Sexually Transmitted Diseases:
Congenital Syphilis: An Economic Evaluation of a Prevention Program in China
Hong, Fu-Chang MD*; Liu, Jiang-Bo MD, PHD†; Feng, Tie-Jian MD*; Liu, Xiao-Li MD*; Pan, Peng MS*; Zhou, Hua MD, PHD*‡; Cai, Yu-Mao MS*; Ling, Li PHD§; Huang, Xi-Ming MS*; Zhang, Dan MS¶; Zhang, Ying-Ji MS¶; Zeegers, Maurice P. PHD†∥**
From the *Department of Dermatology and STD, Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen, China; †Department of Dermatology, Huiyang People's Hospital, Huizhou, Guangdong, China; ‡Department of Dermatology, Bao'an Maternity and Child Health Hospital, Bao'an District, Shenzhen, China; §Department of Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China; ¶Shenzhen Health Bureau, Shenzhen, China; ∥Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, School of Medicine, The University of Birmingham, Birmingham, United Kingdom; and **Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands
Supported by the Programme of Prevention of mother-to-children transmission of Syphilis in Shenzhen (PPSS) and the Fund for Studies on Medical Science and Technology in Guangdong Province (No. B2006143).
Correspondence: Professor Hua Zhou, Department of Dermatology, Bao'an Maternal & Child Health Hospital, Bao'an District, Shenzhen, 518000, China. Or Dr. Jiang-Bo Liu, MD, PHD, Department of Dermatology, Huiyang People's Hospital, Huizhou, Guangdong 516211, China. E-mail: firstname.lastname@example.org.
Received for publication March 11, 2009, and accepted June 18, 2009.
Background: Until now there has been no data to show the effectiveness or benefits of screening for syphilis in gravidas in China. This study was to assess the effectiveness of a program preventing mother-to-child-transmission of syphilis and to reveal factors impacting the benefit.
Methods: A cohort of 159,017 gravidas were screened for syphilis by serologic methods and infected individuals were treated with 3 injections of 2.4 million units of benzathine penicillin in Shenzhen in 2005. The pregnancy outcomes were compared for this cost-effectiveness analysis in 2 scenarios, intervention with screening and treatment versus no intervention.
Results: Eight hundred twenty-seven pregnant women (0.52%) were diagnosed with syphilis and treated subsequently. Of these, 200 gestations ended in miscarriage. Four babies were diagnosed with congenital syphilis; 25 neonates with low birth weight; 1 died after birth. The total cost was $636,748. On average, every $770 identified 1 infected mother. Every $4391 prevented 1 congenital syphilis; every $5135 prevented 1 low birth weight; and every $7075 prevented 1 death. One disability adjusted life year could be saved by $215. In total the program reached a benefit to cost ratio of 21.76. Sensitivity analyses revealed that this ratio was mainly impacted by the prevalence of syphilis in pregnant women and the rate of miscarriage.
Conclusions: Screening for antenatal syphilis combined with intervening during gestation is highly effective in China. Reducing the percentage of spontaneous/induced abortion would be one of the most effective methods of further increasing the benefits of this screening.
Congenital syphilis (CS) is an infectious disease maternally transmitted by Treponema pallidum during pregnancy. CS has been considered as one of the main causes of fetal/neonatal morbidity and mortality in Sub-Saharan Africa.1 Infection of syphilis during gestation can result in not only CS but also low birth weight (LBW, 20%), spontaneous abortion (20%), and perinatal deaths (15%).2–4 It has been estimated that the numbers of fetal/neonatal deaths in Africa each year from untreated maternal syphilis could rival those from HIV infections.3 However, the crisis resulting from this disease has not received sufficient public attention until recent years.
CS can be prevented. Data from both developed and developing countries have shown that early detection and treatment for syphilis during pregnancy can efficiently block transmission of syphilis from mothers to children. All programs of prevention of mother-to-child-transmission (PMTCT) of syphilis in developed countries concluded that screening of syphilis and treating during pregnancy was cost-effective.5–9 These positive effects have also been seen in developing countries. Several studies recently showed high levels of effectiveness not only in preventing CS but also in preventing adverse pregnancy outcomes (APOs) due to syphilis.10–13 In sub-Saharan Africa, every $8.88 to $10.56 (dependent on different lifespan) invested could save one disability adjusted life year (DALY) in 2001.11 Therefore, screening and treatment for maternal syphilis have been recommended by the World Bank and World Health Organization (WHO) as the minimum clinical package for preventing CS, which is now routinely implemented in many countries, leading to a reduction in the incidence of CS.3,14,15
In China, however, the incidence of CS has increased at a worrying rate of 71.9% per year from 0.01 to 19.68 cases per 100,000 live births from 1997 to 2005.16 In Shenzhen, one of the most developed regions in China, the first case of CS was reported in 1996. Since then, the incidence of CS has rapidly increased to one of the highest rates in China, 115.30 per 100,000 neonates in 2002. Besides CS, other severe APOs such as spontaneous abortion, perinatal death, LBW due to syphilis were also significantly increased along with the syphilitic spreading.16 To prevent and control the increasing of CS and other APOs, a Program of PMTCT of Syphilis in Shenzhen (PPSS) was launched in July, 2001.17,18 This was the first CS prevention program conducted in China. This study will evaluate whether the PPSS was cost-effective and how to obtain the highest benefits within the given budgets in contemporary China.
