Prenatal Testing and Treatment of Syphilis

Prenatal Screening for Syphilis in Developing Countries Henry Perry Future Generations 8 June 2005 Outline       Overview of the burden of disease in the fetus/newborn produced by maternal syphilis Clinical characteristics of the disease Epidemiology of maternal syphilis Prevalence of infection among pregnant women in developing countries Recommended screening procedures for pregnant women Recommended treatment for pregnant women Outline (cont.)     Current status of detection and treatment of maternal syphilis in developing countries Cost-effectiveness of screening and treatment of pregnant women One example of program experiences Program implications Burden of Disease     500,000 fetal deaths worldwide each year are attributable to syphilis, resulting in spontaneous abortion or stillbirth 270,000 cases of congenital syphilis occur each year and 270,000 babies with low-birth-weight or prematurity attributable to syphilis are born each year Burden of disease far exceeds that of other neonatal infections, including HIV and neonatal tetanus Compared to 720,000 congenital HIV infections annually and 280,000 deaths from neonatal tetanus Clinical Characteristics of the Disease Causative Organism    Treponema pallidum subspecies pallidum Highly motile tightly coiled helical rod 10-13 mum in length Skin-to-skin transmission of other subspecies (pertenue, carateum and enedmicum cause yaws, pinta and bejel Stages of Syphilis       Incubating syphilis Primary syphilis Secondary syphilis Latent syphilis Late syphilis Congenital syphilis Incubating Syphilis    No symptoms Lasts 3 to 90 days (median 21 days) Early spirochetemia during this phase Primary Syphilis     Primary chancre – single painless papule HIV-infected patients can have multiples chancres Most commonly located on the external genitalia, perianal area, cervix, and mouth Lymphadenopathy Primary Syphilitic Chancre of the Perineum and Penis Secondary (Disseminated) Syphilis    Due to multiplication and dissemination of the spirochete Lasts until a sufficient host response develops to limit replication of the spirochete Begins 2-8 weeks after appearance of chancre of primary syphilis Symptoms of Secondary Syphilis  Skin lesions (90% of cases) – reason that syphilis originally called the “great pox”      Macular rash Maculo-papular rash Papular rash Pustular rash Condyloma latum Mucous patches Erosions Ulcers (aphthous)  Mouth and throat lesions (35% of cases)    Symptoms of Secondary Syphilis (cont.)  Genital lesions (90% of cases)    Chancre Condyloma latum Mucous patch Fever of unknown origin Malaise Pharyngitis/laryngitis Anorexia, weight loss Arthralgias  Constitutional symptoms (70% of cases)      Palmar Lesions of Secondary Syphilis Latent Syphilis      Begins after secondary syphilis stage completed No clinical symptoms, normal chest x-ray, normal cerebro-spinal fluid Treponemal antibody test positive Relapse to active clinical disease can occur (e.g. during pregnancy or with HIV infection) and maternal-fetal transmission of infection can occur Lasts 5-20 years Late Syphilis  Late neurosyphilis Progressive endarteritis obliterans of cerebrovascular system  May be asymptomatic or symptomatic  Symptoms include: hemiparesis, aphasia, seizures, tabes dorsalis, general paresis, personality changes, affect changes, delusions, memory loss, slurred speech  Late Syphilis (cont.)  Late cardiovascular syphilis Aortic aneurysm, especially of the ascending aorta  Other arteries can be involved (e.g., renal artery)   Late benign syphilis (Gumma) Formation of non-specific granulomas  Tumor-like masses in bone, skin, or any organ  Symptoms: nodules, ulcers, fever, tenderness, fracture, joint destruction, cirrhosis  Congenital Syphilis      Signs and symptoms don‟t usually occur until 3 weeks after birth Rhinitis (snuffles – mucopurlent nasal discharge) – 40% of cases Diffuse, maculopapular, desquamative rash (especially on palms and soles) – 40% of cases Rash can be vesicular with bullae Liver is usually infected, producing hepatosplenomegaly, anemia, thrombocytopenia, and jaundice – 20% of cases Congenital Syphilis (cont.)      