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Congenital syphilis
Critical Review CONGENITAL SYPHIL1S PART
I.
~NCIDE.NCE,
TIR.ANS1VLISSIO.N~ AND ])IAG~,!OS~S ~x~
DOI~OT~I~CV. WtalP~L~, M.D., ~ I ) ET~t~L C. DuN~I~,~, M.D., WASm>TGTON, D. C. H I S review includes s u m m a r i e s of the more i m p o r t a n t contributions to the k n o w l e d g e of congenital syphilis t h a t h a v e a p p e a r e d in the T l i t e r a t u r e since the publication of the last discussion of the subject in this jot~rnal. ~a DEFINIT~OIq OF TER~[
The t e r m " c o n g e n i t a l '~ syphilis has been used in this r e p o r t to designate syphilis c o n t r a c t e d b y an i n f a n t before birth. The terlns ' ' eongenital~ ' ' ' ' p r e n a t a l , " and " h e r e d i t a r y " are in more or less comm o n use, but none of them is a l t o g e t h e r satisfactory. The t e r m s "cong e n i t a l " and " h e r e d i t a r y ' ' are f o u n d in the l i t e r a t u r e as e a r l y as 1839, b u t there does not seem to h a v e been a n y clear distinction between t h e m until m u c h later. The t e r m " p r e n a t a l " was used b y K o l m e r a~ as early as ]920.
" C o n g e n i t a l " (congenitus--born t o g e t h e r ) syphilis as used in this r e p o r t is syphilis p r e s e n t in the i n f a n t at birth and acquired f r o m the m o t h e r either b y transmission t h r o u g h the placenta while in utero or d u r i n g passage t h r o u g h the birth ca~al during labor. The disease is, therefore, always p r e s e n t at birth, although it m a y not become maultest until later. There are two objections to the use of the t e r m " c o n g e n i t a l . " ' The first is t h a t it does not indicate t h a t the disease was acquired from the mother, who m u s t necessarily be infected. Other f o r m s of congenital defeets, such as anomalies of the heart, are acquired in utero, b u t t h e y are not necessarily p r e s e n t in the mother. The second objection, which was raised b y both Stokes 5~ and Rietschel, ~~ is t h a t tile t e r m implies an infection acquired at birth, not m e r e l y one p r e s e n t at birth. (This, however, is not the common use of the w o r d as applied to other types of congenital defect.) Stokes ~ considers t h a t " c o n g e n i t a l s y p h i l i s " in the sense of infection acquired d u r i n g labor is rare, and t h a t it r e p r e s e n t s an infection resembling m o r e closely the acquired infection of adults t h a n the o v e r w h e l m i n g tissue invasion and toxemia p r o d u c e d b y t r a n s p l a c e n t a l infection. " P r e n a t a l '~ (prae + natalis--before b i r t h ) is a t e r m i n t r o d u c e d by K o l m e r to indicate t h a t the infection was acquired during i n t r a u t e r i n e life r a t h e r t h a n d u r i n g labor. Thus it answers one objection to the t e r m congenital, but it gives no i n f o r m a t i o n as to the source of the infection. Stokes 55 has accepted this term. " H e r e d i t a r y , " a l t h o u g h often used in the l i t e r a t u r e i n t e r c h a n g e a b l y with " c o n g e n i t a l " or " p r e n a t a l , " is a misleading t e r m because it /~rom
the
Division
of ]~esearch
in Child
Development,
Children's
Bureau,
United
S t a t e s ] D e p a r t m e n t of I~abor, a n d the D e p a r t m e n t of P e d i a t r i c s , School of Medicine, U n i v e r s i t y of P e n n s y l v a n i a . * P a r t I I (to be p u b l i s h e d ) c o n t a i n s t h e r e v i e w of t h e l i t e r a t u r e d e a l i n g w i t h p r e v e n t i o n a n d t r e a t m e n t of c o n g e n i t a l s y p h i l i s . 386
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implies an infection present in either egg or sperm. True h e r e d i t a r y transmission of syphilis m a y be possible, b u t definite proof t h a t it occurs is still lacking. Jeans and Cooke 27 use the terms " h e r e d i t a r y " and " c o n g e n i t a l " interehangeably. They a r g u e that the disease is inherited in the same sense t h a t p r o p e r t y is inherited from a p a r e n t and t h a t the terms do not. necessarily imply participation of the germ p l a s m . This seems an unnecessary confusion of medical and legal terms. INCIDENCE
I n order to estimate the incidence of congenital syphilis in children at the present time and the potential d a n g e r t h a t syphilis m a y be to f u t u r e generations, it is desirable to k n o w the n u m b e r of eases of the disease in the total population. Since the r e p o r t i n g of eases of syphilis is incomplete, statistics on the incidence of the disease in both adults and children are ineomplete and more or less f r a g m e n t a r y . I n 1923 the American Social H y g i e n e Association ~ reported the results of a survey, based on a questionnaire, which showed t h a t 8.3 per cent of a n t e - p a r t u m patients (both white and n e g r o ) in fifteen clinics were syphilitic. I n 1935 the ass6eiation 15 c o n d u c t e d a similar survey in 74 a n t e - p a r t u m clinics and f o u n d t h a t a m o n g 62,516 white women syphilis was present in 6 per cent and t h a t a m o n g 1,708 negro women it was present in 18 per cent. A m o n g the p r i v a t e patients of eightytwo obstetricians the incidence of syphilis r a n g e d from 0 to 3.5 per cent: I n the same y e a r (1935) the a s s o c i a t i o n cooperated in a one-day census of syphilitics which the United States Public Health Service was c o n d u c t i n g in forty-nine representative communities of the United States. 6~ Fi'om this census it was estimated t h a t there are 518,000 new cases of syphilis every year, of which 31 per cent (162,000') are in women. Since m a n y of these women do not receive adequate treatment, the n u m b e r of cases of the disease in an active form accumulates f r o m y e a r to y e a r and at a n y one time there are a p p r o x i m a t e l y 186,000 women in the c o u n t r y suffering f r o m active syphilis. Considering all the cases of the disease both active a n d latent, it was estimated t h a t a p p r o x i m a t e l y one million of the women of the c o u n t r y have or have h a d syphilis and. have had insufficient t r e a t m e n t to p r e v e n t the possibility of transmission of the infection to the child. According' to the 1930 census there are 32,612,792: women in the age group 15 to 49 years, inclusive, and, if one million are syphilitic, then 3 per cent of all women of child-bearing age h a r b o r the infection. I t is interesting to compare this incidence of syphilis of 3 p e r cent in all women with the 6 per cent incidence f o u n d at a p p r o x i m a t e l y the same time b y the questionnaire s u r v e y of white patients in a n t e - p a r t u m clinics. The a n t e - p a r t u m patients represent a selected group in t h a t their exposure to syphilis is p r o b a b l y g r e a t e r t h a n t h a t of other women. The p r o b l e m of syphilis a m o n g p r e g n a n t women is increased when the effect of the infection upon the outcome of p r e g n a n c y is considered. I n almost half the cases of women with u n t r e a t e d syphilis, p r e g n a n c y terminates in the death of the fetus or infant. 33, 39, 89, 62 W h e n the infection in the u n t r e a t e d mother is recent and active, the effects of the disease on the fetus are more u n f a v o r a b l e t h a n when the infection is latent. The Cooperative Clinical Group s f o u n d in a s t u d y of 431 patients t h a t only 57 per cent of the infants born of syphilitic women
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with positive W a s s e r m a n n reactions escaped the infection, as c o m p a r e d with 81 p e r cent of infants b o r n of syphilitic m o t h e r s w i t h n e g a t i v e W a s s e r m a n n reactions. F e t a l deaths c a u s e d b y syphilis occur in the l a t t e r h a l f of p r e g n a n c y , r a r e l y before the fifth month. Syphilis is not a cause of e a r l y abortion, according to m o s t observers, s~ 1 NcCord, 30 however, considers t h a t syphilis m a y be a more f r e q u e n t cause of early f e t a l d e a t h t h a n is now believed. Syphilis not only produces t h e d e a t h of the i n f a n t in utero or of the n e w b o r n child, b u t it p r o d u c e s late m a n i f e s t a t i o n s of the disease in over half of those children who s u r v i v e infancy23, 4o I t seems p r o b a b l e t h a t more t h a n 80 p e r cent of the p r e g n a n c i e s in u n t r e a t e d syphilitic w o m e n end disastrously f o r the infant. I n spite of these f a c t s it is g e n e r a l l y agreed t h a t syphilis does not constitute reason f o r p e r f o r m i n g an abortion since the results of adequate t r e a t m e n t d u r i n g p r e g n a n c y are so satisfactory. ~3 H o w e v e r , Moore thinks t h a t sterilization is socially desirable f o r those prolific w o m e n who are most u n c o o p e r a t i v e concerning the t r e a t m e n t and who h a v e a l r e a d y p r o d u c e d several syphilitic children. The incidence of congenital syphilis in children is even more difficult to determine t h a n t h a t in adults. Because of a general lack of morbidity statistics, concerning t h e disease, data for the whole c o u n t r y are not obtainable, and surveys of isolated groups v a r y m a r k e d l y depending u p o n the composition of the g r o u p s studied. Because of the h i g h m o r t a l i t y f r o m congenital syphilis, the incidence of the disease is g r e a t e r the y o u n g e r the g r o u p studied. The incidence of the disease is higher a m o n g n e g r o t h a n a m o n g w h i t e children a n d varies inversely with the economic levelP 9 F r o m a compilation of reports, in the literature made b y the United States Public ttea]th Service ~s the incidence of congenital syphilis a m o n g all children has been e s t i m a t e d as 2 p e r cent; when these d a t a were r e s t r i c t e d to infants only, the r a t e was 5.6 per cent. Among white children the r a t e is estimated to be 1.7 per cent, but among negro children, 12.2 p e r cent. When tile data were considered in relation to economic status, it was f o u n d t h a t the incidence of congenital syphilis a m o n g white children in clinics was 5.3, whereas a m o n g children of the well-to-do it was less t h a n 1 p e r cent. F r o m the oned a y census the P~iblic H e a l t h Service 59 estimated t h a t of the 683,000 individuals with syphilis c o n s t a n t l y u n d e r observation and t r e a t m e n t in the United States, a t ]east 60,000 were suffering f r o m an infection t r a n s m i t t e d f r o m the parents. ~mtNmulssmhr F o r m a n y y e a r s the literas h a s contained discussions of the m e a n s b y which syphilis is t r a n s m i t t e d f r o m p a r e n t s to children. A t the present time the consensus of opinion in this c o u n t r y is t h a t the usual m e a n s of transmission f r o m a syphilitic m o t h e r to the fetus is t h r o u g h the placenta, even t h o u g h the m o t h e r m a y show no detectable manifestation of the disease. I n f e c t i o n of the fetus p r o b a b l y does not t a k e place before the fifth m o n t h of i n t r a u t e r i n e life, since p e n e t r a t i o n of the p l a c e n t a b y spirochetes before this time has not been d e m o n s t r a t e d . I t is possible, however, f o r f e t a l infection to t a k e place a t a n y time between the f o u r t h and ninth months. ~, a4, ~9 The earlier the placental b a r r i e r is b r o k e n down, the m o r e extensive will be the resulting invasion of the f e t a l tissues and the g r e a t e r will be the chance t h a t the
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result f o r the fetus will be f a t a l either before t e r m or soon t h e r e a f t e r . F e t a l infection late in p r e g n a n c y m a y a c c o u n t f o r the b i r t h of the a p p a r e n t l y h e a l t h y i n f a n t s of u n t r e a t e d syphilitic mothers, m a n y of w h o m are r e p o r t e d to develop the disease m o n t h s or y e a r s a f t e r birth. The old l a w of Kassowitz 2s t h a t the virus of syphilis becomes att e n u a t e d w i t h time and t h a t the infection slowly wears itself out is g r a d u a l l y being discredited as m o r e a n d m o r e r e p o r t s are published in which the disease is shown to be c o n s i d e r a b l y active m a n y y e a r s a f t e r the initial infection. J e a n s a n d Cooke, 27 r e p o r t i n g the f a t e of 3,009 children of 870 syphilitic families, show a r e m a r k a b l e c o n s t a n c y in f e t a l deaths a n d in deaths during e a r l y infancy, r e g a r d l e s s of the duration of the syphilitic infection in the mother. I n g r a h a m 22 studied the relation of the d u r a t i o n of the disease in the m o t h e r to the infection in the offspring and concluded t h a t the difference in the incidence of syphilis in the offspring of syphilitic w o m e n is so little influenced b y the d u r a t i o n of the disease in the m o t h e r t h a t no reliance can be placed upon this criterion f o r prognosis. P a t e r n a l transmission of syphilis is the subject of much discussion23 The t h e o r e t i c a l e x p l a n a t i o n of p a t e r n a l t r a n s m i s s i o n rests u p o n the d e m o n s t r a t i o n of a life-cycle v a r i a n t of the spirochete small enough to adhere to the head of the spermatazoon. No conclusive d e m o n s t r a tion of this h a s as yet been made. The question of the transmission of syphilis to the n e x t generation b y those who themselves acquired the disease in utero (third-generation syphilis) is still debatable a n d will possibly always r e m a i n so. I t is essential to p r o v e t h a t the m o t h e r of a congenitally syphilitic child received her own infection c o n g e n i t a l l y and t h a t she did not acquire syphilis at a n y time d u r i n g h e r life. 7, 44 M a n y r e p o r t s h a v e a p p e a r e d in the l i t e r a t u r e to indicate b e y o n d reasonable d o u b t t h a t t h i r d - g e n e r a t l o n syphilis does occur, a l t h o u g h it is p r o b a b l y n o t a common m e t h o d of t r a n s m i t t i n g the disease. 7, 44, ~, 46 The routine t r e a t m e n t of congenitally syphilitic w o m e n d u r i n g each p r e g n a n c y is a d v o c a t e d b y 1V[oore.~3 DIAGNO'SIS OF COIqG]~NITAL S Y P H I L I S
IN
THE
NEONATAL
PE[RIOD
I n view of the f a c t t h a t it is desirable to t r e a t a syphilitic i n f a n t as soon as possible a f t e r birth, the p r o b l e m of m a k i n g a diagnosis in the e a r l y w e e k s of life is i m p o r t a n t but sometimes difficult, ee I t is possible f o r an i n f a n t at b i r t h to h a r b o r the Spirocheta pallida in his tissues b u t to show no o u t w a r d evidence of the disease. 49 This occasionally occurs in the i n f a n t s of u n t r e a t e d syphilitic women, b u t it occurs w i t h considerable f r e q u e n c y in the i n f a n t s of p a r t i a l l y t r e a t e d syphilitic women, ee There are several procedures in common use for establishing the diagnosis in the fetus or living infant : 1. 2. 3. 4. 5: 6.
