KEY QUESTIONS
What viral and parasitic infections affect the fetus and can alter maternal, fetal, or newborn outcomes?
How are congenital infections prevented, diagnosed, and followed by OB/Gyn providers?
What infections can occur at any gestation, but are seen in and managed while a woman is in labor?
What is the best way to treat and manage infections that affect the fetus?
CASE 34-1
A 36 y.o. woman presented to L&D at 28 weeks gestation with complaints of fever and malaise for 3 days, 1 day of decreased fetal movement, and regular contractions. The pregnancy was the result of IVF for tubal factors. Her husband was born and raised in Peru. Most of the relatives from both sides of the family live in Peru. The patient had visited outside the United States only as a child. There was no recent family history of similar symptoms. During the hospitalization, the patient’s fever was low grade (38.0 degrees C) and intermittent. Workup for chorioamnionitis was negative. She received magnesium sulfate for fetal neuroprophylaxis and betamethasone for fetal lung maturation. On hospital day 4, she went into active preterm labor, and an emergency C-section was performed for FHR abnormality. The baby was admitted to the NICU and started on treatment for possible early-onset sepsis secondary to the preterm delivery and maternal fever. Postdelivery, the patient’s fever increased and became persistent. She developed tachycardia and shortness of breath. Cultures were obtained. Chest X-ray showed findings consistent with atypical pneumonia. The patient was placed on broad-spectrum antibiotics and transferred to the ICU.
Most infections that occur in pregnant women resolve spontaneously or after treatment. These infections typically have no visual effect on the fetus. This chapter will focus on several microorganisms that initially infect the mother and go on to infect and have an effect on the fetus. Different viruses, bacteria, protozoa, and fungi can infect the pregnant woman and cross the placenta. Maternal infectivity and transmission through the placenta to infect the fetus may be increased at a specific gestational age range, or they can occur at any time during gestation. Women may be minimally symptomatic and have few or no clinical signs. Some infections are fatal, causing miscarriage or fetal or newborn death. The same pathogen infecting women at the same or different gestational age may have no effect (or no visible effect, at least) on the fetus or newborn for many years after birth. Other infections may not affect the fetus until the patient is in labor, or they can cause the patient to go into labor.
There are a few generalizations that can assist in the management of infections during pregnancy. There are many ways that infections may present, progress, and respond to treatment. When a patient is exposed to an infectious agent, the virulence, inoculum size, incubation time, portal of entry, maternal immune response, and ability of the organism to penetrate the placental and central nervous system (CNS) barriers all influence the infectivity of the organism and outcome of the pregnancy. In addition, these factors change throughout gestation.
The diagnosis and workup for infections in the fetus may be approached from two main types of presentation:
Findings in the fetus or newborn that lead to the diagnosis. This includes most of the congenital infections.
Maternal findings that initiate further workup. Maternal fever is often the initiator for this approach.
A good history is instrumental in making the diagnosis. Since there are many different infections and ways that these infections present, this chapter has space to only discuss a few in some detail, and several others less completely.
The study of infections that affect the fetus does not easily fit into the approach that medical providers typically use. This chapter will group the diseases to simplify and condense the explanations and to assist the OB/GYN hospitalist in understanding them. The characteristics of the microorganism, medical conditions of the mother or fetus, and even environmental factors can cause overlap in the presentation of these diseases. The presence of HIV infection, other viral infections, sexually transmitted diseases, and immune status of the woman can all change the presentation, pathogenicity, choice of treatment, and effectiveness of treatment for some of these infections.
Although more frequently used in the neonatal literature, a modification of the TORCH classification is used here to help group infections that more typically infect the fetus, usually with less morbidity and lethality in the mother. Congenital infection has been described for these infections. Some infections are common; others are rare. Over 50% of the adult population has immunoglobulin G (IgG) antibodies to cytomegalovirus (CMV) and herpesvirus. Rubella is very rare and has been listed as eradicated in the United States; however, cases of congenital rubella still have been reported. Transmission of infection to the fetus occurs with varying fetal outcomes. Several variations of the TORCH concept of fetal infection classification exist. None are perfect, as there is no easy way to classify this very large group of diseases. This section will list and discuss several, some very briefly. The TORCHES CLAPZ listing is used here, which includes Toxoplasmosis, Rubella, Cytomegalovirus, Herpes virus, Enterovirus, Syphilis, Chickenpox (varicella zoster), Lyme disease (Borellia burgdorferi), AIDS (HIV), Parvovirus B19, and Zika virus. The herpes virus family consists not only of herpes simplex but also CMV and varicella zoster. Tuberculosis (TB) and bacterial infections are also discussed in this chapter. The most significant progress made with the management of most of these infections has come from the recently implemented use of molecular diagnostic testing.
