T h e possibility that thrombosis results from a Shwartzman-like reaction in infants with infection has been suggested recently. 13 While sepsis can never be ruled out completely, there was no bacteriologic or morphologic evidence of infection in the 4 cases of p u l m o n a r y emboli of u n k n o w n source nor in 10 of the 13 infants born to diabetic mothers. O u r findings suggest that toxemia and dystocia are associated with venous thrombosis in infants of diabetic mothers and that these factors are equally important in nondiabetic mothers. T h e m a j o r distinction between the two groups is the higher incidence of toxemia and of hydramnios in diabetic mothers. Renal vein thrombosis in two newborn infants was reported by Avery, Oppenheimer, and Gordon 3 who suggested the importance of maternal diabetes and pointed out two similar cases in the literature. One of the
latter was included in a report of 8 autopsled infants of diabetic women. 14 It is pertinent to note also that adrenal hemorrhage was described in another of these 8 infants. I n a review of renal vein thrombosis in the newborn, Takeuchi and Benirschke 4 found 5 of 16 cases in infants of diabetic mothers. An adrenal infarct with small thrombi was present in one case and adrenal hemorrhage in another. There was a history of maternal hypertension in one and maternal hydramnios in another of these five babies. Because hyperplasia of the islets of Langerhans was found in 7 of the 11 remaining infants, they postulated a prediabetic state in these mothers. Of the 32 infants with thrombosis in the present series in w h o m there was no history of maternal diabetes, 2 showed hyperplasia of islet tissue. There was no eosinophilic inflammatory infiltrate. A glucose tolerance test was not performed on these mothers. However, one m o t h e r had a negative urine glucose test 12 years later, and the other was delivered of a 2,250 g r a m term infant the following year; her antepartum urine was negative for glucose.
554
Oppenheimer and Esterly
October 1965
Table IV. Maternal toxemia and thrombosis
Autopsy No.
Birth weight (Kg.)
Age at death
12824
3.5
36 Hours
0
0
1 Adrenal
Fresh
13369
3.0
Stillborn
+
+
1 Kidney
Organizing and calcifying
Autolysis
17997
2.9
19 Hours
+
+
1 Kidney; lung
Fresh
HMD
20781
2.7
Stillborn
0
0
1 Kidney
Organizing, calcifying, and fresh
23907
3.6
28 Hours
+
+
1 Lung
Fresh
24616
3.0
5 Days
0
0
2 Kidneys with 1 infarct
Fresh and organizing
Dehydration
25701
3.9
4 Days
+
0
1 Kidney with infarct; vena cava
Fresh and organizing
Cesarean section
26968
2.5
12 Days
0
0
2 Adrenals
Fresh
CNS hemorrhage
29324
2.1
Stillborn
(I
0.
1 Kidney
Calcifying and organizing
Aneneephaly
29811
5.4
9 Days
+
l)
1 Adrenal with infarct
Calcifying and organizing
(Case reported)
30837
1.7
37 Hours
+
0
Ductus venosus; lung
Calcifying
Slight aspiration pneumonia ; congenital heart disease; vascular ring around trachea
32049
2.5
17 Hours
+
0
I Kidney; lung
Fresh, calcifying, and organizing
Cesarean section; HMD
33243
5.2
4 Days
~
+
2 Kidneys; 1 infarct ; vena cava; innominate artery and aorta
Calcifying and organizing
Prolapse cord, coarctation ; patent ductus
33298
2.7
8 Hours
0
0
Portal vein; lung
Fresh
Cesarean section
33208
0.8
22 Hours
0
0
Lung
Fresh
CNS hemorrhage
I Diabetes HydTamin mother I nios I Site o[ thrombi
T h r o m b o s i s has b e e n r e p o r t e d i n f r e q u e n t l y in r e v i e w s of the p a t h o l o g y of infants of d i a b e t i c m o t h e r s : 3 in 95 cases, 15 n o n e in 25 cases, 16 a n d one i n s t a n c e of a d r e n a l h e m o r r h a g e in 50 cases. 17 I n a r e c e n t r e p o r t of renal vein t h r o m b o s i s in t h r e e n e w b o r n infants, one was b o r n to a d i a b e t i c m o t h e r , a n d a n o t h e r was b o r n a f t e r a p r e g n a n c y c o m p l i c a t e d by t o x e m i a / * SUMMARY I n a r e v i e w of 4,000 c o n s e c u t i v e autopsies of n e w b o r n infants, 45 cases of v e n o u s t h r o m -
Age o[ thrombi
Other [actors
bosis w e r e found. T h e i n c i d e n c e in infants of d i a b e t i c m o t h e r s was 15.8 p e r c e n t (13 of 82 cases) c o m p a r e d to 0.8 p e r c e n t in the r e m a i n i n g cases. I n v o l v e m e n t of the renal a n d a d r e n a l v e i n e a c h r e p r e s e n t e d app r o x i m a t e l y o n e t h i r d of the total t h r o m boses. T h e infants of d i a b e t i c m o t h e r s surv i v e d s h o r t e r periods a n d t h e t h r o m b i in these cases w e r e m o r e f r e q u e n t l y o r g a n i z e d a n d calcified. T h e i m p o r t a n c e of h y d r a m n i o s , t o x e m i a , a n d d y s t o c i a in t h r o m b o s i s is discussed. Sepsis a n d s u r g e r y w e r e a d d i t i o n a l con-
Volume 67 Number 4
Thrombosis in the newborn
555
T a b l e V. B i r t h t r a u m a a n d t h r o m b o s i s
Autopsy No.
