by Julius H. Hess, M.D.
Among the most important factors producing premature birth syphilis ranks high. It is even more frequently the cause of intrauterine fetal death. The greater the severity of the infection, the greater is the likelihood of still birth; they represent an overwhelming of the fetus by the spirochetes. Infants who show signs of syphilis at birth have a very high mortality percentage and in the case of those prematurely born, almost all die. The prognosis is much better in those developing clinical evidence one or more weeks after birth.
Jeans  found that (in his out-patient department):
"From 10 to 20 per cent of adult males and about 10 per cent of married women are syphilitic and a minimum of 10 per cent of marriages involve a syphilitic individual.
"Seventy-five per cent of all the offspring in a syphilitic family are infected.
"In a syphilitic family 30 per cent of the pregnancies terminate in death at or before term, a waste three times greater than is found in non-syphilitic families.
"Thirty per cent of all the living births in a syphilitic family die in infancy, as compared to a normal rate of 15 per cent in the patients coming under his observation.
"About 5 per cent of our infant population is syphilitic.
"According to St. Louis vital statistics, 3.5 per cent of all infant deaths are ascribed to lues."
Premature infants do not necessarily show symptoms of lues at birth. In fact, in a majority of cases syphilis becomes manifest only after a latent period and this may vary from one week to one or more months. The later the development of the manifestations the more likely is the infant to be viable. Cutaneous manifestations are usually preceded by coryza, splenic enlargement and retarded progress. While some of the infants, and this applies more especially to the later pregnancies of syphilitic mothers, may be well nourished at birth, more often the earlier pregnancies present a characteristic picture, even in the absence of specific cutaneous manifestations. The skin is flabby and wrinkled and the facial expression senile -- approximating the picture of extreme marasmus or athrepsia in older infants. This class usually perish shortly after birth and the postmortem examination reveals marked luetic, visceral changes.
Infants both with luetic eruptions usually evidence a more or less marked degree of visceral change and they run a much more serious course and give a worse prognosis. However, even in the premature the appearance of the cutaneous lesions need not necessarily be associated with marasmus. This is more especially true in cases unassociated with deep-seated visceral changes, hence the clinical picture of lues is enormously variable and all transitions occur from the serious generalized syphilis up to the case involving a single organ or set of organs. When lesions are present at birth, one or more of the following are usually in evidence: Coryza (snuffles), bullae on the hands and feet and splenic tumor.
Mucous Membranes. -- Coryza is most often the first symptom. In its onset it resembles an ordinary cold but is soon characterized by its severity and chronicity. The discharge is profuse, becomes mucopurulent and often tinged with blood. Nasal obstruction results from the formation of crusts. Mouth breathing follows and nursing becomes difficult. Pharyngitis and laryngitis are usually associated with a resulting characteristic hoarseness and aphonia.
Mucous patches and ulcerations develop on the mucous membranes and at the mucutaneous surfaces, especially at the mouth, anus, vulva, and scrotum.
Skin Eruptions. -- When not present at birth the skin eruptions usually follow the development of the coryza but they not necessarily be preceded by it.
The most common lesions, and which are very rarely seen at birth, are of two types, a diffuse more or less generalized skin infiltration. The skin becomes thickened and infiltrated and loses its elasticity and often after a short period the superficial layers crack. The skin in greater part has a waxy appearance with interspersed inflamed areas, more especially at the points of fissuring. This characteristic skin change may involve the entire body or appear in isolated areas, of which latter the face and extremities, more especially the hands and feet, are more likely to be the seat of changes. About the face, the region of the mouth, nose, and eyelids are the sites of predilection, with frequently resulting rhagades in these regions. A massive involvement of the face results in a mask-like appearance. Following fissuring, there frequently results an exudate with later crust formation. When the scalp is involved alopecia usually results and the same may be true when the eyelids are deeply infiltrated. The soles of the feet and palms of the hands usually present a diffuse infiltration and appear firm and shiny, sometimes more reddish or bluish red, at other times a copper-red or brown.
A true paronychia, which is often accompanied by complete destruction of the nails, is an almost constant complication in this type of skin lesions.
The surface is either smooth or shows fissures in the uppermost horny layers of the epidermis, which occasionally sloughs in large, lamellous scales.
