Syphilis, a rarity for some years, is resurgent in many parts of the world. Even in those countries where rates have fallen, focal outbreaks still occur.1,2 Recent meta-analysis by Gomez et al.3 indicates that approximately 52% of pregnancies in mothers with untreated or inadequately treated syphilis result in some adverse pregnancy outcomes (APOs), with estimated proportions: early fetal loss or stillbirth (SB; 21%), neonatal death (9%), low birth weight (LBW) or premature birth (6%), and infection in a live-born infant (15%). 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.4–6 However, the crisis resulting from this disease has not received sufficient public attention until recent years.
Congenital syphilis (CS) has been a global burden, and elimination of CS is one of the millennium development goals of the World Health Organization.7 In China, the incidence of CS has increased at a worrisome rate of 71.9% per year from 0.01 to 19.68 cases per 100,000 live births from 1997 to 2005,8 and even up to 56.76 cases per 100,000 live births in 2008. The first case of CS in Shenzhen 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 2002.8 In addition to CS, severe APOs such as perinatal death, LBW, and abortion due to syphilis were also increased significantly, after increasing syphilis rates in adults.9 There is no doubt that this infectious disease still results in a heavy burden to society.7,10,11 Although many studies have assessed risk factors for CS, previous studies that explored risk factors of CS failed to reach an agreement.8,10,12–14 In addition, it is difficult to find some detailed studies for APOs among pregnant women with syphilis, except for CS in previous studies. Few studies have assessed risk factors for pregnancy loss in syphilitic women, especially in China. Risk factors vary across populations. A clear understanding of the characteristics of women who delivered an infant with CS, or with APOs associated with syphilis, in a community is important to appropriately choose preventive interventions in that community.
To block mother-to-child transmission (MTCT) of syphilis and finish the World Health Organization’s goal of eliminating CS, a program for prevention of MTCT of syphilis was launched as early as in July 2001 in Shenzhen.11,15 This was the first CS prevention program conducted in China. Based on data from the program, we conducted a prospective nested case-control study with the following objectives: (1) to describe the sociodemographic, behavioral, obstetric, and clinical characteristics of maternal syphilis; (2) to assess the determinants of CS and APOs in infants born to mothers with syphilis; and (3) to provide scientific evidence for the prevention and control of pregnancy loss attributable to MTCT of syphilis.
MATERIALS AND METHODS
Recruitment of Study Participants
Recruitment was conducted by the Shenzhen Center for Chronic Disease Control and Prevention from April 2007 to October 2012 and took place in 61 hospitals in Shenzhen. A detailed description of the screening program has been published elsewhere.11,15 All pregnant women visiting any one of these hospitals were offered free syphilis and HIV screening after giving informed consent. Women were offered 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 diagnosis of maternal syphilis was based on TRUST and TPPA test according to sexually transmitted disease (STD) treatment guidelines from the Centers for Disease Control and Prevention.16 Pregnant women who were both TRUST positive and TPPA positive were recruited to participate in the study. The data for analysis in this study were derived from this program. This study was approved by the research ethics review committee of the Shenzhen Center for Chronic Disease Control and Prevention.
Therapy, Inclusion Criteria, and Grouping
The study population comprised pregnant women diagnosed as having syphilis, their live-born and stillborn infants, and their spouses. Pregnant women with untreated syphilis were given 3 injections of 2.4 million units of benzathine penicillin at weekly intervals. At least 1 dose was given if there was too little time to give injections before delivery. Complete syphilis treatment was defined as 3 doses of penicillin at weekly intervals.15 All cases with CS or presumptive CS were given an intramuscular injection of benzathine penicillin G 50,000 units/kg according to the Centers for Disease Control and Prevention guidelines.16
For this evaluation, we included participating women who (a) had positive TRUST and TPPA test result during pregnancy or up to a week after delivery, (b) provided informed consent to be in the evaluation, (c) continued their pregnancy after treatment, (d) participated in the follow-up process and had a complete case report form (CRF), (e) had a pregnancy outcome that could be clearly evaluated, (f) were not allergic to benzathine penicillin G, and (g) had a negative HIV test result.