D e m o n s t r a t i o n of the disease in the parents. E x a m i n a t i o n of the p l a c e n t a and cord. E x a m i n a t i o n of stillborn infant. Clinical e x a m i n a t i o n of living infant. Serologic tests of the living infant. R oentgenolo~c examination of the bones o2 the living infaa~t.
Demonstration of the Disease in the Parents.--The first step in establishing the p r e s e n c e or absence of the disease in the n e w b o r n i n f a n t is t h a t of establishing its presence or absence in the parents. I t is
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manifestly impossible for an i n f a n t t,o suffer from congenital syphilis if it can be p r o v e d t h a t the disease is absent in both parents. Examination of the Placenta a~d Cord.--The syphilitic placenta is l a r g e r than the normal. It is not its absolute weight t h a t is signficant, however, but its increased weight in p r o p o r t i o n to that of the fetus. N o r m a l l y the placenta weighs one-sixth as much as the fetus, b u t in syphilis it m a y weigh one-fonrth, one-third, or even one-half as much as the entire b o d y weight of the fetus. Williams ~ believed t h a t certain changes in the placenta were pathognomonic of syphilis and t h a t these changes f o r m e d a basis for a diagnosis of congenital syphilis in 80 to 90 per cent of infants. L a t e r reports have pointed out difficulties in m a k i n g a positive diagnosis in the i n f a n t on the basis of histologic changes in the placenta. I n g r a h a m and Kahler, 2~ for example, state t h a t the demonstration of syphilis in the placenta indicates only a maternal infection and is not synonymous with infection of the infant. Jeans and C o o k e y on the other hand, state that. in t h e i r opinion it is v e r y doubtful if characteristic changes in the placenta can be found in the absence of syphilis in the infant, l~eCord in 1928 a7 stated t h a t a histologically syphilitic placenta means a syphilitic baby but that the converse is not true. McCord concluded in 1934 as that the histologic examination of a syphilitic placenta, especially in a p r e m a t u r e birth, is laden with so m a n y difficulties t h a t it is not of g r e a t practical value as a routine method of determining congenital syphilitic infection. ]Examination of the umbilical vein has proved a valuable means of detecting syphilis. Philipp and Gornick ~s examined scrapings of the umbilical vein b y d a r k field and f o u n d that they could f r e q u e n t l y demonstrate spirochetes in the umbilical vein b y this m e t h o d even when the placenta was morphologically negative for syphilis. They f o u n d spirochetes in the umbilical vein wall in 5 of 15 dead syphilitic infants from mothers whose placental findings were negative and in 5 of 9 living infants who had negative blood Wassermann reactions. K l a f t e n a~ used the same method and considers it a valuable p r o c e d u r e in m a k i n g a diagnosis of early congenital syphilis. I n g r a h a m ea also r e p o r t e d results of dark-field examinations of scrapings from the umbilical veins of 86 unseleeted infants of syphilitic mothers. Spirochetes were f o u n d in 24 fetuses (5 stillborn and 19 living infants). All but 2 of the 24 i n f a n t s were u l t i m a t e l y p r o v e d to be syphilitic. The finding of spirochetes in the umbilical-vein examinations was the earliest diagnostic evidence of syphilis obtainable in :10 of the 24 infants. In 18 of the 86 cases in which the umbilicalvein scrapings were negative b y dark-field examination, proof of syphilis was subsequently obtained b y other means. I n g r a h a m 2a concluded t h a t the dark-field examination of the umbilical vein is a valuable diagnostic aid in the early detection of syphilis in the asymptomatic infant. W h e n the result of the examination is positive, the i n f a n t has syphilis in almost 100 per cent of the cases, but when negative, syphilis in the i n f a n t is not, of course, excluded. Examination of the Stillborn Infant.--Syphilis is one of the causes of intrauterine death, and, i f the fetus is retained within the uterus, it undergoes rapid deterioration and presents the characteristic picture of maceration when finally e x p e l l e d Y Maceration, however, is not
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pathognomonic of syphilis. Stokes 55 states t h a t " S t r a c h a n could only find 6 syphilitic fetuses among 24 m a c e r a t e d specimens, and K e h r e r f o u n d syphilis the cause of m a c e r a t i o n in 41.3 per cent of his cases. On the other hand, Tenconi f o u n d 80 per cent of macerated fetuses to be syphilitic, and Browne f o u n d 64= per cent in a careful s t u d y of 22 cases." The pathologic picture presented b y syphilis is one in which all of the tissues are involved. The most common t y p e of early change is a diffuse inflammatory hyperplasia, and in general the amount of change is in relation to the function of the p a r t d u r i n g fetal growth, n ' 54 The spleen, liver, and bones suffer g r e a t e r damage than other organs. The spleen becomes enlarged; the liver is r e t a r d e d in development so that at birth there is f r e q u e n t l y persistence of embryonic cells. Occasionally the k i d n e y shows a similar arrest in development. 21, 27, 55 The pancreas shows a widespread fibrosis with a r e t a r d a t i o n in development. The characteristic syphilitic lesion in the lmag is fibrosis with the p r o d u c t i o n of irregular, firm elastic patches (pneumonia alba). 27 Adair 2 finds a t e n d e n c y to a persistence of the nephrogenic zone in the k i d n e y of the congenital syphilitic. The most conclusive diagnosis of syphilis can, of course, be made b y the actual demonstration os the Sp4rocheta pallid'c~ in the tissues. Adair 2 f o u n d spirochetes in the tissue in 41 of 46 syphilitic fetuses; Browne, 8 in 8 of 14 m a c e r a t e d fetuses but in only 1 of 21 n o n m a c e r a t e d syphilitic fetuses. Cruickshank's findings *~ were similar in t h a t he f o u n d spirochetes in 7 0f 9 m a c e r a t e d fetuses but in only 10 of 116 n o n m a c e r a t e d syphilitic fetuses. The g r e a t e r ease with which the organisms can be f o u n d in macerated fetuses m a y be due to the incubator effect of the uterus. Stokes 55 thinks t h a t spirochetes m a y multiply r a p i d l y in dead tissue u n d e r conditions simulating those in the uterus and suggests t h a t these findings j u s t i f y the incubation o2 organs of fetuses suspected of syphilis in the hope of demonstrating spirochetes. McCord, a6 however, finds it more difficult to demonstrate spirochetes either b y dark-field examination or in stained sections when the fetus is macerated. Jeans and Cooke 27 r e p o r t t h a t spirochetes disintegrate a f t e r death and f r e q u e n t l y disappear completely within a day or two a f t e r the death of the fetus. Clinical Examination of the Living Infant.--Clinical signs of syphilis are obvious at birth in only a small p e r c e n t a g e of syphilitic infants, ea W h e n signs and symptoms occur, the most common are snaffles, skin lesions, eye lesions, splenomegaly, ] y m p h a d e n o p a t h y , malnutrition, gastrointestinal disturbances, intracranial hemorrhage, and pseudoparalysis of Parrot. ~ While m a n y of these signs are very suggestive of syphilis and should always arouse suspicion of the presence of the disease, t h e y are not pathognomonie of syphilis and almost all are occasionally encountered in infants entirely free from syphilis. 2~ I n g r a h a m ua listed the most characteristic signs of syphilis and recorded their incidence in the syphilitic and nonsyphilitic infants of 212 syphilitic mothers. He f o u n d t h a t up to the age of 2 months definite obstruction to nasal breathing indicated syphilis in 88 per cent of the infants who showed this sign, splenomegaly in 71, bilateral epitrochlear l y m p h a d e n o p a t h y in 51, m a r k e d scaling and fissuring of the skin at b i r t h in 65, and syphilitic skin lesions and pseudoparalysis of P a r r o t in 100 per cent.