In the second type of rash lesions which are more circumscript are noted. These lesions assume more nearly the characteristics of the skin manifestations in acquired syphilis. The most frequent type of lesions are macules usually circular and slightly elevated, averaging 2 to 5 mm in size. The face and the extensor surfaces of the lower and upper extremities and more especially the hands and feet are usually involved and they may cover the entire body, but more often the chest and abdomen escape. At first red, they soon become darker and assume a coppery hue. More elevated papules similar in character and without an inflammatory base may be interspersed among the macules. A squamous eruption is frequently seen upon the palms and soles and small masses of scales may appear upon the surface of the macules. The eruption may develop abruptly but more frequently it increases progressively during a period of from one to three weeks and under vigorous treatment disappears rapidly except for the remaining pigmentation.
In the most severe types the bullous or pemphigoid lesions may be superimposed upon the macular squamous syphilides or they may be primary. They may lead to deeper ulcerations of the skin with secondary infection and are always a source of danger to others because of the likelihood of the presence of spirochetes in the lesions. The possibility of the confusion of these lesions with non-specific pemphigoid lesions which are of not infrequent occurrence in obstetrical wards should be remembered as the latter are especially prone to affect the premature. This latter type of pemphigus neonatorum is probably a staphyloccus infection. Linear fissures and mucous patches are among the most characteristic features. On account of the fragility of the skin these rhagades easily occur, especially on the lips, nose, about the anus and less frequently about the eyelids. The healing of these lesions usually results in radiating cicatrices which result in the very characteristic "purse-string" deformity.
Umbilical Cord. -- The umbilical cord often heals slowly and the stump has a tendency to become purulent and there is a tendency toward infiltration about the umbilicus. A more or less deep-seated ulcer may result which heals slowly unless constitutional treatment is instituted or mercurials are applied locally. Hemorrhage from the stump and secondary infection, with resulting syphilis hemorrhagica neonatorum are likely to result.
Lymph Glands. -- Only exceptionally to they present a characteristic generalized enlargement in the new-born syphilitic premature. In untreated cases the lymph glands become palpable and this may be due to luetic infection or, again, isolated groups of glands may become involved through secondary infection and go on to suppuration. The small size of the glands makes them difficult of palpation, more especially in well-nourished infants.
Osseous System. -- Osteochondritis syphilitica ranks next in importance to the skin and mucous membrane lesions and splenic tumor in the diagnosis of syphilis. Pathological changes are most frequently seen in the long bones, the junction of the epiphysis with the diaphysis being the seat of predilection.
These lesions are usually bilateral although occasionally only a single lesion can be defined in the living. Involvement of the joints is far less common. While the long cylindrical bones are the seat of the lesions which can most easily be identified clinically, any of the bones may be the seat of a diffuse involvement of the bony structures or a periostitis. Such lesions are more commonly found in cases resulting in early fetal death.
Roentgenography offers one of the best diagnostic methods for syphilis in the fetus and new born. Shipley and his co-workers  found evidence of syphilis in the osseous system of 25 per cent of 100 white fetuses ranging from six months of intra-uterine life to nearly term. Fifteen of these showed advanced luetic osteochondritis. The bone lesions in syphilitic new-born infants present characteristic lesions when there is sufficient involvement to be evidenced in the roentgenographic plates. While any of the bones may suffer, those most commonly involved and easiest of study are the lower end of the femur, upper and lower ends of the tibia, radius and ulna and the metacarpals. In their studies they found that the fetal type of reaction and the changes before birth were to a large extent confined to the epiphyseo-diaphyseal region, at which points there develops an abnormal arrangement and distribution of osseous tissue. After birth the periosteal reaction begins, possibly because of the increased demands made on this tissue by the increased muscular activity, and in young infants this may be the most marked skeletal lesion. The most characteristic lesions described by them were the following:
"The beginning of the process as shown by the roentgen-ray picture is an intensification of the shadow cast by the bone at the epiphyseal line. This line becomes much broader and more homogeneous and seems to form a cap on the ends of the trabeculae of the spongiosa (Fig. 172). This is significant of the beginning of abnormally heavy calcification of the provisional calcified zone. It must be remembered that while the provisional zone of calcification in the cartilage of the normal embryonic bone is, relatively speaking, very narrow, in may cases only one or two cells deep, in the syphilitic bone the calcified cartilage may show on section a width of from 0.5 to 1.5 mm.