Many skeletal findings (osteochronditis, periostitis, osteomyelitis, osteitis) Nervous system can be involved, and mental redardation can occur Nephrotic syndrome, glomerulonephritis Ocular abnormalities Multitude of other rarer findings (saddle nose, Hutchinson‟s teeth, eighth-nerve deafness, etc.) Congenital Syphilis (cont.)  10-40% of cases are premature or have low-birth weight Syphilis in Women of Reproductive Age     Most cases asymptomatic Even if symptomatic ulcers develop in women, they rarely seek treatment Most pregnant women with syphilis are asymptomatic and can be identified only through serological testing Pregnant women who have acquired the infection in the previous two years transmit the infection to the fetus in almost all cases Maternal-to-Child Transmission   Transmission primarily hematogenous Transmission can occur from direct contact with genital lesions Epidemiology of Maternal Syphilis  Spontaneous abortion/intra-uterine fetal death  Pregnant women with syphilis have: 3-5 times increased risk of spontaneous abortion  5 times increased risk of intra-uterine death   5% of all fetal deaths in Ethiopia estimated to be secondary to maternal syphilis Epidemiology of Maternal Syphilis (cont.)  Stillbirth 4 times increased risk of stillbirth  In Zambia, 24% of stillbirths attributed to maternal syphilis  In Malawi, 24% of one group of sero-positive mothers had a stillbirth  In high-prevalence areas, up to one-half of stillbirths can be caused by syphilis  Epidemiology of Maternal Syphilis (cont.)  Perinatal mortality (stillbirths + death in first week of life) 3 times increased risk  20-30% of perinatal mortality in Zambia and Zimbabwe attributable to syphilis  In Malawi (where prevalence of syphilis among pregnant women is 3.5%), 20-25% of perinatal deaths attributable to syphilis  Epidemiology of Maternal Syphilis (cont.)  Neonatal mortality (death in first 28 days of life)  10-12% of infants born to mothers with a positive serology will die during the neonatal period (rate 100-120 per 1,000 live births)  Longer-term sequelae Increased risk of post-neonatal death  Congenital syphilis affects 25-75% of exposed infants  50-75% of infected infants develop severe physical and mental handicaps if child survives  Epidemiology of Maternal Syphilis (cont.)  Overall risk     8 times increased risk of some kind of adverse outcome Even after treatment, the risk of an adverse outcome is increased 2-3 times Active syphilis in pregnancy causes an adverse outcome in 50-80% of pregnancies surviving 12 weeks of gestation 50% of pregnancies among mothers with primary or secondary syphilis result in spontaneous abortion, stillbirth, perinatal death, prematurity, or low-birth-weight Epidemiology of Maternal Syphilis (cont.)  Prematurity and low-birth-weight 3 times increased risk of prematurity when mother is sero-positive  8 times increased risk of low-birth-weight when mother is sero-positive  Premature and low-birth-weight infants at greatly increased risk of death  Syphilis and HIV Transmission   Presence of syphilitic genital ulcer disease associated with greatly increased risk of HIV transmission One of reasons why treatment of sexually transmitted diseases is one of the recommended approaches to reducing HIV transmission – though a recent Cochran review concluded that “there is limited evidence from randomised controlled trials for STI control as an effective HIV prevention strategy.” Syphilis Transmission   Virtually all cases are transmitted through sexual contact Risk of infection after a single exposure is variable – can be as high as 12% Prevalence of Infection among Pregnant Women in Developing Countries       Prevalence in African countries is 4-15% Bangladesh brothels: 7% Chinese men: 0.3-.8% Rural Haiti: 6% Jamaica: 2% Bolivia: 4% Recommended Screening Procedures for Pregnant Women     All pregnant women should undergo a blood test for syphilis Screening and treatment should occur as early as possible in pregnancy and treatment, in order to be effective, should be given at least one month before delivery Until recently, screening required cold storage for testing reagents and an electrically powered centrifuge and rotator Now, rapid tests are available which don‟t require electricity, which use whole blood, require minimum training, no