Syphilis remains an alarming public health problem worldwide. Syphilis in the United States has markedly decreased in recent years to 2.5 cases of primary and secondary syphilis per 100,000 persons in 1999,1 but syphilis rates in some developing nations have been as high as 5–10% of the adult population.2,3 Congenital syphilis trends follow maternal syphilis rates. The Centers for Disease Control and Prevention (CDC) reported 14.3 cases per 100,000 live births in 1999 in the United States,1 a decline of 34% from the prior year. However, the rates of congenital syphilis are substantially higher worldwide, and congenital syphilis remains a major cause of stillbirth and long‐term morbidity globally.
The diagnosis of congenital syphilis in an asymptomatic neonate or a stillborn fetus remains difficult.4,5 Maternal treponemal and nontreponemal immunoglobulin G (IgG) antibodies are transmitted transplacentally complicating the interpretation of neonatal serologic test results. The IgM antibody testing currently available lacks sensitivity,4–6 and polymerase chain reaction (PCR) for Treponema pallidum (T pallidum) is not available routinely. A comprehensive approach to diagnosis is recommended, and at this time the CDC case definition is the working diagnostic guideline.7 However, the CDC case definition is not specific. It was originally designed for epidemiologic reporting, and many infants are treated for congenital syphilis who actually are not infected. Better diagnostic criteria would aid physicians worldwide to target infected neonates requiring treatment including those asymptomatic infants at birth who may develop late manifestations of congenital syphilis. One potential diagnostic modality not currently used in the CDC case definition is placental histopathology. Although the placental pathology of congenital syphilis has been reported,8,9 the predictive value of placental pathology for diagnosing infected infants has not been elucidated.
Our primary objective in this study was to evaluate the contribution of placental pathology to the diagnosis of congenital syphilis in infants delivered to mothers with untreated syphilis. We have attempted to define the pathologic alterations relating to four pregnancy outcomes among these women: live‐born uninfected, live‐born with congenital syphilis, stillborn uninfected, and stillborn with congenital syphilis. In addition, we evaluated the placental alterations to determine if histology could provide insight into the pathogenesis of fetal demise.
MATERIALS AND METHODS
This was a retrospective cohort analysis from January 1, 1986, to December 31, 1998. All pregnant women with untreated syphilis at presentation to the labor and delivery unit at Parkland Memorial Hospital in Dallas, Texas, and who had placental evaluation performed were identified. During the study period, all women admitted for delivery were tested for syphilis using a nontreponemal antibody test (Venereal Disease Research Laboratory or Rapid Plasma Reagin test). A reactive test was confirmed using either the fluorescent treponemal antibody absorption test or the microhemagglutination assay for antibodies to T pallidum. Women diagnosed with syphilis were examined by one investigator (GDW) and assigned a clinical stage by history, physical examination, and dark‐field microscopy of lesions. Dallas County Health Department records were reviewed to confirm a lack of prior treatment for syphilis.
Infants were diagnosed with congenital syphilis if they had abnormalities on 1) physical examination (rash, rhinitis, hepatosplenomegaly, or generalized lymphadenopathy); 2) laboratory evaluation (hematocrit less than 35%, platelet count less than 150,000/mm3 (in the setting of no other clinical etiology), or reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory test; 3) long bone radiographs (osteochondritis, periostitis); 4) serum IgM immunoblot4,10,11; 5) serum, blood, or CSF PCR4,10,12; 6) serum, blood, or CSF rabbit infectivity testing (RIT)4,10,13; or 7) postmortem examination, including microscopic visualization of spirochetes. Placental evaluation was not used for the diagnosis of congenital syphilis.
Placentas were examined according to standard recommendations and generally included a sampling of fetal membranes, one or two umbilical cord cross‐sections, and at least one section of placental parenchyma.14 The placental slides from all cases were retrospectively reviewed independently by two pathologists unaware of the clinical status of the infants or mothers (BBR and LRM). The only clinical information provided to the reviewers was the estimated gestational age at the time of birth. Discrepant diagnoses were resolved with joint reviews of the slides.