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In view of the fact that m a n y syphilitic infants show no clinical evidences of the disease in early infancy, I n g r a h a m 23 concludes t h a t f r o m p u r e l y clinical studies the diagnosis of syphilis c a n n o t be made with any degree of c e r t a i n t y in the first 2 months of life in as m a n y as 5 per cent of the cases. I f it is k n o w n 2a, 12 t h a t the m o t h e r is syphilitic, the presence of coryza, splenomegaly, unexplained malnutrition, or gastrointestinal disturbances, or continued fever of undetermined etiology should lead to the suspicion t h a t the i n f a n t is syphilitic. A diagnosis of syphilis in the child must, however, be confirmed by other means. ~1 Roberts ~1 found clinical signs of syphilis in 27 per cent of 237 syphilitic infants at birth. Syphilis could be diagnosed b y elinieal signs alone in 82 per cent b y the age of 3 months. Spirochetes have been d e m o n s t r a t e d in various tissues and secretions of the living syphilitic infant. T h e y are f r e q u e n t l y f o u n d in the nasal and tile con junetival secretions, in skin lesions, in the blood stream, in the urine, and in the meeonium. 2~ Nianteufel and t t e r z b e r g 42 have diagnosed congenital syphilis in obscure eases by inoculating either cubital or i.nguinal lymph gland emulsion into rabbits. Serologic Diagnosis.--The value in the diagnosis of syphilis of serologic tests (Wassermann or K a h n ) of the umbilical-cord blood or the venous blood of the n e w b o r n i n f a n t has been questioned. Fildes ~ first pointed out t h a t antibodies p r e s e n t in the m o t h e r ' s blood might be t r a n s m i t t e d t h r o u g h the p l a c e n t a and appear transiently in both the cord blood and the blood of the i n f a n t in tile absence of syphilis. In spite of m a n y studies ~, 40. ~s which have substantiated Fildes' original view, the recent literature eontMns such statements as lYreCord's ~9 that " i n the vast m a j o r i t y of cases, a strongly positive cord Wassermann test, p r o p e r l y done, means t h a t the baby has congenital s y p h i l i s , " or Collardi's 9 that " t h e W a s s e r m a n n reaction of the blood of the umbilical cord o~ the n e w b o r n has a. distinct diagnostic value when positive, for it absolutely indicates fetal syphilis." Ingraham 23 has tabulated, in a series of 195 infants, the various combinations of positive and negative cord-blood findings with the ultimate diagnosis in the i n f a n t with r e g a r d to syphilis. He f o u n d t h a t the serologic reaction of the cord blood c o r r e c t l y predicted the condition of the i n f a n t in 64 per cent of the eases and failed to do so in 36 per cent. In those cases in which the cord blood was positive, 83 per cent of the infants developed syphilis, and 17 per cent remained free from all evidence of the disease. In those cases in which the cord blood was negative serotogically, 60' per cent remained free f r o m infection but 40: per cent developed syphilis. On the basis of this s t u d y it appears t h a t the statement that a positive W a s s e r m a n n reaction of the c o r d blood is an absolute diagnostic sign of syphilis in the i n f a n t is not t r u e f o r about 15 per cent of the cases, and the statement t h a t a negative W a s s e r m a n n reaction of the cord blood g u a r a n t e e s a nonsyphilitic i n f a n t is not true for about 40 per cent of the cases. Ki]duffe ~9 states t h a t a positive cord-blood reaction is of value only as indicating f u r t h e r need for, and prolonged study of, the case. J e a n s 26 maintains t h a t results of serologic examination of the inf a n t ' s blood are of absolute diagnostic value a f t e r two months of life
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have passed. Other observers have r e p o r t e d cases in which the blood hag remained seronegative for six months or longer and has then become positive. 23 In nonsyphilitic infants the positive serology seldom persists for as long as two months and usually for a much shorter time. Twenty-two syphilitic infants r e p o r t e d by I n g r a h a m to have positive blood Wassermann reactions at birth developed negative blood W a s s e r m a n n reactions before leaving the hospital at 10 days of age. D u n h a m 13 studied the W a s s e r m a n n reaction of the mother"s blood, the cord blood, and the blood of the i n f a n t in a series of seven cases in which there were no clinical evidences of syphilis in the infants at birth. All of the infants at birth had positive blood Wassermann reactions, but in all seven eases there was g r a d u a l weakening of the reaction until at the end of six months six of the infants had negative reactions. The seventh was not tested until the end of a year, at which time it had a negative reaction. The W a s s e r m a n n reactions were repeated at intervals for a period v a r y i n g between two months and f o u r years, and the tests continued to be negative and no clinical evidences of syphilis developed in any of the infants. F a b e r and Black 16 also studied a group of infants of syphilitic mothers, using a quantitative method for making the Wassermann test. They r e p o r t e d t h a t nonsyphilitie infants with positive Wassermann reactions at birth show a gradual w e a k e n i n g of the reaction until it finally becomes negative, whereas the reactions of syphilitic infants usually show an increasi~g intensity during" t h e same period. I t was f o u n d t h a t by the use of a quantitative technique a change in intensity of the W a s s e r m a n n reaction was usually detectable during the first week of life, and it was suggested t h a t such a change might prove a sufficient basis f o r diagnosis. Christie, 5 using' the quantitative W a s s e r m a n n technique, confirmed the findings of F a b e r and Black. Tests of the cord blood of 14 infants of syphilitic mothers were positive in all but one ease in which the specimen hemolyzed. Quantitative W a s s e r m a n n tests of the blood repeated at intervals t h e r e a f t e r showed a gradual diminution in intensity until t h e y ultimately became negative in 11 infants, none of whom showed a n y evidence of syphilis clinically or in roentgenograms of the long bones. Three of the 14 infants u l t i m a t e l y developed evidences of syphilis. In 2 of the 3 cases the intensity of the Wassermann reaction increased at each examination until other evidence of syphilis appeared. The t h i r d ease was an exception since the blood showed a lessened reaction a f t e r the first examination, only to increase a.fter the development of clinical signs of syphilis. The work of Christie suggests that a comparison of the results of quantitative, serologic examinations of the cord blood and the i n f a n t ' s blood m a y p r o v e valuable in the differentiation of the pseudopositive b u t clinically well infant from the syphilitic i n f a n t at an earlier age than has h e r e t o f o r e been possible. Roentgenologic Examination of the Bones.--Syphilis produces changes in developing bones which are usually recognizable roentgenograpbieally. The r o e n t g e n o g r a p h i e m e t h o d of diagnosis has been in use for thirty-five years. In spite of this long period of use, however, there still exist differences of opinion concerning the specific changes produced in the bone b y the disease and those which r e p r e s e n t the earliest manifestations of these changes in the roentgenogram.
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In order to understa~ld the changes in bone due to syphilis the underlying p a t h o l o g y must. be appreciated. F r o m pathologic studies 47 it has been shown clearly that congenital syphilis produces a fibrosis in developing bone which soon i n t e r f e r e s with the blood supply, causing the formation of granulation tissue. Increased calcium deposition takes place within this granulation tissue without subsequent ossification. A f t e r .granulation tissue has replaced normal vascular areas there m a y be actual pus f o r m a t i o n with easeation and softening. Thus the syphilitic process in bone is characterized by both proliferation and destruction of tissue. 4~ Ill the r o e n t g e n o g r a m this p r o l i f e r a t i o n and destruction of tissue gives the appearance of areas of increased density and of rarefaction. 4. The pathologic changes seen in the r o e n t g e n o g r a m are most m a r k e d in the areas of greatest bone growth, namely, the diaphyso-epiphyseal junctions and the periosteum, producing, respectively, osteochondritis and periostitis. 47 0steochondritis is a v e r y f r e q u e n t lesion of early congenital syphilis. It has been f o u n d present at birth and during the later months of i n t r a u t e r i n e life also. The incidence of the condition decreases as the age of the children examined increases. Periostitis, on the other hand, is a lesion which develops later, usually between the second and fifth months of life. 24 I n g r a h a m 24 eoneludes from his own studies: " W e feel t h a t we m a y assume with a reasonable degree of a c c u r a c y that syphilitic osteoehondritis, other things being equal, becomes roentgenologically manifest about five weeks a f t e r the fetus is infeeted, while syphilitie periostitis requires a p p r o x i m a t e l y four months to develop." IIe believes t h a t it is pgssible to approximate the time of infection of the child or fetus f r o m the stage of the osseous lesions. Aeeording to Ingraham, most syphilitic fetuses are infected in the later months of p r e g n a u e y and are either born with lesions of osteochondritis or develop them within a short period a f t e r birth. Periostitis does not usually develop until the f o u r t h to fifth month a f t e r infection. It is not impossible f o r a fetus to acquire sypMlis early in p r e g n a n c y (any time a f t e r the fifth m o n t h ) , suffer f r o m osteochondritis, and recover f r o m it before birth. The r o e n t g e n o g r a m at birth m a y appear normal b u t later m a y show evidence of periostitis as the first manifest lesion of the disease. 0eeasionally periostitis is f o u n d unassociated with other osseous lesions (5 per cent in lKcLean's 41 series). In such eases I n g r a h a m feels t h a t the osteochondritie process has healed r a t h e r than that it did not exist. I t is, however, more usual to find periostitis accompanying other lesions, especially osteoehondritis. Epiphysitis is f r e q u e n t l y present in the r o e n t g e n o g r a m of syphilitie infants, according to P e n d e r g r a s s and Bromer. 47 0steoehondritis, periostitis, diaphysitis, and epiphysitis are the bone lesions commonly associated with syphilis in the newborn infant. Osteoehondritis does not produce p e r m a n e n t d e f o r m i t y and, in fact, disappears spontaneously without treatment. Sutherland and MitehelP 6 suggest t h a t it is a secondary lesion because of its ephemeral eharaeter. All the bone lesions of early congenital syphilis are widespread in their distribution. P r a e t i e a l l y all the bones, or v e r y few, m a y be affected, although a single bone lesion is n e v e r due to syphilis. 41 The process is not necessarily uniform although multiple involvement is, present. 47 V e r y mild involvement m a y be present in one bone while an e x t r e m e l y
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severe process exists in another. Thus an e x a m i n a t i o n of the entire skeleton is desirable before ruling out syphilis. 47 M c L e a n 4~ f o u n d t h a t bone i n v o l v e m e n t is usually bilateral. The syphilitic process is not the only pathologic one which alters developing bone tissue. A good deal of d i s a g r e e m e n t has arisen over the i n t e r p r e t a t i o n of certain t r a n s v e r s e lines of increased density n e a r the d i a p h y s o - e p i p h y s e a l junction. P e n d e r g r a s s and B r o m e r 47 h a v e described t r a n s v e r s e b a n d s in syphilitic bone. Their explanation of the m e c h a n i s m of f o r m a t i o n of the b a n d is t h a t i r r e g u l a r interference with g r o w t h b y the syphilitic process p r o d u c e s areas of calcification b e y o n d the d e g e n e r a t e p o r t i o n and f o r m s t r a n s v e r s e zones of provisional calcification at different levels. K l a f t e n and P r i e s e P ~ consider t r a n s v e r s e zones in bones to be evidence of successive a t t a c k s of osteoehondritis and correlate t h e m with the time of b e g i n n i n g syphilitic t r e a t m e n t in the mother. They r e p o r t t h a t the earlier the t r e a t m e n t begins, the f u r t h e r the bands have m o v e d in the direction of the diaphysis; the later the treatment, the less the distance of the bands f r o m the ends of the metaphysis. There are p r o b a b l y several mechanisms in addition to syphilis by which these lines are formed. Caffey 4 has shown t h a t bismuth a d m i n i s t e r e d to a w o m a n d u r i n g p r e g n a n c y passes t h r o u g h the p l a c e n t a and is deposited in the long bones in t r a n s v e r s e lines n e a r the d i a p h y s o - e p i p h y s e a l junction. H e states t h a t t h e r e is not enough bismuth deposited in the i n f a n t ' s bone to account e n t i r e l y for the shadow cast in the r o e n t g e n o g r a m . An increased calcium content, induced a p p a r e n t l y b y the presence of a small a m o u n t of bismuth, is responsible for this line, according to Caffey. Before the a d v e n t of b i s m u t h t r e a t m e n t for syphilis Eliot, Souther, and Park, ~ in making roentgenologic studies of children for rickets, observed transverse lines in the bones of these children. They concluded that these lines a p p e a r when for some reason the growth of cartilage is suddenly slowed or stopped and that, conversely, sudden increase in growth produces areas of r a r e f a c t i o n in the long bones. I t seems possible t h a t this m a y be the basic physiologic explanation of all t r a n s v e r s e lines. T h a t is, some f a c t o r i n t e r f e r e s with the n o r m a l g r o w t h of the bone and as a result the t r a b e c u l a e develop l a t e r a l l y instead of vertically, causing an o v e r l a p p i n g a n d lattice f o r m a t i o n with an i n e r e a s e j n p r i m a r y bone formation. This i n t e r f e r e n c e with g r o w t h m a y be due to a m l t r i t i o n a l factor, a d r u g such as bismuth, a poison such as lead, or an infective a g e n t such as the Spirocheta pallida. I f this is true, it m a k e s the diagnosis of syphilis based on an i n t e r p r e t a tion of roentgenographic findings in the bones of newborn infants a difficult procedure. N u m e r o u s r e p o r t s dealing with the relation between the roentgenographic findings and other m a n i f e s t a t i o n s of syphilis have alJpeared. M a n y of t h e m are difficult to i n t e r p r e t because full i n f o r m a t i o n in r e g a r d to findings is not always given. In 14 r e p o r t s ~1 made between 1921 and 1937 the incidence of bone lesions in cases of congenital syphilis v a r i e d f r o m 23 per cent to 100 p e r cent. McLean, 4~ f o r example, f o u n d bone lesions u n i f o r m l y p r e s e n t in a r o e n t g e n o g r a p h i e s t u d y of 102 syphilitic infants and t h o u g h t t h e y were the earliest detectable m a n i f e s t a t i o n of the disease.