"In other bones, in which the osteochondritis is further advanced, it can be seen that on the marrow side of the intensified shadow of the provisional zone there is a band-like area where the shadow is less intense than in the rest of the bone (Fig. 170), giving an appearance of diminished density to the region of the epiphyseal line.
"Bones may also be seen in which the dense shadow at the epiphyseal end of the bone is broken by the presence of one or more small areas of rarefaction so as to give the appearance of irregular density to the end of the bone (Fig. 173).
"At other times the bone appears to end in a double line, so that two lines of heavily calcified tissue are seen, separated from one another by a zone in which lime salts are less heavily deposited. This zone is a region which histological preparations show to contain a great deal of delicate granulation tissue. This picture becomes more and more intensified as growth goes on. The areas of dense shadow and the fine clearer band between them grow wider and the surfaces bounding them become more and more irregular and jagged until the end of the bone has an irregular appearance (Fig. 171). During the course of the disease the calcification of the infected areas is not only abnormally heavy but also most irregular, so that the epiphyseal border of the shadow cast by the bone has a notched, saw-toothed or serrated appearance (Fig. 175).
"Periostitits, when it occurs near term in the severe cases of lues, may be present throughout the length of the bone or only at the extremities. It is shown in roentgen-ray plates by a more or less wide, almost homogeneous, shadow or with longitudinal striations separated from the external surface of the cortex by a narrow clear area which bounds the bone (Fig. 174).
"One other feature of these pictures appears worth noting. It may be seen that in many luetic bones the cortex is separated from the spongiosa by a very narrow clear zone which gives the cone of spongy bone the appearance of being suspended unattached within the cortical cavity (Fig. 175). In the roentgen-ray picture the trabeculae of the syphilitic bone appear to be finer than those of the normal bone.
"Two other conditions which are encountered in children may give roentgen-ray pictures which closely resemble, and in some cases are identical with, the picture described above. Scurvy and rickets, when the latter disease is healing under the influence of cod-liver oil therapy, may be difficult or impossible to differentiate by roentgenographic means from osteal syphilis of the fetal type. Fortunately, however, in the early weeks of life neither of these conditions need be seriously considered in diagnosticating hereditary lues, since there is no good evidence to show that fetal rickets ever occurs and it is agreed that scorbutus is rare before the sixth month of life has been reached."
Liver. -- It may be stated that not less than 50 per cent of prematurely born, syphilitic infants show a distinct enlargement of the liver. A fair percentage of the cases show a marked increase in size and consistency to such an extent that the abdominal distension in its upper half is visible to the naked eye. These latter cases are usually associated with marked jaundice, dilated veins and an impairment of hepatic function and a high mortality. Because of the relatively large liver of the premature new born normally present, difficulty may be experienced in the diagnosis of a moderate increase in size due to syphilis. It is also to be remembered that many other factors predisposing to premature birth have a direct influence on the size of the liver. The characteristic pathological findings are interstitial infiltration of the connective tissues between the acini and about the vessels. Small gummata, often the seat of central necrosis are more exceptionally found. The frequent involvement of the liver is readily explained by the peculiarity of the fetal circulation. The placental blood passing through the portal circulation by way of the umbilical veins, conveys the spirochetes into the liver substance.
Spleen. -- Enlargement of the spleen, while usually moderate, is one of the most important confirmatory signs but is in itself of lesser diagnostic importance than the skin and mucous membrane lesions. An easily palpable and hard splenic tumor in the first three months of life, that is, before the advent of rickets in the premature, should always be looked upon with suspicion. The enlargement is usually due to hyperplasia of the pulp, with occasional presence of foci of myeloid cells. Cellular infiltration of the interstitial tissue may be present.
Respiratory System. -- The lesions of the nasal mucous membranes have been described. Frequently there is a chronic catarrhal laryngitis and perichondritis, with involvement of the epiglottis. In the fetus and in infants dying soon after birth the so-called "pneumonia alba" or "white pneumonia" is often present. In these cases a considerable portion of the pulmonary tissue appears whitish-gray, airless and smooth on section, due to cellular infiltration of the interstitial tissue, filling of the alveoli and bronchi with degenerated epithelium and proliferation of the intima of the vessel walls. Not infrequently the pleura is the seat of small gumma-like nodular infiltrations. Massive involvement of the lungs is rarely compatible with life. Because of their lowered vitality, syphilitic infants are subject to secondary bronchial and pulmonary infection, pneumonia being a frequent cause of death.