The seroprevalence of Toxoplasma in reproductive-age women in the United States is 9.1%.1 This is rarer than many providers believe. Approximately 1 in 10,000 live births are affected.2 The incidence is much higher in other parts of the world. The seroprevalence in France for pregnant women was 43.8% in 2003,3 and for the women in France age 1 to 64 the seroprevalence was 55.4% in 1999.
Toxoplasmosis gondii is an intracellular parasite that exists as a trophozoite, cyst, or oocyst. Primary human infection occurs with consumption of the cyst. Congenital infection can occur from placental transfer of the organism from a primary infection, reactivation of a previous infection in the mother, or reinfection with a different strain of the organism. The parasite reproduces sexually in the feline family. Exposure to cat feces can lead to infection. In the United States, human infection may occur more commonly with exposure (usually oral), from exposure to contaminated soil or vegetables, and eating undercooked wild meat that has been infected. Undetected contamination of water by oocytes frequently causes human infection.4 Infection is usually asymptomatic. When present (appearing in 10% of infected adults), the most common findings are firm, nontender, often unilateral lymphadenopathy, fever, malaise, and myalgia. The probability of congenital infection increases proportionally with the gestational age of the fetus at the time of maternal infection. The risk of congenital infection is 6% at 13 weeks gestation, 40% at 26 weeks, and 72% at 36 weeks.5 There is a strong inverse correlation between the time of maternal infection and the severity of the disease, with the most severe congenital disease occurring with first-trimester infection. Subclinical congenital toxoplasmosis has significant delayed morbidity and mortality. Even with an adequate immune response and findings consistent with chronic infection, large amounts of actively dividing and tissue-destroying tachyzoites have been found in the fetal brain.6 This may be the reason why there is a high incidence of neural-optical, delayed-onset, congenital toxoplasmosis.
The organism can be identified microscopically and can be grown in tissue culture; however, this is not the usual method used for maternal diagnosis. The foundation of diagnosis of toxoplasmosis is based on serologic testing. There is a marked immunoglobulin M (IgM) response soon after a primary infection, which lasts for several months to over a year. IgG starts to form in 7 to 10 days. High IgM and IgG titers indicate an acute infection within the last 3 months. A negative IgM and positive IgG indicates a remote infection and minimal chance for congenital infection. Since false positive and false negative tests occur, serologic testing should be repeated in 2 to 3 weeks. Once toxoplasmosis has had positive serologic testing, IgG avidity testing should be done through a reference laboratory. Low avidity is indicative of a primary infection within the last 5 months.
The fetus or newborn may show intracranial calcifications, hydrocephalus, ascites, and hepatosplenomegaly on ultrasound examination. An amniocentesis is recommended at 18 weeks gestation to confirm fetal infection. Performing a polymerase chain reaction (PCR) test on amniotic fluid obtained at 18 weeks increases the accuracy compared to an earlier amniocentesis and allows time to arrange for fetal treatment.
Treatment for toxoplasmosis is directed on one of two pathways, depending on the gestation when the woman is suspected of acquiring the infection (<18 weeks or ≥18 weeks).7 If the infection is acquired <18 weeks of gestation, the treatment plan consists of spiramycin, amniocentesis at 18 weeks or as soon afterward as feasible, and monthly fetal ultrasounds. If the amniotic fluid PCR is negative, spiramycin (which has minimal placental penetration) is continued until delivery or until an ultrasound anomaly is seen. If the PCR is positive or there are ultrasound findings, then pyrimethamine, sulfadiazine, and folinic acid (with placental and fetal penetrance as well as teratogenic effects) is administered until delivery. If maternal infection occurs ≥18 weeks gestation, pyrimethamine, sulfadiazine, and folinic acid are given, an amniocentesis is done, and monthly ultrasounds are performed. If the PCR and the sonograms are negative, treatment should be continued until delivery.