Study Population and Intervention
The data for analyses were derived from the PPSS office and the subjects were gravidas screened for syphilis in 2005. The PPSS was organized and supervised by the Shenzhen Center for Chronic Disease Control and Prevention. Recruitment took place in 61 hospitals in Shenzhen. These hospitals included public and private hospitals, maternity and child health hospitals, and chronic disease hospitals, providing antenatal care services. A detailed description of the screening program has been published elsewhere.17,18 In short, all pregnant women visiting any one of these hospitals were offered free syphilis screening after giving informed consent. This included a physical examination, a toluidine red unheated serum test (TRUST, Shanghai Rongsheng Biotech Co, Ltd, Shanghai, China) and a dark field microscopy examination for primary syphilis. An additional Treponema pallidum particle agglutination (TPPA) test was performed if the result of TRUST was positive. The included cases were those with positive dark field microscopy examination results or a reactive TPPA test without routine treatment, according to the sexually transmitted diseases treatment guidelines19 before gestation. These women with untreated syphilis were given 3 injections of 2.4 million units of benzathine penicillin at a weekly interval. At least 1 dose was given if there was too little time to give injections before delivery.
The cohort was followed-up for APOs including LBW (birth weight, <2500 g), death (including miscarriage, stillbirth, and neonatal death) and CS. CS was diagnosed according to one of the following criteria: (a) a positive darkfield or fluorescent antibody test of body fluid; (b) an abnormal physical examination that was consistent with secondary syphilis and a TRUST titer that was fourfold higher than the mother's titer; or (c) a reactive TPPA test until 18 months after birth.19 All the children with CS or suspicion CS were injected with penicillin.19 These children were followed up until the TRUST turned negative or the titer decreased 4-fold. The study was ethically approved by the Institutional Review Board of Shenzhen Center for Chronic Disease Control and Prevention.
The total cost of the PPSS included both institutional and individual expenses. Institutional expenses included the fee for screening and diagnosis for syphilis and CS, personnel, transportation, following-up, and supervising the running of the PPSS. Data relating to institutional expenses were derived from the 2005 finance report forms of the PPSS office. Individual expenses included those costs that were paid by patients or their families themselves such as (a) medical expenses of the infected mothers, their spouses, and their infected children; (b) lost income because of missed working time due to treatment of syphilis; and (c) travel expenses for screening and treatment of syphilis. Data relating to individual expenses were derived from the medical bills and a survey of 98 mothers who were randomly sampled from the whole cohort of infected mothers using a random number generator.
An indicator of the success of the PPSS was the rate of prevented APOs due to maternal syphilis. This was defined by the observed number of APOs in this study divided by the expected number of APOs if no intervention was given. The latter was derived from a WHO report on the global burden of sexual transmitted infections.2,20 The WHO model showed that without intervention mothers with syphilis would deliver neonates with CS, LBW or suffer spontaneous abortion, 20% in each case, and be confronted with perinatal death in 15% of the cases. Five percent of infants with LBW or CS would be dead in countries with level B health care such as China.20
Calculating YLLs, YLDs, and DALYs
According to Global Burden of Disease (GBD) methods,21 years of life lost (YLLs), years lived with disability (YLDs), and DALYs were calculated using the following formulas with nonzero discounting and age weighting.22
where N is the number of deaths; L is standard life expectancy at the average age of death; r is the discount rate (GBD standard value: 0.03); C is the age-weighting correction constant (GBD standard value is 0.1658); β is the parameter from the age-weighting function (GBD standard value: 0.04); and a is the age of onset.
Equation (Uncited)Image Tools
where I is the number of incident cases in the referred period; DW is the disability weight (ranged from 0–1); and L is the average duration of disability (measured in years). The values of a, r, C, and β are consistent with those in calculating YLLs.
