Congenital syphilis

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Congenital syphilis
Hutchinson teeth congenital syphilis PHIL 2385.rsh.jpg
Notched incisors known as Hutchinson's teeth which are characteristic of congenital syphilis
Specialty Infectious diseases   OOjs UI icon edit-ltr-progressive.svg
Symptoms Rash, fever, large liver and spleen, skeletal abnormalities [1]
Usual onsetUnborn baby, newborn baby or later [1]
DurationLifelong
TypesEarly & late [2]
Causes Treponema pallidum [2]
Diagnostic method Signs, symptoms, blood tests, CSF tests
PreventionAdequate screening and treatment in pregnant mother [2]
Treatment Antibiotic [3]
Medication Penicillin by injection; Procaine benzylpenicillin, benzylpenicillin, benzathine penicillin G [3]
Edvard Munch's Inheritance (1897-99) depicts a baby with congenital syphilis and its mother. Edvard Munch - Inheritance - Google Art Project.jpg
Edvard Munch's Inheritance (1897–99) depicts a baby with congenital syphilis and its mother.

Congenital syphilis is syphilis that occurs when a mother with untreated syphilis passes the infection to her baby during pregnancy or at birth. [4] It may present in the fetus, infant, or later. [1] [5] Clinical features vary and differ between early onset, that is presentation before 2-years of age, and late onset, presentation after age 2-years. [4] Infection in the unborn baby may present as poor growth, non-immune hydrops leading to premature birth or loss of the baby, or no signs. [2] [4] Affected newborns mostly initially have no clinical signs. [4] They may be small and irritable. [4] Characteristic features include a rash, fever, large liver and spleen, a runny and congested nose, and inflammation around bone or cartilage. [2] [4] There may be jaundice, large glands, pneumonia (pneumonia alba), meningitis, warty bumps on genitals, deafness or blindness. [4] [6] [7] Untreated babies that survive the early phase may develop skeletal deformities including deformity of the nose, lower legs, forehead, collar bone, jaw, and cheek bone. [4] There may be a perforated or high arched palate, and recurrent joint disease. [2] [4] Other late signs include linear perioral tears, intellectual disability, hydrocephalus, and juvenile general paresis. [4] Seizures and cranial nerve palsies may first occur in both early and late phases. [4] Eighth nerve palsy, interstitial keratitis and small notched teeth may appear individually or together; known as Hutchinson's triad. [4]

Contents

It is caused by the bacterium Treponema pallidum subspecies pallidum when it infects the baby after crossing the placenta or from contact with a syphilitic sore at birth. [4] [5] It is not transmitted during breastfeeding unless there is an open sore on the mother's breast. [4] The unborn baby can become infected at any time during the pregnancy. [4] Most cases occur due to inadequate antenatal screening and treatment during pregnancy. [8] The baby is highly infectious if the rash and snuffles are present. [4] The disease may be suspected from tests on the mother; blood tests and ultrasound. [9] Tests on the baby may include blood tests, CSF analysis and medical imaging. [10] Findings may reveal anemia and low platelets. [4] Other findings may include low sugars, proteinuria and hypopituitarism. [4] The placenta may appear large and pale. [4] Other investigations include testing for HIV. [10]

Prevention is by safe sex to prevent syphilis in the mother, and early screening and treatment of syphilis in pregnancy. [6] One intramuscular injection of benzathine penicillin G administered to a pregnant woman early in the illness can prevent congenital syphilis in her baby. [11] Treatment of suspected congenital syphilis is with penicillin by injection; benzylpenicillin into vein, or procaine benzylpenicillin into muscle. [3] [10] During times of penicillin unavailability, ceftriaxone may be an alternative. [10] Where there is penicillin allergy, antimicrobial desensitisation is an option. [10] [12]

