Original Article
Congenital Syphilis Presenting in Infants after the Newborn Period
N Engl J Med 1990; 323:1299-1302November 8, 1990
- Abstract
- Abstract
Background and Methods.
There has been a recent, dramatic increase in the incidence of congenital syphilis, particularly in urban areas. We describe seven infants seen during one year who were first given a diagnosis of congenital syphilis at 3 to 14 weeks of age, when symptoms developed. We reviewed these infants' charts in order to ascertain the reasons for the failure to diagnose syphilis at birth and to identify the signs and symptoms of congenital syphilis in this group of infants.
Results.
At delivery, four of the infants and their mothers had negative qualitative rapid-plasma-reagin tests for syphilis. The other three mothers had been seronegative during the pregnancy and were therefore not tested at delivery; two of their infants were seronegative at birth, and one was not tested. When the infants became symptomatic between 3 and 14 weeks of age and were admitted to the hospital, all seven infants and the five mothers available for testing were found to be seropositive for syphilis. Four infants presented with a characteristic diffuse rash; the other three presented with fever and were found on admission to have aseptic meningitis. All these infants had multisystem disease, as evidenced by hepatomegaly, increased aminotransferase and alkaline phosphatase levels, anemia, and monocytosis. In all the infants syphilis responded to parenteral penicillin.
Conclusions.
Congenital syphilis may be missed if serologic tests are not performed for both the mother and her infant at the time of delivery. Even when these tests are performed, some infants are not identified as having syphilis, probably because the infection is very recent and there has been insufficient time for an antibody response to develop. Some infants with congenital syphilis of later onset do not present with a typical rash; therefore, at least in areas where the disease is prevalent, serologic tests for syphilis should be included in the evaluation of all febrile infants, even those with negative results on serologic testing at birth. (N Engl J Med 1990; 323:1299–302.)
Article Activity
- Article
THE identification of newborns at risk for congenital syphilis depends on the results of serologic tests performed during pregnancy and at the time of delivery. It is generally accepted that if both mother and baby are seronegative, the infant is free of infection. In the past year, seven infants between 3 and 14 weeks of age were admitted to our hospital with symptomatic congenital syphilis, even though there was no suspicion at the time of delivery that either mother or baby had syphilis, since the serologic tests were negative. For four of the infants, the diagnosis of congenital syphilis was considered in the emergency room because a rash involving the palms and soles was present. Three babies had none of the classic symptoms, but presented with fever as their primary symptom.
In this paper, we examine factors that may allow congenital syphilis to go undiagnosed in the neonatal period and review the clinical and laboratory characteristics of congenital syphilis that presents after the newborn period.
Methods
We evaluated the records of children with a diagnosis of congenital syphilis who were admitted to the pediatric wards of the hospitals affiliated with the Albert Einstein College of Medicine from December 1988 through November 1989. Infants were included if the diagnosis of congenital syphilis was not suspected at birth, both mother and infant had had a previous negative serologic test, and the mother had not received treatment for syphilis before delivery or in the perinatal period. A total of seven infants who met these criteria were identified. In all cases information about the mother's pregnancy and events during labor and delivery were also reviewed.
Results
Serologic Data
A qualitative rapid-plasma-reagin test was used as the initial serologic screening test at the hospitals in which these seven babies were born. A quantitative rapid-plasma-reagin test and fluorescent treponemal antibody-absorption test were performed on serum samples that tested positive. The mothers who received prenatal care were found to be seronegative during pregnancy, and two who were retested at delivery remained negative (Table 1Table 1
Results of Serologic Tests for Syphilis.*). Two were not retested because a negative test during pregnancy was considered sufficient to rule out maternal syphilis in the hospitals in which they delivered their babies. One mother who was seronegative during pregnancy declined to undergo blood tests at delivery. The two women who did not receive prenatal care were seronegative when tested at delivery. A negative result on testing of a cord-blood sample was recorded for six of the seven babies. One baby (Patient 7) was not tested at birth because the hospital did not test newborns if the mother's prenatal serologic test was negative.When the infants were admitted after they became symptomatic, they and the five mothers available for testing had positive results on rapid-plasma-reagin and fluorescent treponemal antibody-absorption tests. One mother had a syphilitic eruption at the time her infant was admitted, but the others had no clinical symptoms. Because of the increased risk of infection with human immunodeficiency virus type 1 (HIV-1) in patients with syphilis, we requested permission to perform serologic testing for HIV infection in these infants. The three who could be studied were antibody-negative for HIV.