equipment, and cost $ 0.45-1.00 Recommended Treatment for Pregnant Women     Centers for Disease Control and World Health Organization recommend treatment of incubating, primary, secondary and early latent syphilis with a single intra-muscular dose of 2.4 million units of benzathine penicillin G or 3 doses over three weeks if the infection has been present for at least a year Some evidence that one dose is sufficient No alternatives at present to penicillin injection for pregnant women – desensitization required if patient allergic However, preliminary evidence exists that a single oral dose of 2 grams of azithromycin may be effective Current Status of Detection and Treatment of Maternal Syphilis in Developing Countries      1.6 million pregnant women with syphilis in SubSaharan Africa go undetected each year Among these 1.6 million women, 1.0 million receive prenatal care 73% of the population of Sub-Saharan Africa live in countries in which antenatal screening for syphilis is part of the national health care policy Only 38% of women in Sub-Saharan Africa who receive prenatal care also undergo screening for syphilis Only 28% of pregnant women in Sub-Saharan Africa under screening for syphilis Cost-Effectiveness of Screening and Treatment of Pregnant Women      Cost of screening – $ 0.20 – 0.60 per test Cost of treatment – $ 1.00 per dose, $ 3.00 per treatment if 3 doses given If 1% prevalence, total cost of screening and treatment would be $ 0.42 per woman screened If 5% prevalence, cost of $38 per case treated For 25% prevalence, cost of $9 per case treated Cost-Effectiveness of Screening and Treatment of Pregnant Women (cont.)      Cost to prevent an adverse outcome associated with pregnancy in Sub-Saharan Africa- $12 If prevalence 1%, $70 to prevent an adverse pregnancy outcome or syphilis-associated death In comparison, cost to prevent a measles death through immunization is $40 Assuming prevalence of 8%, $318 to prevent a stillbirth and $44187 to prevent all adverse pregnancy outcomes (compared to $507 for preventing a case of mother-to-child transmission of HIV) Cost per DALY saved: $4-19 compared to $19 for prevention of mother-to-child transmission of HIV Examples of Program Experiences  Hospital Albert Schweitzer in Haiti Before decentralized screening only one-quarter of patients who tested positive were treated  After decentralized screening, rates of congenital syphilis declined five-fold  Changes in Rates of Congenital Syphilis after Making Testing Available at Health Centers Reference: DW Fitzgerald et al., American Journal of Public Health 2003 Program Implications     Need to determine the prevalence of syphilis among pregnant women in the program population If 1% or more, strongly consider adding prenatal screening Consider small-scale “operations research” or pilot projects at the outset PVOs/NGOs need technical guidelines and encouragement from donors for this References for New Diagnostic Tools    Peeling RW, Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 2004; 82: 439-46. World Health Organization. Sexually transmitted disease diagnostic initiative: htpp://www.who.int/std_diagnostics World Health Organization. htpp://www.google.com/u/who?q=Bulk+Procuremen t&sitesearch=who.int&domains=who.int Reverse Equity Hypothesis “We propose a correlate of the inverse equity hypothesis, that medical research on novel health technologies is a higher priority than research on equitable distribution of existing technologies because higher socioeconomic groups „control‟ research agendas and are much more interested in acquiring new health technologies for themselves than sharing existing technologies with the poor.” Fitzgerald and Behets, JAMA, 2002 The Challenge to Child Survival Programs “Tools to prevent congenital syphilis have been available for more than 50 years, and cost less than $1. So why do babies still die of syphilis?” RW Peeling, D Mabey, DW Fitzgerald, D WatsonJones, Lancet 2004 Challenge to HIV/PMTC Programs Cases exist in which a mother comes for VCT, tests positive for HIV infection, receives shortcourse anti-retroviral therapy for prevention of MTCT, but the baby dies of congenital syphilis RW Peeling, D Mabey, DW Fitzgerald, D WatsonJones, Lancet 2004