Congenital Syphilis Diagnosed Beyond the Neonatal Period in the United States: 2014–2018

CS is a reportable condition in all 50 states and the District of Columbia, and the CDC receives case report data through the National Notifiable Diseases Surveillance System. According to the accepted Council of State and Territorial Epidemiologists surveillance definition, CS cases include (1) liveborn infants with clinical evidence of CS through direct detection of Treponema pallidum or with reactive nontreponemal syphilis test results and findings on physical examination, radiographs, or cerebrospinal fluid (CSF) analysis and (2) liveborn or stillborn infants delivered to mothers with untreated or inadequately treated syphilis.⁹  A CSF white blood cell (WBC) count of >15 WBCs per mm³ or CSF protein level >120mg/dL is considered elevated for infants aged ≤30 days, and a CSF WBC count of >5 WBCs per mm³ or CSF protein level >40mg/dL is considered elevated for infants aged >30 days, without other causes for elevation.⁹  CS surveillance data include maternal and infant demographic and clinical information, with data collected by state or local health department staff through provider documentation, laboratory reports, and medical record reviews.

We reviewed infants delivered during 2014–2018 and reported to the CDC as surveillance cases of CS; 2019 case report data were not available at the time of analysis. We included liveborn infants diagnosed with CS beyond the neonatal period (after age 28 days) and with reported signs or symptoms consistent with CS (symptomatic) to identify those with clinically relevant disease. Infants were defined as symptomatic if they had a reactive nontreponemal test result and 1 of the following signs or symptoms reported: condyloma lata, snuffles, syphilitic rash, hepatosplenomegaly, jaundice due to syphilitic hepatitis, pseudoparalysis, edema, or other signs of CS on physical examination; long-bone radiographic findings consistent with CS; elevated protein or WBC count in the CSF; or a reactive venereal disease research laboratory (VDRL) test result in the CSF. We excluded infants with evidence of birth outside the United States because one of our objectives was to investigate possible intervention points during the birth hospitalization. For twins, the duplicate maternal record was excluded. Age at diagnosis was calculated by subtracting the infant’s birthdate from the reported date of the infant’s first reactive nontreponemal test result.

Demographic and clinical characteristics of symptomatic infants with CS diagnosed beyond the neonatal period and their mothers were described. Possible missed opportunities for maternal diagnosis were described by calculating proportions of mothers reported to have received prenatal care, defined as ≥1 prenatal care visit, and syphilis testing during pregnancy and at delivery. Maternal seroconversion is defined as report of a negative syphilis test result early in pregnancy followed by a reactive syphilis test result later in pregnancy, around delivery, or up to 90 days after delivery.

Possible missed opportunities for infant diagnosis at birth were described by calculating the timing of maternal syphilis diagnoses. Timing of maternal syphilis diagnoses was categorized as during pregnancy (>3 days before infant’s birthdate), at delivery (3 days before or after infant’s birthdate), and after delivery (>3 days after infant’s birthdate). These were calculated by using maternal reactive nontreponemal and treponemal test result dates compared with the infant’s birthdate and the infant’s reactive nontreponemal test result date. Descriptive analyses were performed by using Stata version 16 (Stata Corp, College Station, TX).

During 2014–2018, the annual number of CS cases reported to the CDC increased 183% (from 462 to 1306 cases) (Fig 1). Of the 3834 infants with CS delivered in this time frame, 2120 (55.5%) were reported as liveborn and asymptomatic at the time of identification, 1455 (38.1%) were reported as liveborn and symptomatic, 245 (6.4%) were reported as stillborn, and 14 (0.4%) were reported with unknown or missing vital status.

Overall, 84 (2.2%) infants with CS were diagnosed beyond the neonatal period. Of these, 2 were reported as asymptomatic, 14 had incomplete data on signs and symptoms, and 68 were reported as symptomatic at the time of diagnosis. The 68 symptomatic infants diagnosed beyond the neonatal period included 1 set of twins and 1 infant with evidence of birth outside the United States. As a result, 67 infants and 66 mothers were included in analyses. Although the number of liveborn, symptomatic infants with CS has increased over time, the proportion diagnosed beyond the neonatal period decreased from 5.9% in 2014 to 3.9% in 2018 (Fig 1). Seventeen (25%) of the 67 symptomatic infants diagnosed beyond the neonatal period were born in 2018 (Table 1). The median age at diagnosis was 67 days (interquartile range [IQR]: 46–100, range: 29–249 days). Twenty-one infants (31%) were diagnosed after age 3 months, with 4 (6%) diagnosed after 6 months of age. Most of the 67 infants were born to non-Hispanic white (n=25, 37%) or non-Hispanic Black (n=22, 33%) mothers, but diagnoses beyond the neonatal period occurred among all racial and ethnic groups. Most infants were reported from the South (n = 24, 36%) or West (n = 21, 31%) US census regions, but all 4 regions and 30 states were represented. The median gestational age at delivery was 38 weeks, and 78% were born term (≥37 weeks).