The patient can be switched to spiramycin, or since there is concern for the need to continue fetal treatment, the decision may be to continue with pyrimethamine, sulfadiazine, and folinic acid. Spiramycin is not easily available, and pyrimethamine may cause megaloblastic anemia, thrombocytopenia, or agranulocytosis. An infectious disease consult is often requested. Infants with congenital toxoplasmosis are typically treated for 1 year.
PRACTICE POINTS
Toxoplasmosis is not as common as many believe.
Infection can occur and cause congenital disease in any trimester.
Toxoplasmosis can be treated in the fetus antenatally.
Rubella is a viral illness that was declared eliminated from the United States in 2004; however, it is still commonly transmitted in many parts of the world. As a result, several cases of rubella are reported every year. The disease was common in the United States prior to the licensing of the vaccine in 1969. Worldwide, an estimated 100,000 infants are born with congenital rubella syndrome (CRS) annually. From 2005 to 2011, 4–18 cases were reported each year in the United States, with 42% being importations.8 Almost all cases are in people from either other countries or Americans who have recently visited another country. The near (but not total) eradication of rubella is a success story for childhood immunization, preconception and early pregnancy testing, and postpartum immunization. About 20% of reproductive-age women are not immune to rubella, many from losing their immunity after vaccination. These women are at risk of infection during pregnancy.
Rubella is an enveloped, positive, single-stranded RNA virus classified as a rubivirus in the Togaviridae family. The virus is transmitted primarily through direct or droplet contact from nasopharyngeal secretions. Humans are the only natural hosts. Incubation time is from 12 to 23 days. The disease presents as a maculopapular rash that begins on the upper thorax or face and then spreads in a wavelike fashion to the thorax, abdomen, and then extremities over 3 days. The rash is typical of rubella but can also occur with echovirus and coxsackie virus infections. Arthralgia occurs in up to 70% of those infected. Postauricular lymphadenopathy is common and can be present from prior to the rash to up to several weeks after the rash is gone. People infected with rubella are most contagious when the rash is present, but can be contagious from 7 days before to 7 days after the rash appears.
CRS occurs when the infection is transmitted to the fetus from an infected mother. The injury is most severe when the fetus is infected in the first trimester. The more advanced gestational age is after the 10th week, the lower the probability of overt fetal involvement. If a woman is infected in the first trimester of pregnancy, there is a 90% chance of the fetus having CRS. The risk of CRS is 25% if maternal infection occurs at the end of the second trimester.9,10 The mother will develop immunizing antibodies soon after the infection. The baby sheds the rubella virus for months after delivery.11
Rubella needs to be considered when a patient develops a febrile rash, is unvaccinated, and especially if she recently traveled internationally or were exposed to someone with a febrile rash. Throat, nasal, and urine specimens can be collected for viral detection by PCR testing, and they are especially helpful for diagnosis in the neonate. Blood should be sent optimally 5 days after the onset of symptoms for serologic testing. IgM antibody testing will be positive over 90% of the time when collected on day 5. On day 1 of the rash, IgM testing will be positive in only 50% of cases, and a second sample should be collected. IgM testing also gives false positives, though. Antirubella IgG testing is done on all serum samples received by the Centers for Disease Control and Prevention (CDC). IgG avidity testing may be done especially in early pregnancy, where low avidity indicates a probable first-trimester infection, which carries the highest risk for CRS, as already noted.
Testing the fetus for CRS can be difficult. Many congenital abnormalities are not identified by ultrasound examination, such as cataracts, glaucoma, hearing loss, and developmental delay. Other possible findings that may be seen via ultrasound are micrognathia, hepatosplenomegaly, pulmonary artery hypoplasia, and cardiac abnormalities.
There is no treatment for rubella or congenital rubella. Infected patients should be placed in isolation for 7 days after the rash develops. A single case should be considered as a potential outbreak, and there should be active surveillance for two incubation cycles (i.e. 46 days) to protect other pregnant women. Infected pregnant women should be followed for several weeks after the rash disappears to identify and manage possible rare sequelae (encephalitis, hepatitis, endocarditis, hemolytic uremia). When diagnosed early in pregnancy, medically indicated abortion is sometimes considered. A fetus with congenital infection should be followed from diagnosis through birth and even beyond by specialists because of the potential multiple defects and handicaps. The key to the management of rubella is immunizing susceptible women after delivery and before the next pregnancy. Immunization is not done during pregnancy because of the theoretical risk of transplacental transmission of the virus particles in the vaccine, causing congenital infection.