The women with syphilis were divided into 3 groups. Group I consisted of women who had a normal birth outcome. Group II included newborn infants who were diagnosed as having CS. Group III comprised those who have at least 1 of APOs including preterm birth (PB), LBW, huge baby (HB), postterm pregnancy (PP), intrauterine fetal death (IUFD), SB, spontaneous abortion (SA), and early neonatal deaths (ENDs).
Definitions for CS and APOs
A CS diagnosis required one of the following criteria: (1) a positive dark-field or fluorescent antibody test of body fluid (i.e., mucous membranes), (2) an abnormal physical examination that was consistent with secondary syphilis and a TRUST titer that was fourfold higher than the mother’s titer, (3) a positive fluorescent treponemal antibody absorption test with a fluorochrome-labeled antihuman IgM on fractionated sera (FTA-ABS 19S IgM test), or (4) a reactive TPPA test 18 months after birth.16 Preterm birth was defined as a delivery at less than 37 weeks’ gestation; LBW was defined as less than 2500 g; HB was defined as greater than 4000 g; PP was defined as a delivery at more than 42 weeks’ gestation; IUFD was defined as a fetal death at 22 weeks or less of gestation,; SB was defined as the delivery of a dead fetus of more than 22 weeks’ gestation; SA was defined as a spontaneous delivery at less than 28 weeks’ gestation; and END was defined as this status that “born alive, but died during first week of life.”
All women were followed up every month during their pregnancy and were tested for syphilis using the TRUST test and, if positive, were retreated. Their sex partners (we mainly took the biological fathers into account) were invited to be tested and, if positive, were treated. These children were followed up until their TRUST results turned negative or the titer decreased 4-fold. A standardized CRF developed by experts was used to collect information by specially trained nurses. For participating women, we collected data about their sociodemographic characteristics (i.e., age, education, occupation, race, residency status, and marital status), behavioral characteristics (i.e., history of cocaine/crack use, history of syphilis or other STDs in the past 2 years, extramarital or premarital sexual relations, age at first sex, number of sexual partners in the past 2 years, and condom use in the past 2 years), obstetric characteristics (i.e., prenatal care [PNC], age at first sex and menarche, existing number of children, number of pregnancies and parity, and previous pregnancy loss), and clinical characteristics (i.e., titers of nontreponemal antibodies, syphilis stage, gestational week [GW] for first penicillin treatment during pregnancy, length of time between the end of the first treatment to childbirth, and whether or not complete treatment during pregnancy). For fathers, we also collected data (i.e., age, education, occupation, race, residency status, history of cocaine/crack use, history of syphilis or other STDs in the past 2 years, infectious status of current syphilis, and status of epidemiology treatment). For infants, we evaluated birth outcomes. All serological test results for syphilis (TRUST, TPPA, FTA-ABS 19S IgM, and others) were read by 2 experienced technicians. Maternal syphilis was categorized as early syphilis (<2 years) and late syphilis (≥2 years or syphilis of unknown duration). When we did not get duration of syphilis infection, maternal syphilis was categorized as late syphilis.
Categorical variables were described using frequencies and percentages, and the continuous variables were described using means and SDs. Proportions and means were compared using χ2, Fisher exact test, and Student t tests, as appropriate. Rates and 95% confidence intervals (CIs) were calculated for each measure. Odds ratios (ORs) and their 95% CI were used to demonstrate the level of association. The crude ORs (cOR) and adjusted ORs (aOR) were calculated by logistic regression. All factors that were associated with CS and APOs at the α level of 5% in the univariate analysis were included in the multivariable logistic regression. The coefficient of determination (R2) was used to assess the quality of logistic regression model fitting. All analyses were performed using SAS v9.1 (SAS Institute Inc, Cary, NC).