For the 67 infants diagnosed beyond the neonatal period, the median nontreponemal titer at diagnosis was 1:256 (IQR: 1:32–1:512, range: 1:1–1:2048) (Table 2). Forty-five (67%) were reported to have physical examination findings consistent with CS. The most commonly reported physical examination finding was rash (n = 28, 42%), followed by snuffles (n = 11, 16%) and hepatosplenomegaly (n = 9, 13%), with 17 (25%) reported with other or unspecified signs of CS. The majority (n = 55, 82%) of infants were reported to have radiographs performed, with 10 (15%) reported as not performed and 2 unknown. Among those with radiographs, 38 (69%) had abnormal long-bone radiographs consistent with CS. Among the 50 (75%) infants with reported CSF VDRL test results, 18 (36%) had reactive results. Eleven infants (16%) were reported as not having a CSF VDRL test performed and 6 were unknown. Among the 44 (66%) infants with reported CSF counts, 22 (50%) had an elevated protein level and/or WBC count in the CSF. Seven infants had neither CSF VDRL tests nor cell counts performed. Most infants (n = 61, 91%) were treated with the recommended 10-day course of intravenous or intramuscular penicillin, but 6 (9%) were treated with either a single dose of benzathine penicillin or another regimen.

Most of the 66 mothers (n = 55, 83%) were reported to have had at least 1 prenatal care visit (Table 3). One-half (n = 35, 53%) had early stages of syphilis, including primary, secondary, and early nonprimary nonsecondary (early latent) syphilis. Sixteen (24%) mothers had evidence of seroconversion during pregnancy, with 12 diagnosed with syphilis after delivery. Five mothers (8%) had no reported syphilis testing during pregnancy or at delivery, although 3 had least 1 prenatal care visit. Nine (14%) mothers had evidence of syphilis diagnoses during pregnancy, with 5 diagnosed ≥30 days before delivery, and 8 (12%) were diagnosed at delivery. Thus, 17 mothers (26%) had syphilis diagnoses during pregnancy or at delivery. Twenty-eight mothers (42%) did not have confirmed syphilis diagnoses until after delivery, of which 15 (23%) were diagnosed after the infant’s diagnosis. The timing of syphilis diagnosis could not be determined for 21 (32%) mothers because maternal test results reported to the CDC were missing or nonreactive. Three mothers were reported as having received syphilis diagnosis and treatment at least 30 days before delivery; reinfection, treatment failure, or inadequate spacing of doses might have contributed to their infants’ diagnosis of CS at age 36 to 100 days.

In 1990, Dorfman and Glaser were surprised to identify 7 infants diagnosed with CS after age 3 weeks in New York City given the attention placed on detecting and treating sexually transmitted infections at that time.¹  We identified 67 infants with symptomatic CS diagnosed beyond the neonatal period during 2014–2018, highlighting continued concerns for delayed diagnosis and treatment in the current CS epidemic.

Although the 3834 infants with CS in the United States during 2014–2018 represent failures of public health, clinicians, and health care systems,^2,5,10  the 67 infants diagnosed beyond the neonatal period and the 245 stillbirths are ultimate failures. CS diagnoses beyond the neonatal period occurred in all US regions and among all racial and ethnic groups, representing widespread problems in provision of or access to recommended care for pregnant people and their infants in communities across the United States. Although the declining proportion of symptomatic infants diagnosed with CS beyond the neonatal period suggests an improvement in early diagnoses over time, rates of syphilis in women and CS continue to increase. Collaboration between public health and clinical sectors is needed to prevent further increases and to ensure that all infants with CS are identified and treated early.^5,10  Infants diagnosed beyond the neonatal period had high nontreponemal titers and a high prevalence of bone and central nervous system involvement. Infants with symptomatic CS at diagnosis and those diagnosed and treated later in life are at increased risk for developing sequelae.^5,7 

The CDC Sexually Transmitted Infections Treatment Guidelines contain specific instructions for evaluation, treatment, and follow-up of infants exposed to syphilis.⁸  All neonates born to mothers with reactive nontreponemal and treponemal test results should be evaluated with a serum nontreponemal quantitative test, either a rapid plasma regain (RPR) or VDRL test, and be examined thoroughly for evidence of CS. Neonates with abnormal physical examinations consistent with CS, with direct detection of T pallidum, or with a nontreponemal titer that is fourfold higher than the mother’s titer should be evaluated with a complete blood cell count and CSF analysis, including a VDRL test, and long-bone radiographs and should be treated with 10 days of intravenous or intramuscular penicillin.⁸  Neonates who appear normal but were born to mothers with untreated or inadequately treated syphilis should be evaluated with blood and CSF analyses and long-bone radiographs and treated with 10-day or 1-dose penicillin therapy, depending on the results of the complete evaluation. Infants and children older than age 1 month with reactive syphilis serology should undergo a full evaluation, including CSF analysis, and 10 days of treatment with penicillin. Eleven infants in this analysis were reported with no CSF VDRL test performed and 6 did not receive recommended treatment. Completing the recommended evaluation and treatment is necessary to identify complications and prevent sequelae of CS.

