Pregnancy syphilis epidemic trends, clinical features, APOs risk factors, pregnancy-induced hypertension epidemics and related factors, in Northeast China Jilin Maternity Hospital 2013-2017

Background. It is of great public health significance to monitor the global meiosis mother-to-child transmission plan proposed by WHO and monitor the prevalence of maternal syphilis and the factors affecting mother-to-child transmission. Methods. We collected 271 medical records of prenatally diagnosed (from 87286 pregnant women) of syphilis among pregnant women a maternity hospital in Jilin Province China from 2013 to 2017. The chi-square test and Logistic multiple regression analysis were used to describe the clinical characteristics of pregnant women with syphilis and the related factors of adverse pregnancy outcome. Results. The average prevalence of maternal syphilis is 0.31% (95%CI: 0.27%-0.35%). The mean age of 271 pregnant women with syphilis is 27.62±5.4 years old. The maternal syphilis prevalence of absence of paid occupation is 73.8%; rural population accounts for 43.6%. Maternal women with a history of abortion accounted for 43.1%, of which 53.1% had abortion ≥2; The average rate of treatment in pregnancy is 25.5% (95%CI: 25.4%-25.6%). The prevalence rate of APOs are 43.9% (95%CI: 38.1%-49.9%), declined in five years (P<0.05). APOs was significantly higher in women at 30–34 age group than that in 0-24 age group (OR= 2.916, 95%CI: 1.298-6.549) and higher in Un-treatment in pregnancy than that in receive treatment (OR=2.469, 95%CI:1.225-4.975). PROM occurrence (OR=2.702, 95%CI:1.219-5.988); CRP elevation (≥10 mg/L) and RPR high titer (≥1:8) are related to the occurrence of APOs. Abortion, prematurity and low birth weight are associated with no treatment during pregnancy (P<0.05). Comparison of 42 cases of pregnancy-induced hypertension and non-pregnancy-induced hypertension, Dysmenorrhea (OR= 3.654, 95%CI:1.812-7.369)


Introduction
Maternal syphilis is an important public health problem in Perinatal health. In 2007, WHO proposed to eliminate mother-to-child transmission (MTCT) of syphilis as a public health problem [1],and in 2016, it indicated about 2 million new cases of syphilis among pregnant women and 60% of which will be transmitted by MTCT worldwide each year [2]. The world trend of syphilis and maternal syphilis is that most occur in sub-Saharan Africa (SSA) and lower in developed countries such as the United States and Europe [3,4]. Since the 1990s, the incidence of maternal syphilis has been increasing in China [5], China's government officially launched a national program in 2010, specifically and directly aimed at controlling syphilis through expanding active screening for syphilis followed by treatment of infected patients in high-risk groups and pregnant women [6]. Free HIV, syphilis, and HBV tests are provided to all pregnant women. In 2013, the syphilis testing coverage in pregnant women was 96.40% in china [7]. The prevalence of maternal syphilis varies from region to region in China, the incidence of syphilis or maternal syphilis in northern China is lower than in the economically developed southern region. According to research conducted by data from various provinces, the prevalence of maternal syphilis in Beijing from 2013 to 2014 was 0.11%-0.14% [8], in Shanghai decreased from 0.38% to 0.10% in 2005-2015 [9]. Some studies of maternal syphilis in maternity hospital shows that the prevalence in Shenzhen was from 0.49% to 0.12% in 2005-2017[10]. There are few studies on the prevalence of maternal syphilis in northeastern China, and there have been reports that Liaoning Province was 0.10% in 2010 [11].
Syphilis in pregnancy can induce adverse pregnancy outcomes (APOs), including stillbirth, preterm birth, low birth weight, neonatal death and congenital infection among infants [12]. A high proportion of Syphilis in pregnancy are untreated or inadequately treated and the risk of APOs is 4.5 times that of undiagnosed pregnant women [13,14].
Domestic research shows large proportions of women are not detected and treated at an early pregnancy stage, and the treatment rate varied from 69.8% to 96.8% and remained 83.6% in China 2015 [5,9].
In addition, other pregnancy-specific diseases can have a major impact on pregnant women and babies. Pregnancy hypertension affects 10% of pregnancies and is the second direct cause of maternal death worldwide [15,16] and will have a greater impact on pregnant women and fetuses. The adverse perinatal outcomes associated with hypertensive disorders and Gestational diabetes are generally referable to stillbirth, miscarriage, fetal growth restriction, placental insufficiency, and premature birth related complications [17][18][19]. Studies have shown that the difference in the prevalence of pregnancy induced hypertension in HIV positive and negative pregnant women (p=0.06) approached significance [20].