Birth weight (Kg.)
Age at death
Diabetes in mother
12858
3.0
8 Days
0
1 Adrenal with infarct
Calcified
13884
4.0
23 Hours
0
1 Adrenal with infarct
Fresh
15387
3.0
2 Days
0
2 Adrenals with infarct
Fresh
Tentorial tear and hemorrhage
16789
2.3
36 Hours
0
1 Adrenal with infarct
Fresh
Cyanotic heart disease
17494
3.5
32 Hours
0
1 Adrenal with infarct; pituitary
Fresh
Pneumonia
19366
4.8
Stillborn
+
1 Adrenal; 1 kidney
Fresh
21967
2.2
5 Days
0
Dural sinus
Fresh
CNS hemorrhage
24753
4.2
Stillborn
+
1 Adrenal
Fresh
Prolapsed cord
25131
3.7
32 Hours
0
2 Adrenals with I infarct; liver; brain
Fresh
Erb's paralysis
28041
4.3
15 Hours
+
1 Adrenal with infarct
Fresh
Intracranial hemorrhage
28522
3.7
5 Days
0
Umbilicus; lung
Fresh
Tentorial tear and hemorrhage ; thrombocytopenia ; omphalitis; sepsis
tributing
factors
in infants
of n o n d i a b e t i c
Sites o[ thrombi
mothers. The photomicrographs for this paper were made by Mr. Raymond Lund.
REFERENCES 1. Ahvenainen, E. K., and Hallman, N.: Thrombosis of deep veins in childhood: I and II, Ann. paediat, Fenniae I: 1, 1954-55; 1: 105, 1954-55. 2. Traggis, D. C., and Ellison, M. M.: Unilateral renal vein thrombosis, J. PEDIAT. 48: 229, 1956. 3. Avery, M. E., Oppenheimer, E. H., and Gordon, H. H.: Renal vein thrombosis in newborn infants of diabetic mothers, New England J. Med. 256: 1134, 1957. 4. Takeuchi, A., and Benirschke, K.: Renal vein thrombosis of the newborn and its relation to maternal diabetes, Biol. Neonat. 3: 237, 1961. 5. Potter, E. L.: Pathology of the fetus and infant, ed. 2, Chicago, 1961, Yearbook Medical Publishers, p. 476. 6. Morison, J. E.: Foetal and neonatal pathology, ed. 2, London, 1963, Butterworth and Co., Ltd., p. 267. 7. Osier, M.: Body water in newborn infants of diabetic mothers, Acta endoerinol. 34: 261, 1960.
"'Age" o/ thrombi T-E fistula; surgical repair of imperforate anus
8. Cheek, D. B., Maddison, T. G., Malinek, M., and Coldbeck, J. H.: Further observations on the corrected bromide space of the neonate and investigation of the water and electrolyte status in infants born of diabetic mothers, Pediatrics 28: 861, 1961. 9. Fee, B. A., and Well, W. B., Jr.: Body composition of infants of diabetic mothers by direct analysis, Ann. New York Acad. Sc. 110: 869, 1963. 10. Osler, M.: Neonatal changes in body composition of infants born to diabetic mothers, Acta endocrinol. 34: 299, 1960. 11. Browne, F. J.: Discussion on stillbirths and neonatal deaths. IV. Neonatal death, Brit. M. J. 2" 590, 1922. 12. Snelling, C. E., and Erb, I. H.: Hemorrhage and subsequent calcification of the suprarenal, J. PEDIAT. 6: 22, 1935. 13. Groniowski, I.: Thrombotic arteriolar lesions in the lungs of newborn, Arch. Path. 75: 144, 1963. 14. Farquhar, J. W.: The child of the diabetic woman, Arch. Dis. Childhood 34: 76, 1959. 15. Driscoll, S. G., Benirschke, K., and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers, Am. J. Dis. Child. 100: 818, 1960. 16. Cardell, B. S.: The infants of diabetic mothers, J. Obst. & Gynaec. Brit. Emp. 60: 834, 1953. 17. Warren, S., and LeCompte, P. M.: The pathology of diabetes mellitus, ed. 3, Philadelphia, 1952, Lea & Febiger, p. 248.