Equation (Uncited)Image Tools
As the disability weight of LBW due to syphilis is unknown,23 DALYs saved were calculated only for CS and death by using the formula: DALYs = YLLs + YLDs. The standard life expectancy (72.4 years) in China in 2005 was obtained from the WHO Statistical Information System (available at: http://www.who.int/research/en/). Data on disability weights (0.315 for CS)24 and duration of disability (3 years for CS)23 were used to calculate YLLs, YLDs, and DALYs. The impact of the PPSS on DALYs was measured by calculating DALYs in 2 scenarios: with and without the PPSS.
Saved DALYs were calculated according to the formulas given above. Cost for per saved DALY was described for cost-benefit analysis, which equaled the total costs divided by saved DALYs.
The benefit to cost ratio is calculated by dividing gross domestic product (GDP) per capita of Shenzhen in 2005 ($4683) (the GDP of 56,483 million US dollars divided by the population (including both 1.71 million registered permanent residents and 10.35 million temporary/floating residents) in Shenzhen in 2005, which is not same with the figure of $7483 released by the Government because some floating population were not included in the later) by the cost for per saved DALY. A ratio over one was considered effective. Sensitivity analyses were performed to evaluate the impact of the prevalence rate of syphilis in pregnant women, the percentage of abortion (including spontaneous and induced abortion) among infected mothers and the varying expected prevalences of APOs reported in WHOs model. Both spontaneous and induced abortions were considered as loss of life at the age of zero, equaling perinatal death. A series of assumptions were made in order to perform the sensitivity analyses. First, the stage of the maternal syphilis was ignored although it is known that it may have effect on the birth outcomes.11 Second, in the sensitivity analyses, all the covariates were fixed except the independent variables.
Screening and the Prevalence of Syphilis in Pregnant Women
There were 165167 pregnant women recorded and 159,107 (95.77%) of these were screened from January to December in 2005 in Shenzhen.18 The spontaneous abortion and stillbirth in general population was 2.86% (4728/165167). Out of the 159,107 screened pregnant women, 827 (0.52%) individuals were diagnosed with untreated syphilis.
The Demographic Characteristics of the Infected Mothers
Of the 827 cases, 30% were under the age of 24 (Table 1) and 71% were educated at the level of junior high school or lower. Ninety-eight cases (11.82%) were unmarried and more than 50% were jobless. Almost all cases were temporary residents (92.27%), which is normal in Shenzhen as it is a new immigrant city built in the last 30 years. A total of 484 (58.52%) mothers were screened before the gestational age of 28 weeks. The titer of TRUST in 268 (32.41%) cases was ≥1:8. There was no significant difference between the sample and the whole cohort in respect of demography, social status, and the titer of antibodies to syphilis (data not shown here).
Adverse Pregnancy Outcomes
Sixty (7.26%) of the 827 mothers suffered from spontaneous abortion or stillbirth; 140 (16.93%) mothers choose to stop pregnancy via induced abortion; and 584 (70.62%) mothers gave birth to living infants. Forty-three (5.2%) mothers were lost for following-up. Therefore, the cost-effectiveness analysis was performed on 784 mothers and their pregnancy outcomes. Of these, 4 babies were diagnosed with CS; 25 neonates were born with LBW; 1 died after birth. A total of 554 babies were healthy. The PPSS successfully prevented 97% of CS, 83% of LBW, and 31% of fetus/neonatal death (including abortion and perinatal death) (Table 2). The total success rate of the PPSS in averting APOs was 61%.
The total institution costs were $292,666 (45.96%). The individual costs were $344,082 (54.04%). The total costs of the PPSS in 2005 added up to $636,748 (Table 3). On average, every 4 dollars could screen 1 pregnant woman; the costs to identify 1 infected mother were $770. Every $4391 prevented 1 CS; every $5135 prevented 1 LBW; and every $7075 prevented 1 death.
In total, 2959 DALYs were saved at the scenario of the WHOs model. In contrast, 1 DALY could be saved by every $215 (Table 3). We varied the WHOs expected values by a 75% discount and recalculated the benefits in order to avoid a false result with cost-effectiveness due to an overestimate. At this scenario the cost for saving 1 DALY was $1047, approximately 1 quarter of the GDP per capita (Table 3).
The benefit to cost ratio of the PPSS reached 21.76 in 2005. The cost for saving 1 DALY increased with decreasing prevalence of syphilis in pregnant women (Fig. 1). The benefit to cost ratio would be greater than unity even if the prevalence was as low as 0.024%. Another univariate sensitivity analysis revealed a nearly linear relation between the abortion rate and the benefit to cost ratio (Fig. 2). The saved DALYs would be doubled when the percentage of abortion would drop to 14% and the prevalence rate of syphilis in pregnant women was fixed to the present level of 0.52%. When the abortion rate was consistent with the rate of spontaneous abortion in the general population (≈2.86% described above), the benefit to cost ratio of the PPSS reached its highest value of 64.