As rates of syphilis in adult women and CS continue to increase in every region of the United States,²  pediatric providers should know how to identify, evaluate, and treat infants with CS. CS should be on the list of potential diagnoses for infants with any of the signs or symptoms of CS, such as rash, nasal secretions, hepatosplenomegaly, or more rare presentations like pseudoparalysis, perirectal mass, or isolated fever.^1,3–5 ,11  CS should be considered even if the mother does not have a known history of syphilis because the majority of mothers in this analysis did not have known diagnoses of syphilis during pregnancy or at delivery.

Missed opportunities for earlier maternal and infant diagnosis were identified. Performing maternal and infant testing at delivery could have led to early diagnosis and treatment of the 5 infants whose mothers were not tested at all and the 12 infants whose mothers seroconverted and were diagnosed after delivery. The 17 infants whose mothers had evidence of syphilis diagnoses during pregnancy or at delivery should have been diagnosed and treated during the birth hospitalization. Pediatric providers can prevent these missed opportunities by confirming maternal syphilis status and advocating for maternal testing at delivery before discharging the newborn from the birth hospital. To accurately confirm maternal syphilis status, pediatric providers should be familiar with the types of syphilis screening tests and the syphilis screening algorithm used in the hospitals in their community.⁵  Pediatric providers can partner with maternal care providers to ensure that syphilis testing is performed at delivery for mothers with no previous testing and for mothers with indications for repeat testing.⁸  Pediatric providers can also partner with maternal care providers to identify missed prevention opportunities and work with local or statewide CS case review boards to support systemic changes to prevent CS.^10,12 

Early diagnosis and treatment of the infant, especially for infants who are asymptomatic at birth, depends on identifying maternal syphilitic infection during pregnancy or at delivery. Although the majority of states (n = 42) have laws that require universal syphilis screening at least once during pregnancy, as of 2018, less than one-half of these states (n = 19) had legislation requiring screening in the third trimester, and only 11 states required screening at delivery.¹³  Pediatric providers should be familiar with the laws in their state around syphilis testing during pregnancy and at delivery, as well as the recommendations from the CDC, American Academy of Pediatrics, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, and the US Preventive Services Task Force.^14,15  Pediatric providers should be aware of syphilis rates in their communities, per CDC Sexually Transmitted Disease Surveillance Reports and Atlas,^2,16  and risk factors for syphilis acquisition to advocate for appropriate maternal testing at delivery. Individual risk factors may include a history of multiple sexually transmitted infections, homelessness, transactional sex, and substance misuse.^17,18  With rising rates of opioid use disorder among pregnant people and the intersection of heterosexual syphilis and drug use epidemics in the United States, providers should assess for maternal substance misuse.^17,19  Only one-half of pregnant people with syphilis in 2012–2016 reported traditional individual risk factors, highlighting the limitations of risk factor–based screening and the importance of prevalence in the community and in sexual networks.²⁰ 

This analysis is subject to limitations because of the nature of national CS surveillance data. First, an infant who meets the surveillance case definition may not always be considered to have a clinically relevant case of CS; however, all infants included in this analysis had CS-related signs or symptoms. Case report data may capture only 75% of signs or symptoms of CS among reported cases, which could lead to underascertainment of symptomatic infants and underestimates of all clinical characteristics (unpublished CDC data). Variability in provider documentation and in health department collection of clinical evidence may contribute to this underascertainment of symptomatic infants. Additionally, CS case report data currently include only 2 sets of dates and results for maternal nontreponemal tests, which may lead to misclassification of timing of maternal syphilis diagnosis and underestimates of maternal seroconversion. CS case report data include only the first reactive infant nontreponemal test, but it is possible that a subsequent test date was reported, resulting in misclassification of timing of infant diagnosis, or that a previous nonreactive test result was obtained. Finally, CS case report data may not be complete or accurate because of the complex and time-consuming nature of CS investigations, especially for overburdened health departments. The CDC was unable to confirm the reported clinical information or identify additional clinical information, such as details on symptoms or treatment, through medical record review.

As the number of symptomatic infants and infants diagnosed beyond the neonatal period in the United States continues to increase, the number of children with late manifestations of CS will likely increase. Pediatric providers can prevent physical and neurologic sequelae of CS through early diagnosis and treatment. Pediatric providers should be aware of recommendations for management of pregnant people with syphilis, follow the guidelines for evaluation and management of newborns exposed to syphilis in utero, and confirm maternal syphilis status before discharging newborns from the birth hospital. Pediatric providers should consider a diagnosis of CS in any infant with signs or symptoms, regardless of maternal syphilis history. As the number of CS cases in the United States is higher than it has been in >20 years, many pediatric providers may be evaluating and treating infants with CS for the first time in their careers and should be prepared to do so.

CDC

Centers for Disease Control and Prevention

CS

congenital syphilis

CSF

cerebrospinal fluid

IQR

interquartile range

RPR

rapid plasma regain

VDRL

venereal disease research laboratory test

WBC

white blood cell