5 56
Oppenheimer and Esterly
18. Stark, H.: Renal vein thrombosis in infancy, Am. J. Dis. Child. 108: 430, 1964. APPENDIX
J. P. was born to a lnother who had previously been delivered of 3 large infants (4.7 kilograms, 4.5 kilograms, and 6.4 kilograms). Five days before her confinement, the membranes ruptured, and she was treated with antibiotics. She had hypertension (150/94-110), and had 3 plus albuminuria with 1 plus pretibial edema. A glucose tolerance test was abnormal (fasting 120 mg. per cent; ~2 hour 252 mg. per cent; 1 hour 225 mg. per cent; 2 hour 153 rag. per cent; 3 hour 99 rag. per cent). The infant was delivered spontaneously and had good color and breathed and cried well. He. weighed 5.4 kilograms and looked edematous. Later he was said to be cyanotic, even with oxygen. On the second day he vomited and became icteric (bilirubin 18.2 mg. per cent, all indirect). He was transferred to The Johns Hopkins Hospital on the third day. Respiration was rapid (88 per minute), but there was no retraction and the hlngs were normal by physical examination and x-ray. The peripheral white blood cell count was 15,800. Blood cultures were negative. Nevertheless, he was treated with antibiotics. Blood chemistries showed glucose, 60 mg. per cent; CO.,, 20 mEq. per liter; C1, 114 mEq. per liter; Na, 166 mEq. per liter; K, 7.1 mEq. per liter; and Ca, 9.4 mg. per cent. The hemawerit was 73 per cent. The bilirubin fell to 10.6 rag. per cent on the fourth day. Following a generalized convulsion the day after admission, a lumbar puncture produced grossly bloody cerebrospinal fluid. Vomiting was persistent. On the twelfth day of life, the infant developed periods of apnea and died despite repeated resuscitative nleasures. The clinical impression was subaraehnoid hemorrhage,
October 1965
possible meningitis and pneumonia, secondary to aspiration. Autopsy (No. 29811) was performed 14 hours after death. The infant weighed 5.4 kilograms. There was excessive pale yellow subcutaneous fat. The lungs were heavy (120 grams) with irregular dark red-brown consolidation in all lobes but especially in the dependent portions. The skull was intact but there was over-riding of the suture lines, with a small subgaleal hemorrhage, and focal areas of hemorrhage in the internal periosteum. The brain weighed 500 grams. There was air extensive subarachnoid hemorrhage. The adrenals were most interesting. The right adrenal weighed 2.5 grams and measured 4 x 2 x 1 cm. Its architectural pattern was normal. The left adrenal weighed 7.5 grams and measured 5 x 2.5 x 1.5 cm. The enlargement was caused hy a 2.5 x l x 1 cm. yellow "tumor" occupying one pole of the gland. It was surrounded by a firm yellow rim with a necrotic center. The other pole of this adrenal had a normal architectural pattern duplicating that seen in the right adrenal. The microscopic appearance of lhe right adrenal and the uninvolved pole of the left ~as normal with nearly complete involution of the fetal zone (Fig. 2). The "tmnor" consisted of an infarct showing a partially calcitied fossilization of a "fetal" adrenal, retaining its wide provisional zone (Figs. 1 and 3). Disintegrating and calcified remnants of thrombi filled the medullary veins of the infarcted portion. No bacteria or fungi could be stained in this lesion. There was extensive acute lobular pneunmnia. Bacterial stains were negative, but hyphae and yeast forms of Candida albicans were identified. The tracheal lumen was filled with masses of this fungus and a culture of heart's blood grew C. albicans. The islets of Langerhans were large and numerous.