Recruitment of Study Participants
During the 66-month study period, we screened 279,334 pregnant women and identified 838 women with syphilis. The overall incidence of maternal syphilis, for 66 months, was 0.30% (95% CI, 0.28%–0.32%). The annual incidence rates, from 2007 to 2012, were 0.41%, 0.36%, 0.31%, 0.29%, 0.25%, and 0.21%, respectively. Of these, 11% of women (n = 89) selected termination of pregnancy by artificial abortion (n = 57) or induction of labor (n = 32), 3.5% of women (n = 29) also selected termination of pregnancy for ectopic pregnancy, 1.6% (n = 13) were infected with HIV, and 7.0% (n = 59) refused to participate. Of the 648 remaining, almost 13.4% (n = 87) were lost to follow-up, 3.5% (n = 23) did not have a complete CRF, 15.3% (n = 99) were still pregnant at the time of follow-up, and 3.4% (n = 22) were excluded because they were allergic to benzathine penicillin G. Finally, 417 pregnant women with syphilis were included for analysis (Fig. 1). There were no significantly statistical differences in the sociodemographic characteristics between women who were included (n = 417) and those who were excluded (n = 421) from 838 pregnant women with syphilis (P = 0.063–0.875).
At the end of follow-up, 34 infants (8.2%; 95% CI, 5.8%–11.3%) were diagnosed as having CS (group II; 29 infants were identified as positive by FTA-ABS 19S IgM test and had an abnormal physical examination result that was consistent with secondary syphilis and a TRUST titer that was 4-fold higher than the mother’s titer, and the other 5 were retrospectively diagnosed by a reactive TPPA test 18 months after birth). One hundred three women (24.7%; 95% CI, 20.7%–29.2%) who had at least 1 of APOs were categorized as group III. The proportions of APOs were listed as follows: PB (8.2%), LBW (7.2%), HB (1.2%), PP (1.0%), IUFD or SB or SA (9.4%), and END (1.9%).
Sociodemographic Characteristics of Mothers and Associated Birth Outcomes
The mean (SD) age of women was 29 (4.7) years, and age ranged between 18 and 43 years. Nearly a quarter of pregnant women were not married, and 93.1% were temporary residents. More than half had an education of junior high school or below. More than 50% of these women occurred in unemployed women. There were no significant differences in the sociodemographic characteristics, except for marital status and education level between groups II and I and between groups III and I (Table 1).
Characteristics of Biological Fathers and Associated Birth Outcomes
The mean (SD) age of fathers was 33.6 (6.7) years, with a range from 19 to 60 years. Almost 86.0% were temporary residents. More than half (57.9%) completed high school or above. Only 4.9%, 13.5%, and 5.9% of biological fathers acknowledged that they had a history of cocaine/crack use, syphilis, and other STDs, respectively. Currently, 22.4% of these men were diagnosed as having syphilis and 25.3% had an unconfirmed syphilis status due to refusal of testing. Only 24.8% of them agreed to accept epidemiology treatment (3 injections of 2.4 million units of benzathine penicillin at a weekly interval or at least 1 dose was given). There were no significant difference in sociodemographic characteristics of fathers, except for history of cocaine/crack use and current syphilis infection between groups II and I and between groups III and I (Table 2).
Behavioral, Obstetric, and Clinical Characteristics of Mothers and Associated Birth Outcomes
All women acknowledged having a history of extramarital or premarital sexual relations with a range of number from 1 to 10. However, only 30% of these women acknowledged that they had their first sexual experience before the age of 18 years. The rate of condom use in approximately three quarters of women was less than 25% in the past 2 years. Almost 5.4%, 29.0%, and 10.1% acknowledged a history of cocaine/crack use, syphilis, and STDs, except for syphilis, respectively. Most women (83%) had a history of pregnancy loss, such as SA (14.4%), intrauterine growth retardation (IUGR; 4.5%), PB (1.1%), SB (9.3%), induced abortion (69.4%), CS (1.4%), and ectopic pregnancy (9.1%).