PRACTICE POINTS
Rubella is considered as eradicated in the United States; however, there are still cases of rubella and congenital rubella every year.
Without continued vigilance, a recurrence of rubella may occur. It is essential to vaccinate against this virulent disease.
CMV is the most commonly recognized congenital infection. It occurs in 0.2% to 2.2% of all neonates. Prevalence of CMV antibody varies by geographic region, socioeconomic status, and ethnicity, and it increases with age. In the United States, women of childbearing age have a seroprevalence of 40% to 83%. There is increased exposure with breastfeeding, contact with infants and toddlers, poor hygiene, and promiscuity.
CMV is a herpes virus made of double-stranded DNA. It can infect the fetus either by a primary infection or a recurrent infection, which could be by reactivation of the virus from a prior infection or a new infection from a different strain. Women who have a primary infection are usually asymptomatic. When present, the symptoms may include fever, chills, and malaise. The woman may also present with leukocytosis, lymphocytosis, lymphadenopathy, and abnormal liver function tests. Transplacental transmission has the highest risk of causing clinical sequela. Infection is more common in the third trimester, but the more serious fetal disease occurs after first-trimester infection. At birth, 12% to 18% of infected fetuses show signs of infection, and 25% of infected fetuses will develop signs of infection sometime after birth.
PCR testing or viral culture of infected blood, urine, saliva, cervical secretions, or breast milk will detect CMV. Detectable viremia lasts for 2 to 3 weeks in a primary infection; thus direct testing of the virus is often not diagnostic. Diagnosis is most reasonably made by running two serum samples drawn 3 to 4 weeks apart. Seeing a conversion from negative to positive IgG or a fourfold increase in IgG titer indicates primary infection. Diagnosis may be difficult, as testing for IgG and IgM may not give the diagnosis (different from many diseases, the presence of IgM does not usually indicate a primary infection, as only 10% to 30% of those infected have IgM). Low-avidity IgG with positive IgM is seen with a primary infection, which has occurred in the last 2 to 4 months.
Maternal treatment is supportive. The antiviral ganciclovir has been tried with limited success. There is no fetal treatment for congenital CMV. Early diagnosis of the fetal infection is important to allow the patient time to consider termination.
PRACTICE POINTS
CMV is the most common of the TORCHES CLAPZ congenital infections.
Fetal infection can be primary, it can be from a different strain, or it can reactivate from a prior infection.
Herpes virus is a virus family that has shown infectivity in the general population and increased virulence in the immunocompromised, including various gestations in pregnancy and the fetus. CMV is a herpes virus. Other herpes virus organisms include herpes simplex type 1 (HSV1) and type 2 (HSV2); varicella zoster, which causes chickenpox; and herpes zoster, which causes shingles. A majority of women have been exposed to herpes viruses early in life. A study of teenage girls showed a prevalence of 59.6% for HSV1, and 13.5% for HSV2. By the end of the study, 8.9% acquired HSV1 and 7.4% acquired HSV2. None of the cases were symptomatic, and almost half of the HSV2 seroconverters had HSV2 DNA identified on vaginal swabs.12 The seroprevalence for reproductive women presenting to an urban Emergency Department (ED) in Baltimore was 54.4%.13 The prevalence continues to increase with age. In women with no genital lesions and a positive test for HSV2 at delivery, HSV is identified in 9% of placentas and 1.1% of the neonates.14
Herpes is a double-stranded DNA virus. HSV is differentiated into HSV1 and HSV2. HSV1 is the usual agent causing herpes labialis, gingivostomatits, and keratoconjunctivitis. Most HSV genital infections are caused by HSV2. Genital HSV1 infections are becoming more common. Transmission occurs by person-to-person, direct contact with open skin or mucus membranes. Incubation is from 2 to 12 days. The virus replicates in the skin, causing painful ulcers without red or raised edges. There is often discomfort at the site 1 to 2 days prior to the ulcers being visible. Dysuria and dyspareunia can be extreme when the ulcers are present. The virus moves into the sensory ganglia, where it becomes latent and may reactivate to cause infective recurrent lesions or asymptomatic viral shedding, even in the presence of specific antibodies. Only 11.9% of those infected with HSV2 are symptomatic.15
The disease also can cause a disseminated infection, which is fatal if it occurs in pregnancy without treatment. The infection can be primary, or it can be reactivated. Reactivated disease may be asymptomatic. Congenital disease is much more likely to occur with primary infection; however, it can occur after an outbreak of reactivated disease. Congenital infection has been described and presents as chorioretinitis, microcephaly, and skin lesions.16,17 Infections acquired before birth are extremely rare, and clinical findings overlap with CMV.18 Almost all congenital infections occur during the birth process, usually by fetal contact with maternal vaginal mucosa containing the virus or while ascending the birth canal, from the vaginal or cervical mucosal cells to the fetus.