THE
PEDIATRICS OCTOBER
1965
Volume
67
Number
4
Thrombosis in the newborn: Comparison betveen infants of diabetic and nondiabetic mothers Venous thrombosis was present in 45 newborn in[ants in a series o[ 4,000 cases reviewed. The incidence in in[ants o[ diabetic mothers was 15.8 per cent (13 o[ 82 cases), compared to an incidence o[ less than 1 per cent in the remaining cases. The adrenal and renal veins were most [requently involved, each comprising one third o[ the cases. Thrombosis was associated with hydramnios, toxemia, birth trauma, sepsis, and recent surgery. Injection and surgery were contributing [actors in in[ants o[ nondiabetic mothers, whereas a history o[ hydramnios and toxemia occurred more [requently in in[ants born to diabetic women. T h e latter survived [or shorter periods, and the thrombus in these cases showed more [requent organization and calcification, suggesting intrauterine [ormation.
Ella H. Oppenheimer, M.D., and John R. Esterly, M.D.* BALTIMORE, MD.
VENOUS T H R O M B O S I S in the newborn infant is an infrequent finding and has been described primarily in renal and intracranial veins? Because of successful treatment of unilateral renal vein occlusion, the clinical diagnosis of this condition may be lifesaving.2 Since the first report of the occurrence of renal vein thrombosis in infants of diabetic
mothers a ( I D M ) , the association has been confirmed and extended to include infants of prediabetic mothersr Thrombosis of dural sinuses and cerebral veins occurs in infants with infection and dehydration, but when seen in the newborn is usually associated with birth t r a u m a ? Adrenal hemorrhage is also seen in eases of perinatal distress, but thrombosis of the adrenal or other visceral veins is considered decidedly uncommon. 6 This report reviews our experience with
From the Department o[ Pathology, The Johns Hopkins University School o[ Medicine and Hospital. *Address, Department o] Pathology, The Johns Hopkins Hospital, Baltimore 5, Md.
549
5 50
Oppenheimer and Esterly
October 1965
thrombosis in the newborn and contrasts the findings in the infants of diabetic mothers with infants of nondiabetic mothers (IN-DM). OBSERVATIONS
The records of 4,000 infants under 2 weeks of age who were autopsied consecutively between 1933 and 1964 were reviewed. All stillborn infants weighing more than 400 grams were included. In 82 cases there was a documented history of maternal diabetes mellitus; in these cases hyperplasia of the islets of Langerhans was a consistent finding. Thrombosis was found at autopsy in 45 babies. Of these, 13 were offspring of diabetic mothers. The sites of thrombosis are listed in Table I. The renal and adrenal vein each represent approximately one third of the total. In 3 cases (1 IDM, 2 IN-DM) there were thrombi in both the renal and adrenal veins. Renal vein thrombosis was bilateral in 5 of the 11 infants of nondiabetic mothers. Similarly both adrenal veins were affected in 4 of the 10 cases of adrenal vein thrombosis in the I N - D M group. There were 4 cases (1 IDM, 3 I N - D M ) of puhnonary embolization, source unknown, making a total of 45 cases with thrombosis. In addition, pulmonary emboli were present in 13 instances of known venous thrombosis (4 IDM, 9 INDM). In 14 cases (2 IDM, 12 I N - D M ) ,
thrombi were present in multiple vessels, either as isolated thrombi, or as extensions into adjacent venous branches. The incidence of thrombosis in the 4,000 cases reviewed was 15.8 per cent in the 82 offspring of diabetic mothers in contrast to 0.8 per cent in the 3,918 infants of nondiabetic mothers, and 1.1 per cent over-all. The duration of life in the 45 cases with thrombosis is listed in Table II. Death occurred in utero, at birth, or within the first 24 hours in over half the infants of diabetic mothers. In infants of nondiabetic mothers, 80 per cent survived more than one day and 50 per cent survived more than 4 days. A majority (80 per cent) of the thromboses was recent or terminal in the absence of maternal diabetes, whereas almost half of the thrombi in infants born to diabetic mothers showed organization or calcification. Some of the factors which have been thought to predispose to neonatal thrombosis are listed in Table III. A difficult or prolonged labor was present in 11 cases, and with no difference in proportion in the two groups. Of the 13 cases of thrombosis in infants with sepsis, 10 were infants of nondiabetic mothers. Dehydration could not be documented with certainty from the case records and is not tabulated. All 5 postoperative thromboses occurred in infants of nondiabetic mothers. Polycythemia (hemato-
Table I. Distribution and incidence of venous thrombosis in infants of diabetic mothers (IDM) and infants of nondiabetic mothers (IN-DM) In 82 in[ants of diabetic mothers
In 3,918 in[ants of nondiabetic mothers
R e n a l vein 5 (1 bilateral) 9 (4 A d r e n a l vein 4 9 (3 A d r e n a l a n d renal veins 1 2 (1 I n t r a c r a n i a l veins 0 3 U m b i l i c a l vein 1 2 L i v e r ( p o r t a l veins, d u c t u s venosus) 1 1 Splenic veins (/ 1 M e s e n t e r i c veins I) 1 Iliac a n d v e n a c a v a 0 1 P u l m o n a r y e m b o l i : Source u n k n o w n ~ 1 3 Totalst 13 32 Incidence (%) 15.8 0.8 *Pulmonary emboli from venous thromboses were present in 4 II)M and 9 IN-DM. tThe totals include 14 cases (2 IDM and 12 IN-DM) with multiple sites of venous
bilateral) bilateral) bilateral)
thrombosis.