Clinical Data
The seven babies, three boys and four girls, became symptomatic between 3 and 14 weeks of age. Three were born at the Bronx Municipal Hospital Center, and four were born elsewhere in the New York area. Four presented with a diffuse eruption characteristic of congenital syphilis, and three had no obvious manifestations of syphilis and presented with fever. It is our policy to evaluate all children under two months of age who have a temperature of at least 38.1°C with a sepsis workup, including a lumbar puncture. The three infants who presented with fever had an abnormal spinal-fluid sample consistent with aseptic meningitis; this finding prompted an evaluation for possible causes, including syphilis.
All our patients had clinical and laboratory evidence of multisystem disease (Table 2Table 2
Clinical and Laboratory Findings on Admission in Infants with No Serologic Evidence of Syphilis at Birth.*). The liver was markedly enlarged in all the babies and could be palpated 3 to 5 cm below the costal margin. Although the infants' aminotransferase levels were abnormal, they were markedly elevated in only two of the babies. Considerable elevation of the alkaline phosphatase was uniformly observed, but hyperbilirubinemia and jaundice were not present. Four babies had a diffuse maculopapular eruption that involved the palms and soles. Rhinitis, which was neither purulent nor bloody, was noted in four babies, but a darkfield-microscopical examination of the nasal discharge was not performed. Four of the seven infants had abnormalities in the cerebrospinal fluid, but none had obvious clinical symptoms referable to disease in the central nervous system. Two babies had pleocytosis, an elevated total protein level, and a reactive cerebrospinal-fluid Venereal Disease Research Laboratory (VDRL) test. One had only a reactive cerebrospinal-fluid sample, and one infant had pleocytosis, an increased protein level, and a nonreactive cerebrospinal-fluid sample. Hematologic abnormalities were seen in all the infants and consisted mainly of anemia, leukocytosis, and monocytosis. Radiologic evidence of bone involvement was seen in three of the six patients who underwent radiologic studies, but no child had symptoms of bone involvement. Renal disease was seen only in the youngest child, a three-week-old boy who had severe nephrosis. Ten days after admission, his urinalysis and serum albumin level returned to normal. A Jarisch—Herxheimer reaction, consisting of a marked, sudden elevation of temperature with no other systemic signs, occurred in all the children within two to six hours after they received the first dose of antibiotics.1 Discussion
The Centers for Disease Control has recently documented a dramatic increase in the incidence of syphilis, especially in large urban centers.2 This increase has been attributed to socioeconomic conditions, the widespread use of "crack" cocaine, and the prostitution often used to support a "crack" habit.3 An especially large increase in the frequency of syphilis among young women has been responsible for the concomitant increase in congenital disease. In 1986, New York City reported only 57 cases of congenital syphilis; the number of reported cases in New York for 1989 was well over 1000.4
With increased attention being paid to the detection and treatment of sexually transmitted diseases in New York, it was surprising to us that seven infants beyond the newborn period were admitted during the past year with symptomatic but previously undiagnosed congenital syphilis.5 In the cases in which both mother and baby had been seronegative at delivery (Patients 1, 2, 3, and 4), the mother's acquisition of infection late in pregnancy is probably the best explanation for the development of unsuspected congenital disease. Spirochetes gain access to the circulation soon after mucocutaneous inoculation, but it may take weeks for antibody titers to become elevated. A negative serologic test may also be due to the prozone phenomenon, which occurs when the concentration of antibody in a given specimen is so high that flocculation is not apparent.6 , 7 A recent letter in the Journal describes false negative results on the rapid-plasma-reagin test caused by a prozone in two mothers whose newborn infants clearly had congenital syphilis.8 We were unable to test this possibility in our patients, since none of the laboratories routinely saved serum samples that tested negative. Three of our patients (Patients 5, 6, and 7) might have been identified earlier if serologic tests had been performed on samples from both mother and baby at birth. The hospitals in which two of these babies were born had not had a case of congenital syphilis in more than 10 years, and it was assumed, on the basis of their experience, that a single negative test during pregnancy was sufficient to rule out the disease. The most recent guidelines from the Centers for Disease Control recommend testing for syphilis at the first prenatal visit and again at delivery, with an additional test during the third trimester in high-risk situations.9 On the basis of our experience, patients at risk may be difficult to identify since two of our babies came from intact families and their mothers had regular prenatal care.