The diagnosis of HSV can be made by viral detection with cultures and antigen PCR. This is often done when lesions are present, and the sample is taken from the ulcer. A negative result does not exclude an infection. Serology is also used for diagnosis; it can differentiate between HSV1 and HSV2, with either being able to cause genital infection. The presence of IgM indicates a primary infection, and IgG without IgM indicates a prior infection. Antibody titers are not usually done, as the treatment would not change based on the results. Because of the low incidence of congenital or newborn HSV infection, and since fetal and neonatal infection can occur with negative cultures, antepartum screening in asymptomatic patients is not recommended in the United States.19
Acyclovir, the antibiotic most used to treat HSV, crosses the placental barrier20 and has not been shown to be teratogenic to the fetus. Because HSV infection cannot be cured, the aim of the treatment is to minimize the number of active viruses and the amount of time that they are present. Treating the primary infection aggressively in pregnancy may minimize the infectious risk to the fetus, decrease the frequency of recurrence, and possibly even lessen the viral load of a recurrence. Recurrences should be treated. Women with active recurrent genital herpes should be offered suppressive viral therapy at or beyond 36 weeks of gestation.19
For severe or disseminated disease, acyclovir 5 to 10 mg/kg, intravenously (IV) every 8 hours for 2 to 7 days, then oral therapy for primary infection to complete 10 days. Valacyclovir also may be used with a different dosage. Table 34-1
| Indication | Pregnancy Recommendation |
| Primary or first episode infection |
|
| Symptomatic recurrent infection (episodic therapy) |
|
| Daily suppression |
|
Although it does not completely prevent vertical transmission of HSV, cesarean delivery is recommended by the American Congress of Obstetricians and Gynecologists (ACOG) for women who have active genital lesions or prodromal symptoms at the time of labor.
PRACTICE POINTS
Over 50% of pregnant women have been seroconverted to HSV.
Congenital infection is rare and can occur at any time; most infections occur around birth.
Acyclovir can be used to treat the mother, fetus, and newborn.
Enteroviruses are part of the family Picornaviridae. They are small, nonenveloped, single-stranded RNA viruses. Of the 12 species, there are 5 serotypes: (1) coxsackievirus (of which type B3 (CVB3) seems the most pathogenic for the fetus; (2) echovirus; (3) enterovirus; (4) human rhinovirus; and (5) poliovirus.
Nonpolio enteroviruses are very common, and most pregnant women are exposed to some of them during their pregnancy. Immunity is developed to the specific serotype, and there is some crossover immunity. Several enteroviruses have caused general population outbreaks. Coxsackievirus A16 is the most common cause of hand, foot, and mouth disease. Coxsackievirus A24 and enterovirus 70 have caused outbreaks of conjunctivitis. Echoviruses 13, 18, and 30 can cause meningitis. Enterovirus 71 has caused outbreaks in other parts of the world, with severe neurologic sequelae. In 2014, enterovirus D68 caused an outbreak of severe respiratory illness. The spread of infection is higher in the summer and fall but can occur year round. When a mother seroconverts during pregnancy, both coxsackievirus and echovirus are transmitted to the fetus during delivery 30% to 50% of the time. The rate of transplacenta transmission is unknown.
Enteroviruses are transmitted by fecal-to-oral and oral-to-oral means. The majority of infections are either asymptomatic or of limited nonspecific fever with respiratory symptoms (cough, runny nose). Some infected people can develop a rash, mouth blisters, and myalgia. A severe infection can lead to meningitis, flaccid paralysis, endocarditis, and myocarditis. Newborns may develop sepsis. When infections occur, they tend to occur as outbreaks. The incubation period is highly variable, depending on multiple inoculum and host factors.