Syphilis affects around one million pregnancies a year. [13] In 2016, there were around 473 cases of congenital syphilis per 100,000 live births and 204,000 deaths from the disease worldwide. [14] Of the 660,000 congenital syphilis cases reported in 2016, 143,000 resulted in deaths of unborn babies, 61,000 deaths of newborn babies, 41,000 low birth weights or preterm births, and 109,000 young children diagnosed with congenital syphilis. [15] Around 75% were from the WHO's African and Eastern Mediterranean regions. [2] Serological tests for syphilis were introduced in 1906, and it was later shown that transmission occurred from the mother. [16]

Signs and symptoms

Untreated early syphilis infections results in a high risk of poor pregnancy outcomes, including saddle nose, lower extremity abnormalities, miscarriages, premature births, stillbirths, or death in newborns. Some infants with congenital syphilis have symptoms at birth, but many develop symptoms later. Symptoms may include rash, fever, large liver and spleen, and skeletal abnormalities. [17] Newborns will typically not develop a primary syphilitic chancre but may present with signs of secondary syphilis (i.e. generalized body rash). Often these babies will develop syphilitic rhinitis ("snuffles"), the mucus from which is laden with the T. pallidum bacterium, and therefore highly infectious. If a baby with congenital syphilis is not treated early, damage to the bones, teeth, eyes, ears, and brain can occur. [17]

Neurosyphilis in newborns may present as cranial nerve palsies, cerebral infarcts (strokes), seizures or eye abnormalities. [18]

Many newborns with congenital syphilis, 55% by some estimates, do not exhibit any symptoms initially, with signs and symptoms developing days to months later. [18]

Early

The face of a newborn infant displaying snuffles indicative of congenital syphilis The face of a newborn infant with Congenital Syphilis.tif
The face of a newborn infant displaying snuffles indicative of congenital syphilis
Infant shown with Congenital Syphilis Syphilis, Congenital 1.jpg
Infant shown with Congenital Syphilis

Newborns may be asymptomatic and are only identified on routine prenatal screening. If not identified and treated, these newborns develop poor feeding and runny nose. [17] By definition, early congenital syphilis occurs in children between 0 and 2 years old. [19]

Late

Gerard de Lairesse, Dutch Baroque painter who had congenital syphilis. Portrait of Gerard de Lairesse MET rl1975.1.140.R.jpg
Gérard de Lairesse, Dutch Baroque painter who had congenital syphilis.
Severe facial disfigurement caused by congenital syphilis, 1880 Syphilis face 1.jpg
Severe facial disfigurement caused by congenital syphilis, 1880

Congenital syphilis that is diagnosed after 2 years of age, either because it was not diagnosed earlier or because it was incompletely treated, is classified as late congenital syphilis. [19] The signs of late congenital syphilis tend to reflect early damage to developing tissues that does not become apparent until years later, [20] such as Hutchinson's triad of Hutchinson's teeth (notched incisors), keratitis and deafness. [21] [22]

Symptoms include: [21]

Treatment (with penicillin) before the development of late symptoms is essential. [23]

Clinical signs include:

Death from congenital syphilis is usually due to bleeding into the lungs.[ citation needed ]

Transmission

Syphilis may be transmitted from mother to the fetus during any stage of pregnancy. [18] It is most commonly transmitted via cross placental transfer of Treponema pallidum bacteria from mother to the fetus during pregnancy with transmission via exposure to genital lesions during childbirth being less common. [18] The highest rate of transmission occurs in mothers with early syphilis (infection present for less than 1 year), which is responsible for 50-70% of infections, with syphilis being present for more than 1 year thought to be responsible for about 15% of transmission. [18] It is not transmitted during breastfeeding unless there is an open sore on the mother's breast. [4]