The histopathology review included a specific determination of the presence or absence of necrotizing funisitis, acute chorioamnionitis, villous enlargement relative to gestational age, increased nucleated fetal erythrocytes (erythroblastosis or nucleated red blood cells), avascular villi (fetal vasculopathy), acute or chronic villitis, and plasma cell infiltrates in the decidua. Necrotizing funisitis required the presence of tissue necrosis accompanying severe acute perivascular inflammation in the umbilical cord. Avascular villi were considered present when foci of avascular villi conforming to a villous tree were seen surrounded by otherwise viable placental parenchyma.15 Avascular villi in the distribution of a villous tree likely represent the downstream effects of clinically significant vasculopathy, and have previously been described in congenital syphilis.16 We did not assess syphilitic proliferative vasculopathy in our cases because it is difficult to discriminate these changes from the vascular remodeling that occurs in stillbirths.17
Statistical analysis was performed using analysis of variance and Tukey‐Kramer multiple comparisons for continuous variables, χ2 analysis for nominal variables, and logistic regression to adjust for gestational age at delivery. Logistic regression analysis is sensitive to empty cells as these become denominators for odds ratios. The Cochran‐Mantel‐Haenszel procedure is a pooling across strata to estimate an adjusted odds ratio and P value, whereas in our case the strata are gestational age. This procedure is robust to small sample size.
During the study period, 67 women admitted for delivery had untreated syphilis and had placentas available for pathologic review. The study cohort consisted of 33 stillborn infants with congenital syphilis, 18 live‐born infants with congenital syphilis, 15 uninfected live‐born infants, and one stillborn infant without congenital syphilis. For statistical analyses, the one stillborn infant without congenital syphilis was excluded.
Table 1 depicts the criteria used to diagnose congenital syphilis before placental evaluation. The 15 live‐born, uninfected infants had normal physical examinations, long bone radiographs, and negative laboratory evaluations. Live‐born and stillborn infants diagnosed with congenital syphilis had abnormal physical examinations, long bone radiographs, reactive CSF Venereal Disease Research Laboratory tests, positive serum, blood, or CSF IgM immunoblots, or a positive blood/serum PCR or RIT. One additional stillbirth was classified as not having congenital syphilis because the physical examination and bone radiographs were normal. Autopsy findings were not diagnostic of congenital syphilis, and no spirochetes were identified by Steiner staining of the tissues. This infant did not have IgM immunoblotting, PCR, or RIT performed.
Table 2 defines the characteristics of the study population by neonatal outcomes. There were no statistical differences among the three groups relating to maternal age, race, or the percentage receiving prenatal care. The majority of the women were either black or Hispanic, and only 39% received prenatal care. The maternal stage of syphilis did not differ significantly among the groups. The majority of the women (85%) were diagnosed with early syphilis: primary, secondary, or early latent disease. One woman was diagnosed with the human immunodeficiency virus. She delivered a full‐term infant who had a normal physical examination, normal long bone radiographs, negative serum IgM immunoblot, negative blood PCR and RIT, and a normal placenta. Stillborn infants with congenital syphilis were more likely to be preterm than live‐born infants with or without congenital syphilis (P < .001).
Placental and umbilical cord histopathology results are listed in Table 3 and depicted in Figure 1. Significant differences were seen when comparing either liveborn or stillborn infants with congenital syphilis with uninfected live births. Necrotizing funisitis, villous enlargement, and acute villitis were more common in infants with congenital syphilis. Fetal vasculopathy and erythroblastosis were more common in stillborns with congenital syphilis than either live‐born group. The one stillborn infant who did not have evidence of congenital syphilis by conventional testing had necrotizing funisitis, villous enlargement, and chronic villitis, suggesting that he was infected with T pallidum.
Gestational age at delivery differed significantly among the three groups (Table 2). Thus, logistic regression was used to analyze the placental and umbilical cord findings in relation to gestational age (Table 4). Live‐born infants without congenital syphilis by clinical criteria were used as normal controls. Villous enlargement remained significantly different in both groups compared with uninfected live‐born infants. Necrotizing villitis and acute villitis were more common in infants with congenital syphilis compared with live‐born infants without congenital syphilis. Erythroblastosis was much more common in stillborns with congenital syphilis, with an odds ratio of 16 (95% confidence interval 1, 370). Avascular villi did not remain a significant finding after adjusting for gestational age. The sample size limits the extent of logistic regression analyses that can be made beyond this. Table 4 includes seven multiple logistic regression analyses. Stillborns with congenital syphilis were then compared directly with live‐born infants with congenital syphilis after adjusting for gestational age (Figure 2). Erythroblastosis was the only finding that differed significantly (odds ratio 10.5, 95% confidence interval 1.6, 69.0).
The addition of histologic evaluation (one of the following present: necrotizing funisitis, villous enlargement, acute villitis, and/or erythroblastosis) to conventional diagnostic evaluations (physical examination, long bone radiographs, and laboratory evaluation) improved the detection rate for congenital syphilis from 67% to 89% in live‐born infants and 91% to 97% in stillborn infants.