Postmortem studies of infants with congenital syphilis suggest that hepatitis was uncommon in the era before antibiotics became available, although hepatomegaly occurred frequently and spirochetes were usually seen in tissue sections from the liver.10 , 11 Although all our patients had hepatomegaly, abnormalities were also seen on liver-function tests and were consistent with a pattern described for early syphilitic hepatitis.12 The alkaline phosphatase level was notably elevated in all the babies and alkaline phosphatase was not fractionated, but the highest levels were seen in patients with no radiologic evidence of bone disease. In six patients, the enlarged liver and abnormal results on liver-function tests returned to normal within several days of the initiation of specific therapy. In one patient (Patient 7), however, the aminotransferase levels continued to rise during therapy and peaked two weeks after admission. Such marked hepatocellular dysfunction, which occurs soon after the beginning of penicillin therapy, has been ascribed to products of treponemal lysis that appear to be cytotoxic or to an autoimmune reaction that damages liver cells in some way.13 , 14
Hematologic abnormalities, including anemia, monocytosis, and thrombocytopenia, occur frequently in congenital syphilis. Among our patients, however, mild thrombocytopenia occurred in only one child and was not clinically important. Whitaker et al. reported that clinically important hemolysis occurs in patients with symptomatic congenital syphilis,15 but only one of our patients (Patient 3) required blood transfusions. A reactive monocytosis is also common in both congenital and acquired disease and was seen in most of our patients.15 16 17
Infants with symptomatic congenital syphilis, such as those described here, may have evidence of central nervous system infection on laboratory tests; the abnormalities are quite variable.18 , 19 Asymptomatic babies who have been fully evaluated only because their mothers have had a positive serologic test rarely have abnormal spinal fluid, however.19 The recommendations for treating congenital syphilis now include a regimen that is effective for neurosyphilis, since spirochetes have been recovered by culture from patients who have otherwise normal spinal fluid.9 , 20 Because it may be difficult to achieve adequate levels of penicillin in the cerebrospinal fluid, we chose a dose, for these infants, of 250,000 units of aqueous penicillin per kilogram of body weight per day. It has been stated that even with mild inflammation this regimen will yield mean penicillin levels of 0.3 to 0.8 μg per milliliter in the spinal fluid; in vitro, treponemes appear to be inactivated at a level of 0.1 μg of penicillin per milliliter.21 , 22
The negative results of serologic tests performed in these babies and their mothers at the time of delivery were probably due to the mother's acquisition of syphilis toward the end of the pregnancy. In some of the cases we studied, however, this assumption may not be justified, because serologic testing of both the mother and baby was not performed at birth. During the present epidemic, it is advisable to test all mothers during pregnancy and to test all mothers and babies at the time of delivery. Despite this precaution, some cases of congenital syphilis will go undiagnosed until symptoms develop in the baby. Because infants do not always present with signs and symptoms that are specific for congenital syphilis, a serologic test should be performed for all infants who have fever with aseptic meningitis, hepatomegaly, or hematologic abnormalities, even if previous tests for syphilis have been negative.