Diagnosis

Direct observation of Treponema pallidum from one of the lesions in the mother or infant is diagnostic and can be carried out using dark field microscopy, direct fluorescent antibody testing or immunohistochemical staining, however these tests are not readily available in many settings. [18] Serological testing is more commonly carried out on the mother and the infant to diagnose maternal and congenital syphilis. In the mother, a serologic diagnosis of syphilis is made using a nontreponemal test for syphilis such as the Venereal Disease Research Laboratory test (VDRL) or Rapid plasma reagin (RPR) followed by a treponemal test, such as the Treponema pallidum particle agglutination assay (TP-PA) (the sequence of testing may be reversed with a treponemal test followed by a non-treponemal test in the reverse diagnostic sequence). [18] Positivity of both tests indicates active syphilis or previous infection that was treated. [18] Quantitative non-treponemal tests are monitored for disease activity and response to treatment, with RPR is expected to decrease by a factor of four compared to pre-treatment levels after successful treatment of syphilis in the mother. [18] Failure of non-treponemal titers to decrease after treatment may indicate treatment failure or re-infection. [18] A confirmed cure in the mother does not exclude the possibility of congenital syphilis as transmission to the fetus may have occurred prior to maternal cure. [18]

Diagnosis of congenital syphilis in the fetus is based on a combination of laboratory, imaging and physical exam findings. Ultrasound findings associated with congenital syphilis intrauterine infection (which are seen after 18 weeks gestation) include fetal hepatomegaly (enlarged liver)(seen in greater than 80% of cases), anemia (as measured by the peak systolic velocity of the middle cerebral artery)(33%), placentomegaly(an enlarged placenta)(27%), polyhydramnios (an excess of amniotic fluid in the amniotic sac)(12%) and hydrops fetalis (edema in the fetus)(10%). [18] The absence of these ultrasound findings does not rule out congenital syphilis in the fetus. [18] These ultrasound abnormalities usually resolve several weeks after successful treatment of syphilis in the mother. [18]

Immunohistochemical staining or nucleic acid amplification of the amniotic fluid may also aid in the diagnosis. [18] Diagnosis of syphilis in the neonate may be challenging as maternal treponemal antibodies (as non-treponemal titers) can cross the placenta and persist in the infant for many months after birth in the absence of neonatal syphilis, complicating the diagnosis. [18] The passively transferred non-treponemal titers should be cleared from the infant within 15 months of birth (with most titers being cleared by 6 months), and persistently elevated titers 6 months after birth should prompt investigation into neonatal syphilis including CSF analysis for neurosyphilis. Pleocytosis, raised CSF protein level and positive CSF serology suggest neurosyphilis. [31] CSF VDRL is 50-90% specific for neurosyphilis. [18] 60% of newborns with congenital syphilis also have neurosyphilis. [18] Non-treponemal titers should be monitored in the newborns every 2-3 months to ensure an adequate response to treatment. [18]

Treatment

Centers for Disease Control and Prevention infographic about congenital syphilis. Syphilis infographic about pregnancy from CDC.jpg
Centers for Disease Control and Prevention infographic about congenital syphilis.

If a pregnant mother is identified as being infected with syphilis, treatment can effectively prevent congenital syphilis from developing in the fetus, especially if she is treated before the sixteenth week of pregnancy or at least 30 days prior to delivery. [18] [2] Mothers with primary syphilis can be treated with a single dose of intramuscularly injected penicillin, whereas late-latent, secondary syphilis, or disease of an unknown duration is treated with once weekly penicillin injections for three weeks. [18] The mother's partner should also be evaluated and treated. [18]

The fetus is at greatest risk of contracting syphilis when the mother is in the early stages of infection, but the disease can be passed at any point during pregnancy, even during delivery. An affected child can be treated using antibiotics much like an adult; however, any developmental symptoms are likely to be permanent. [32]

The greater the duration between the infection of the mother and conception, the better the outcome for the infant including less chance of stillbirth or developing congenital syphilis. [33]

The Centers for Disease Control and Prevention recommends treating symptomatic or babies born to an infected mother with unknown treatment status with procaine penicillin G, 50,000 U/kg dose IM a day in a single dose for 10 days. [34] Treatment for these babies can vary on a case-by-case basis. Treatment cannot reverse any deformities, brain, or permanent tissue damage that has already occurred. [32]

A Cochrane review found that antibiotics may be effective for serological cure but in general the evidence around the effectiveness of antibiotics for congenital syphilis is uncertain due to the poor methodological quality of the small number of trials that have been conducted. [35]

