Clinical manifestations

Presentation and course

Because of the protean manifestations in humans, syphilis has been called the “Great Mimicker,” and congenital syphilis represents an aspect of it (40).

Syphilis is transmitted mainly during sexual activity by direct contact with the mucocutaneous lesions of the primary or secondary stages of the disease. Vertical transmission can occur transplacentally at any time during gestation because of maternal spirochetemia but can also occur through contact with a genital lesion at the time of delivery.

Transplacental transmission rates vary depending on the stage of maternal infection: they are nearly 100% during the secondary phase, 70% to 100% during the primary phase, and 30% during the latent phase. The risk of fetal infection increases as the stage of pregnancy advances (26). Fetal syphilis is only detected on prenatal ultrasound after 18 weeks, when the immunocompetent fetus can generate the immunologic response necessary to cause abnormalities on ultrasound (46).

Congenitally infected subjects can present with either early congenital syphilis or late congenital syphilis.

Early congenital syphilis. Clinical manifestations may begin in the first 24 months of life but are usually present at birth or in the first few months. The longer the interval between maternal infection and pregnancy, the more benign the outcome in the infant (Kassowitz law) (22). Between 30% and 40% of infected fetuses are stillborn (08). Infants can present with intrauterine growth retardation, failure to thrive, fever, hepatosplenomegaly, ascites, jaundice, and generalized lymphadenopathy with particular involvement of the epitrochlear nodes. About 50% will have mucocutaneous lesions with purulent or bloody rhinitis or "snuffles," maculopapular or vesiculobullous rash characteristically involving the palms and soles, and mucous patches and condyloma lata around the anus and external genitalia. Some patients have bony abnormalities including periostitis and osteochondritis that are self-limited but lead to painful pseudoparalysis of Parrot or pathologic fractures. The metaphysitis with metaphysical destruction, the classic Wimberger sign, and other bony changes can be seen on x-ray. Besides pseudoparalysis, the painful swellings of the extremities may be mistaken for nonaccidental trauma (34).

Other organ involvement includes pneumonitis; glomerulonephritis or nephrotic syndrome with hypertension, hematuria, proteinuria, hypoproteinemia, hypercholesterolemia, and hypocomplementemia; leptomeningitis; and ophthalmologic abnormalities including interstitial keratitis, uveitis, optic atrophy, and papilledema.

Table 1. Clinical Manifestations of Early Congenital Syphilis

General
	• Intrauterine growth retardation • Failure to thrive • Fever • Generalized lymphadenopathy
Skin
	• Cutaneous maculopapular or vesiculobullous rash • Condyloma lata
Bone
	• Periostitis • Osteochondritis • Painful pseudoparalysis • Pathological features
Mucosa
	• Purulent or bloody rhinitis • Mucous patches
Kidney
	• Glomerulonephritis • Nephrotic syndrome
Eyes
	• Uveitis • Papilledema • Optic atrophy • Keratitis
CNS
	• Leptomeningitis • Cerebrovascular accidents
Lungs
	• Pneumonia
Laboratory
	• Leukocytosis • Leukopenia • Coombs-negative hemolytic anemia • Thrombocytopenia • Increased liver enzymes • CSF pleocytosis • CSF increased protein

Early congenital syphilis may present with life-threatening manifestations (See Table 2) secondary to liver failure, severe anemia, leukemoid reaction, thrombocytopenia, disseminated intravascular coagulation, hypoglycemia, acidosis, meningoencephalitis, respiratory failure secondary to pneumonia alba, or diaphragmatic compromise from ascites or hepatosplenomegaly. Pancreatitis, necrotizing enterocolitis, nephrotic syndrome with anasarca, and failure to thrive (56) are other severe presentations.

Table 2. Life-Threatening Manifestations

• Nonimmune hydrops • Liver failure • Severe anemia • Leukemoid reaction • Thrombocytopenia • Disseminated intravascular coagulation • Hypoglycemia • Failure to thrive • Acidosis • Meningoencephalitis • Respiratory failure • Pancreatitis • Necrotizing enterocolitis • Nephrotic syndrome

Laboratory abnormalities include leukocytosis or leukopenia, Coombs-negative hemolytic anemia, thrombocytopenia, and increased liver enzymes. The CSF may show an increased protein or a mainly lymphocytic pleocytosis. Premature infants born with early congenital syphilis have a higher tendency towards positive CSF findings (36).

Early congenital syphilis has been associated with persistent hypoglycemia and hypopituitarism (21).

Coinfection with HIV is associated with an accelerated progression to early neurosyphilis with optic neuritis, meningitis, or cerebrovascular accidents; neurosyphilis may be the first sign of HIV infection (22).