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Ingraham 24 states that the roentgenogram offers the most reliable means of diagnosis of syphilis in early infancy. He found t hat 29.1 per cent of the infants of his series showed characteristic roentgenologic changes during the first week of life, and that 78.8 per cent of the 90 syphilitic infants showed bone lesions in the roentgenogram during the first few months of life. Christie, 6 on the other hand, found the roentgenogram of help in diagnosing congenital syphilis in the neonatal period in only 2 of 83 eases. I t is difficult to come to any conclusions concerning the usefulness of the roentgenogram in the early diagnosis of congenital syphilis from a study of the published reports. F[eLean 41 describes the following changes in the roentgenogram as pathognomonic of syphilis: (a) Well-defined saw-tooth metaphyses in well-calcified bones; (b) deep zones in the longitudinal axis of submetaphyseal rarefaction; (e) multiple separation of epiphyses with or without impaetion in bones which are not rachitie; (d) bilateral symmetrical osteomyelitis of the proximal mesial aspects of tibia; (e) multiple areas of circumscribed osteomyelitis of long bones shown by the roentgen ray as patchy areas of rarefaction; (f) multiple longitudinal areas of rarefaction (osteomyelitis) in the shafts of the long bones, sometimes resulting in fractures; (g) destructive lesions at the mesial or lateral aspects of the metaphyses (foci of rarefaction) ; (h) multiple areas of cortical destruction generally seen within a centimeter of the ends of the bones; (i) double zone of rarefaction at ends of bones; (j) localized periosteal cloaking occurring in more than one bone. These lesions are all those of advanced syphilis and are quite generally accepted as pathognomonic of syphilis. The controversy arises over the early signs of pathology and their differentiation from those produced by agents other than syphilis. The changes that are most likely to cause confusion in establishing the positive diagnosis of syphilis by the roentgenogram are (a) submetaphyseal rarefaction produced by very rapid growth; 14, 41 (b) transverse bands near the diaphyso-epiphyseal junction produced by nutritional disorders which temporarily slow up or stop bone growth; .4 (e) transverse bands formed by the administration of bismuth to the mother during pregnancy. Occasionally these bands are so dense that the bone immediately distal to them has by contrast a rarefied appearance;4 (d) apparent thickening of the cortex of the bones of very rapidly growing premature infants. The more rapid calcification of the periostemn than of the shaft may be confused with syphilitic periostitis. It is usually more regularly distributed along the length of the bone framework than is the periostitis of congenital syphilis. 4., ~ After a review of the available literature one is forced to conclude that the diagnosis of congenital syphilis in the newborn infant is often extremely difficult. I~EFER.ENCES 1. Adair, F . J . : Some Remarks on the Relationship of Syphilis to Abortion, Miscarriage, and F e t a l Abnorma]itles, Am. J. Obst. 78: 678~ 1918. 2. Adair~ F . L . : Syphilis of the Fetus and N e w b o r n I n f a n t , Am. J. Obst. & Gynec. 23" 11:1, 1932. 3. Brown% Francis J.: Stillbirth: I t s Causes, Pathology, and Prevention, Brit. ]Y[. ft. 2: 140, 1921. 4. Caffey~ John: Changes in the Growing Skeleton A f t e r the Administration of Bismuth, Am. ft. Dis. Child. 53: 56, 1937.
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5. Christie, Alnos U.: The Diagnosis of Syphilis in Newborn Infants. Use of Quantitative Wassermann Test as a Method of Study. In press. 6. Christie, Amos If.: The Value of Roentgen Examination in the Diagnosis of Infantile Congenital Syphilis. Unpublished manuscript. 7: Clark, J. C.: Third-Generation Syphilis, J. A. M. A. 109: ]038, 1937. 8. Cole, ]:Iarold N., and others: Syphilis in pregnancy, Ven. Dis. Inform. 15: 83, 1934. 9. Collard:, F r a n c e : On the Specificity of the Seroreaetion According to Wasserm a n n and :Miiller in Obstetrics, Ann. di ostet, e ginec. 51: ]368, 1929. 10. Crulckshank, J. T.: M a t e r n a l Syphilis as a Cause of D e a t h of the Foetus and of the Newborn Child. Medical Research Council, Great Britain, Special Report Series No. 82, pp. 67, 1924. 11. Davidsohn, It.: Congenital Syphilis, Ztschrft. f. i~rztl. ]~'ortbild. 22: 390, 1925. 12. Dennie, C. C.: Some Phases of Congenital Syphilis, J. I~ansas M. Soc. 34: 170, 1933. 13. Dunham, E. C.: The Diagnosis of Congenital Syphilis in the Newborn, Am. J. Dis. Child: 43: 317, 1932. 14. Eliot, lVL M., Souther, S. P., and P a r k , E. A.: T r a n s v e r s e Lines in X-Ray P l a t e s of the Long Bones of Children, Bull. J o h n s Hopkins Hosp. 41: 364, 1927. 15. Exner, Max J.: Syphilis in Pregnancy, J. A. M. A. 106: 488, 1936. /6. Faber, H. K., a n d Black, W . C . : Q u a n t i t a t i v e W a s s e r m a n n Tests in Diagnosis of Collgenital Syphilis, Am. J. Dis. Child. 51: 1257, 1936. 17. Fildes, P a u l : The Prevalence of Congenital Syphilis Amongst the Newly Born of the E a s t E n d of London, J. Obst. & Gynaec. Brit. Emp. 27: 124, 1915. 18. Fordyce, J. A., a n d Rosen, I.: L a b o r a t o r y F i n d i n g s in E a r l y and Late Syphilis, J. A. IV[. A. 77: 1696, I92L 19. Gr~fenberg, Dr.: The Influence of Syphilis on Posterity, Arch. f. Gyn~k. 87: 190, 1909. 20. H o f m a n n , E.: E a r l y Diagnosis of Congenital Syphilis, Deutsche reed. Wchnschr. 49: 753, 1923. 21. Holt, L. Emmett~ a n d Howland, J o h n : Diseases of I n f a n c y and Childhood: A T e x t b o o k for the Use of S t u d e n t s and P r a c t i t i o n e r s . Revised b y L. E m m e t t tIolt~ Jr., and Rustin McIntosh, ed. 10, New York, 1933, D. Appleton-Century Company, Inc., pp. 1240. 22. Ingraham~ N . R . : The Diagnosis of I n f a n t i l e Congenital Syphilis During the Period of Doubt, Am. J. Syph. & Neuroh 19: 54:7, ]935. 23. Ingraham~ /q. R.: Roentgen-Positive Serouegative I n f a n t i l e Congenital Syphilis, Am. J. Dis. Child. 50: 144:4:, 1935. 24:. I n g r a h a m , N. R.: The Lag P h a s e in E a r l y Congenital Osseous Syphilis, Am. J. M. Sc. 191: 819, 1936. 25. I n g r a h a m , N. R., J r , a n d Kahler, J. E.: The Diagnosis and T r e a t m e n t of Syphilis Complicating Pregnancy, Am. J. Obst. ~ Gynec. 27: 134:, 1934. 26. Jeans, P. C.: I-Iereditary Syphilis, P e n n s y l v a n i a M. J. 33: 47, 1929. 27. Jeans, P. C, a n d Cooke, J. V.: P r e p u b e s c e n t Syphilis, New York, 1930, D. A p p l e t o n - C e n t u r y Company, Inc., pp. 295. 28. Kassowitz, M.: I n h e r i t a n c e of Syphilis, Med. J a h r b u c h e r red. yon. S. Stricker, Wien, 1875, pp. 359-4:95. 29. Kilduffe, R . A . : The Serology of Congenital Syphilis, J..M. See. New J e r s e y 27: 973, 1930. 30. I~laften, E.: Diagnosis, Prophylaxis, and T h e r a p y of Congenital Syphilis, Z e n t r a l b h f. Gyn~k. 49: p a r t ], 30, 1925. 31. K l a f t e n , E., and Priesel, R.: F u r t h e r Research on Bone Changes in Congenital Syphilis, Fortschr. a. d. Geb. d. R 5 n t g e n s t r a h l e n 4:7: 59, 1933. 32. I(olmer, J o h n A.: P r e n a t a l Syphilis, W i t h a P l e a for I t s Study and Prevention, Am. J. Dis. Child. 19: 344, 1920. 33. Laurent, C.: P r o p h y l a x i s of H e r e d i t a r y Syphilis, Urol. & Cutan. Rev. 33: 24:2, 1929. 34. Levaditi, C., Goldman, M , and Rousset-Chabaud (Mme.): 5Ieehanism of H e r e d i t a r y Syphilitic Infection, Compt. rend. Soc. de biol. 120: 854, 1935. 35. Lombardo, C.: Pathogenesis of Congenital Syphilis, Gior. ital. dl dermat, e sif. 67: 187, 1926. 36. MeCord, J. R.: Two H u n d r e d and F o r t y - T h r e e F e t a l Autopsies~ J. A. M. A. 88: 626~ 1927.