The mean (SD) GW at first treatment was 19.1 (8.7) weeks (range from 4 to 43 weeks). Overall, the risk of CS and APOs were increased with the increasing GW at first treatment (χ2trend = 23.697 and Ptrend = 0.000 for CS; χ2trend = 44.903 and Ptrend = 0.000 for APOs). Similarly, the risk of CS and APOs were also increased (χ2trend = 64.502 and Ptrend = 0.000 for CS; χ2trend = 17.774 and Ptrend = 0.000 for APOs) along with the increase of titers of maternal TRUST test. Almost one third of women still did not receive complete treatment during pregnancy, and of these, the incidences of CS and APOs were up to 18.5% and 48.1%, respectively. Latent syphilis in pregnant women substantially prevailed, and only 23 (5.7%) were diagnosed as having early syphilis.
There were significantly statistical differences between groups I and II in certain behavioral, obstetric, and clinical characteristics including history of syphilis, GW at first treatment, length of time between the end of the first treatment to childbirth, treatment in pregnancy, TRUST titer, syphilis stage, and PNC (Table 3). There were also significantly statistical differences between groups I and III in characteristics such as history of cocaine/crack use, syphilis and ectopic pregnancy, GW at first treatment, length of time between the end of the first treatment to childbirth, treatment in pregnancy, TRUST titer, syphilis stage, and PNC.
Findings From Univariate Logistic Regression Analysis
By univariate logistic regression analysis (Tables 1–3), the characteristics from mothers including old age (cOR30–35 vs. <25, 0.55), higher education levels (cORsecondary school, 0.35; cORhigh school, 0.41; cORcollege, 0.80), history of syphilis (cOR, 0.18), complete treatment (cOR, 0.09), and enough PNC (cOR, 0.11) during pregnancy were negatively associated with CS. However, unmarried mothers (cOR, 2.39), maternal history of IUGR (cOR, 3.60), mothers infected with early syphilis (cOR, 33.24), and fathers with a history of cocaine/crack use (cOR, 4.53) and infected with syphilis (cOR, 4.76) were positively with CS. Moreover, mothers with a higher TRUST titer (>1:8) were more likely to have a risk of transmitting the infection to their offspring (cOR, 16.75), and every 2-fold increase of TRUST titer increased the risk of CS (cOR, 2.31). Every week of delay in treatment of maternal syphilis also increased the risk of infants becoming infected by 144% (cOR, 2.44). A shorter length of time between the end of the first treatment to childbirth was also strongly associated with a higher risk of CS (cOR, 20.50).
Maternal age of greater than 35 years (cOR, 1.16), unmarried mothers (cOR, 2.36), maternal history of cocaine/crack use (cOR, 3.56) and ectopic pregnancy (cOR, 6.58), early syphilis (cOR, 16.98), TRUST titer greater than 1:8 (cOR, 3.96), and fathers with a history of cocaine/crack use (cOR, 3.26) and infected with syphilis (cOR, 1.31) were positively associated with APOs. In addition, every 2-fold increase of maternal TRUST titer increased the risk of APOs (cOR, 1.35). Every week of delay in treatment to maternal syphilis increased the risk of APOs by 109% (cOR, 2.09). A shorter length of time between the end of the first treatment to childbirth was also associated with a higher risk of APOs (cOR, 7.32). However, when mothers had a higher education level (cORsecondary school, 0.44; cORhigh school, 0.58; cORcollege, 0.70) and history of syphilis (cOR, 0.37) and got enough PNC (cOR, 0.26) and complete treatment (cOR, 0.14) during pregnancy, the risk of APOs in offspring was decreased.