Late congenital syphilis. The late manifestations of congenital syphilis are the result of either scarring from early untreated systemic disease or a hypersensitivity reaction. Approximately 40% of surviving infants will have late manifestations if untreated (25). Sir Jonathan Hutchinson (1828-1913) established the fact that interstitial keratitis is almost always due to congenital syphilis and described a triad consisting of notched incisors, interstitial keratitis, and eighth cranial nerve deafness, which is sudden and usually occurs around 8 to 10 years of age. Other signs include frontal bossing, short maxilla, saddle nose, protruding mandible, high-arched palate, mulberry molars, perioral fissures (rhagades), bilateral knee effusions, sternoclavicular thickening, saber shins, flaring scapulas, mental retardation, and hydrocephalus (06).

Table 3. Clinical Manifestations of Late Congenital Syphilis

	• Hutchinson triad
		- notched incisors - interstitial keratitis - eighth cranial nerve deafness
	• Frontal bossing • Short maxilla • Saddle nose • Protruding mandible • High-arched palate • Mulberry molars • Perioral fissures (rhagades) • Bilateral knee effusions • Sternoclavicular thickening • Saber shins • Flaring scapulas • Mental retardation • Hydrocephalus

Prognosis and complications

Late congenital syphilis should be considered an avoidable complication of congenital syphilis because it is almost completely prevented when early congenital syphilis, asymptomatic or symptomatic, is treated appropriately and careful serologic followup is carried out. Approximately 40% of surviving infants will have late manifestations if untreated (25).

Interstitial keratitis is the most common late finding, appearing close to puberty and even occurring in the face of adequate therapy (49). Other complications include eighth nerve deafness, Hutchinson teeth (peg-shaped, notched upper incisors), frontal bossing, saddlenose deformity, mulberry molars, rhagades, saber shins, hydrocephalus, and mental retardation. With regard to sensorineural hearing loss, it is recommended that a repeat audiologic testing be performed at 24 to 30 months of age in an infant with congenital syphilis. Interestingly, in a systematic review of sensorineural hearing loss in congenital syphilis, Chau and colleagues found no cases of progressive or delayed hearing loss due to congenital syphilis in children with previously normal testing (18).

Clinical vignette. Lanata and associates describe an infant with a delayed diagnosis of congenital syphilis in Ohio, USA (33).

A 7-week-old term African-American male infant born via uncomplicated vaginal delivery presented for evaluation of fever to 102 degrees Fahrenheit, 2 days of increased irritability, and decreased movement of the left leg. Of note, he had experienced nasal congestion since birth. He had also developed a rash with discrete “sores” on his face and extremities that had peeled 1 week prior to presentation. Review of systems was negative; there was no known trauma. Maternal prenatal care had been adequate and included treatment for bacterial vaginosis and Candida vaginitis during the first trimester. Laboratory work and serologies were negative.

Aside from the fever, the patient’s other vital signs were within normal limits. Physical exam revealed a fussy but consolable infant, mild congestion without rhinorrhea, a hoarse cry, oral thrush, and hepatomegaly. Small, discrete, hypochromic macular lesions with fine desquamation of the borders were noted along bilateral cheeks, chin, arms, and legs. The left hip and knee were held in a flexed position; movement of the contralateral hip caused discomfort.

Radiograph of his right femur showed a nondisplaced fracture of the distal metaphysis. Skeletal survey revealed additional fractures of the bilateral tibia, scattered areas of cortical destruction, and diffuse periostitis of long bones. Computed tomography (CT) scan of the head was normal. Laboratory results were as follows: white blood cell count was 8.9 × 10⁹/L; hemoglobin was 6.9 g/dL; hematocrit was 22.6%; platelets were 528 × 10⁹/L; and reticulocyte count was 8.5%. The direct Coombs testing, uric acid, lactate dehydrogenase, serum electrolytes, parathyroid hormone, and urinalysis were unremarkable. Aspartate aminotransferase was normal (37 U/L), but alanine aminotransferase (74 U/L) and alkaline phosphatase (905 U/L) were elevated. Respiratory viral testing returned positive for coronavirus.