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37. MeCord, J . R . : The Results of T r e a t m e n t of Syphilis in P r e g n a n t Women: Influence E x e r t e d b y Such T r e a t m e n t in the tIistologic Appearance of t h e Placenta, South. M. J. 21: 229, 1928. 38. McCord, J. R.: Syphilis of the P l a c e n t a : The Iiistologic E x a m i n a t i o n of 1,085 P l a c e n t a s of )/[others W i t h S t r o n g l y Positive Blood W a s s e r m a n n Reactions, Am. J. Obst. & Gynec. 28: 743, 1936. 39. ~IcCord, J . R . : Syphilis a n d P r e g n a n c y : A Clinical Study of 2,150 Cases, J. A. M. A. 105: 89, 1935. 40. McI~elvey, J. L , and Turner, T . B . : Syphilis a n d Pregnancy. An Analysis of the Outcome of P r e g n a n c y in Relation to T r e a t m e n t in 963 Cases, J. A. M. A. 102: 503) 1934. 41. 1YIcLean, Stafford: The Osseous Lesions of Congenital Syphilis, Am. J. Dis. Child. 41: 1611, ]931. 42. Manteufel, P., and tterzberg, I<.: P r o o f of Virus b y the I n j e c t i o n of Glands Into a L i v i n g Congenitally Syphilitic, Dermat. Ztschr. 56: 340, 1929. 43. Moore, J. E.: The ~r T r e a t m e n t of Syphilis, Springfield, Ill., 1933, Charles C. Thomas, pp. 535. 44. N a b a r r o , David: Third-Generation Syphilis, Brit. J. Ven. Dis. 9: 1, 1933. 45. P a r k e r , Valeria I-I.: A S t u d y of P r e n a t a l Clinics W i t h Special Reference to the Diagnosis and T r e a t m e n t of Syphilis in the P r e g n a n t Woman, IV[. W o m a n ' s J. 34: 330, 1927. 46. Paterson, D. I-I.: T r a n s m i t t e d Congenital Syphili% Brit. J. Child. Dis. 17: 197, 1920. 47. Pendergrass, E. P , a n d Bromer, R . S . : Congenital Bone Syphilis. P r e l i m i n a r y Report; Roentgenologle S t u d y W i t h Notes on the Histology a n d P a t h o l o g y of the Condition. Am. J. Roentgeno]. 22: 1, 1929. 48. Phi]ipp, E , and Gornick, P.: Diagnosis of Syphilis b y ~r of Darkfield E x a m i n a t i o n of Umbilical Vein, Zentralbl. f. Gyn~k. 50: 1811, 1926. 49. Podlasky, It. B., and Enzer, N.: The C o m p a r a t i v e Value of the Serologic and Roentgenologie Diagnoses of Cengenital Syphilis, Radiology 20: 337, 1933. 50. Rietschel, 1Sans: General P a t h o l o g y of Congenital Syphilis. In J a d a s s o h n ' s t t a n d b u c h der ]-[aut- u n d G e s c h l e e h t s k r a ~ k h e l t e n 19: ], 1927. 51. Roberts, M. Itines: Congenital Syphilis, Am. J. Dis. Child. 45: 461, 1933. 52. Rosenbaum, Karold A., a n d Faulkner, I-Iarry L.: T h i r d Generation Syphilis, J. PEDIA'r. 7: 797, 1935. 53. Round Table Conference on Syphilis, J. PEDIAT. 6: 262, 1935. 54. Schneider, P.: Changes in the Organs in Congenital E a r l y Syphilis, Centralb]. f. allg. P a t h . u. path. Anat. 43: 11~ 1928. 55. Stokes, J o h n H.: Modern Clinical Syphilology, ed. 2, Philadelphia, .]936, W. B. Saunders Company, pp. 1400. 56. Sutherland, G. )~., and Mitchell, J. If.: Effects of T r e a t m e n t on Bone Lesions in Syphilis, J. A. M. A. 81: 1752, 1923. 57. Thomson, Christine J.: The P a t h o l o g y of Foetal 5/[aceratien, J. Obst. & Gynaec. Brit. Emp. 34: 40, 1927. 58. U. S. Public I-Iealth Service, Proceedings of Conference on Venereal Disease Control Work, Dec. 28-30, 1936. Supp. No. 3 to Ven. Dis. Inform., pp. 154, Washington, 1937. 59. Usilton, Lida J.: Syphilis in ~/fothers a n d Children in the U n i t e d States~ Med. W o m a n ' s J. 44: 164, 1937. 60. Usilton, Lida J.: T r e n d of Syphilis a n d Gonorrhea in the U n i t e d States. Based on Treated Cases, Ven. Dis. Inform. 16: 147, 1935. 61. Whipple~ D. V., and Dunham, E. C.: Congenital Syphilis; Review of the Literature. To be published b y the U n i t e d S t a t e s Children's Bureau. 62. White, P. J., and Veeder, Borden S.: A S t u d y of 443 Cases of t I e r e d i t a r y Syphilis W i t h Especial Reference to Results of Treatment, Am. J. Syph. 6: 353, 1922. 63. Wile, Udo J., and Shaw, J. W.: The P r e n a t a l T r e a t m e n t of Syphilis W i t h Especial Reference to E a r l y Syphilis in the Mother, J. A. M. A. 95: 1791, 1930. 64. Wi]liams, J . W . : The Value of the W a s s e r m a n n Reaction in Obstetrics, Based Upon the S t u d y of 4,547 Consecutive Cases, Bull. J o h n s Hopkins Itosp. 31: 335j 1920.
I.
~NCIDE.NCE,
TIR.ANS1VLISSIO.N~ AND ])IAG~,!OS~S ~x~
DOI~OT~I~CV. WtalP~L~, M.D., ~ I ) ET~t~L C. DuN~I~,~, M.D., WASm>TGTON, D. C. H I S review includes s u m m a r i e s of the more i m p o r t a n t contributions to the k n o w l e d g e of congenital syphilis t h a t h a v e a p p e a r e d in the T l i t e r a t u r e since the publication of the last discussion of the subject in this jot~rnal. ~a DEFINIT~OIq OF TER~[
The t e r m " c o n g e n i t a l '~ syphilis has been used in this r e p o r t to designate syphilis c o n t r a c t e d b y an i n f a n t before birth. The terlns ' ' eongenital~ ' ' ' ' p r e n a t a l , " and " h e r e d i t a r y " are in more or less comm o n use, but none of them is a l t o g e t h e r satisfactory. The t e r m s "cong e n i t a l " and " h e r e d i t a r y ' ' are f o u n d in the l i t e r a t u r e as e a r l y as 1839, b u t there does not seem to h a v e been a n y clear distinction between t h e m until m u c h later. The t e r m " p r e n a t a l " was used b y K o l m e r a~ as early as ]920.
" C o n g e n i t a l " (congenitus--born t o g e t h e r ) syphilis as used in this r e p o r t is syphilis p r e s e n t in the i n f a n t at birth and acquired f r o m the m o t h e r either b y transmission t h r o u g h the placenta while in utero or d u r i n g passage t h r o u g h the birth ca~al during labor. The disease is, therefore, always p r e s e n t at birth, although it m a y not become maultest until later. There are two objections to the use of the t e r m " c o n g e n i t a l . " ' The first is t h a t it does not indicate t h a t the disease was acquired from the mother, who m u s t necessarily be infected. Other f o r m s of congenital defeets, such as anomalies of the heart, are acquired in utero, b u t t h e y are not necessarily p r e s e n t in the mother. The second objection, which was raised b y both Stokes 5~ and Rietschel, ~~ is t h a t tile t e r m implies an infection acquired at birth, not m e r e l y one p r e s e n t at birth. (This, however, is not the common use of the w o r d as applied to other types of congenital defect.) Stokes ~ considers t h a t " c o n g e n i t a l s y p h i l i s " in the sense of infection acquired d u r i n g labor is rare, and t h a t it r e p r e s e n t s an infection resembling m o r e closely the acquired infection of adults t h a n the o v e r w h e l m i n g tissue invasion and toxemia p r o d u c e d b y t r a n s p l a c e n t a l infection. " P r e n a t a l '~ (prae + natalis--before b i r t h ) is a t e r m i n t r o d u c e d by K o l m e r to indicate t h a t the infection was acquired during i n t r a u t e r i n e life r a t h e r t h a n d u r i n g labor. Thus it answers one objection to the t e r m congenital, but it gives no i n f o r m a t i o n as to the source of the infection. Stokes 55 has accepted this term. " H e r e d i t a r y , " a l t h o u g h often used in the l i t e r a t u r e i n t e r c h a n g e a b l y with " c o n g e n i t a l " or " p r e n a t a l , " is a misleading t e r m because it /~rom
the
Division
of ]~esearch
in Child
Development,
Children's
Bureau,
United
S t a t e s ] D e p a r t m e n t of I~abor, a n d the D e p a r t m e n t of P e d i a t r i c s , School of Medicine, U n i v e r s i t y of P e n n s y l v a n i a . * P a r t I I (to be p u b l i s h e d ) c o n t a i n s t h e r e v i e w of t h e l i t e r a t u r e d e a l i n g w i t h p r e v e n t i o n a n d t r e a t m e n t of c o n g e n i t a l s y p h i l i s . 386
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implies an infection present in either egg or sperm. True h e r e d i t a r y transmission of syphilis m a y be possible, b u t definite proof t h a t it occurs is still lacking. Jeans and Cooke 27 use the terms " h e r e d i t a r y " and " c o n g e n i t a l " interehangeably. They a r g u e that the disease is inherited in the same sense t h a t p r o p e r t y is inherited from a p a r e n t and t h a t the terms do not. necessarily imply participation of the germ p l a s m . This seems an unnecessary confusion of medical and legal terms. INCIDENCE
I n order to estimate the incidence of congenital syphilis in children at the present time and the potential d a n g e r t h a t syphilis m a y be to f u t u r e generations, it is desirable to k n o w the n u m b e r of eases of the disease in the total population. Since the r e p o r t i n g of eases of syphilis is incomplete, statistics on the incidence of the disease in both adults and children are ineomplete and more or less f r a g m e n t a r y . I n 1923 the American Social H y g i e n e Association ~ reported the results of a survey, based on a questionnaire, which showed t h a t 8.3 per cent of a n t e - p a r t u m patients (both white and n e g r o ) in fifteen clinics were syphilitic. I n 1935 the ass6eiation 15 c o n d u c t e d a similar survey in 74 a n t e - p a r t u m clinics and f o u n d t h a t a m o n g 62,516 white women syphilis was present in 6 per cent and t h a t a m o n g 1,708 negro women it was present in 18 per cent. A m o n g the p r i v a t e patients of eightytwo obstetricians the incidence of syphilis r a n g e d from 0 to 3.5 per cent: I n the same y e a r (1935) the a s s o c i a t i o n cooperated in a one-day census of syphilitics which the United States Public Health Service was c o n d u c t i n g in forty-nine representative communities of the United States. 6~ Fi'om this census it was estimated t h a t there are 518,000 new cases of syphilis every year, of which 31 per cent (162,000') are in women. Since m a n y of these women do not receive adequate treatment, the n u m b e r of cases of the disease in an active form accumulates f r o m y e a r to y e a r and at a n y one time there are a p p r o x i m a t e l y 186,000 women in the c o u n t r y suffering f r o m active syphilis. Considering all the cases of the disease both active a n d latent, it was estimated t h a t a p p r o x i m a t e l y one million of the women of the c o u n t r y have or have h a d syphilis and. have had insufficient t r e a t m e n t to p r e v e n t the possibility of transmission of the infection to the child. According' to the 1930 census there are 32,612,792: women in the age group 15 to 49 years, inclusive, and, if one million are syphilitic, then 3 per cent of all women of child-bearing age h a r b o r the infection. I t is interesting to compare this incidence of syphilis of 3 p e r cent in all women with the 6 per cent incidence f o u n d at a p p r o x i m a t e l y the same time b y the questionnaire s u r v e y of white patients in a n t e - p a r t u m clinics. The a n t e - p a r t u m patients represent a selected group in t h a t their exposure to syphilis is p r o b a b l y g r e a t e r t h a n t h a t of other women. The p r o b l e m of syphilis a m o n g p r e g n a n t women is increased when the effect of the infection upon the outcome of p r e g n a n c y is considered. I n almost half the cases of women with u n t r e a t e d syphilis, p r e g n a n c y terminates in the death of the fetus or infant. 33, 39, 89, 62 W h e n the infection in the u n t r e a t e d mother is recent and active, the effects of the disease on the fetus are more u n f a v o r a b l e t h a n when the infection is latent. The Cooperative Clinical Group s f o u n d in a s t u d y of 431 patients t h a t only 57 per cent of the infants born of syphilitic women
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with positive W a s s e r m a n n reactions escaped the infection, as c o m p a r e d with 81 p e r cent of infants b o r n of syphilitic m o t h e r s w i t h n e g a t i v e W a s s e r m a n n reactions. F e t a l deaths c a u s e d b y syphilis occur in the l a t t e r h a l f of p r e g n a n c y , r a r e l y before the fifth month. Syphilis is not a cause of e a r l y abortion, according to m o s t observers, s~ 1 NcCord, 30 however, considers t h a t syphilis m a y be a more f r e q u e n t cause of early f e t a l d e a t h t h a n is now believed. Syphilis not only produces t h e d e a t h of the i n f a n t in utero or of the n e w b o r n child, b u t it p r o d u c e s late m a n i f e s t a t i o n s of the disease in over half of those children who s u r v i v e infancy23, 4o I t seems p r o b a b l e t h a t more t h a n 80 p e r cent of the p r e g n a n c i e s in u n t r e a t e d syphilitic w o m e n end disastrously f o r the infant. I n spite of these f a c t s it is g e n e r a l l y agreed t h a t syphilis does not constitute reason f o r p e r f o r m i n g an abortion since the results of adequate t r e a t m e n t d u r i n g p r e g n a n c y are so satisfactory. ~3 H o w e v e r , Moore thinks t h a t sterilization is socially desirable f o r those prolific w o m e n who are most u n c o o p e r a t i v e concerning the t r e a t m e n t and who h a v e a l r e a d y p r o d u c e d several syphilitic children. The incidence of congenital syphilis in children is even more difficult to determine t h a n t h a t in adults. Because of a general lack of morbidity statistics, concerning t h e disease, data for the whole c o u n t r y are not obtainable, and surveys of isolated groups v a r y m a r k e d l y depending u p o n the composition of the g r o u p s studied. Because of the h i g h m o r t a l i t y f r o m congenital syphilis, the incidence of the disease is g r e a t e r the y o u n g e r the g r o u p studied. The incidence of the disease is higher a m o n g n