Up to 40% of pregnant women treated for congenital syphilis will develop a Jarisch-Herxheimer reaction, which is a temporary reaction that usually occurs within a few hours of starting penicillin and resolves by 24 hours. The reaction is characterized by cramping, fever, muscle aches and a rash. Treatment is supportive and fetal heart rate monitoring is recommended. [18]

Epidemiology

Syphilis affects around one million pregnancies a year. [13] In 2016, there were around 473 cases of congenital syphilis per 100,000 live births and 204,000 deaths from the disease worldwide. [14] Of the 660,000 congenital syphilis cases reported in 2016, 143,000 resulted in deaths of unborn babies, 61,000 deaths of newborn babies, 41,000 low birth weights or preterm births, and 109,000 young children diagnosed with congenital syphilis. [15] Around 75% were from the WHO's African and Eastern Mediterranean regions. [2]

Cases of congenital syphilis in the United States have been rising since the early 2010s. The Centers for Disease Control and Prevention (CDC) reported 918 cases for 2017, which is more than twice the yearly incidence of the preceding four years. [36] The incidence in the United States has increased by 754% from 2012 to 2021 with a higher incidence seen in those with a lower socioeconomic status, as well as Black people, Native Americans and Native Hawaiians. [18] Reports in 2023 show a rise of more than 900 percent in Mississippi over the preceding five years. [37]

History

Congenital syphilis was first described in Europe during the fifteenth century by the Spanish physician Gaspar Torrella  [ es ]. [18] [38] Nineteenth century physicians held the belief that congenital syphilis was contracted from contaminated semen at time of conception. [16] Serological tests for syphilis were introduced in 1906, and it was later shown that transmission occurred from the mother. [16]

Related Research Articles

<span class="mw-page-title-main">Syphilis</span> Sexually transmitted infection

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms depend on the stage it presents: primary, secondary, latent or tertiary. The primary stage classically presents with a single chancre though there may be multiple sores. In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet. There may also be sores in the mouth or vagina. Latent syphilis has no symptoms and can last years. In tertiary syphilis, there are gummas, neurological problems, or heart symptoms. Syphilis has been known as "the great imitator" because it may cause symptoms similar to many other diseases.

<i>Treponema pallidum</i> Species of bacterium

Treponema pallidum, formerly known as Spirochaeta pallida, is a microaerophilic, gram-negative, spirochaete bacterium with subspecies that cause the diseases syphilis, bejel, and yaws. It is known to be transmitted only among humans and baboons. T. pallidum can enter the host through mucosal membranes or open lesions in the skin and is primarily spread through sexual contact. It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide. T. pallidum's lack of both a tricarboxylic acid cycle and processes for oxidative phosphorylation results in minimal metabolic activity. As a chemoorganoheterotroph, Treponema pallidum is an obligate parasite that acquires its glucose carbon source from its host. Glucose can be used not only as a primary carbon source but also in glycolytic mechanisms to generate ATP needed to power the bacterium given its minimal genome. The treponemes have cytoplasmic and outer membranes. Using light microscopy, treponemes are visible only by using dark-field illumination. T. pallidum consists of three subspecies, T. p. pallidum, T. p. endemicum, and T. p. pertenue, each of which has a distinct related disorder. The ability of T. pallidum to avoid host immune defenses has allowed for stealth pathogenicity. The unique outer membrane structure and minimal expression of surface proteins of T. pallidum has made vaccine development difficult. Treponema pallidum can be treated with high efficacy by antibiotics that inhibit bacterial cell wall synthesis such as the beta-lactam antimicrobial penicillin-G.

<span class="mw-page-title-main">Yaws</span> Medical condition

Yaws is a tropical infection of the skin, bones, and joints caused by the spirochete bacterium Treponema pallidum pertenue. The disease begins with a round, hard swelling of the skin, 2 to 5 cm in diameter. The center may break open and form an ulcer. This initial skin lesion typically heals after 3–6 months. After weeks to years, joints and bones may become painful, fatigue may develop, and new skin lesions may appear. The skin of the palms of the hands and the soles of the feet may become thick and break open. The bones may become misshapen. After 5 years or more, large areas of skin may die, leaving scars.