The WHO and China have put forward the goal of eradicating mother-to-child transmission of syphilis, and have made various efforts to achieve effective control in some areas. However, pregnancy syphilis is different in different parts of the world, and the control effect is affected by many factors and China's goal of eliminating mother-to-child transmission is rarely compared and reported in various regions. This study included all pregnant syphilis and newborns admitted to a maternity hospital in Jilin, China for 13-17 years. Case data, analysis of its prevalence, clinical characteristics and main factors affecting APOs, to explore the maternal and child health hazards of pregnancy-specific diseases, and to explore the prevalence of pregnancy-induced diseases in pregnancyinduced syphilis and related factors for protection Maternal and child health and the completion of the final elimination of syphilis mother-to-child transmission goals provide research basis.

Clinical Data Collection and Patient Selection
From 2013 to 2017, a total of 87,286 women were admitted to a maternity hospital in Changchun, China. The number of women admitted each year is 16,134, 20,244, 12,595, 20,545, and 17768. The syphilis, HIV, and hepatitis B tests in this hospital are 100% covered. A total of 271 cases of maternal medical records diagnosed as syphilis all will be included in the study, among them, there are 230 cases of pregnant women with live births. Diagnostic criteria for pregnancy syphilis [21]: ①pregnant woman or spouse has a history of syphilis infection, ②treponema pallidum particle agglutination (TPPA) and rapid plasma regain (RPR) are positive, ③have clinical symptoms of syphilis And signs. The diagnostic criteria for neonatal syphilis infection are positive for serological tests of mother and newborn syphilis. Adverse pregnancy outcomes (APOs) of syphilis were de fined as abortions or stillbirth and, in live-born infants, premature birth, low birth weight and neonatal asphyxia (1minute APGAR scores ≤ 7).
The comorbidities studied in this study included anemia, hepatitis B, pregnancy with hypertension, pregnancy with diabetes, and pregnancy with intrahepatic cholestasis. To investigate the association between syphilis in pregnancy and maternal syphilis complicated with pregnancy-induced hypertension, we conducted an unmatched casecontrol study. Cases were syphilis among pregnant women diagnosed with any type of pregnancy-induced hypertension before discharge. 42 pregnant women with pregnancyinduced hypertension were classified as the pregnancy-induced hypertension group (PIH), and the rest were assigned to the non-pregnancy-induced hypertension group (NPIH).

Statistical Analysis
We calculated the crude incidence of maternal syphilis and its 95% confidence interval (CI). We performed the bivariate analyses between the potential risk factors and the outcome and estimated the odds ratios (OR) and respective 95% confidence intervals (95%CI). The variables that presented p-value ≤0.05 were included in the multivariate analysis model. We used multivariate logistic regression models to assess relevant factors with APOs in patients with maternal syphilis and P values <0.5 were regarded as statistically significant. Statistical analysis was done using SPSS for Windows (version  Table 1).
The average age of the 271 pregnant women with syphilis is 27.0±5.4 years old, age range is 19-43 years old. Table 2 shows the demo-graphic characteristics of these infected pregnant women, the prevalence of absence of paid occupation is 73.8%, the urban population accounts for 43.9%, the town population is 12.5%, and the rural accounts for 43.6%. Regarding the Past history of pregnant women with syphilis, which have the history of Abortion is 53.1%, and the number of abortions ≥2 times accounted for 46.5%. The average pregnancy treatment rate for five years is 25.5% 74.5% did not receive anti-syphilis treatment during pregnancy. In addition, serological testing of   Prevalence and related factors of maternal APOs in pregnancy with syphilis from 2013 to 2017 In our study, APOs in 271 cases are 119(43.9%), and the prevalence was 33.85%-55.77% in 2013-2017 ( Figure 2), the prevalence χ2 trend test was statistically significant (P<0.05) (  The rate of treatment of syphilis during pregnancy during 2013-2017 is 21.4%-30.2% ( Figure 2). The prevalence χ2 trend test was not statistically significant (P>0.05) ( Table   2). A total of 14 abortions in 119 APOS cases, none of which received anti-syphilis treatment. APOs were analyzed with or without anti-syphilis treatment, and the difference was statistically significant, and abortion, prematurity and low birth weight are associated with un-treatment (Table 5).   From the prevalence of maternal syphilis in this study, the control effect of maternal syphilis in northeastern China is not as good as in the south. This reminds us that if we want to achieve the goal, we should not neglect the cold spot where syphilis or maternal syphilis prevalence is low. We must increase the implementation of policies. Otherwise, it will be difficult to completely eliminate the mother-to-child transmission of syphilis.