This study analyzing data collected over a 13‐year period is a comprehensive look at maternal, fetal, neonatal, and placental characteristics associated with the spectrum of congenital syphilis (asymptomatic infants to stillbirths with congenital syphilis). Sixty‐seven women diagnosed with untreated syphilis at delivery who had placentas available for evaluation were identified and analyzed on the basis of four neonatal outcomes: live‐born without congenital syphilis, live‐born with congenital syphilis, stillborn without congenital syphilis, and stillborn with congenital syphilis. Demographic characteristics were similar among the groups with only 40% receiving prenatal care (96% of our general obstetric population receives prenatal care). This represents a lost opportunity for prevention of congenital syphilis.
There are no absolute pathologic placental findings associated with congenital syphilis.9 However, there are certain histologic features that suggest the diagnosis. The “syphilis triad” includes enlarged hypercellular (immature) villi, proliferative vascular changes, and acute or chronic villitis.8,9,18–25 Decidual plasma cell infiltration has also been reported.9,18 These findings are present to varying degrees in an affected placenta and are not specific for syphilis. Necrotizing funisitis also may occur in the setting of syphilis, although it is not a specific finding (Benirschke K. Congenital syphilis and necrotizing funisitis [letter]. JAMA 1989;262:904).26–28 Many of these pathologic findings have been studied in the setting of maternal syphilis, without confirmation of congenital syphilis in the fetus or newborn. Placental and umbilical cord histopathologic evaluation in the setting of definitive congenital syphilis is lacking in reported series. In our cohort, necrotizing funisitis, villous enlargement, and acute villitis were significantly more common in both stillborn and live‐born infants with congenital syphilis.
The pathophysiology of fetal syphilis has been the subject of much debate. It is known that T pallidum attaches to human umbilical vein endothelial cells, traverses or enters these cells, and activates the umbilical vein and placental endothelial cells. This activation leads to initiation of an inflammatory cascade resulting in the histopathologic and clinical features of syphilitic infection.29,30 Animal and human studies have shown a similar course of events at the site of a syphilitic lesion. Initial edema with mild perivascular neutrophilic infiltration occurs followed by lymphocytic and macrophage invasion with marked vasculitis and mild thrombosis. Finally, mononuclear cells infiltrate with an abundance of lymphocytes and plasma cells in both superficial and deep perivascular areas.29–31 Thrombosis and fibrin deposition were common at this stage. We found similar results in the placentas of congenitally infected infants. Decidual plasma cells and chronic villitis were common in all the placentas, regardless of fetal infection. These findings may reflect maternal disease rather than fetal infection. However, when the fetus becomes infected, acute villitis and villous enlargement with or without edema become prominent placental findings. Finally, those infants with congenital syphilis who were stillborn, the extreme of the clinical continuum, were more likely to have erythroblastosis reflective of fetal anemia or stress.
Recent evidence from periumbilical blood sampling in fetal syphilis cases supports our finding that hematologic abnormalities (eg, anemia) occur later in the course of in utero infection and are associated with more severe infection.32 Furthermore, Young and Crocker33 found nucleated red blood cells in the placentas of five stillborn fetuses with congenital syphilis. They attributed this to fetal anemia and chronic fetal hypoxia. These findings combined with our observation of placental erythroblastosis almost entirely in our syphilitic stillbirths suggest that anemia is an important factor in fetal death from congenital syphilis.
The diagnosis of congenital syphilis in an asymptomatic neonate is difficult. If untreated, the sequelae of congenital syphilis can be lifelong, including neurologic abnormalities, bone and joint malformations, and deafness secondary to eighth nerve involvement.34,35 We have shown that by performing a physical examination, basic hematologic and CSF laboratory analyses, and placental histology, 89% of live‐born infants with congenital syphilis can be identified compared with physical examination and laboratory analysis alone (67%).
The diagnosis of congenital syphilis in a stillborn is also difficult. Autopsy may show evidence of fetal syphilis unless tissues are markedly macerated.16,36 We identified 94% of the stillborns with congenital syphilis using placental histology, and we would have only diagnosed 92% without placental histology. Combining these two evaluations, we were able to diagnose congenital syphilis in 97% of the stillborn infants.
We feel that histopathologic evaluation of the placenta and umbilical cord should be an integral part of the evaluation for congenital syphilis. We confirmed that there are placental findings that correlate with definitive congenital syphilis diagnosed using modern diagnostic criteria and that there is a continuum of histologic findings that relate to the clinical spectrum of disease. Most importantly, we believe that these histologic findings will add to the diagnostic criteria used to define congenital syphilis.
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