<span class="mw-page-title-main">Tabes dorsalis</span> Medical condition of late-stage neurosyphilis

Tabes dorsalis is a late consequence of neurosyphilis, characterized by the slow degeneration of the neural tracts primarily in the dorsal root ganglia of the spinal cord. These patients have lancinating nerve root pain which is aggravated by coughing, and features of sensory ataxia with ocular involvement.

<span class="mw-page-title-main">Venereal Disease Research Laboratory test</span> Blood test for syphilis

The Venereal Disease Research Laboratory test (VDRL) is a blood test for syphilis and related non-venereal treponematoses that was developed by the eponymous US laboratory. The VDRL test is used to screen for syphilis, whereas other, more specific tests are used to diagnose the disease.

<span class="mw-page-title-main">Argyll Robertson pupil</span> Medical condition

Argyll Robertson pupils are bilateral small pupils that reduce in size on a near object, but do not constrict when exposed to bright light. They are a highly specific sign of neurosyphilis; however, Argyll Robertson pupils may also be a sign of diabetic neuropathy. In general, pupils that accommodate but do not react are said to show light-near dissociation.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

Pinta is a human skin disease caused by infection with the spirochete Treponema carateum, which is morphologically and serologically indistinguishable from the bacterium that causes syphilis and bejel. The disease was previously known to be endemic to Mexico, Central America, and South America; it may have been eradicated since, with the latest case occurring in Brazil in 2020.

<span class="mw-page-title-main">Nonvenereal endemic syphilis</span> Medical condition

Bejel, or endemic syphilis, is a chronic skin and tissue disease caused by infection by the endemicum subspecies of the spirochete Treponema pallidum. Bejel is one of the "endemic treponematoses", a group that also includes yaws and pinta. Typically, endemic trepanematoses begin with localized lesions on the skin or mucous membranes. Pinta is limited to affecting the skin, whereas bejel and yaws are considered to be invasive because they can also cause disease in bone and other internal tissues.

<span class="mw-page-title-main">Vertically transmitted infection</span> Infection caused by pathogens that use mother-to-children transmission

A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It can occur when the mother has a pre-existing disease or becomes infected during pregnancy. Nutritional deficiencies may exacerbate the risks of perinatal infections. Vertical transmission is important for the mathematical modelling of infectious diseases, especially for diseases of animals with large litter sizes, as it causes a wave of new infectious individuals.

<span class="mw-page-title-main">Group B streptococcal infection</span> Medical condition

Group B streptococcal infection, also known as Group B streptococcal disease or just Group B strep infection, is the infectious disease caused by the bacterium Streptococcus agalactiae. Streptococcus agalactiae is the most common human pathogen belonging to group B of the Lancefield classification of streptococci—hence the name of group B stretococcal (GBS). Infection with GBS can cause serious illness and sometimes death, especially in newborns, the elderly, and people with compromised immune systems. The most severe form of group B streptococcal disease is neonatal meningitis in infants, which is frequently lethal and can cause permanent neuro-cognitive impairment.

<span class="mw-page-title-main">Neurosyphilis</span> Infection of the central nervous system in a patient with syphilis

Neurosyphilis is the infection of the central nervous system in a patient with syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been reported in HIV-infected patients. Meningitis is the most common neurological presentation in early syphilis. Tertiary syphilis symptoms are exclusively neurosyphilis, though neurosyphilis may occur at any stage of infection.

The fluorescent treponemal antibody absorption (FTA-ABS) test is a diagnostic test for syphilis. Using antibodies specific for the Treponema pallidum species, such tests would be assumed to be more specific than non-treponemal testing such as VDRL but have been shown repeatedly to be sensitive but not specific for the diagnosis of neurosyphilis in cerebrospinal fluid (CSF). In addition, FTA-ABS turns positive earlier and remains positive longer than VDRL. Other treponemes, such as T. pertenue, may also produce a positive FTA-ABS. The ABS suffix refers particularly to a processing step used to remove nonspecific antispirochetal antibodies present in normal serum.