Child abuse consultants reviewed the findings and became concerned for congenital syphilis based on the cutaneous lesions found on the palms and soles. Rapid plasma reagin (RPR) testing was performed and infectious diseases specialists were consulted. The patient’s serum RPR titer was 1:512 and the Treponema pallidum particle agglutination (TP-PA) test was reactive, confirming the diagnosis of congenital syphilis. Cerebrospinal fluid collected to evaluate for possible neurosyphilis revealed 1 red blood cell/mm³, 6 white blood cells/mm³ (45% polymorphonuclear neutrophils; 35% lymphocytes; 20% monocytes), normal glucose (45 mg/dL), elevated protein (61 mg/dL), and nonreactive venereal disease research laboratory (VDRL) testing. Ophthalmologic examination was normal. After establishing the diagnosis, his mother recalled that she had first noticed his left lower extremity pseudoparalysis on his fourth day of life, but was reassured after evaluation by his pediatrician.

The infant received 10 days of intravenous (IV) aqueous penicillin G (50,000 units/kg/dose every 6 hours). Four hours after the first dose, he developed a Jarisch-Herxheimer reaction characterized by fever and tachycardia that self-resolved. His left lower extremity pseudoparalysis and pain resolved prior to discharge. On follow-up, the patient remained well, reaching normal growth parameters and developmental milestones. At 7 months of age, the serum RPR titer had decreased to 1:4.

The parents were referred to the health department for confirmatory testing. The mother’s RPR titer was 1:32 with a reactive fluorescent treponemal antibody absorption (FTA-ABS) test. She was found to have hyperpigmented lesions on the palms and soles and was ultimately diagnosed with secondary syphilis. The father’s RPR test was nonreactive. Both parents received a single intramuscular injection of benzathine penicillin G (2.4 mU).

Biological basis

Etiology and pathogenesis

In 1905, Fritz Schaudin identified the spirochete Treponema pallidum as the causative organism of syphilis (42).

T pallidum is a thin spiral that measures about 0.2 m in width and 5 to 15 m in length; the organism is tightly wound, and the turns around its spiral are spaced from each other by a distance of 1 μm. They are actively motile, corkscrewing constantly along their major axes. In addition, 3 sheathed flagella are located at each end. The spirals are so thin that dark-field illumination or immunofluorescence is necessary for visual detection of T pallidum. It is a human pathogen and has never been cultured with certainty in artificial media, fertilized eggs, or tissue cultures. The organism can remain viable in stored blood or plasma at 4°C for up to 24 hours (31).

The treponeme has a glycosaminoglycan layer (that may have an antiphagocytic capacity), 6 major proteins in the outer membrane, and a double wall that contains cardiolipin (some of which may be incorporated from damaged host tissues). Antibodies to the cardiolipin form the basis for the nontreponemal serologic tests (22). Further advances in the understanding of the disease are anticipated now that the complete sequencing of the genome of the Treponema Pallidum, the syphilis spirochete, has been done (23).

Treponema pallidum gains entry into the fetus either by hematogenous or transplacental spread or by contamination with vaginal or vulvar active lesions at the time of passage through the birth canal. As a result of fetal infection, there is increased production of inflammatory cytokines IL2, IFN-gamma, TNF-alfa, and prostaglandins. This and the intense fetal inflammatory response elicited by the activation of macrophages by treponemal lipoproteins may cause fetal death, preterm birth, intrauterine growth retardation, and other manifestations of congenital syphilis (40).

In a perinatal autopsy study of 21 stillborn fetuses, common findings showed chronic stress of the thymus, hydrops, and hepatosplenomegaly. Common placental findings showed placentomegaly and amniotic fluid infection (32).

Following incubation, the classic findings of obliterative endarteritis occur, which include endothelial and fibroblastic proliferation and thickening and infiltration with plasma cells, lymphocytes, and histiocytes. This lesion can be found in the central nervous system, in the cardiovascular system, or in the chancres seen in the primary stage. Gummas are nonspecific granulomas that are found in tertiary syphilis. They may occur in any organ and may be single or multiple. Gummas cause local destruction, and typically occur in the palate, liver, or brain (22). The infected placenta is thick and enlarged with prominent vascular proliferations, villous immaturity and hypercellularity, chronic villitis, and foci of acute villitis (45). The treponemes can cross the placenta at any stage of the disease and at any time of pregnancy. Controversy exists regarding the association with first trimester loss: some believe that passage of treponemes in the first 20 weeks is associated with only a mild inflammatory reaction in the placenta (54), whereas others have found spirochetes in fetal tissue from spontaneous abortions at 9 weeks to 10 weeks of gestation (26). Although antibodies are formed in response to this infection, the disease progresses. Likewise, acquired syphilis may occur in individuals who have had the congenital form of the disease (22).