In 4,000 neonates 14 13 3 3 3 2 1 I 1 4 45 1 1
Volume 67 Number 4
Thrombosis in the newborn
crit of 72) was considered a contributing factor in one case of a cyanotic congenital cardiac malformation in the absence of maternal diabetes. In this case as well as 2 of the postoperative deaths, arterial thrombi were also found. In only one offspring of a diabetic mother was arterial thrombosis found. This infant had thrombi in the innominate artery and aorta. These were interpreted as paradoxical emboli produced in utero from extensive thrombosis of the renal veins. Hydramnios was present in four mothers, all diabetic. The incidence of toxemia was higher in the diabetic group. The relationship to toxemia and the time of thrombosis are illustrated in the case recorded in detail in the appendix. In this 5,400 gram infant of a mother with diabetes and toxemia, adrenal thrombosis and infarction preserved the fetal adrenal architecture (Fig. 1). The other adrenal showed almost complete resolution of the fetal zone at death on the ninth day (Fig. 2). In 5 cases (1 IDM, 4 IN-DM) no ma-
Table II. Age at death and "age" of thrombi in[ants o[ diabetic mothers
In 32 in[ants o[ nondiabetic mothers
3 4 3 2 1
3 4 6 4 15
7 1 4
26 4 1
1
1
In 13
Age at death Stillborn ~24 Hours 24 to 48 Hours 2 to 4 Days > 4 Days Thrombus morphology Fresh Early organization Organization with calcification Calcification
55 1
ternal abnormalities which could be related to the thrombosis were found. DISCUSSION Venous thrombi were present in 15.8 per cent of the autopsied infants of diabetic mothers and in less than 1 per cent of the remaining newborn infants in this series. There was a sharp contrast in thrombus morphology and duration of life in these groups. The majority of infants of nondiabetic mothers in whom thrombosis was found, had survived the first day of life and only terminal thrombi were found at autopsy. Correlation with clinical factors, such as surgery or sepsis, was frequent. In contrast, the infants born to mothers with diabetes survived a shorter period, but showed more evidence of "age" in thrombus architecture. Hydramnios was present only in these cases, and toxemia was present in a higher proportion than in the infants of nondiabetic mothers (61 per cent compared to 21 per cent) (Table IV). It is generally agreed that much of the increased weight of the infants of diabetic mothers is fat. Total body water in these infants both by indirect 7, s and direct 9 measurement is decreased. There is evidence suggesting that further water loss occurs with the metabolism of glycogen stores so that in the first days of life this deficiency remains unchanged. 1~ Dehydration could not be evaluated in these cases, but its predisposing role in thrombosis is well known. Potential birth trauma indicated by a difficult or prolonged labor occurred in approximately one quarter of the cases in each group. In 4 of the 11 cases with this history (1 IDM, 3 I N - D M ) there was intracranial hemorrhage (Table V). Adrenal hemorrhage and thrombosis were present in all the
Table III. Factors associated with thrombosis
IDM (13 eases) IN-DM (32 cases) Total (45 cases)
Prolonged or di~cult labor
Sepsis
Postoperative complication
Maternal h~dramnios
Maternal toxemia
3 8 11
3 10 13
0 5 5
4 0 4
8 7 15
552
Oppenheimer and Est
October
Fig. 1. N o r m a l right adrenal. Note differentiated " a d u l t " cortex, with collapsed s t r o m a of previous provisional zone, A. A small g r o u p of m e d u l l a r y cells can be seen to the right of the venous channel, B. ( H e m a t o x y I i n a n d eosin, x65.)