<span class="mw-page-title-main">Blueberry muffin baby</span> Purplish skin bumps on a newborn due to overproduction of blood

Blueberry muffin baby, also known as extramedullary hematopoiesis, describes a newborn baby with multiple purpura, associated with several non-cancerous and cancerous conditions in which extra blood is produced in the skin. The bumps range from 1-7 mm, do not blanch and have a tendency to occur on the head, neck and trunk. They often fade by three to six weeks after birth, leaving brownish marks. When due to a cancer, the bumps tend to be fewer, firmer and larger.

<span class="mw-page-title-main">Congenital cytomegalovirus infection</span> Medical condition

Congenital cytomegalovirus (cCMV) is cytomegalovirus (CMV) infection in a newborn baby. Most have no symptoms. Some affected babies are small. Other signs and symptoms include a rash, jaundice, hepatomegaly, retinitis, and seizures. It may lead to loss of hearing or vision, developmental disability, or a small head.

<i>Treponema pallidum</i> particle agglutination assay Assay used for detection and titration of antibodies against the causative agent of syphilis

The Treponema pallidum particle agglutination assay is an indirect agglutination assay used for detection and titration of antibodies against the causative agent of syphilis, Treponema pallidum subspecies pallidum. It also detects other treponematoses.

<span class="mw-page-title-main">History of syphilis</span>

The first recorded outbreak of syphilis in Europe occurred in 1494/1495 in Naples, Italy, during a French invasion. Because it was spread geographically by French troops returning from that campaign, the disease was known as "French disease", and it was not until 1530 that the term "syphilis" was first applied by the Italian physician and poet Girolamo Fracastoro. The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann in 1905 at the Charité Clinic in Berlin. The first effective treatment, Salvarsan, was developed in 1910 by Sahachiro Hata in the laboratory of Paul Ehrlich. It was followed by the introduction of penicillin in 1943.

<span class="mw-page-title-main">Meningeal syphilis</span> Medical condition

Meningeal syphilis is a chronic form of syphilis infection that affects the central nervous system. Treponema pallidum, a spirochate bacterium, is the main cause of syphilis, which spreads drastically throughout the body and can infect all its systems if not treated appropriately. Treponema pallidum is the main cause of the onset of meningeal syphilis and other treponemal diseases, and it consists of a cytoplasmic and outer membrane that can cause a diverse array of diseases in the central nervous system and brain.

HIV in pregnancy is the presence of an HIV/AIDS infection in a woman while she is pregnant. There is a risk of HIV transmission from mother to child in three primary situations: pregnancy, childbirth, and while breastfeeding. This topic is important because the risk of viral transmission can be significantly reduced with appropriate medical intervention, and without treatment HIV/AIDS can cause significant illness and death in both the mother and child. This is exemplified by data from The Centers for Disease Control (CDC): In the United States and Puerto Rico between the years of 2014–2017, where prenatal care is generally accessible, there were 10,257 infants in the United States and Puerto Rico who were exposed to a maternal HIV infection in utero who did not become infected and 244 exposed infants who did become infected.

<span class="mw-page-title-main">Neonatal infection</span> Human disease

Neonatal infections are infections of the neonate (newborn) acquired during prenatal development or within the first four weeks of life. Neonatal infections may be contracted by mother to child transmission, in the birth canal during childbirth, or after birth. Neonatal infections may present soon after delivery, or take several weeks to show symptoms. Some neonatal infections such as HIV, hepatitis B, and malaria do not become apparent until much later. Signs and symptoms of infection may include respiratory distress, temperature instability, irritability, poor feeding, failure to thrive, persistent crying and skin rashes.