Findings From Multiple Logistic Regression Analysis
When multiple logistic regression was used to adjust for confounders, results demonstrated that with every 2-fold increase in the TRUST titer, there was a 113% increased risk of CS (aOR, 2.13). Women undergoing PNC (aOR, 0.11) and completing treatment during pregnancy (aOR, 0.20) could reduce risk of CS by 89% and 80%, respectively. When women were infected with early syphilis, the risk of CS was increased 22 times higher (aOR, 21.56). A shorter length of time between the end of the first treatment to childbirth was correlated with a higher risk of CS (aOR, 11.93). Every week of delay in treatment of maternal syphilis increased the risk of CS by 163% (aOR, 2.63). Compared with those without a history of cocaine/crack use, fathers with this history (aOR, 15.44) had a 15 times higher risk of transmitting syphilis to infants. Fathers with a positive (aOR, 5.84) or unknown (aOR, 5.55) status of syphilis test also increased the risk of CS compared with those without syphilis (Table 4).
Mothers with a higher level of education, with history of syphilis, and undergoing PNC or complete treatment in pregnancy were at a lower risk for APOs, and the aOR was 0.89, 0.44, 0.29, and 0.25, respectively. However, unmarried mothers (aOR, 2.41), early syphilis (aOR, 8.89), maternal history of cocaine/crack use (aOR, 3.79) and ectopic pregnancy (aOR, 5.91), and shorter length of time between the end of the first treatment to childbirth (aOR, 2.52) were positively associated with APOs. Every 2-fold increase of titer in the TRUST test increased the risk of APOs by 30% (aOR, 1.30). Similarly, fathers having an unknown status of syphilis test (aOR, 2.02) also had a 2 times higher risk of APOs than did those without syphilis (Table 4).
Notwithstanding being easily detectable and treatable in pregnancy, presently, syphilis remains an important cause of birth loss.17,18,19 Pregnant women infected with syphilis are often accompanied by CS and a variety of APOs. In the present study of syphilis-infected women who presented to PNC at various stages of pregnancy, almost 8.2% of mothers delivered an infant with CS despite most having received appropriate treatment. For mothers who did not receive complete treatment during pregnancy, 18.5% delivered an infant with CS and 48.1% resulted in APOs. In addition, many women were appropriately treated but still went on to have babies with CS or APOs because they presented for PNC late in pregnancy or not at all. Much has been published about risk factors for CS, and those identified in our study are, in general, similar to what has been reported in the medical literature.10,14,20–22 However, risk factors for APOs and CS were still rarely reported in China. The most important parameter of risk factors for pregnancy loss was the small number of prenatal visits, which is consistent with published research.14,18,23 This highlights the importance of absent or insufficient PNC as an independent risk factor for CS or APOs. The present study showed that the lack of PNC had almost a 26 times and 4-fold greater risk of CS and APOs. Prenatal care is not only the best opportunity to treat gestational syphilis; it is also important for the control of a pregnant woman who had received documented adequate treatment of syphilis before pregnancy.14
Maternal age was positively associated with APOs, where an increase of 5 years increased the risk of APOs by 43% (OR, 1.43). However, every 5-year increase in age reduced the risk of CS by 14% (OR, 0.86). A previous article showed that the maternal syphilis in younger women was more likely to be early syphilis, which was more likely to lead to CS.24 Historical data suggest that the risks and sequelae of congenital transmission are highest in primary and secondary syphilis and decrease with the duration of untreated maternal infection.18,25,26 Evidence that the duration of infection is important and is supported by the observation that mothers with high nontreponemal titers, as seen in earlier stages of infection, are most at risk for passing on infection to their infants.18 Support for these findings comes from the present study, in which women with early syphilis and higher titers had a 22 times and 14-fold higher risk of CS, and 9 times and 2.5-fold higher risk of occurring in APOs, respectively. Unmarried women also had a higher risk of APOs (OR, 2.41), which indicates that the prenatal health education should be highlighted for unmarried women. In general, if a woman has a history of syphilis, then she will also have a history of treatment, which could improve patients’ PNC and reduce the occurrence of birth loss. The finding in our study confirmed this hypothesis. For example, the risk of APOs (OR, 0.44) and CS (OR, 0.18) has been reduced by 56% and 82%, respectively, in mothers with a history of syphilis.