Extramedullary hematopoiesis is seen in the liver and may be observed in the spleen, stomach, intestine, pancreas, and lung. Inflammatory reactions are seen in the liver, spleen, stomach, intestine, and pancreas. The "pneumonia alba" consists of an obliterative fibrosis, with increased connective tissue in the septa and interstitium and, on gross inspection, large, firm yellow-white lungs. Immune complex deposition occurs in the renal glomeruli and may or may not include complement.

Widespread involvement of long bones and ribs is prevalent, with osteochondritis, osteomyelitis, and periostitis. The trabeculae are eroded and fibrosis occurs (22).

Neurosyphilis takes either the meningovascular or the parenchymatous form. In both forms, the infectious process begins in the meninges as a widespread diffuse arachnoiditis with inflammation concentrated around the meningeal vessels and the branches that penetrate into the cortex. Small meningeal vessels can show thickening and infiltration of the adventitia as well as intimal proliferation; syphilitic phlebitis is less common, though both can result in infarction with localized lesions of the brain or spinal cord.

Obstructive or communicating hydrocephalus can result from meningeal fibrosis and obliteration of the subarachnoid spaces.

Diffuse meningeal inflammation of the secondary stage can be carried over into the tertiary stage with increased fibrosis of the meninges and the formation of small, often miliary gummas.

In parenchymatous congenital neurosyphilis, as in juvenile paresis, diffuse degeneration occurs with cerebral and cerebellar atrophy. Microscopic changes include round-cell meningeal and perivascular infiltration, loss and degenerative changes in the nerve cells with an increase in microglia and astroglia, a disturbance of normal cytoarchitecture, deposition of iron pigment, and presence of spirochetes (54).

Epidemiology

Risk factors. Congenital syphilis is contracted from an infected mother via transplacental transmission of T pallidum any time during the pregnancy, or at birth from contact with maternal lesions. Among women with untreated early syphilis, up to 40% of pregnancies result in spontaneous abortion, stillbirth, or perinatal death. The rate of transmission is 60% to 100% during primary and secondary syphilis and decreases with later stages of maternal infection – 40% with early latent and 8% with late latent infection.

Prevention of congenital syphilis relies on identifying and adequately treating pregnant women with syphilis. All women should be screened serologically early in pregnancy. In areas where prevalence is high and women are at high risk for infection, serologic testing should also be performed at 28 to 32 weeks’ gestation and at delivery, given the fact that false-negative test results are possible in recent infection and that syphilis can be acquired later in pregnancy after initial testing (01).

Changes in the population incidence of primary and secondary syphilis among women are usually followed by similar changes in the incidence of congenital syphilis (11). Syphilis is rare in much of the industrialized world but persists in the United States as well as in resource-limited countries (01).

Case definition. For public health surveillance purposes, the Centers for Disease Control and Prevention published a new case definition of congenital syphilis in 2018. A presumptive case of congenital syphilis follows:

1) An infant whose mother had untreated or inadequately treated syphilis at delivery, regardless of signs in the infant

Or

2) An infant or child who has a reactive nontreponemal test for syphilis (VDRL, RPR)

Or

3) Equivalent serologic methods and any one of the following:

	• Any evidence of congenital syphilis on physical examination (see clinical description)
	• Any evidence of congenital syphilis on radiographs of long bones
	• A reactive CSF venereal disease research laboratory test (VDRL) test
	• In a nontraumatic lumbar puncture, an elevated CSF leukocyte (white blood cell, WBC) count or protein (without other cause)

Suggested parameters for abnormal CSF WBC and protein values:

	• During the first 30 days of life, a CSF WBC count of >15 WBC/mm3 or a CSF protein >120 mg/dl is abnormal.
	• After the first 30 days of life, a CSF WBC count of >5 WBC/mm3 or a CSF protein >40 mg/dl, regardless of CSF serology (16).

Incidence. The rate of congenital syphilis decreased in the United States during 1991 to 2005, but increased slightly during 2005 to 2008 (13). The congenital syphilis rate among infants less than 1 year of age increased 23%, from 8.2 cases per 100,000 live births in 2005 to 10.1 during 2008. This increase followed a 38% increase in the primary and secondary syphilis rate among females from 2004 to 2007. From 2005 to 2008, the congenital syphilis rate among infants born to Hispanic, white, and black mothers increased; most of the increase in congenital syphilis cases and rate occurred in infants born to black mothers. This increase was observed in infants born to black mothers primarily in the South. The increases in primary and secondary syphilis among black women in the South were linked to crack cocaine use and commercial sex work (11).

