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Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South Florida, Tampa. He can be reached at DrLockwood@ubm.com.
Faced with the rapid increase in a potentially deadly-but preventable-congenital disease, it’s time for states to take action to require appropriate screening
Rates of congenital syphilis have taken an ominous uptick over the past few years and are now at a 20-year high. The Centers for Disease Control and Prevention (CDC) reports that rates of primary and secondary syphilis in the general US population have increased 72.7% from 5.5 cases per 100,000 in 2013 to 9.5 per 100,000 in 2017 when a total of 30,644 cases were reported.1 The number of cases of congenital syphilis have increased simultaneously. After years of decline reaching a nadir in 2012, cases of congenital syphilis increased from 362 in 2013 to 918 in 2017 including 64 stillbirths and 13 infant deaths.1 During this time, the largest rate increases occurred in the Western United States (362.5%). Rates were highest among blacks (58.9 cases per 100,000 live births), followed by Native (indigenous) Americans (35.5 per 100,000), Hispanics (33.5 per 100,000), whites (9.7 per 100,000), and Asians/Pacific Islanders (4.3 per 100,000).
The consequences of congenital syphilis are so severe, and its prevention so straightforward, that this increase represents a public health tragedy. Thus, it is time to ensure that all pregnant women are adequately screened and expeditiously treated to eliminate this disease entirely. Fortunately, a few states are leading the way in curbing this epidemic and provide useful lessons for the rest of the nation.
Syphilis is caused by the spirochete Treponema pallidum. Primary syphilis is marked by presence of a chancre that heals in 3 to 6 weeks. Secondary syphilis, manifest by lymphadenopathy and/or a maculopapular rash on the palms, soles and mucous membrane, occurs in a quarter of cases6 weeks to 6 months after the chancre first appeared and lasts 2 to 5 weeks. Early latent syphilis occurs in the first full year, and late latent occurs thereafter. Tertiary syphilis is now rare with its classical gumma lesions and cardiac defects while neurosyphilis can begin with early disease and slowly progress to paresis if untreated.
Screening can employ either traditional or reverse sequence approaches.2 The former includes initial nontreponemal testing such as a quantitative Rapid Plasma Reagin (RPR) assay followed by confirmatory treponemal testing (e.g., Fluorescent treponemal antibody absorption test (FTA-ABS) or T. pallidum particle agglutination assay [TPPA]). Reverse sequence screening begins with an initial treponemal chemoluminescent or enzyme immunoassay with reflex testing of positive results (false positive results occur in 50% to 90% of cases) using a non-treponemal test such as quantitative RPR. If the RPR is positive it is diagnostic, but if negative, a final TPPA or FTA-ABS study is required to exclude the diagnosis.2
Treatment depends on the stage of the disease. For primary, secondary, and early latent disease a single dose of penicillin G benzathine (2.4 million units) is given intramuscularly. For late latent and tertiary disease, three weekly doses are required. Neurosyphilis requires inpatient parental therapy. While non-penicillin treatments (e.g., tetracycline) can be used in non-pregnant women, only penicillin G benzathine is appropriate in pregnancy. Thus, if pregnant patients are allergic, desensitization is needed. The biggest risk of treatment is the Jarisch-Herxheimer reaction occurring within 2 hours of treatment which can trigger preterm labor.
Transplacental passage of Treponema pallidum can occur at any stage of the disease with the greatest risk occurring with primary, secondary, and early latent disease.3 It can also occur at any gestational age. Because it is the fetal immune reaction that produces the pathological stigmata, more severe effects are seen in the second half of pregnancy. Fetal manifestations include hepatomegaly, placentomegaly, anemia, hydrops, and death. There is an 80% risk of congenital syphilis if mothers remain untreated. Fortunately, adequate and prompt treatment is almost always curative.
Thus, the key to prevention is detection. Women at highest risk include those who have a partner in a high-risk sexual network, and those with a history of incarceration or substance abuse. However, Trivedi and associates analyzed national case report data including risk behavior statistics and concluded that half of affected women had no traditional risk factors.3 Nonetheless, the current recommendation by the CDC and the American College of Obstetricians and Gynecologists (ACOG) is for universal screening at the first prenatal appointment with re-screening in the third trimester and at delivery for women at high personal risk or who live in areas with high rates of syphilis.4
There is clear evidence that such screening reduces risk. A recent US Preventive Services Task Force (USPSTF) report noted that increasing screening of pregnant women in Shenzhen, China from 89.8% to 97.2% between 2002 and 2012 reduced prevalence of congenital syphilis from 109.3 cases per 100,000 livebirths to 9.4 per 100,000.2,4 This resulted in a reduction in adverse outcomes from 42.7% of affected pregnancies to 19.2%. The primary “harm” associated with screening are false-positive results primarily when using the “reverse sequence” strategy and relatively rare false negatives (2.9%) from traditional screening using the RPR as a screen due to the “prozone phenomenon.” The latter occurs when undiluted serum contains high titers of nonspecific antibodies which bind antigen sites preventing flocculation.2 The USPSTF concluded that screening “for syphilis in pregnant women is associated with reduced incidence of congenital syphilis and available evidence supports the need for reflexive testing for positive test results.”2
Causes of the current epidemic and novel mitigation strategies
So why have rates of congenital infection climbed despite universal first-trimester screening and the availability of a very effective treatment? One explanation is failure to perform third-trimester screening because the patient is not known to be high risk. Providers can be hesitant to ask uncomfortable questions about sexual histories. Reinfection is another cause as many providers assume a treated patient will remain infection-free and do not retest previously treated patients in the third trimester.5 Moreover, as noted, up to half of all cases occur in low-risk women.2 Albright et al. used a decision support model to show that universal re-screening in the third trimester would be a cost-effective way of reducing associated morbidity.6 For example, re-screening all pregnant women in the United States would prevent 60 cases of congenital syphilis annually, seven stillbirths and four neonatal deaths at a cost of $419,842 for each case prevented. Louisiana requires rescreening in the third trimester for all pregnant women and the Arizona Department of Health recently began recommending universal screening at the first prenatal visit, in the third trimester and at delivery.5
In response to high rates of congenital infection, especially in Caddo Parish which includes Shreveport, Louisiana has become an exemplar in the fight against congenital syphilis.5 The state established regional review boards to identify factors leading to cases and propose effective interventions. Of the 79 cases occurring there over an 18-month period, roughly one-third involved providers failing to perform adequate screening. The State has now hired a nurse practitioner to conduct grand rounds and raise provider awareness about screening. In about another third, treatment was either not given (e.g., the patient never returned for care), was incomplete or was delayed. Because treatment for late latent disease requires three weekly doses of penicillin with the need to repeat the series if more than a week elapses between therapies, the state is assessing whether visiting nurses administering injections at home improves adherence. However, in 40% of cases affected patients never received prenatal care for a variety of reasons (e.g., lack of awareness of their condition, no transportation, fear of receiving care related to substance abuse or domestic violence). Tackling these social determinants presents a far bigger challenge with no simple solutions.
Rates of congenital syphilis have been rising sharply over the past few years from multiple causes. At a minimum universal screening should be done at the first visit with re-screening in high-risk women in the third trimester and at delivery. However, I believe the time has come for all states, and certainly those with the highest incidence, to require universal re-screening in the third trimester and a third screen at delivery in high-risk women.