Our study suggested that mothers with a history of cocaine/crack use were at a higher risk for APOs (OR, 3.79). However, in our study, cocaine/crack use in mothers was not associated with CS. In a previous study,27 independent of the effect of other factors, the odds of being exposed to cocaine were 3.9 times greater among cases than controls, which suggested that the epidemic of CS may be related to the increase in cocaine use among delivering mothers. In fact, the association between drug addiction and CS is well established.27,28 Previous pregnancy loss may also increase the risk of APOs but reduce risk of CS. However, in previous studies, this association between previous pregnancy loss and APOs or CS did not receive much attention. Although pregnancy loss could lead to an increased use of PNC,21 thereby causing more opportunities for the detection and treatment of syphilis, the finding in present study did not confirm an association between previous pregnancy loss and reduced CS risk. The strong protective association of previous pregnancy loss with CS is difficult to interpret.21Losses other than induced abortions might lead a woman with a desired pregnancy to seek better PNC and prompt treatment of syphilis. Consistent with previous reports,29 clinical features from pregnant women with syphilis, such as high titers of nontreponemal antibodies, short length of time between the end of the first treatment to childbirth, lack of complete treatment, and postponement of GW for first treatment, were independent risk factors of adverse birth outcomes.
In contrast to previous studies, finding from the present study showed that fathers’ cocaine/crack use and syphilis infection status also dominated the risk of adverse birth outcomes. Based on these results, it is recommended that a series of intervention targeting pregnant women’s sexual partners, such as health education, syphilis monitoring, and follow-up management, should be strengthened in the future. Culturally appropriate partner notification techniques, which are sensitive to the dynamics of domestic relationships, need to be developed.
There are some limitations in our study. First, some respondents may conceal their risk behavior, such as extramarital affairs and cocaine/crack use, and underestimated the association between pregnancy loss and risk factors. Second, representativeness of the sample was also considered as a potential limitation. Furthermore, when assessing the risk factors of APOs, we did not include pregnant women without syphilis; therefore, it is difficult to estimate pregnancy loss attributable to syphilis and has likely greatly blunted some of our findings. Taking the small sample size of any single APO into account, we only evaluated the risk factors for poor pregnancy outcomes. Last, with regard to SB, SA, IUFD, or END cases, we did not take measures to determine whether the fetus or neonates were infected with syphilis, which might weaken the association because CS is an important cause of fetal death.
In summary, findings from this present study confirm the impact from maternal syphilis on pregnancy loss. Some significant risk factors of CS and APOs have been identified, which will help to block or reduce the occurrence of pregnancy loss. These findings can be extrapolated to other similar populations in which health interventions should be improved for pregnant women who have a greater risk for pregnancy loss and who do not adequately use traditional health care systems. Any contact of the pregnant woman with a health service should be an opportunity for a possible diagnosis and adequate treatment of gestational syphilis. The quality of PNC specifically directed to the poorest pregnant women and those with risk behaviors needs to improve. The strategies should be targeted to each profile to become more effective. Health education for pregnant women should continue to reinforce the message that untreated maternal syphilis is a danger to the unborn infant, that syphilis can be diagnosed and treated, and that women should attend an antenatal clinic that can perform syphilis screening as soon as they suspect that they are pregnant. Future studies should examine potentially important associations that were not available for analysis in this study. Further education on proper syphilis testing and follow-up, as well as techniques for motivating and educating patients, should be provided to clinicians and other health care providers in both prenatal and STD clinics. Systematic attention to testing, treatment, education, and contact tracing in pregnancy and subsequent late trimester retesting of women at high risk will lower adverse birth outcomes. To become more effective, the strategies for prevention of CS and APOs that developing a check list tool or some kind of training that alerts women to be aware of factors associated with CS and APOs should be considered.
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