Circulatory System. -- Most characteristic lesions are found in the small blood vessels and careful examination shows the presence of spirochetes in the vessel walls. These findings are most easily demonstrated in the parenchymatous organs. The characteristic lesions following such involvement are those of coagulation necrosis, with secondary hemorrhages, following rupture of the vessel walls. These lesions may result in more or less generalized or local hemorrhagic skin lesions and those from the various mucous membranes. Intracranial lesions frequently result from degeneration of the blood vessels, even in the absence of trauma.
Digestive System. -- Chronic catarrhal pharyngitis is a common early symptom which may later be followed by ulcerations of the pharynx, tonsils and fauces. Only rarely is the stomach involved and the lesions of the intestines which are also infrequent are usually seen as hyperplasia of the solitary follicles and Peyer's patches which may become necrotic and result in hemorrhages. Scattered areas of necrosis not associated with the lymphoid tissue, but due directly to blood vessel degeneration may be found throughout the intestines. Peritonitis is a more frequent finding in the still born than in viable infants. It may be of the acute type but in most instances it is of the chronic type and may result in formation of adhesions. Localized or generalized ascites may result.
The pancreas, thymus gland, suprarenal bodies and thyroid gland occasionally exhibit interstitial inflammation, gummata or other syphilitic manifestations. Small cystic formations are frequently found in the thymus gland, usually varying in size from 1 to 5 mm. It is a question whether they are due to arrest of development or necrosis. Purulent material with which they are filled contains spirochetes.
Kidneys. -- While all types of nephritis have been described, those of greatest importance are the interstitial and hemorrhagic. Interstitial nephritis is a serious complication because of the danger of late secondary contraction. It is frequently overlooked because of the absence of marked urinary findings. The hemorrhagic types are usually associated with hemorrhages from some of the other mucous membranes. The dangers of overmedication with arsenic and mercury preparations, in the presence of kidney lesions must not be overlooked. Hecker  states that he has been able to demonstrate microscopic changes in 90 per cent of his autopsies.
Nervous System. -- Involvement of the brain and its meninges is more frequent than that of the cord. The most frequent lesions in the still born and those dying shortly after birth is a meningoencephalitis, involving the pia and the cortex. The pia is infiltrated and covered by an exudate composed of plasma cells and lymphocytes. Similar areas are seen in the cortex and the medulla may be involved. The most frequent lesion in viable infants is a meningitis serosa interna and externa, which is not usually noted until after the first few weeks of life. It may develop acutely or insidiously and usually results in a more or less marked hydrocephalus. Because of the late development in some infants and the early appearance of rickets in the premature it should not be confused with megacephalus so commonly seen in the latter. Pachymeningitis hemorrhagica less frequently seen than the former, usually develops after the first weeks of life. Intracranial hemorrhages are probably a more frequent cause of extra-uterine death than is commonly supposed. Gummatous meningitis and ependymitis are among the rare lesions. Increased intracranial pressure, as evidenced by increased tension over the fontanelles, and which is usually accompanied by hyperexcitability on the part of the infant, should lead to a lumbar puncture for diagnostic purposes. Increased pressure and an increase in the number of lymphocytes in the spinal fluid are always suggestive but not positive evidence. A Wasserman and Lange reaction when positive may usually be considered as conclusive evidence. When these reactions are negative, in the presence of other positive signs, a careful search should be made for spirochetes.
Any of the lesions of the central nervous system may result in retarded mental and physical development.
Eyes. -- The most frequent lesions are choroiditis, optic neuritis, iritis and parenchymatous keratitis. They are of frequent occurrence in the still born and may develop in the first weeks of life.
Ears. -- The organs of hearing are occasionally involved by lesions which may be described as specific. The most common is an involvement of the eighth nerve. Involvement of the organs of the internal ear early in life is difficult of proof. Otitis media as usually seen is due to a secondary infection.
Laboratory Diagnosis. -- Whenever there is a suspicion of the presence of syphilis during pregnancy the blood of both parents should be examined so as to give both the mother and fetus the benefit of treatment. This will be given further consideration.