From 2008 to 2012, the number of congenital syphilis cases declined in the United States from 10.5 to 8.4 cases per 100,000 live births, reflecting declining trends in rates of primary and secondary syphilis among women, from 1.5 to 0.9 cases per 100,000 women. Presently, all regions of the United States have experienced a decrease in congenital syphilis rates except for the Midwest, where the rate increased from 4.2 to 6.8 cases per 100,000 live births, attributed primarily to increases in Illinois and Ohio. The increased congenital syphilis rates were seen 1 to 2 years after observed increases in primary and secondary syphilis among women in these states. Racial disparities between non-Hispanic black and non-Hispanic white congenital syphilis rates increased during 2008 to 2012; relative decreases in rates of congenital syphilis were higher among whites (21%) than blacks (11%) (13).

Since 2012, the rate of reported congenital syphilis has subsequently increased each year (15). The rate in 2014 was the highest congenital syphilis rate reported since 2001: 11.6 cases per 100,000 live births (13). By 2017, the national rate was 23.3 cases per 100,000 live births, with a total of 918 reported cases, including 64 syphilitic stillbirths and 13 infant deaths. Following historic trends, this increase in congenital syphilis rate has paralleled increases in primary and secondary syphilis among all women and reproductive aged women during 2013 to 2017 (155.6% and 142.8% increases, respectively). During 2013 to 2017, the increase in reported congenital syphilis cases was primarily due to an increase in the West. In 2017, the highest congenital syphilis rates were reported from the West (37.0 cases per 100,000 live births), followed by the South (29.5 cases per 100,000 live births). Rates were highest among blacks (58.9 cases per 100,000 live births), followed by American Indian/Alaskan Native (35.5 cases per 100,000 live births) (15).

In June 2020, a new Centers for Disease Control and Prevention study showed that half of United States congenital syphilis cases in 2018 occurred due to gaps in testing and treatment during prenatal care. The most missed opportunities for preventing congenital syphilis cases occurred in mothers who were diagnosed but inadequately treated (31% of cases) or in mothers who did not have timely prenatal care (28% of cases). Prevention gaps varied by region; nearly 9 in 10 congenital syphilis cases were in the South and West. In the South (34% of cases), lack of adequate treatment was the most common missed prevention opportunity whereas in the West, lack of timely prenatal care was most common (41% of cases) (17).

Global epidemiology. Worldwide, syphilis is a leading cause of adverse pregnancy outcomes (ie, stillbirth and neonatal death). Screening and treatment for syphilis during pregnancy remains suboptimal in low- and middle-income countries despite feasible and cost-effective diagnosis and prevention of maternal-to-child transmission (53).

In 2007, the World Health Organization (WHO) launched a global initiative to eliminate congenital syphilis. This was followed by the Global Guidance on Criteria and Processes for Validation of Elimination of Mother-to-Child Transmission of HIV and Syphilis, launched in 2014. To be considered for elimination of maternal-to-child transmission of syphilis, countries must have met WHO criteria for 2 years for process indicators and 1 year for the impact indicator before review by regional and global validation committees to confirm elimination. The impact indicator was case rate of congenital syphilis less than or equal to 50 cases per 100,000 live births. Process indicators included (1) antenatal care coverage of at least 1 visit greater than or equal to 95%; (2) coverage of syphilis testing of pregnant women greater than or equal to 95%; and (3) treatment of syphilis-seropositive pregnant women greater than or equal to 95%.

In June 2017, a global meeting of experts convened by the WHO Department of Reproductive Health and Research and the Bill and Melinda Gates Foundation reviewed the progress made to eliminate congenital syphilis since the 2007 initiative. Only 9% of Global Aid Monitoring (GAM)-reporting countries achieved the milestone of greater than or equal to 95% testing of women who received antenatal care and greater than or equal to 95% treatment of pregnant women who test positive. This data falls short of the 2020 milestone of 70% of countries. Meeting participants felt that this limited progress could be attributed to challenges such as limited access to and performance of syphilis testing in antenatal care clinics, limited availability and provider use of benzathine benzylpenicillin (only recommended treatment for pregnant women with syphilis), etc. (55).

Prevention

United States. Prevention and detection of congenital syphilis lies in identifying syphilis in pregnant women. This is accomplished through routine serologic screening of pregnant women (14). The CDC advises rescreening in women at high risk at 28 weeks of gestation and again at delivery (35). As part of the management of pregnant women who have syphilis, the CDC recommends obtaining information concerning ongoing risk behaviors and treatment of sex partners to assess the risk for reinfection. The CDC also recommends that no mother or newborn infant should leave the hospital after birth without maternal serologic status having been documented at least once during pregnancy and preferably again at delivery if at risk (14).