Fig. 2. I n f a r c t e d portion of left adrenal, same magnification. I n contrast to width of n o r m a l adrenal, only a portion of the infarcted fetal zone can be included at this magnificati~m. Focal calcification c a n be seen at p e r i p h e r y of infarct, A, a n d in a small t h r o m b u s , B ( ) u t e r rim of viable cortex remains at, C. (•
1965
Volume 67 Number 4
Thrombosis in the newborn
553
Fig. 3. A portion of the infarcted fetal zone of left adrenal. Fetal zone cells can be recognized in spite of calcium precipitation. A small disintegrating thrombus is present at, A. (x170.) infants of diabetic mothers in this group. This m a y be more than a fortuitous association because of the high incidence of adrenal hemorrhage in infants with a history of intrauterine distress and birth trauma. 11' 12 T h e possibility that thrombosis results from a Shwartzman-like reaction in infants with infection has been suggested recently. 13 While sepsis can never be ruled out completely, there was no bacteriologic or morphologic evidence of infection in the 4 cases of p u l m o n a r y emboli of u n k n o w n source nor in 10 of the 13 infants born to diabetic mothers. O u r findings suggest that toxemia and dystocia are associated with venous thrombosis in infants of diabetic mothers and that these factors are equally important in nondiabetic mothers. T h e m a j o r distinction between the two groups is the higher incidence of toxemia and of hydramnios in diabetic mothers. Renal vein thrombosis in two newborn infants was reported by Avery, Oppenheimer, and Gordon 3 who suggested the importance of maternal diabetes and pointed out two similar cases in the literature. One of the
latter was included in a report of 8 autopsled infants of diabetic women. 14 It is pertinent to note also that adrenal hemorrhage was described in another of these 8 infants. I n a review of renal vein thrombosis in the newborn, Takeuchi and Benirschke 4 found 5 of 16 cases in infants of diabetic mothers. An adrenal infarct with small thrombi was present in one case and adrenal hemorrhage in another. There was a history of maternal hypertension in one and maternal hydramnios in another of these five babies. Because hyperplasia of the islets of Langerhans was found in 7 of the 11 remaining infants, they postulated a prediabetic state in these mothers. Of the 32 infants with thrombosis in the present series in w h o m there was no history of maternal diabetes, 2 showed hyperplasia of islet tissue. There was no eosinophilic inflammatory infiltrate. A glucose tolerance test was not performed on these mothers. However, one m o t h e r had a negative urine glucose test 12 years later, and the other was delivered of a 2,250 g r a m term infant the following year; her antepartum urine was negative for glucose.
554
Oppenheimer and Esterly
October 1965
Table IV. Maternal toxemia and thrombosis
Autopsy No.
Birth weight (Kg.)
Age at death
12824
3.5
36 Hours
0
0
1 Adrenal
Fresh
13369
3.0
Stillborn
+
+
1 Kidney
Organizing and calcifying
Autolysis
17997
2.9
19 Hours
+
+
1 Kidney; lung
Fresh
HMD
20781
2.7
Stillborn
0
0
1 Kidney
Organizing, calcifying, and fresh
23907
3.6
28 Hours
+
+
1 Lung
Fresh
24616
3.0
5 Days
0
0
2 Kidneys with 1 infarct
Fresh and organizing
Dehydration
25701
3.9
4 Days
+
0
1 Kidney with infarct; vena cava
Fresh and organizing
Cesarean section
26968
2.5
12 Days
0
0
2 Adrenals
Fresh
CNS hemorrhage
29324
2.1
Stillborn
(I
0.
1 Kidney
Calcifying and organizing
Aneneephaly
29811
5.4
9 Days
+
l)
1 Adrenal with infarct
Calcifying and organizing
(Case reported)
30837
1.7
37 Hours
+
0
Ductus venosus; lung
Calcifying
Slight aspiration pneumonia ; congenital heart disease; vascular ring around trachea
32049
2.5
17 Hours