In cases in which the diagnosis has not been made before labor and the possibility of syphilis exists the placenta should be examined histologically and the placental cord blood should be examined for a Wasserman reaction. It is estimated that about 50 per cent of placentae will show more or less diffuse lesions upon microscopic examination. Jeans and Cooke  found that 57 per cent of their syphilitic infants gave a positive Wassermann reaction on their cord blood. They found that in every instance in which the placenta was noted as showing syphilitic changes the infant was later found to have syphilis. While a positive Wasserman reaction may be regarded as nearly specific, a negative reaction must not be regarded as indicating an absence of the disease when made during the first days or weeks of life, as a large group of infants show little or no tendency to give a positive Wasserman before the end of the second month of life. In fact, some of them do not react before the end of the third or fourth month. Negative findings in the presence of lesions or suspicion of infection on the part of the mother should, therefore, lead to an examination of maternal and paternal blood. The variability in the reaction of a new born to the Wasserman test is best evidenced by the report of one positive and one negative reaction in each of a pair of twins by DeBuys  and Gerstenberger .
The blood taken from the infant during the first week or two of life shows a somewhat higher average of positive serum reaction than examination of the placental blood taken from the same cases. In the premature the blood can be taken from the longitudinal sinus, a scalp vein or by a small incision in the heel. The application of the luetin test offers serious objection in premature infants, because of the danger of secondary infection. In full-term infants it averages a higher percentage of positives than the Wassermann.
Demonstration of spirochetae in the open skin lesions and bullae as well as from the scraping of the mucous membrane ulcerations, makes the diagnosis absolute when the Treponema pallidum is found.
While spinal and ventricular punctures are to be avoided when possible in premature infants, examination of the cerebrospinal fluid may be necessary when other findings are negative in the presence of possible clinical nervous system syphilis. About 25 per cent of new-born infants will show spinal fluid changes of sufficient importance to have a diagnostic value. These changes consist of a positive Wassermann, which when present, is usually associated with a definite albumin and globulin increase. More often the cell count reveals a moderate pleocytosis.
Prophylaxis. -- It is almost needless to say that luetic individuals should not be permitted to marry. With the improved methods of laboratory diagnosis of today -- luetin, Lange and Wasserman tests -- it is now possible in a relatively high percentage of cases to discover if an individual has a latent or active syphilis. When there is the slightest suspicion of a specific infection during pregnancy, the mother should be treated intensively. This offers the only hope of preventing a similar infection of the infant with its consequences, or of ameliorating the condition. It is noteworthy that women with luetic histories do much better if under treatment during pregnancy, so that prematurity and still birth may often be avoided. In the absence of specific therapy the child, instead of being born healthy, may show active syphilitic manifestations or develop them later.
As in the prophylaxis of any infection of infancy, extreme care must be exercised with reference to the sterilization of feeding and bathing utensils and clothing.
Nursing. -- Whenever a mother bears an infant evidencing lues, if she is at all able, she should nurse her infant. It seems well established today that the mother is syphilitic, whether or not her history is positive, and even in the absence of clinical manifestations. The older controversies as to the possibility of infection of the mother by the child and vice versa consequently do not enter into consideration. Where an adequate supply of milk is present it is of the utmost importance that the premature infant be suckled. If the mother objects to nursing her infant at the breast because of nasal and mouth lesions a shield may be used or the milk expressed and hand fed.
Where the mother is unable to nurse her child a wet-nurse should not be employed to suckle the child at her own breasts because of the obvious danger of infection of the nurse. Expressed milk is, of course very desirable.
Active Treatment. -- In syphilis neonatorum, which so frequently is associated with serious visceral changes and so commonly affects children born prematurely, the prognosis is in general serious. Very commonly the infants with serious forms of pemphigus, even with early instituted treatment and with human milk feedings, die in the first days or weeks of life. An essentially better prognosis is offered by the cases with maculo-papular or papulo-bullous syphilides provided always that the internal organs are not seriously damaged.
As soon as the diagnosis is made certain, antiluetic treatment should be immediately instituted. Healthy infants and those free from symptoms but born from luetic parents should be treated prophylactically.