Among the subjects included in the study, the number of pregnant women under the age of 29 infected with syphilis was as high as 69.4%, and the proportion of syphilis ≤ 24 years old accounted for 28.8%. We note that the younger age in this study seems to be related to maternal syphilis, this may be related to the sexual activity period of the lower age group; this survey is more likely to be an influencing factor in rural and townships.
The results were consistent with other similar studies conducted at home or abroad [24]. Therefore, for low-age people, we must pay close attention to it and give publicity and education. Pregnant women with risky sexual behavior or more than 2 abortions are recommended for pre-pregnancy screening and early treatment to avoid mother-to-child transmission. Women living in rural areas and women who are unemployed or housewives/farmers are often socially disadvantaged. In our study, we found that this less dominant population accounted for a large proportion of maternal syphilis cases. Former studies have shown that active infection with Treponema pallidum (T.P) in women belonging to low socioeconomic level were disquieting. This is probably due to illiteracy and high proportion of unsafe sexual behavior [25]. Particular attention should be paid to promoting the use of pre-pregnancy syphilis screening and treatment adherence to these vulnerable groups.
Previous research confirmed the history of abortion is the risk factors of maternal syphilis [26]. In our study, half of all pregnant syphilis patients have a history of abortion, of which 53.1% are pregnant women with abortion ≥2 times. Which reminds us that pregnant women with habitual abortion should be forced to carry out syphilis screening before pregnancy. At the same time, we found that the risk of neonatal syphilis infection in this study region is very high (45.8%). According to reports, in 2012, global neonatal syphilis infection accounted for 11.0% (102,000/930,000) [27]. It is worth noting that the The treatment during pregnancy is directly related to congenital syphilis and patients with maternal syphilis who do not receive treatment or have inadequate treatment during pregnancy may increase the risk of congenital syphilis [31,32]. In our study, the untreated rate of maternal syphilis infection was significantly higher (74.5%) than other reports at home and abroad [5,33]. The reason may be that the infection of syphilis is in an incubation period. As with HIV, women infected with syphilis might not exhibit any symptoms, indirectly leads to untreated or untimely and inadequate treatment during pregnancy, which is why screening during pregnancy is critical. Studies have shown that the prevalence of latent syphilis in Chinese maternal syphilis reached 67.6% in 2013 [5].
Faced with such a high prevalence of latent syphilis, we should pay more attention to prepregnancy syphilis screening. Second, the hospital's prenatal screening coverage for maternal women can reach 100%, this is an effective means to prevent mother-to-child transmission of syphilis. But in 2003 China officially cancelled the compulsory marriage check, which led to the lack of syphilis screening in the area before pregnancy. On the other hand, although the prevalence of maternal syphilis is not high, the treatment rate is low, the study found that the treatment of pregnant women during pregnancy was associated with a variety of adverse pregnancy outcomes such as Abortion, prematurity and low birth weight (p<0.05). This reminds us of the huge impact of no treatment during pregnancy on APOs in pregnant women. This study found that RPR high titers (≥1:8) in pregnant syphilis patients have a higher risk of developing APOs, which is the same as the findings of similar studies [38,39]. At the same time, we noticed that the risk of APOs in maternal syphilis patients with elevated CRP was five times (p<0.05) higher than that of normal CRP pregnant women in us study.
The latest study found that viral infections may cause an increase in CRP levels [40], which is similar to our results, reminding us that syphilis infection may also affect CRP expression.
In the research background, we pointed out that syphilis or certain viral infections can cause inflammation in the body, and the latest research shows that the chronic inflammation leads to many chronic diseases including cancer, cardiovascular diseases, etc [41]. Gestational hypertension has a certain prevalence in this study, the prevalence of maternal syphilis combined with pregnancy hypertension is 15.5%. But the incidence of pregnancy hypertension in the normal population (4.1%-19.4%) [16,42,43]. Studies have shown that maternal syphilis combined with pregnancy-induced hypertension has no significant association with age (p<0.05). It is well known that the risk of developing pregnancy-induced hypertension in older women is significantly increased [44], which is clearly inconsistent with our findings, and this reminds us that in clinical practice, monitoring of patients with syphilis in the young age should be strengthened to prevent hypertension during pregnancy. We think this may be due to syphilis infection. Novikov Iu has found that syphilis can cause small blood vessel inflammation [45,46]. And an excessive maternal innate immune response is sufficient to cause vascular inflammation and endothelial dysfunction, which contributes to the development of pregnancy hypertension during pregnancy [47][48][49]. Therefore, whether syphilis has the potential to cause pregnancy-induced hypertension and the relationship between viral infectious diseases and chronic diseases requires further research to confirm.