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  22. ↑ Pessoa, Larissa; Galvão, Virgilio (2011). "Clinical aspects of congenital syphilis with Hutchinson's triad". Case Reports. 2011: bcr1120115130. doi:10.1136/bcr.11.2011.5130. PMC   3246168 . PMID   22670010.
  23. ↑ "Sexually Transmitted Diseases Treatment Guidelines - 2002". Cdc.gov. Retrieved 2013-01-21.
  24. ↑ "Anemia: Overview". The Lecturio Medical Concept Library. Retrieved 28 June 2021.
  25. ↑ Voelpel, James H.; Muehlberger, Thomas (1 March 2011). "The du Bois Sign". Annals of Plastic Surgery. 66 (3): 241–244. doi:10.1097/SAP.0b013e3181ea1ed8. PMID   21263293.
  26. ↑ Frangos, Constantinos C; Lavranos, Giagkos M; Frangos, Christos C (2011). "Higoumenakis' sign in the diagnosis of congenital syphilis in anthropological specimens". Med Hypotheses. 77 (1): 128–31. doi:10.1016/j.mehy.2011.03.044.
  27. ↑ Pessoa, Larissa; Galvão, Virgilio (2011). "Clinical aspects of congenital syphilis with Hutchinson's triad". Case Reports. 2011: bcr1120115130. doi:10.1136/bcr.11.2011.5130. PMC   3246168 . PMID   22670010.
  28. ↑ Hillson, S; Grigson, C; Bond, S (1998). "Dental defects of congenital syphilis". Am J Phys Anthropol. 107 (1): 25–40. doi:10.1002/(SICI)1096-8644(199809)107:1<25::AID-AJPA3>3.0.CO;2-C. ISSN   0002-9483. PMID   9740299.
  29. ↑ Darville, T. (1 May 1999). "Syphilis". Pediatrics in Review. 20 (5): 160–165. doi:10.1542/pir.20-5-160. PMID   10233174.
  30. ↑ Pineda, Carlos; Mansilla-Lory, Josefina; Martínez-Lavín, Manuel; Leboreiro, Ilán; Izaguirre, Aldo; Pijoan, Carmen (2009). "Rheumatic Diseases in the Ancient Americas: The Skeletal Manifestations of Treponematoses". JCR: Journal of Clinical Rheumatology. 15 (6): 280–283. doi:10.1097/RHU.0b013e3181b0c848. PMID   19734732.
  31. ↑ South, Mike (2012). Practical Paediatrics (7th ed.). Churchill Livingstone Elsevier. pp. 368, 830. ISBN   9780702042928.
  32. 1 2 Arnold, S; Ford-Jones, L (November–December 2000). "Congenital syphilis: A guide to diagnosis and management". Paediatrics & Child Health. 5 (8): 463–469. doi:10.1093/pch/5.8.463. PMC   2819963 . PMID   20177559.
  33. ↑ Singh, Ameeta E.; Romanowski, Barbara (1 April 1999). "Syphilis: Review with Emphasis on Clinical, Epidemiologic, and Some Biologic Features". Clinical Microbiology Reviews. 12 (2): 187–209. doi:10.1128/CMR.12.2.187. PMC   88914 . PMID   10194456.
  34. ↑ "Sexually Transmitted Diseases: Treatment Guidelines, 2010 By: the CDC" . Retrieved July 21, 2019.
  35. ↑ Walker, GJ; Walker, D; Molano Franco, D; Grillo-Ardila, CF (15 February 2019). "Antibiotic treatment for newborns with congenital syphilis". The Cochrane Database of Systematic Reviews. 2019 (2): CD012071. doi:10.1002/14651858.CD012071.pub2. PMC   6378924 . PMID   30776081.
  36. ↑ "A Devastating Surge in Congenital Syphilis: How Can We Stop It?". Medscape. Retrieved 2023-02-15.
  37. ↑ Yang, Maya (2023-02-12). "Mississippi sees 900% rise in number of infants born with congenital syphilis". The Guardian. ISSN   0261-3077 . Retrieved 2023-02-15.
  38. ↑ Dendi, Alvaro; Sobrero, Helena; Mattos Castellano, María; Maheshwari, Akhil (2024). "Congenital Syphilis". Principles of Neonatology: 274–278. doi:10.1016/B978-0-323-69415-5.00034-5. ISBN   978-0-323-69415-5.

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