Certain facts already enumerated in the general care of premature infants should be especially emphasized in the care of this same class of infants born of syphilitic parents, even though they show no manifestations at the time of their birth. Practically all of them show more or less evidence of malnutrition and therefore, in this class of infants, as in no other, is breast-feeding indicated. Every effort should be made to stimulate the breast-milk supply on the part of the mother because of the difficulty encountered in obtaining a sufficient supply from other sources, as well as the danger to a healthy wet-nurse.
In the presence of a syphilitic history or positive laboratory findings in the parents, or the findings of clinical manifestations in the infant a vigorous course of treatment should be instituted without regard to the presence or absence of a Wassermann reaction. In every case in which treatment is instituted the fetal age and general condition of the infant must be taken into consideration and the effect of medication, whether mercurial or arsenic preparations, carefully noted. Early dosage with each form of medication should, therefore, be small, however, maximum administration for the given infant should be attained as early as possible.
Mercury Therapy. -- Three routes of administration deserve consideration: Oral, external and intravenous.
In the treatment of older infants and children many clinicians of large experience advocate the use of arsenic preparations as of first importance and while mercurial preparations are considered as absolutely necessary to effect a cure, they are given a secondary place. In view of this tendency it is well that we recall our earlier good results in the treatment of congenital syphilis before the discovery of these newer preparations. It is our belief that mercury should rank first in the treatment of syphilis in the premature and that arsenic therapy should rank second in importance: (1) Because of the lesser danger, and (2) because of the rapid improvement which may be expected in a large majority of the cases. However, the dangers of overmedication, both by mouth and injection with mercury must also not be overlooked. These are usually evidenced by a lack of progress on the part of the infant, diarrhea and evidences of hepatitis and nephritis.
For internal use the favorite preparations are hydrargyrum cum creta, 0.005 to 0.03 gm. (1/10 to 1/2 gr.), or hydrargyrum iodidum flavum in doses of 0.002 to 0.005 gm. (1/20 to 1/10 gr.) three times daily. It is well to begin with small doses, preferably of the former and increase rapidly to the maximum dose in the absence of diarrhea. in the presence of diarrhea the dose should be reduced. The intramuscular treatment must be administered with even greater forethought. For this purpose 0.0005 gm. (1/100 gr.) of bichloride in 0.2 cm. (3 mm.) of distilled water or oil, for each kilogram of body weight (2 1/2 pounds) are recommended. The injections are to be given once or twice weekly and should be made deep into the muscle. The gluteal muscles offer one of the best sites for injections. The skin surface should be sterilized with a not too concentrated tincture of iodine and the injection is made deep into the muscle by the use of a short needle, preferably of about a 20 gauge (for oil) and 1/2 to 3/4 inch in length. Care should be used so that none will be deposited in the subcutaneous tissues. A course of four to eight injections, covering a period of four weeks, is recommended, these are to be followed by a rest period of four weeks, during which arsenic injections are given. The oral administration of mercury should be continued throughout this period. Sublimate baths may be successfully used in all moist forms, especially in all exanthemata associated with vesicle formation -- 0.2 gm. (3 gr.) for a bath of about 4 liters (1 gallon) of water.
Inunction are applicable in infants in whom the skin is not too sensitive and are one of the best forms of treatment. In the presence of local skin irritation it becomes necessary to stop this form of treatment. The danger of overmedication with mercury must, however, be borne in mind. Mercurial ointment is especially valuable for local application to ulcerated lesions and may be applied to the deeper seated lesions of the hands and feet by the use of mittens and stockings. For these purposes the official mercurial ointment should be mixed with 2 parts of lanolin. In the more mature infants it should be carefully rubbed into the abdominal wall, axillae or thighs and the same site used only at infrequent intervals in order that cutaneous irritation be avoided. For a local lesion 2 per cent of yellow oxide of mercury ointment will do. In the presence of snuffles a 1 per cent yellow oxide of mercury ointment should be used. The ointment is introduced into each nostril directly from a small compressible tube. It may be necessary to carefully remove any excessive secretions with a pledget of cotton or by washing with a normal salt solution before applying the ointment.
It is advisable to continue mercurial treatment for at least a year, decreasing the dose in the second six months, and repeating three months of such therapy during the second and third years, even in the absence of symptoms. As in treating older infants, there should be short periods when treatment is discontinued.