+
0
I Kidney; lung
Fresh, calcifying, and organizing
Cesarean section; HMD
33243
5.2
4 Days
~
+
2 Kidneys; 1 infarct ; vena cava; innominate artery and aorta
Calcifying and organizing
Prolapse cord, coarctation ; patent ductus
33298
2.7
8 Hours
0
0
Portal vein; lung
Fresh
Cesarean section
33208
0.8
22 Hours
0
0
Lung
Fresh
CNS hemorrhage
I Diabetes HydTamin mother I nios I Site o[ thrombi
T h r o m b o s i s has b e e n r e p o r t e d i n f r e q u e n t l y in r e v i e w s of the p a t h o l o g y of infants of d i a b e t i c m o t h e r s : 3 in 95 cases, 15 n o n e in 25 cases, 16 a n d one i n s t a n c e of a d r e n a l h e m o r r h a g e in 50 cases. 17 I n a r e c e n t r e p o r t of renal vein t h r o m b o s i s in t h r e e n e w b o r n infants, one was b o r n to a d i a b e t i c m o t h e r , a n d a n o t h e r was b o r n a f t e r a p r e g n a n c y c o m p l i c a t e d by t o x e m i a / * SUMMARY I n a r e v i e w of 4,000 c o n s e c u t i v e autopsies of n e w b o r n infants, 45 cases of v e n o u s t h r o m -
Age o[ thrombi
Other [actors
bosis w e r e found. T h e i n c i d e n c e in infants of d i a b e t i c m o t h e r s was 15.8 p e r c e n t (13 of 82 cases) c o m p a r e d to 0.8 p e r c e n t in the r e m a i n i n g cases. I n v o l v e m e n t of the renal a n d a d r e n a l v e i n e a c h r e p r e s e n t e d app r o x i m a t e l y o n e t h i r d of the total t h r o m boses. T h e infants of d i a b e t i c m o t h e r s surv i v e d s h o r t e r periods a n d t h e t h r o m b i in these cases w e r e m o r e f r e q u e n t l y o r g a n i z e d a n d calcified. T h e i m p o r t a n c e of h y d r a m n i o s , t o x e m i a , a n d d y s t o c i a in t h r o m b o s i s is discussed. Sepsis a n d s u r g e r y w e r e a d d i t i o n a l con-
Volume 67 Number 4
Thrombosis in the newborn
555
T a b l e V. B i r t h t r a u m a a n d t h r o m b o s i s
Autopsy No.
Birth weight (Kg.)
Age at death
Diabetes in mother
12858
3.0
8 Days
0
1 Adrenal with infarct
Calcified
13884
4.0
23 Hours
0
1 Adrenal with infarct
Fresh
15387
3.0
2 Days
0
2 Adrenals with infarct
Fresh
Tentorial tear and hemorrhage
16789
2.3
36 Hours
0
1 Adrenal with infarct
Fresh
Cyanotic heart disease
17494
3.5
32 Hours
0
1 Adrenal with infarct; pituitary
Fresh
Pneumonia
19366
4.8
Stillborn
+
1 Adrenal; 1 kidney
Fresh
21967
2.2
5 Days
0
Dural sinus
Fresh
CNS hemorrhage
24753
4.2
Stillborn
+
1 Adrenal
Fresh
Prolapsed cord
25131
3.7
32 Hours
0
2 Adrenals with I infarct; liver; brain
Fresh
Erb's paralysis
28041
4.3
15 Hours
+
1 Adrenal with infarct
Fresh
Intracranial hemorrhage
28522
3.7
5 Days
0
Umbilicus; lung
Fresh
Tentorial tear and hemorrhage ; thrombocytopenia ; omphalitis; sepsis
tributing
factors
in infants
of n o n d i a b e t i c
Sites o[ thrombi
mothers. The photomicrographs for this paper were made by Mr. Raymond Lund.
REFERENCES 1. Ahvenainen, E. K., and Hallman, N.: Thrombosis of deep veins in childhood: I and II, Ann. paediat, Fenniae I: 1, 1954-55; 1: 105, 1954-55. 2. Traggis, D. C., and Ellison, M. M.: Unilateral renal vein thrombosis, J. PEDIAT. 48: 229, 1956. 3. Avery, M. E., Oppenheimer, E. H., and Gordon, H. H.: Renal vein thrombosis in newborn infants of diabetic mothers, New England J. Med. 256: 1134, 1957. 4. Takeuchi, A., and Benirschke, K.: Renal vein thrombosis of the newborn and its relation to maternal diabetes, Biol. Neonat. 3: 237, 1961. 5. Potter, E. L.: Pathology of the fetus and infant, ed. 2, Chicago, 1961, Yearbook Medical Publishers, p. 476. 6. Morison, J. E.: Foetal and neonatal pathology, ed. 2, London, 1963, Butterworth and Co., Ltd., p. 267. 7. Osier, M.: Body water in newborn infants of diabetic mothers, Acta endoerinol. 34: 261, 1960.