e g r o t h a n a m o n g w h i t e children a n d varies inversely with the economic levelP 9 F r o m a compilation of reports, in the literature made b y the United States Public ttea]th Service ~s the incidence of congenital syphilis a m o n g all children has been e s t i m a t e d as 2 p e r cent; when these d a t a were r e s t r i c t e d to infants only, the r a t e was 5.6 per cent. Among white children the r a t e is estimated to be 1.7 per cent, but among negro children, 12.2 p e r cent. When tile data were considered in relation to economic status, it was f o u n d t h a t the incidence of congenital syphilis a m o n g white children in clinics was 5.3, whereas a m o n g children of the well-to-do it was less t h a n 1 p e r cent. F r o m the oned a y census the P~iblic H e a l t h Service 59 estimated t h a t of the 683,000 individuals with syphilis c o n s t a n t l y u n d e r observation and t r e a t m e n t in the United States, a t ]east 60,000 were suffering f r o m an infection t r a n s m i t t e d f r o m the parents. ~mtNmulssmhr F o r m a n y y e a r s the literas h a s contained discussions of the m e a n s b y which syphilis is t r a n s m i t t e d f r o m p a r e n t s to children. A t the present time the consensus of opinion in this c o u n t r y is t h a t the usual m e a n s of transmission f r o m a syphilitic m o t h e r to the fetus is t h r o u g h the placenta, even t h o u g h the m o t h e r m a y show no detectable manifestation of the disease. I n f e c t i o n of the fetus p r o b a b l y does not t a k e place before the fifth m o n t h of i n t r a u t e r i n e life, since p e n e t r a t i o n of the p l a c e n t a b y spirochetes before this time has not been d e m o n s t r a t e d . I t is possible, however, f o r f e t a l infection to t a k e place a t a n y time between the f o u r t h and ninth months. ~, a4, ~9 The earlier the placental b a r r i e r is b r o k e n down, the m o r e extensive will be the resulting invasion of the f e t a l tissues and the g r e a t e r will be the chance t h a t the
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result f o r the fetus will be f a t a l either before t e r m or soon t h e r e a f t e r . F e t a l infection late in p r e g n a n c y m a y a c c o u n t f o r the b i r t h of the a p p a r e n t l y h e a l t h y i n f a n t s of u n t r e a t e d syphilitic mothers, m a n y of w h o m are r e p o r t e d to develop the disease m o n t h s or y e a r s a f t e r birth. The old l a w of Kassowitz 2s t h a t the virus of syphilis becomes att e n u a t e d w i t h time and t h a t the infection slowly wears itself out is g r a d u a l l y being discredited as m o r e a n d m o r e r e p o r t s are published in which the disease is shown to be c o n s i d e r a b l y active m a n y y e a r s a f t e r the initial infection. J e a n s a n d Cooke, 27 r e p o r t i n g the f a t e of 3,009 children of 870 syphilitic families, show a r e m a r k a b l e c o n s t a n c y in f e t a l deaths a n d in deaths during e a r l y infancy, r e g a r d l e s s of the duration of the syphilitic infection in the mother. I n g r a h a m 22 studied the relation of the d u r a t i o n of the disease in the m o t h e r to the infection in the offspring and concluded t h a t the difference in the incidence of syphilis in the offspring of syphilitic w o m e n is so little influenced b y the d u r a t i o n of the disease in the m o t h e r t h a t no reliance can be placed upon this criterion f o r prognosis. P a t e r n a l transmission of syphilis is the subject of much discussion23 The t h e o r e t i c a l e x p l a n a t i o n of p a t e r n a l t r a n s m i s s i o n rests u p o n the d e m o n s t r a t i o n of a life-cycle v a r i a n t of the spirochete small enough to adhere to the head of the spermatazoon. No conclusive d e m o n s t r a tion of this h a s as yet been made. The question of the transmission of syphilis to the n e x t generation b y those who themselves acquired the disease in utero (third-generation syphilis) is still debatable a n d will possibly always r e m a i n so. I t is essential to p r o v e t h a t the m o t h e r of a congenitally syphilitic child received her own infection c o n g e n i t a l l y and t h a t she did not acquire syphilis at a n y time d u r i n g h e r life. 7, 44 M a n y r e p o r t s h a v e a p p e a r e d in the l i t e r a t u r e to indicate b e y o n d reasonable d o u b t t h a t t h i r d - g e n e r a t l o n syphilis does occur, a l t h o u g h it is p r o b a b l y n o t a common m e t h o d of t r a n s m i t t i n g the disease. 7, 44, ~, 46 The routine t r e a t m e n t of congenitally syphilitic w o m e n d u r i n g each p r e g n a n c y is a d v o c a t e d b y 1V[oore.~3 DIAGNO'SIS OF COIqG]~NITAL S Y P H I L I S
IN
THE
NEONATAL
PE[RIOD
I n view of the f a c t t h a t it is desirable to t r e a t a syphilitic i n f a n t as soon as possible a f t e r birth, the p r o b l e m of m a k i n g a diagnosis in the e a r l y w e e k s of life is i m p o r t a n t but sometimes difficult, ee I t is possible f o r an i n f a n t at b i r t h to h a r b o r the Spirocheta pallida in his tissues b u t to show no o u t w a r d evidence of the disease. 49 This occasionally occurs in the i n f a n t s of u n t r e a t e d syphilitic women, b u t it occurs w i t h considerable f r e q u e n c y in the i n f a n t s of p a r t i a l l y t r e a t e d syphilitic women, ee There are several procedures in common use for establishing the diagnosis in the fetus or living infant : 1. 2. 3. 4. 5: 6.
D e m o n s t r a t i o n of the disease in the parents. E x a m i n a t i o n of the p l a c e n t a and cord. E x a m i n a t i o n of stillborn infant. Clinical e x a m i n a t i o n of living infant. Serologic tests of the living infant. R oentgenolo~c examination of the bones o2 the living infaa~t.
Demonstration of the Disease in the Parents.--The first step in establishing the p r e s e n c e or absence of the disease in the n e w b o r n i n f a n t is t h a t of establishing its presence or absence in the parents. I t is
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manifestly impossible for an i n f a n t t,o suffer from congenital syphilis if it can be p r o v e d t h a t the disease is absent in both parents. Examination of the Placenta a~d Cord.--The syphilitic placenta is l a r g e r than the normal. It is not its absolute weight t h a t is signficant, however, but its increased weight in p r o p o r t i o n to that of the fetus. N o r m a l l y the placenta weighs one-sixth as much as the fetus, b u t in syphilis it m a y weigh one-fonrth, one-third, or even one-half as much as the entire b o d y weight of the fetus. Williams ~ believed t h a t certain changes in the placenta were pathognomonic of syphilis and t h a t these changes f o r m e d a basis for a diagnosis of congenital syphilis in 80 to 90 per cent of infants. L a t e r reports have pointed out difficulties in m a k i n g a positive diagnosis in the i n f a n t on the basis of histologic changes in the placenta. I n g r a h a m and Kahler, 2~ for example, state t h a t the demonstration of syphilis in the placenta indicates only a maternal infection and is not synonymous with infection of the infant. Jeans and C o o k e y on the other hand, state that. in t h e i r opinion it is v e r y doubtful if characteristic changes in the placenta can be found in the absence of syphilis in the infant, l~eCord in 1928 a7 stated t h a t a histologically syphilitic placenta means a syphilitic baby but that the converse is not true. McCord concluded in 1934 as that the histologic examination of a syphilitic placenta, especially in a p r e m a t u r e birth, is laden with so m a n y difficulties t h a t it is not of g r e a t practical value as a routine method of determining congenital syphilitic infection. ]Examination of the umbilical vein has proved a valuable means of detecting syphilis. Philipp and Gornick ~s examined scrapings of the umbilical vein b y d a r k field and f o u n d that they could f r e q u e n t l y demonstrate spirochetes in the umbilical vein b y this m e t h o d even when the placenta was morphologically negative for syphilis. They f o u n d spirochetes in the umbilical vein wall in 5 of 15 dead syphilitic infants from mothers whose placental findings were negative and in 5 of 9 living infants who had negative blood Wassermann reactions. K l a f t e n a~ used the same method and considers it a valuable p r o c e d u r e in m a k i n g a diagnosis of early congenital syphilis. I n g r a h a m ea also r e p o r t e d results of dark-field examinations of scrapings from the umbilical veins of 86 unseleeted infants of syphilitic mothers. Spirochetes were f o u n d in 24 fetuses (5 stillborn and 19 living infants). All but 2 of the 24 i n f a n t s were u l t i m a t e l y p r o v e d to be syphilitic. The finding of spirochetes in the umbilical-vein examinations was the earliest diagnostic evidence of syphilis obtainable in :10 of the 24 infants. In 18 of the 86 cases in which the umbilicalvein scrapings were negative b y dark-field examination, proof of syphilis was subsequently obtained b y other means. I n g r a h a m 2a concluded t h a t the dark-field examination of the umbilical vein is a valuable diagnostic aid in the early detection of syphilis in the asymptomatic infant. W h e n the result of the examination is positive, the i n f a n t has syphilis in almost 100 per cent of the cases, but when negative, syphilis in the i n f a n t is not, of course, excluded. Examination of the Stillborn Infant.--Syphilis is one of the causes of intrauterine death, and, i f the fetus is retained within the uterus, it undergoes rapid deterioration and presents the characteristic picture of maceration when finally e x p e l l e d Y Maceration, however, is not
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pathognomonic of syphilis. Stokes 55 states t h a t " S t r a c h a n could only find 6 syphilitic fetuses among 24 m a c e r a t e d specimens, and K e h r e r f o u n d syphilis the cause of m a c e r a t i o n in 41.3 per cent of his cases. On the other hand, Tenconi f o u n d 80 per cent of macerated fetuses to be syphilitic, and Browne f o u n d 64= per cent in a careful s t u d y of 22 cases." The pathologic picture presented b y syphilis is one in which all of the tissues are involved. The most common t y p e of early change is a diffuse inflammatory hyperplasia, and in general the amount of change is in relation to the function of the p a r t d u r i n g fetal growth, n ' 54 The spleen, liver, and bones suffer g r e a t e r damage than other organs. The spleen becomes enlarged; the liver is r e t a r d e d in development so that at birth there is f r e q u e n t l y persistence of embryonic cells. Occasionally the k i d n e y shows a similar arrest in development. 21, 27, 55 The pancreas shows a widespread fibrosis with a r e t a r d a t i o n in development. The characteristic syphilitic lesion in the lmag is fibrosis with the p r o d u c t i o n of irregular, firm elastic patches (pneumonia alba). 27 Adair 2 finds a t e n d e n c y to a persistence of the nephrogenic zone in the k i d n e y of the congenital syphilitic. The most conclusive diagnosis of syphilis can, of course, be made b y the actual demonstration os the Sp4rocheta pallid'c~ in the tissues. Adair 2 f o u n d spirochetes in the tissue in 41 of 46 syphilitic fetuses; Browne, 8 in 8 of 14 m a c e r a t e d fetuses but in only 1 of 21 n o n m a c e r a t e d syphilitic fetuses. Cruickshank's findings *~ were similar in t h a t he f o u n d spirochetes in 7 0f 9 m a c e r a t e d fetuses but in only 10 of 116 n o n m a c e r a t e d syphilitic fetuses. The g r e a t e r ease with which the organisms can be f o u n d in macerated fetuses m a y be due to the incubator effect of the uterus. Stokes 55 thinks t h a t spirochetes m a y multiply r a p i d l y in dead tissue u n d e r conditions simulating those in the uterus and suggests t h a t these findings j u s t i f y the incubation o2 organs of fetuses suspected of syphilis in the hope of demonstrating spirochetes. McCord, a6 however, finds it more difficult to demonstrate spirochetes either b y dark-field examination or in stained sections when the fetus is macerated. Jeans and Cooke 27 r e p o r t t h a t spirochetes disintegrate a f t e r death and f r e q u e n t l y disappear completely within a day or two a f t e r the death of the fetus. Clinical Examination of the Living Infant.--Clinical signs of syphilis are obvious at birth in only a small p e r c e n t a g e of syphilitic infants, ea W h e n signs and symptoms occur, the most common are snaffles, skin lesions, eye lesions, splenomegaly, ] y m p h a d e n o p a t h y , malnutrition, gastrointestinal disturbances, intracranial hemorrhage, and pseudoparalysis of Parrot. ~ While m a n y of these signs are very suggestive of syphilis and should always arouse suspicion of the presence of the disease, t h e y are not pathognomonie of syphilis and almost all are occasionally encountered in infants entirely free from syphilis. 2~ I n g r a h a m ua listed the most characteristic signs of syphilis and recorded their incidence in the syphilitic and nonsyphilitic infants of 212 syphilitic mothers. He f o u n d t h a t up to the age of 2 months definite obstruction to nasal breathing indicated syphilis in 88 per cent of the infants who showed this sign, splenomegaly in 71, bilateral epitrochlear l y m p h a d e n o p a t h y in 51, m a r k e d scaling and fissuring of the skin at b i r t h in 65, and syphilitic skin lesions and pseudoparalysis of P a r r o t in 100 per cent.