Using 2018 national congenital syphilis surveillance data and a previously developed framework, the CDC identified missed opportunities for congenital syphilis prevention based on an increase in reported congenital syphilis cases in the United States from 2013 to 2018. Nationally, the most commonly missed prevention opportunities were (1) a lack of adequate maternal treatment despite the timely diagnosis of syphilis (30.7%) and (2) a lack of timely prenatal care (28.2%), with variation by geographic region (17).

Globally. For global elimination of congenital syphilis, the World Health Organization (WHO) identified 4 pillars for action in 2007: (1) ensure sustained advocacy and political commitment for successful health initiative; (2) increase access to and quality of maternal and newborn health services; (3) screen and treat all pregnant women and partners; (4) establish surveillance, monitoring, and evaluation systems (28). These pillars will not only impact congenital syphilis, but also improve maternal health, infant mortality, HIV/AIDS, and other diseases. Hossain and colleagues analyzed the implementation of this plan (low to mid prevalence of congenital syphilis countries versus high prevalence of congenital syphilis countries) and found that implementation was variable in the 14 countries analyzed (28). Interestingly, the financial resources, though a limiting factor, were not an insurmountable barrier to improvement.

Differential diagnosis

Congenital syphilis is now part of a group of congenital infections that since 1971 has been known as TORCH, or toxoplasmosis, other, rubella, cytomegalovirus, and herpes (39). The acronym was devised to focus attention on a group of microbial agents that cause such clinically similar manifestations in newborns that testing for one should mean testing for all (39). The emergence of human immunodeficiency virus infection and the reemergence of congenital syphilis have led to modifications of the TORCH acronym, for example STORCH (syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpesvirus) and STARCH (syphilis, toxoplasmosis, acquired immunodeficiency syndrome, rubella, cytomegalovirus, and herpesvirus), that more appropriately reflect current pathogens (05).

Diagnostic workup

The majority of cases of early congenital syphilis occur without symptoms, hence, the need for maternal serologic screening during pregnancy and at the time of delivery. A thorough evaluation of the newborn should take place if the mother meets 1 of the criteria mentioned in Table 4.

The evaluation should include parameters shown in Table 5:

Table 5. Evaluation for Congenital Syphilis

	• Physical examination
	• Quantitative nontreponemal and a treponemal serologic test for syphilis on infant's serum sample (not on cord blood because false positive and false negative results can occur)
	• Determination of antitreponemal IgM antibody by a CDC approved method, if available.
	• CSF cell count, protein, and VDRL
	• Long bone x-rays (unless the diagnosis has already been otherwise established)
	• CBC, platelet count
	• Other tests such as liver function tests, chest x-ray as indicated.
	• If available, pathologic examinations of the placenta or umbilical cord using fluorescent antitreponemal antibody staining

The physical examination of the infant should focus on the myriad of manifestations of early syphilis, many of which will not be present in the immediate neonatal period. Long-bone radiographs will show pathologic changes in 20% of asymptomatic patients and in 90% of symptomatic patients (07), with diaphyseal periostitis and osteochondritis. The diagnosis of congenital syphilis in symptomatic infants rarely poses a problem, but a problem frequently arises when the infant is asymptomatic at birth (approximately 60% of cases). Early identification and treatment of at-risk neonates are essential to prevention of long-term consequences (47).

Table 6. The Serological Tests Used in Congenital Syphilis

Nontreponemal (detect anticardiolipin antibody and are reported as a titer)
	Standard tests
		• VDRL • rapid plasma regain (RPR)
	Experimental tests
		• VDRL ELISA IgG AND IgM
Treponemal (detect the immune response to antigens on the spirochete cell surface and are reported as positive and negative)
	Standard tests
		• fluorescent treponemal antibody • fluorescent treponemal antibody-absorption • treponema pallidum particle agglutination
	Experimental tests
		• 19S-IgM fluorescent treponemal antibody-absorption • T pallidum ELISA for IgG • T pallidum Western blot • rabbit infectivity test • polymerase chain reaction for T pallidum • T pallidum antigen-capture ELISA

As with adults, the serologic testing of newborns is neither 100% sensitive nor 100% specific--hence, the attempts at devising a way to detect not only the infected infant, but also the uninfected infant. The present recommendation is to begin with nontreponemal tests for screening and to use the treponemal tests to confirm presumed diagnosis (02). Quantitative nontreponemal tests are helpful in determining not only the adequacy of treatment but also the occurrence of reinfection and relapse. Testing for HIV should be done in all cases of syphilis (02). The treponemal tests are cumbersome and expensive and some are not widely available. Although the treponemal tests are highly specific, their sensitivity is about 75% to 80% (24; 51; 37).