"'Age" o/ thrombi T-E fistula; surgical repair of imperforate anus
8. Cheek, D. B., Maddison, T. G., Malinek, M., and Coldbeck, J. H.: Further observations on the corrected bromide space of the neonate and investigation of the water and electrolyte status in infants born of diabetic mothers, Pediatrics 28: 861, 1961. 9. Fee, B. A., and Well, W. B., Jr.: Body composition of infants of diabetic mothers by direct analysis, Ann. New York Acad. Sc. 110: 869, 1963. 10. Osler, M.: Neonatal changes in body composition of infants born to diabetic mothers, Acta endocrinol. 34: 299, 1960. 11. Browne, F. J.: Discussion on stillbirths and neonatal deaths. IV. Neonatal death, Brit. M. J. 2" 590, 1922. 12. Snelling, C. E., and Erb, I. H.: Hemorrhage and subsequent calcification of the suprarenal, J. PEDIAT. 6: 22, 1935. 13. Groniowski, I.: Thrombotic arteriolar lesions in the lungs of newborn, Arch. Path. 75: 144, 1963. 14. Farquhar, J. W.: The child of the diabetic woman, Arch. Dis. Childhood 34: 76, 1959. 15. Driscoll, S. G., Benirschke, K., and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers, Am. J. Dis. Child. 100: 818, 1960. 16. Cardell, B. S.: The infants of diabetic mothers, J. Obst. & Gynaec. Brit. Emp. 60: 834, 1953. 17. Warren, S., and LeCompte, P. M.: The pathology of diabetes mellitus, ed. 3, Philadelphia, 1952, Lea & Febiger, p. 248.
5 56
Oppenheimer and Esterly
18. Stark, H.: Renal vein thrombosis in infancy, Am. J. Dis. Child. 108: 430, 1964. APPENDIX
J. P. was born to a lnother who had previously been delivered of 3 large infants (4.7 kilograms, 4.5 kilograms, and 6.4 kilograms). Five days before her confinement, the membranes ruptured, and she was treated with antibiotics. She had hypertension (150/94-110), and had 3 plus albuminuria with 1 plus pretibial edema. A glucose tolerance test was abnormal (fasting 120 mg. per cent; ~2 hour 252 mg. per cent; 1 hour 225 mg. per cent; 2 hour 153 rag. per cent; 3 hour 99 rag. per cent). The infant was delivered spontaneously and had good color and breathed and cried well. He. weighed 5.4 kilograms and looked edematous. Later he was said to be cyanotic, even with oxygen. On the second day he vomited and became icteric (bilirubin 18.2 mg. per cent, all indirect). He was transferred to The Johns Hopkins Hospital on the third day. Respiration was rapid (88 per minute), but there was no retraction and the hlngs were normal by physical examination and x-ray. The peripheral white blood cell count was 15,800. Blood cultures were negative. Nevertheless, he was treated with antibiotics. Blood chemistries showed glucose, 60 mg. per cent; CO.,, 20 mEq. per liter; C1, 114 mEq. per liter; Na, 166 mEq. per liter; K, 7.1 mEq. per liter; and Ca, 9.4 mg. per cent. The hemawerit was 73 per cent. The bilirubin fell to 10.6 rag. per cent on the fourth day. Following a generalized convulsion the day after admission, a lumbar puncture produced grossly bloody cerebrospinal fluid. Vomiting was persistent. On the twelfth day of life, the infant developed periods of apnea and died despite repeated resuscitative nleasures. The clinical impression was subaraehnoid hemorrhage,
October 1965
possible meningitis and pneumonia, secondary to aspiration. Autopsy (No. 29811) was performed 14 hours after death. The infant weighed 5.4 kilograms. There was excessive pale yellow subcutaneous fat. The lungs were heavy (120 grams) with irregular dark red-brown consolidation in all lobes but especially in the dependent portions. The skull was intact but there was over-riding of the suture lines, with a small subgaleal hemorrhage, and focal areas of hemorrhage in the internal periosteum. The brain weighed 500 grams. There was air extensive subarachnoid hemorrhage. The adrenals were most interesting. The right adrenal weighed 2.5 grams and measured 4 x 2 x 1 cm. Its architectural pattern was normal. The left adrenal weighed 7.5 grams and measured 5 x 2.5 x 1.5 cm. The enlargement was caused hy a 2.5 x l x 1 cm. yellow "tumor" occupying one pole of the gland. It was surrounded by a firm yellow rim with a necrotic center. The other pole of this adrenal had a normal architectural pattern duplicating that seen in the right adrenal. The microscopic appearance of lhe right adrenal and the uninvolved pole of the left ~as normal with nearly complete involution of the fetal zone (Fig. 2). The "tmnor" consisted of an infarct showing a partially calcitied fossilization of a "fetal" adrenal, retaining its wide provisional zone (Figs. 1 and 3). Disintegrating and calcified remnants of thrombi filled the medullary veins of the infarcted portion. No bacteria or fungi could be stained in this lesion. There was extensive acute lobular pneunmnia. Bacterial stains were negative, but hyphae and yeast forms of Candida albicans were identified. The tracheal lumen was filled with masses of this fungus and a culture of heart's blood grew C. albicans. The islets of Langerhans were large and numerous.