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In view of the fact that m a n y syphilitic infants show no clinical evidences of the disease in early infancy, I n g r a h a m 23 concludes t h a t f r o m p u r e l y clinical studies the diagnosis of syphilis c a n n o t be made with any degree of c e r t a i n t y in the first 2 months of life in as m a n y as 5 per cent of the cases. I f it is k n o w n 2a, 12 t h a t the m o t h e r is syphilitic, the presence of coryza, splenomegaly, unexplained malnutrition, or gastrointestinal disturbances, or continued fever of undetermined etiology should lead to the suspicion t h a t the i n f a n t is syphilitic. A diagnosis of syphilis in the child must, however, be confirmed by other means. ~1 Roberts ~1 found clinical signs of syphilis in 27 per cent of 237 syphilitic infants at birth. Syphilis could be diagnosed b y elinieal signs alone in 82 per cent b y the age of 3 months. Spirochetes have been d e m o n s t r a t e d in various tissues and secretions of the living syphilitic infant. T h e y are f r e q u e n t l y f o u n d in the nasal and tile con junetival secretions, in skin lesions, in the blood stream, in the urine, and in the meeonium. 2~ Nianteufel and t t e r z b e r g 42 have diagnosed congenital syphilis in obscure eases by inoculating either cubital or i.nguinal lymph gland emulsion into rabbits. Serologic Diagnosis.--The value in the diagnosis of syphilis of serologic tests (Wassermann or K a h n ) of the umbilical-cord blood or the venous blood of the n e w b o r n i n f a n t has been questioned. Fildes ~ first pointed out t h a t antibodies p r e s e n t in the m o t h e r ' s blood might be t r a n s m i t t e d t h r o u g h the p l a c e n t a and appear transiently in both the cord blood and the blood of the i n f a n t in tile absence of syphilis. In spite of m a n y studies ~, 40. ~s which have substantiated Fildes' original view, the recent literature eontMns such statements as lYreCord's ~9 that " i n the vast m a j o r i t y of cases, a strongly positive cord Wassermann test, p r o p e r l y done, means t h a t the baby has congenital s y p h i l i s , " or Collardi's 9 that " t h e W a s s e r m a n n reaction of the blood of the umbilical cord o~ the n e w b o r n has a. distinct diagnostic value when positive, for it absolutely indicates fetal syphilis." Ingraham 23 has tabulated, in a series of 195 infants, the various combinations of positive and negative cord-blood findings with the ultimate diagnosis in the i n f a n t with r e g a r d to syphilis. He f o u n d t h a t the serologic reaction of the cord blood c o r r e c t l y predicted the condition of the i n f a n t in 64 per cent of the eases and failed to do so in 36 per cent. In those cases in which the cord blood was positive, 83 per cent of the infants developed syphilis, and 17 per cent remained free from all evidence of the disease. In those cases in which the cord blood was negative serotogically, 60' per cent remained free f r o m infection but 40: per cent developed syphilis. On the basis of this s t u d y it appears t h a t the statement that a positive W a s s e r m a n n reaction of the c o r d blood is an absolute diagnostic sign of syphilis in the i n f a n t is not t r u e f o r about 15 per cent of the cases, and the statement t h a t a negative W a s s e r m a n n reaction of the cord blood g u a r a n t e e s a nonsyphilitic i n f a n t is not true for about 40 per cent of the cases. Ki]duffe ~9 states t h a t a positive cord-blood reaction is of value only as indicating f u r t h e r need for, and prolonged study of, the case. J e a n s 26 maintains t h a t results of serologic examination of the inf a n t ' s blood are of absolute diagnostic value a f t e r two months of life
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have passed. Other observers have r e p o r t e d cases in which the blood hag remained seronegative for six months or longer and has then become positive. 23 In nonsyphilitic infants the positive serology seldom persists for as long as two months and usually for a much shorter time. Twenty-two syphilitic infants r e p o r t e d by I n g r a h a m to have positive blood Wassermann reactions at birth developed negative blood W a s s e r m a n n reactions before leaving the hospital at 10 days of age. D u n h a m 13 studied the W a s s e r m a n n reaction of the mother"s blood, the cord blood, and the blood of the i n f a n t in a series of seven cases in which there were no clinical evidences of syphilis in the infants at birth. All of the infants at birth had positive blood Wassermann reactions, but in all seven eases there was g r a d u a l weakening of the reaction until at the end of six months six of the infants had negative reactions. The seventh was not tested until the end of a year, at which time it had a negative reaction. The W a s s e r m a n n reactions were repeated at intervals for a period v a r y i n g between two months and f o u r years, and the tests continued to be negative and no clinical evidences of syphilis developed in any of the infants. F a b e r and Black 16 also studied a group of infants of syphilitic mothers, using a quantitative method for making the Wassermann test. They r e p o r t e d t h a t nonsyphilitie infants with positive Wassermann reactions at birth show a gradual w e a k e n i n g of the reaction until it finally becomes negative, whereas the reactions of syphilitic infants usually show an increasi~g intensity during" t h e same period. I t was f o u n d t h a t by the use of a quantitative technique a change in intensity of the W a s s e r m a n n reaction was usually detectable during the first week of life, and it was suggested t h a t such a change might prove a sufficient basis f o r diagnosis. Christie, 5 using' the quantitative W a s s e r m a n n technique, confirmed the findings of F a b e r and Black. Tests of the cord blood of 14 infants of syphilitic mothers were positive in all but one ease in which the specimen hemolyzed. Quantitative W a s s e r m a n n tests of the blood repeated at intervals t h e r e a f t e r showed a gradual diminution in intensity until t h e y ultimately became negative in 11 infants, none of whom showed a n y evidence of syphilis clinically or in roentgenograms of the long bones. Three of the 14 infants u l t i m a t e l y developed evidences of syphilis. In 2 of the 3 cases the intensity of the Wassermann reaction increased at each examination until other evidence of syphilis appeared. The t h i r d ease was an exception since the blood showed a lessened reaction a f t e r the first examination, only to increase a.fter the development of clinical signs of syphilis. The work of Christie suggests that a comparison of the results of quantitative, serologic examinations of the cord blood and the i n f a n t ' s blood m a y p r o v e valuable in the differentiation of the pseudopositive b u t clinically well infant from the syphilitic i n f a n t at an earlier age than has h e r e t o f o r e been possible. Roentgenologic Examination of the Bones.--Syphilis produces changes in developing bones which are usually recognizable roentgenograpbieally. The r o e n t g e n o g r a p h i e m e t h o d of diagnosis has been in use for thirty-five years. In spite of this long period of use, however, there still exist differences of opinion concerning the specific changes produced in the bone b y the disease and those which r e p r e s e n t the earliest manifestations of these changes in the roentgenogram.
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In order to understa~ld the changes in bone due to syphilis the underlying p a t h o l o g y must. be appreciated. F r o m pathologic studies 47 it has been shown clearly that congenital syphilis produces a fibrosis in developing bone which soon i n t e r f e r e s with the blood supply, causing the formation of granulation tissue. Increased calcium deposition takes place within this granulation tissue without subsequent ossification. A f t e r .granulation tissue has replaced normal vascular areas there m a y be actual pus f o r m a t i o n with easeation and softening. Thus the syphilitic process in bone is characterized by both proliferation and destruction of tissue. 4~ Ill the r o e n t g e n o g r a m this p r o l i f e r a t i o n and destruction of tissue gives the appearance of areas of increased density and of rarefaction. 4. The pathologic changes seen in the r o e n t g e n o g r a m are most m a r k e d in the areas of greatest bone growth, namely, the diaphyso-epiphyseal junctions and the periosteum, producing, respectively, osteochondritis and periostitis. 47 0steochondritis is a v e r y f r e q u e n t lesion of early congenital syphilis. It has been f o u n d present at birth and during the later months of i n t r a u t e r i n e life also. The incidence of the condition decreases as the age of the children examined increases. Periostitis, on the other hand, is a lesion which develops later, usually between the second and fifth months of life. 24 I n g r a h a m 24 eoneludes from his own studies: " W e feel t h a t we m a y assume with a reasonable degree of a c c u r a c y that syphilitic osteoehondritis, other things being equal, becomes roentgenologically manifest about five weeks a f t e r the fetus is infeeted, while syphilitie periostitis requires a p p r o x i m a t e l y four months to develop." IIe believes t h a t it is pgssible to approximate the time of infection of the child or fetus f r o m the stage of the osseous lesions. Aeeording to Ingraham, most syphilitic fetuses are infected in the later months of p r e g n a u e y and are either born with lesions of osteochondritis or develop them within a short period a f t e r birth. Periostitis does not usually develop until the f o u r t h to fifth month a f t e r infection. It is not impossible f o r a fetus to acquire sypMlis early in p r e g n a n c y (any time a f t e r the fifth m o n t h ) , suffer f r o m osteochondritis, and recover f r o m it before birth. The r o e n t g e n o g r a m at birth m a y appear normal b u t later m a y show evidence of periostitis as the first manifest lesion of the disease. 0eeasionally periostitis is f o u n d unassociated with other osseous lesions (5 per cent in lKcLean's 41 series). In such eases I n g r a h a m feels t h a t the osteochondritie process has healed r a t h e r than that it did not exist. I t is, however, more usual to find periostitis accompanying other lesions, especially osteoehondritis. Epiphysitis is f r e q u e n t l y present in the r o e n t g e n o g r a m of syphilitie infants, according to P e n d e r g r a s s and Bromer. 47 0steoehondritis, periostitis, diaphysitis, and epiphysitis are the bone lesions commonly associated with syphilis in the newborn infant. Osteoehondritis does not produce p e r m a n e n t d e f o r m i t y and, in fact, disappears spontaneously without treatment. Sutherland and MitehelP 6 suggest t h a t it is a secondary lesion because of its ephemeral eharaeter. All the bone lesions of early congenital syphilis are widespread in their distribution. P r a e t i e a l l y all the bones, or v e r y few, m a y be affected, although a single bone lesion is n e v e r due to syphilis. 41 The process is not necessarily uniform although multiple involvement is, present. 47 V e r y mild involvement m a y be present in one bone while an e x t r e m e l y
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severe process exists in another. Thus an e x a m i n a t i o n of the entire skeleton is desirable before ruling out syphilis. 47 M c L e a n 4~ f o u n d t h a t bone i n v o l v e m e n t is usually bilateral. The syphilitic process is not the only pathologic one which alters developing bone tissue. A good deal of d i s a g r e e m e n t has arisen over the i n t e r p r e t a t i o n of certain t r a n s v e r s e lines of increased density n e a r the d i a p h y s o - e p i p h y s e a l junction. P e n d e r g r a s s and B r o m e r 47 h a v e described t r a n s v e r s e b a n d s in syphilitic bone. Their explanation of the m e c h a n i s m of f o r m a t i o n of the b a n d is t h a t i r r e g u l a r interference with g r o w t h b y the syphilitic process p r o d u c e s areas of calcification b e y o n d the d e g e n e r a t e p o r t i o n and f o r m s t r a n s v e r s e zones of provisional calcification at different levels. K l a f t e n and P r i e s e P ~ consider t r a n s v e r s e zones in bones to be evidence of successive a t t a c k s of osteoehondritis and correlate t h e m with the time of b e g i n n i n g syphilitic t r e a t m e n t in the mother. They r e p o r t t h a t the earlier the t r e a t m e n t begins, the f u r t h e r the bands have m o v e d in the direction of the diaphysis; the later the treatment, the less the distance of the bands f r o m the ends of the metaphysis. There are p r o b a b l y several mechanisms in addition to syphilis by which these lines are formed. Caffey 4 has shown t h a t bismuth a d m i n i s t e r e d to a w o m a n d u r i n g p r e g n a n c y passes t h r o u g h the p l a c e n t a and is deposited in the long bones in t r a n s v e r s e lines n e a r the d i a p h y s o - e p i p h y s e a l junction. H e states t h a t t h e r e is not enough bismuth deposited in the i n f a n t ' s bone to account e n t i r e l y for the shadow cast in the r o e n t g e n o g r a m . An increased calcium content, induced a p p a r e n t l y b y the presence of a small a m o u n t of bismuth, is responsible for this line, according to Caffey. Before the a d v e n t of b i s m u t h t r e a t m e n t for syphilis Eliot, Souther, and Park, ~ in making roentgenologic studies of children for rickets, observed transverse lines in the bones of these children. They concluded that these lines a p p e a r when for some reason the growth of cartilage is suddenly slowed or stopped and that, conversely, sudden increase in growth produces areas of r a r e f a c t i o n in the long bones. I t seems possible t h a t this m a y be the basic physiologic explanation of all t r a n s v e r s e lines. T h a t is, some f a c t o r i n t e r f e r e s with the n o r m a l g r o w t h of the bone and as a result the t r a b e c u l a e develop l a t e r a l l y instead of vertically, causing an o v e r l a p p i n g a n d lattice f o r m a t i o n with an i n e r e a s e j n p r i m a r y bone formation. This i n t e r f e r e n c e with g r o w t h m a y be due to a m l t r i t i o n a l factor, a d r u g such as bismuth, a poison such as lead, or an infective a g e n t such as the Spirocheta pallida. I f this is true, it m a k e s the diagnosis of syphilis based on an i n t e r p r e t a tion of roentgenographic findings in the bones of newborn infants a difficult procedure. N u m e r o u s r e p o r t s dealing with the relation between the roentgenographic findings and other m a n i f e s t a t i o n s of syphilis have alJpeared. M a n y of t h e m are difficult to i n t e r p r e t because full i n f o r m a t i o n in r e g a r d to findings is not always given. In 14 r e p o r t s ~1 made between 1921 and 1937 the incidence of bone lesions in cases of congenital syphilis v a r i e d f r o m 23 per cent to 100 p e r cent. McLean, 4~ f o r example, f o u n d bone lesions u n i f o r m l y p r e s e n t in a r o e n t g e n o g r a p h i e s t u d y of 102 syphilitic infants and t h o u g h t t h e y were the earliest detectable m a n i f e s t a t i o n of the disease.