Arsenic Therapy. -- It is indicated in most cases as an adjunct to mercurial treatment. Neoarsphenamine is the preparation of choice for use with the premature because of the fact that it can be administered in more concentrated solution, its greater solubility and the lack of necessity for neutralization. It can be administered intravenously in water or by intramuscular injections in a bland oil.
The average dose is 0.01 gm. for each kilogram of body weight. The dose should be diluted with 2 cc of sterile, freshly distilled water for intravenous use. It is advisable to give one-half of this quantity per kilogram for the first treatment. A course of four intramuscular, or, when possible, preferably intravenous injections are given at weekly intervals to be followed by a rest period of four weeks when the treatment is to be repeated. During the period of administration of neoarsphenamine the mercurial injections should be discontinued but the oral administration continued.
Complications following the intramuscular injection of neoarsphenamine, such as abscesses and infiltrations can, to a large degree, be avoided by the use of special needles, which permit the solution to be injected deep into the muscle. After injection, the needle is rapidly withdrawn and a cotton pledget is pressed firmly over the site of injection for a few minutes.
For intravenous administration the best sites are scalp veins or the external jugular vein. For administration into the latter site the infant should lie with the shoulders elevated and the head extended and rotated. Only in very exceptional cases should cutting down on a vein be practised. The longitudinal sinus route for arsenic injection is not to be considered because of the danger of passing through the sinus and extravasating the preparation over the brain tissue.
The general plan of treatment should, therefore, be as follows: One of the mercury preparations should be administered in suitable doses three times daily per mouth, and once or twice weekly during the first four weeks an intramuscular injection of one of the mercurial preparations should be given. During the second month the oral administration should be continued but the mercurial injection should be replaced by neoarsphenamine, preferably intravenously, once each week. Mercurial ointment as inunctions or local applications are to be used when indicated.
This plan of treatment should be continued throughout the first year, in the absence of toxic symptoms and at least three months of treatment should be given during the second and third years. Treatment should be continued for at least six months after all evidence of activity has disappeared. This includes a negative Wassermann test. At no time should a negative Wassermann in early infancy be considered as sufficient evidence to interfere with the general course of treatment as outlined.
 Am. Jour. Syph., St. Louis, 1919, No. 1, vol. 3.
 Shipley, P.G., Peason, J. W., Weech, A. A., and Greene, C. H.: Bull. Johns Hopkins Hospital, March, 1921, p. 75.
 Beitrag zur Histologie and Pathologie der kongenitalen Syphilis sowie zur normalen Anatomie des Fötus und neugeborenen, Deutsch. Arch. f. klin. Med., 1898, 61, 1.
 Trans. Am. Pediat. Soc., 1920, vol. 32.
 Jour. Obst. and Dis. Women and CHild., January, 1913, p. 65.
 Personal communication.
Fig. 167. Congenital syphilis. Secondary lesions on feet. Lesions first appeared during fourth week.
Fig. 168. Congenital syphilis. Secondary lesions on face. Lesions first appeared during fourth week.
Fig. 169. Congenital syphilis. Baby A. Fissures about mouth. Large liver and spleen. Six weeks later.
Fig. 170. Osteochondritis syphilitica.
Fig. 171. Hand and forearm of human fetus to show extreme progressive calcification of the provisional area with irregular prolongation of the provisional calcified zone into the area of proliferative cartilage. Note the presence of the same lesions in the metacarpals and phalanges. (Shipley)
Fig. 172. Radius and ulna from human fetus showing beginning resorption of the area of intense calcification at the epiphyseo-diaphyseal junction. Resorption shown by areas of decreased intensity of shadow, each resorptive area surrounding a small nucleus of persistent trabecular tissue. (Shipley)
Fig. 173. Roentgen-ray picture of syphilitic osteochondritis of the bones of the hand and forearm of a human fetus showing a zone of rarefaction between two zones of abnormal calcification. Note the lesion in the phalanges and metacarpals. (Shipley)
Fig. 174. Syphilitic periostitis of both bones of the forearm. Note the longitudinal striation of the thick periosteal shadow which is nearly in contact with the shafts of the bone. (Shipley)
Fig. 175. Distal end of radius and ulna. This plate shows intense calcification of the provisional zone with resorption areas on the marrow side of the epiphyseal line. Both bones show syphilitic periostitis and there is separation of the cortex from the spongiosa in the ulna. (Shipley)