Of the enteroviruses, coxsackie type B3 seems the most virulent to the fetus. Echovirus is usually subclinical, and no teratogenicity has been identified. There is a report of infection with echovirus as a cause of death in an 18-week fetus.21 There are case reports of several of these viruses causing fetal and/or neonatal disease, but these are very rare, and other than the two types mentioned here, none of the viruses can be specifically linked to major fetal anomalies. Coxsackievirus can cause fetal loss, congenital heart disease, and type 1 diabetes. Of women who miscarry before the 13th week of pregnancy, 42% will have had a recent infection with coxsackievirus types B 1–5, with 18% of pregnant women at the same gestation testing positive. When compared to a control group, there is no difference in the rate of maternal CVB infection (coxsackie virus type B) when pregnancy loss occurs between 13 and 27 weeks of gestation.22
In cases of population outbreaks, the CDC can do molecular testing, serotype identification, sequencing, and virus isolation. In the absence of an outbreak, the gold standard for testing uses viral cell culture. In a cell culture, cytopathic effects can be seen in 2 to 6 days. Cultures can be positive for up to 8 weeks after onset of infection. The culture is taken from stool or a rectal swab. Oropharyngeal swabs may be positive early in the disease. Serology can be difficult to interpret. A fourfold rise in titer in acute and convalescent sera can lead to the diagnosis. PCR has a 66% to 90% sensitivity. Typically, testing is not done unless neonatal infection is suspected. Cerebrospinal fluid (CSF) is needed to make the diagnosis of viral meningitis. Since coxsackie virus is the most pathogenic of the enteroviruses, a coxsackievirus antibody panel (types B 1–6) can be done.
There is no medical treatment for enterovirus infection other than supportive care.
PRACTICE POINTS
Congenital enterovirus infection is not as pathogenic as once thought.
Spread is fecal–oral or oral–oral.
Congenital coxsackie infection may cause heart abnormalities and increase the incidence of type 1 childhood diabetes.
Syphilis is caused by an elongated spiral bacterium called Treponema pallidum. This organism has acted as a sexually transmitted disease for hundreds to thousands of years. There is evidence indicating its presence in the Americas prior to Columbus and is described in writings in Europe in the late 1400s, at the time that it appears the disease began to spread across the continent.23 Syphilis has been described as the most common congenital infection worldwide.24 In 2007, the World Health Organization (WHO) launched an initiative to eradicate congenital syphilis.
Worldwide, maternal syphilis decreased 38% from 2008 to 2012. Congenital syphilis decreased by 39%.25 Unfortunately, this trend has not continued in the United States, where syphilis decreased from 2008 to 2012, and then increased to 11.6 cases per 100,000 live births in 2014 (the highest rate since 2001). The rate has increased in all regions of the United States.26 Many infections are missed or not treated in pregnancy and are identified in the newborn or infant.27
Congenital syphilis occurs when an infected pregnant mother transmits the infection to her unborn child before or at delivery. Of fetuses diagnosed with congenital syphilis, the mortality is 6.5%, of which 81.8% are stillbirths. Morbidity (strong evidence of congenital disease) is 33.6%, and the rest are nonmorbid or unknown.28 In 69% of women with inadequately treated syphilis, the infection is transmitted to the fetus.29
The Treponema organism is not a typical Gram-negative bacteria. It is from 5 to 20 µ long and 0.2 µ wide, which is longer and narrower than a typical bacterium. The shape is in a spiral, and it is motile. Because of the narrow width, the organism cannot usually be seen by light microscopy. There is a cell wall, which is the reason for its penicillin sensitivity. The organism grows best at 35 to 36°C and is destroyed at 40.5°C. It infects through the mucous membranes, predominantly from coitus. The primary lesions may occur on the labia, vaginal wall, or cervix. Extragenital primary sites may occur as well.
The disease is classified by several stages and presentations. Primary syphilis occurs once the organism penetrates the mucus membranes and replicates. Lymphocytes, polymorphic neutrophils, and then macrophages appear. The number of viable spirochetes decreases, and a chancre (a papule breaking down into a painless ulcer with rolled margins) appears in 5 days to several weeks. Untreated, the chancre disappears in 2 to 8 weeks. The infection then disseminates from the site of infection to the regional lymph nodes. These buboes are usually enlarged, firm, and tender lymph nodes. From these regional nodes, the disease spreads hematogenously. Secondary syphilis usually occurs 3 to 6 weeks after the primary chancre has occurred.
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