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Ingraham 24 states that the roentgenogram offers the most reliable means of diagnosis of syphilis in early infancy. He found t hat 29.1 per cent of the infants of his series showed characteristic roentgenologic changes during the first week of life, and that 78.8 per cent of the 90 syphilitic infants showed bone lesions in the roentgenogram during the first few months of life. Christie, 6 on the other hand, found the roentgenogram of help in diagnosing congenital syphilis in the neonatal period in only 2 of 83 eases. I t is difficult to come to any conclusions concerning the usefulness of the roentgenogram in the early diagnosis of congenital syphilis from a study of the published reports. F[eLean 41 describes the following changes in the roentgenogram as pathognomonic of syphilis: (a) Well-defined saw-tooth metaphyses in well-calcified bones; (b) deep zones in the longitudinal axis of submetaphyseal rarefaction; (e) multiple separation of epiphyses with or without impaetion in bones which are not rachitie; (d) bilateral symmetrical osteomyelitis of the proximal mesial aspects of tibia; (e) multiple areas of circumscribed osteomyelitis of long bones shown by the roentgen ray as patchy areas of rarefaction; (f) multiple longitudinal areas of rarefaction (osteomyelitis) in the shafts of the long bones, sometimes resulting in fractures; (g) destructive lesions at the mesial or lateral aspects of the metaphyses (foci of rarefaction) ; (h) multiple areas of cortical destruction generally seen within a centimeter of the ends of the bones; (i) double zone of rarefaction at ends of bones; (j) localized periosteal cloaking occurring in more than one bone. These lesions are all those of advanced syphilis and are quite generally accepted as pathognomonic of syphilis. The controversy arises over the early signs of pathology and their differentiation from those produced by agents other than syphilis. The changes that are most likely to cause confusion in establishing the positive diagnosis of syphilis by the roentgenogram are (a) submetaphyseal rarefaction produced by very rapid growth; 14, 41 (b) transverse bands near the diaphyso-epiphyseal junction produced by nutritional disorders which temporarily slow up or stop bone growth; .4 (e) transverse bands formed by the administration of bismuth to the mother during pregnancy. Occasionally these bands are so dense that the bone immediately distal to them has by contrast a rarefied appearance;4 (d) apparent thickening of the cortex of the bones of very rapidly growing premature infants. The more rapid calcification of the periostemn than of the shaft may be confused with syphilitic periostitis. It is usually more regularly distributed along the length of the bone framework than is the periostitis of congenital syphilis. 4., ~ After a review of the available literature one is forced to conclude that the diagnosis of congenital syphilis in the newborn infant is often extremely difficult. I~EFER.ENCES 1. Adair, F . J . : Some Remarks on the Relationship of Syphilis to Abortion, Miscarriage, and F e t a l Abnorma]itles, Am. J. Obst. 78: 678~ 1918. 2. Adair~ F . L . : Syphilis of the Fetus and N e w b o r n I n f a n t , Am. J. Obst. & Gynec. 23" 11:1, 1932. 3. Brown% Francis J.: Stillbirth: I t s Causes, Pathology, and Prevention, Brit. ]Y[. ft. 2: 140, 1921. 4. Caffey~ John: Changes in the Growing Skeleton A f t e r the Administration of Bismuth, Am. ft. Dis. Child. 53: 56, 1937.
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5. Christie, Alnos U.: The Diagnosis of Syphilis in Newborn Infants. Use of Quantitative Wassermann Test as a Method of Study. In press. 6. Christie, Amos If.: The Value of Roentgen Examination in the Diagnosis of Infantile Congenital Syphilis. Unpublished manuscript. 7: Clark, J. C.: Third-Generation Syphilis, J. A. M. A. 109: ]038, 1937. 8. Cole, ]:Iarold N., and others: Syphilis in pregnancy, Ven. Dis. Inform. 15: 83, 1934. 9. Collard:, F r a n c e : On the Specificity of the Seroreaetion According to Wasserm a n n and :Miiller in Obstetrics, Ann. di ostet, e ginec. 51: ]368, 1929. 10. Crulckshank, J. T.: M a t e r n a l Syphilis as a Cause of D e a t h of the Foetus and of the Newborn Child. Medical Research Council, Great Britain, Special Report Series No. 82, pp. 67, 1924. 11. Davidsohn, It.: Congenital Syphilis, Ztschrft. f. i~rztl. ]~'ortbild. 22: 390, 1925. 12. Dennie, C. C.: Some Phases of Congenital Syphilis, J. I~ansas M. Soc. 34: 170, 1933. 13. Dunham, E. C.: The Diagnosis of Congenital Syphilis in the Newborn, Am. J. Dis. Child: 43: 317, 1932. 14. Eliot, lVL M., Souther, S. P., and P a r k , E. A.: T r a n s v e r s e Lines in X-Ray P l a t e s of the Long Bones of Children, Bull. J o h n s Hopkins Hosp. 41: 364, 1927. 15. Exner, Max J.: Syphilis in Pregnancy, J. A. M. A. 106: 488, 1936. /6. Faber, H. K., a n d Black, W . C . : Q u a n t i t a t i v e W a s s e r m a n n Tests in Diagnosis of Collgenital Syphilis, Am. J. Dis. Child. 51: 1257, 1936. 17. Fildes, P a u l : The Prevalence of Congenital Syphilis Amongst the Newly Born of the E a s t E n d of London, J. Obst. & Gynaec. Brit. Emp. 27: 124, 1915. 18. Fordyce, J. A., a n d Rosen, I.: L a b o r a t o r y F i n d i n g s in E a r l y and Late Syphilis, J. A. IV[. A. 77: 1696, I92L 19. Gr~fenberg, Dr.: The Influence of Syphilis on Posterity, Arch. f. Gyn~k. 87: 190, 1909. 20. H o f m a n n , E.: E a r l y Diagnosis of Congenital Syphilis, Deutsche reed. Wchnschr. 49: 753, 1923. 21. Holt, L. Emmett~ a n d Howland, J o h n : Diseases of I n f a n c y and Childhood: A T e x t b o o k for the Use of S t u d e n t s and P r a c t i t i o n e r s . Revised b y L. E m m e t t tIolt~ Jr., and Rustin McIntosh, ed. 10, New York, 1933, D. Appleton-Century Company, Inc., pp. 1240. 22. Ingraham~ N . R . : The Diagnosis of I n f a n t i l e Congenital Syphilis During the Period of Doubt, Am. J. Syph. & Neuroh 19: 54:7, ]935. 23. Ingraham~ /q. R.: Roentgen-Positive Serouegative I n f a n t i l e Congenital Syphilis, Am. J. Dis. Child. 50: 144:4:, 1935. 24:. I n g r a h a m , N. R.: The Lag P h a s e in E a r l y Congenital Osseous Syphilis, Am. J. M. Sc. 191: 819, 1936. 25. I n g r a h a m , N. R., J r , a n d Kahler, J. E.: The Diagnosis and T r e a t m e n t of Syphilis Complicating Pregnancy, Am. J. Obst. ~ Gynec. 27: 134:, 1934. 26. Jeans, P. C.: I-Iereditary Syphilis, P e n n s y l v a n i a M. J. 33: 47, 1929. 27. Jeans, P. C, a n d Cooke, J. V.: P r e p u b e s c e n t Syphilis, New York, 1930, D. A p p l e t o n - C e n t u r y Company, Inc., pp. 295. 28. Kassowitz, M.: I n h e r i t a n c e of Syphilis, Med. J a h r b u c h e r red. yon. S. Stricker, Wien, 1875, pp. 359-4:95. 29. Kilduffe, R . A . : The Serology of Congenital Syphilis, J..M. See. New J e r s e y 27: 973, 1930. 30. I~laften, E.: Diagnosis, Prophylaxis, and T h e r a p y of Congenital Syphilis, Z e n t r a l b h f. Gyn~k. 49: p a r t ], 30, 1925. 31. K l a f t e n , E., and Priesel, R.: F u r t h e r Research on Bone Changes in Congenital Syphilis, Fortschr. a. d. Geb. d. R 5 n t g e n s t r a h l e n 4:7: 59, 1933. 32. I(olmer, J o h n A.: P r e n a t a l Syphilis, W i t h a P l e a for I t s Study and Prevention, Am. J. Dis. Child. 19: 344, 1920. 33. Laurent, C.: P r o p h y l a x i s of H e r e d i t a r y Syphilis, Urol. & Cutan. Rev. 33: 24:2, 1929. 34. Levaditi, C., Goldman, M , and Rousset-Chabaud (Mme.): 5Ieehanism of H e r e d i t a r y Syphilitic Infection, Compt. rend. Soc. de biol. 120: 854, 1935. 35. Lombardo, C.: Pathogenesis of Congenital Syphilis, Gior. ital. dl dermat, e sif. 67: 187, 1926. 36. MeCord, J. R.: Two H u n d r e d and F o r t y - T h r e e F e t a l Autopsies~ J. A. M. A. 88: 626~ 1927.
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