In developing countries where the availability of on-site testing versus off-site testing is an important issue, tests such as the on-site treponemal immunochromatographic strip (ICS) test, though more expensive than the off-site RPR test, has been cost effective because the prevalence of maternal syphilis is high (20).

Cerebrospinal fluid should be analyzed for all children suspected of congenital syphilis because neurosyphilis is believed to occur in 40% to 60% of infants with congenital syphilis (43). This diagnosis is difficult to establish because of passive transfer of nontreponemal IgG antibodies from serum into CSF (52). The CSF abnormalities supportive of the diagnosis include an increased protein and leukocyte count and a positive VDRL. The interpretation of these results in neonates is difficult because their CSF protein can be normal up to 150 mg/dL and their leukocyte count can reach 35 cells/mm3 in term neonates and 45 cells/mm3 in low-birthweight premature infants. Negative CSF VDRL or FTA-ABS does not exclude CNS involvement. Hence, if CSF test results cannot exclude infection in an infant evaluated for congenital syphilis, the infant should be treated (02). Using CSF rabbit infectivity test to identify infants with T pallidum infection of CNS, Michelow and colleagues showed that overall CNS infection was best predicted by IgM immunoblotting of serum or PCR assay of serum or blood (38). However, because such testing is not routinely available and because the risk of CNS involvement is high in congenital syphilis, infants diagnosed as having congenital syphilis by physical examination, conventional laboratory tests, and radiological examination should be treated with 10-day course of aqueous penicillin G or penicillin G procaine for presumed CNS infection.

Other tests as clinically indicated include chest radiography for pneumonia alba, complete blood count for leukemoid reaction, blood smear and Coombs test for hemolytic anemia, platelet count, liver function tests for hepatitis, urinalysis for hematuria and proteinuria, and HIV/TORCH titers.

Management

Identification and treatment of congenital syphilis at birth or within 3 months of life prevents late sequelae (46). Parenteral penicillin G remains the preferred drug for syphilis at any stage. Parenteral penicillin is the only documented effective therapy for patients who have syphilis during pregnancy and for those with neurosyphilis, and it is strongly recommended whenever possible in HIV-infected patients. Higher CSF penicillin levels are reached with aqueous penicillin G than with procaine penicillin G (04).

Due to the diagnostic limitations of congenital syphilis, the Centers for Disease Control and Prevention developed treatment recommendations based on clinical scenarios (46). Management decisions are based on the following: (1) identifying the syphilis in the mother; (2) comparing the maternal (at delivery) and infant nontreponemal serologic titers by using the same test and preferably the same laboratory; (3) determining the adequacy of maternal treatment for syphilis; and (4) determining if the infant has clinical, laboratory, or radiological evidence of syphilis (10).

For management purposes, the neonates can be divided into 3 groups (Centers for Disease Control and Prevention 2002; 02):

(1) Symptomatic infants with proven disease, as demonstrated by (A) evidence of active disease on physical, radiological, or laboratory examination, or (B) the placenta, umbilical cord, or body fluids are positive for treponemes using specific fluorescent treponemal antibody staining or darkfield examination.

(2) Asymptomatic infants born to mothers who were untreated, whose treatment was not documented, or who received inadequate treatment during pregnancy (See Table 4). (A) presumed disease in those: infants whose evaluation (serologic, radiologic, and CSF examination) is abnormal, or (B) no apparent disease in infants whose evaluation is normal.

(3) Asymptomatic infants born to mothers who received adequate treatment for syphilis; for example, a mother who was treated more than 4 weeks before delivery with an appropriate penicillin regimen and whose nontreponemal antibody titer in early syphilis decreased 4-fold, or the low titer remained stable and low in late syphilis and the mother has no evidence of reinfection or relapse.

If a neonate has proven or presumed congenital syphilis, aqueous crystalline penicillin G is preferred. The dosage should be based on chronologic, not gestational, age. The recommended dosage is 100,000 to 150,000 U/kg per day (given as 50,000 U/kg/dose intravenously every 12 hours during the first 7 days and then every 8 hours thereafter for a total of 10 days). Alternately, some experts recommend aqueous procaine penicillin G (50,000 U/kg/dose once a day, intramuscularly) for 10 days. If more than 1 day of therapy is missed, the entire course should be restarted.

Asymptomatic infants born to mothers whose treatment for syphilis may have been inadequate (See Table 4) should be fully evaluated and treated with aqueous crystalline or procaine penicillin G for 10 days. Some experts treat with a single dose of 50,000 U/kg of benzathine penicillin G intramuscularly if the clinical and laboratory evaluation, including CSF findings and x-rays (long bones and chest), was normal and the follow-up can be ensured.