A program of free screening for syphilis among pregnant women in Shenzhen (the PPSS) was launched in July 2001 to prevent and control the transmission of syphilis from mothers to children. We have conducted the first cost-effectiveness analysis of such a program in China.
Two characteristics distinguished this study from previous studies elsewhere. First, we calculated the expected APOs values due to untreated syphilis on the basis of the estimate used in calculating the global burden of sexually transmitted diseases.2,20 It may have been more valid to have received this data from an embedded randomized clinical trial in which mothers would have been grouped into those with or without the intervention and then comparing the differences between groups. However, this ideal design could not be implemented due to practical constraints and ethical disapproval. We therefore used a uniform criterion2,20 to calculate expected APOs due to maternal syphilis that could also be used for comparison between studies. Recently, Terris-Prestholt et al obtained values of APOs for those that did not receive an intervention from local historical medical records.11 Although this may have been suitable for the local situation it would have harmed the comparability with other studies. Other studies did not clearly describe the theoretical values of APOs due to syphilis, although all consistently concluded that antenatal syphilis screening was highly cost-effective.7,8,12
Second, neither spontaneous nor induced abortion has been considered in previous cost-effectiveness analyses.1,3,7,11,12,14,25–27 Because spontaneous abortion is one of the syphilis related APOs and because it can be significantly reduced by intervention,11,28–30 its prevention should be considered as a potential benefit from any PMTCT program. In this study, after intervention, the cases of spontaneous abortion dropped markedly from 157 to 60. However, 17.86% (140/784) of the mothers choose to stop gestation by induced abortion after they were informed about their positive infection status. One of the reasons reported for this was that they were afraid of the adverse impact of syphilis on their children. Another reason for the high rate of induced abortion was that 68 single (unmarried) mothers were recruited who choose induced abortion due to traditional cultural reasons. Nevertheless, the program still saved 90 fetuses/infants from death.
Some other benefits from the PPSS were not included in this study. For example, the treatments not only controlled syphilis in parents but also stopped the transmission of syphilis. It could also have limited the opportunity of transmitting other sexually transmitted diseases (such as HIV and gonorrhea).2 Furthermore, the prevention of LBW in infants by the PPSS was not included in the benefits equation. It is well known that infants with LBW would be hospitalized longer and expend more money than normal ones due to premature delivery complications. Moreover, spontaneous abortion due to nonsyphilis was not excluded in the APOs, which would decrease the benefit of the PPSS somewhat. It is also well known that the infection of syphilis in pregnant women will increase the risk of preterm birth. However, this adverse outcome of pregnancy was not included in this analysis because of lack of basal data for calculating DALYs from saved preterm births. All these excluded benefits would have increased the benefit to cost ratio if they were considered in this analysis.
Previous studies consistently concluded that the benefit to cost ratio of the intervention for maternal syphilis could be modified by the prevalence rate of syphilis in pregnant women,3,7,11,12,25,27 which was confirmed in the current study. A lower prevalence indicated a higher cost to find 1 case in the population. However, our sensitivity analyses showed that even a marked drop of the prevalence did not substantially increase the cost for intervention in today's China. Even if the prevalence rate were as low as 0.1%, the cost per DALY saved would still be $1118 and the benefit to cost ratio would still be as high as 4 (Fig. 1). In the absence of screening, it is reasonable to expect that some cases would be treated, which would decrease the ratio somewhat. According to the sensitivity analysis, the screening program would be still cost-effective even 95% infected women seeking treatment regardless of screening (which meant the prevalence of untreated syphilis dropping from 0.52% to 0.026%).
The percentage of spontaneous/induced abortion had a substantial effect on the benefit to cost ratio according to the result of sensitivity analyses. Several reasons could be given for the high abortion rate observed in our population studied. First, 343 (41.48%) mothers consulted their doctors for their first prenatal care after 28 weeks of gestation (Table 1). The delayed finding of syphilis and intervention could therefore not prevent the very early spontaneous abortion. Second, the infected mothers and their families were afraid that a diagnosis with syphilis would have adverse effects on the fetus and they wished to re-gestate after the infection was cured completely. This thought was understandable because sexually transmitted diseases such as syphilis are frightening and disgraceful in China.
Syphilis has been spreading in China and congenital syphilis is increasing at a surprisingly rapid pace.16 The question of how to control and prevent congenital syphilis has become a public health priority. For the first time, this study analyzed the costs and effectiveness of a program implemented in China to prevent syphilis transmitting from mothers to children. It can be concluded that this program is cost-effective. Decreasing the high rate of abortion in infected mothers would be an effective method to further increase the benefit to cost ratio of the program.
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