Source Information
From the Bronx Municipal Hospital Center (D.H.D.) and Albert Einstein College of Medicine (J.H.G.), Bronx, N.Y. Address reprint requests to Dr. Glaser at Albert Einstein College of Medicine, Rm. 803—Jacobi, Pelham Pky. and East-chester Rd., Bronx, NY 10461.
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- Citing Articles (20)
Citing Articles
1
Pablo J. Sánchez, Janna C. Patterson, Amina Ahmed. 2012. Toxoplasmosis, Syphilis, Malaria, and Tuberculosis. , 513-537.
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Arnold P. Oranje, Robert A.C. Bilo, Nico G. Hartwig. 2011. Sexually Transmitted Diseases in Children and Adolescents. , 153.1-153.23.
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Tobias R. Kollmann, Simon Dobson. 2011. Syphilis. , 524-563.
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Avinash K. Shetty, Yvonne A. Maldonado. 2011. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Infant. , 622-660.
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Bennie H. Jeng, Gary N. Holland, Careen Y. Lowder, William F. Deegan, Michael B. Raizman, David M. Meisler. (2007) Anterior Segment and External Ocular Disorders Associated with Human Immunodeficiency Virus Disease. Survey of Ophthalmology 52:4, 329-368
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2007. Dermatologische Erkrankungen des Neugeborenen. , 15-71.
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David Ingall, Pablo J. Sanchez, Carol J. Baker. 2006. Syphilis. , 545-580.
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Yvonne A. Maldonado. 2006. Acquired Immunodeficiency Syndrome in the Infant. , 667-692.
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H. Schöfer, N. H. Brockmeyer, H.-J. Hagedorn, O. Hamouda, W. Handrick, W. Krause, U. Marcus, D. Münstermann, K. U. Petry, H. Prange, A. Potthoff, G. Gross. (2005) Syphilis. Der Hautarzt 56:11, 1084-1100
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Pablo J. Sánchez, Amina Ahmed. 2005. Toxoplasmosis, Syphilis, Malaria, and Tuberculosis. , 530-550.
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Estella M. Alonso, Byung-Ho Choe, Jorge A. Bezerra, William F. Balistreri. 2005. Transplantation for Cholestatic Liver Disease in the Pediatric Patient. , 303-321.
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Van Tine, Brian A.Shaw, George M., Aldrovandi, Grace, . (1999) Mother-to-Infant Transmission of the Human Immunodeficiency Virus during Primary Infection. New England Journal of Medicine 341:20, 1548-1548
Full Text13
Konrad Wicher, Harold W Horowitz, Victoria Wicher. (1999) Laboratory methods of diagnosis of syphilis for the beginning of the third millennium. Microbes and Infection 1:12, 1035-1049
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G-M Lackmann, U Willnow, V Wahn, H Schroten. (1999) The importance of reading test results. The Lancet 353:9149, 290
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J. MeŠtrović, V. Krželj, L. Balarin, M. Meštrovič, V. Škrabič. (1997) Congenital Syphilis Associated with Hyperlipoproteinemia. Pediatric Dermatology 14:3, 226-228
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John H. Y. How, John D. P. Bowditch. (1994) Syphilis in Pregnancy: Experience From a Rural Aboriginal Community. The Australian and New Zealand Journal of Obstetrics and Gynaecology 34:4, 383-389
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Curtis E. Margo, Latif M. Hamed. (1992) Ocular syphilis. Survey of Ophthalmology 37:3, 203-220
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Patricia O'shea. (1992) Case 3 Congenital Syphilis in a Twin Gestation. Fetal & Pediatric Pathology 12:6, 865-870
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(1991) Congenital Syphilis. New England Journal of Medicine 324:15, 1063-1065
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McIntosh, Kenneth, . (1990) Congenital Syphilis — Breaking through the Safety Net. New England Journal of Medicine 323:19, 1339-1341
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