Asymptomatic infants born to mothers whose treatment for syphilis was adequate should be examined and followed monthly until their serologic test results become negative. If adequate follow-up is not feasible, some experts recommend treating these infants with a single dose of benzathine penicillin.

Infants over 1 month of age with possible congenital syphilis or who have neurologic involvement should be treated with aqueous crystalline penicillin, 200,000 to 300,000 U/kg per day, intravenously (administered every 4-6 hours), for 10 days. This regimen should also be used to treat children older than 2 years of age who have late and previously untreated congenital syphilis. Further, some experts also suggest giving such patients a single dose of benzathine penicillin G, 50,000 U/kg, intramuscularly, after 10 days of intravenous aqueous penicillin. If the CSF examination and CSF-VDRL are negative, some experts would recommend treating with 3 weekly doses of benzathine penicillin G 50,000 U/kg (02).

If there is shortage of aqueous crystalline penicillin G, some or all of the doses may be substituted with daily doses of procaine penicillin. If both the aqueous and the procaine penicillin G are not available, ceftriaxone may be used in consultation with a specialist in the treatment of congenital syphilis. Ceftriaxone must be used with caution in jaundiced infants, and because studies strongly supporting ceftriaxone for the treatment of congenital syphilis have yet not be done, infants will need clinical and serologic follow-up (10).

In cases of penicillin allergy, skin testing should be done and will be negative in most patients. Desensitization should be performed in the remaining patients. The administration of penicillin to "allergic" individuals with such precautions has been safe.

The Jarisch-Herxheimer reaction, including fever, chills, hypotension, tachycardia, tachypnea, and leukocytosis, occurs in some newborns within a few hours after treatment. It has been treated with prednisone to mitigate symptoms. Treatment with penicillin should not be discontinued (22).

After appropriate therapy for congenital syphilis, follow-up should be performed on both symptomatic and asymptomatic neonates (50). A careful physical examination should be performed at 2, 4, 6, and 12 months of age. Nontreponemal serologic testing should be performed every 2 to 3 months until the test becomes negative or the titer has decreased by at least 4-fold. After successful treatment for congenital syphilis, titers should decline by 3 months and become nonreactive by 6 months. If titers increase, fail to decline, or are still present after 6 to 12 months after initial treatment, the infant should be reevaluated, including CSF examination, and retreated with parenteral penicillin G for 10 days (02).

Because treponemal tests can remain positive in spite of effective treatment, they are not used to evaluate the response to therapy. Following therapy, the infants usually seroconvert by 18 months of age. A reactive treponemal test at 18 months of age requires full reevaluation and treatment for congenital syphilis (02; 48).

Outcomes

If congenital syphilis is diagnosed and treated appropriately and in a timely fashion, prognosis for this disease is excellent. However, there is an increased risk for worse outcomes and possible death in premature infants; those who have a delay or do not receive proper treatment; patients who display an extensive spread of the disease with multiple organ failure; and infants with a severe Jarisch-Herxheimer reaction on treatment. Delayed diagnosis and treatment can lead to late and persistent clinical features of intellectual disability, skin gummas, scarring, hearing deficits, and skeletal abnormalities (29).

Special considerations

Pregnancy

The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend universal screening of all women early in pregnancy, then at delivery and after an exposure to an infected partner (03). Additionally, screening in the beginning of the third trimester is recommended for high-risk pregnant women, such as those who use illicit drugs, and for women in areas of high prevalence of syphilis. Both the American Academy of Pediatrics and American College of Obstetricians and Gynecologists recommend the use of nontreponemal screening tests (VDRL or RPR) initially followed by confirmatory test using treponemal antibody test if the VDRL or RPR is positive. Hersh and colleagues reported that repeat screening in the first and third trimester results in fewer maternal and neonatal adverse outcomes and is both cost effective and results in improvement of outcomes (27). This data supports updated screening guidelines, moving towards repeat screening as standard-of-care.

Although rare, congenital syphilis should be considered in the differential diagnosis of nonimmune fetal hydrops (due to fetal anemia), which, in severe cases, can result in stillbirth or neonatal death. Doppler flow studies showing increased peak systolic velocity in the middle cerebral artery is strongly suggestive of fetal anemia, the severity of which can then be confirmed by cordocentesis. Chen and colleagues reviewed the published cases of syphilitic nonimmune hydrops and reported successful outcome with intrauterine transfusion in a case of nonimmune hydrops due to congenital syphilis (19).