ABSTRACT

OBJECTIVE:

To analyze the factors associated with prematurity in reported cases of congenital syphilis in the city of Fortaleza, Ceará, Brazil.

METHODS:

Cross-sectional study conducted in ten public maternity hospitals in Fortaleza, Ceará, Brazil. A total of 478 reported cases of congenital syphilis were included in 2015, and data were collected from notification forms, from mothers’ and babies’ medical records and from prenatal cards. For the bivariate analysis, Pearson’s chi-squared and Fisher’s exact tests were used, considering p < 0.05. Multiple logistic regression was conducted, presenting odds ratio (OR) with a 95% confidence interval.

RESULTS:

We found 15.3% prematurity in pregnant women with syphilis. The titration of the VDRL test > 1:8 at delivery (OR 2.46; 95%CI: 1.33–4.53; p = 0.004) and the non-treatment of the pregnant women or treatment with drugs other than penicillin during prenatal care (OR 3.52; 95%CI: 1.74–7.13; p< 0.001) were associated with higher chances of prematurity.

CONCLUSION:

The prematurity due to congenital syphilis is a preventable condition, provided that pregnant women with syphilis are treated appropriately. Weaknesses in prenatal care are associated with this outcome, which highlights the importance of public policies oriented to improve the quality of prenatal care.

DESCRIPTORS:
Syphilis, Congenital; Infectious Disease Transmission, Vertical; Prenatal Care; Infant, Premature; Penicillin G

INTRODUCTION

Syphilis is a systemic infection that, when affecting the pregnant woman, can be transmitted to the baby, causing congenital syphilis (CS), with severe consequences, including prematurity¹1. Domingues RMSM, Leal MC. Incidência de sífilis congênita e fatores associados à transmissão vertical da sífilis: dados do estudo Nascer no Brasil. Cad Saude Publica. 2016;32(6):e00082415. https://doi.org/10.1590/0102-311X00082415
https://doi.org/10.1590/0102-311X0008241... . The etiology of preterm delivery is multifactorial, and infectious causes, including sexually transmitted infections (STI), are relevant, given their high prevalence and association, when untreated, with undesirable obstetric outcomes²2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84. https://doi.org/10.1016/S0140-6736(08)60074-4
https://doi.org/10.1016/S0140-6736(08)60... . In this context, syphilis takes a leading role³3. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, et al. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396. https://doi.org/10.1371/journal.pmed.1001396
https://doi.org/10.1371/journal.pmed.100... .

According to the World Health Organization (WHO), in 2016, about 1 million pregnant women were infected with syphilis, which had the consequence of children with early and late clinical manifestations of CS⁴4. Korenromp EL, Rowley J, Alonso M, Mello MB, Wijesooriya NS, Mahiané SG, et al. Global burden of maternal and congenital syphilis and associated adverse birth outcomes: estimates for 2016 and progress since 2012. PLOS One. 2019;14(2):e0211720. https://doi.org/10.1371/journal.pone.0211720
https://doi.org/10.1371/journal.pone.021... . In the Americas, the incidence rate of CS has been increasing over the years, and the reported Brazilian cases have contributed considerably⁵5. Organización Panamericana de la Salud. Eliminación de la transmisión maternoinfantil del VIH y la sífilis en las Américas: actualización 2016. Washington, DC: OPS; 2017..

In Brazil, in 2018 alone, reported cases included 158,051 of acquired syphilis, 62,599 of syphilis in pregnant women, and 26,219 of CS. The state of Ceará is among those with the highest rates⁶6. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Boletim epidemiológico sífilis. Brasília, DF: Ministério da Saúde; 2019., and its capital, Fortaleza, reported in that same year 827 cases of CS⁷7. Secretaria de Saúde. Governo do Estado do Ceará. Boletim epidemiológico de sífilis. Fortaleza: Secretaria de Saúde; 2019., with an incidence rate always increasing over the years⁸8. Cardoso ARP, Araújo MAL, Cavalcante MS, Frota MA, De Melo SP. Análise dos casos de sífilis gestacional e congênita nos anos de 2008 a 2010 em Fortaleza, Ceará, Brasil. Cienc Saude Colet. 2018;23(2):563-74. https://doi.org/10.1590/1413-81232018232.01772016
https://doi.org/10.1590/1413-81232018232... .

Considering the severity of outcomes, control measures have been recommended⁹9. Organización Mundial de la Salud. Orientaciones mundiales sobre los criterios y procesos para la validación de la eliminación de la transmisión maternoinfantil del VIH y la sifilis. Ginebra: OMS; 2015.. The reduction of CS is contemplated in the Sustainable Development Goals, which seek to eliminate preventable deaths of newborns and children under 5 years, reduce neonatal mortality and fight communicable infections¹⁰10. United Nations Organization. Transforming our world: the 2030 Agenda for Sustainable Development; 2015 [cited 2020 may 13]. Available from: https://www.un.org/ga/search/view_doc.asp?symbol=A/RES/70/1&Lang=E.
https://www.un.org/ga/search/view_doc.as... . In this context, prematurity is highlighted, since it is the leading cause of death in children under 5 years in the world¹¹11. França EB, Lansky S, Rego MAS, Malta DC, França JS, Renato Teixeira R, et al. Leading causes of child mortality in Brazil, in 1990 and 2015: estimates from the Global Burden of Disease study. Rev Bras Epidemiol. 2017;20 Suppl 1:46-60. https://doi.org/10.1590/1980-5497201700050005
https://doi.org/10.1590/1980-54972017000... ^,1212. Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016;388(10063):3027-35. https://doi.org/10.1016/S0140-6736(16)31593-8
https://doi.org/10.1016/S0140-6736(16)31... , contributing to increase neonatal mortality in poor and developing countries¹³13. Katz J, Lee ACC, Kozuki N, Lawn JE, Cousens S, Blencowe H, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet. 2013;382(9890):417-25. https://doi.org/10.1016/S0140-6736(13)60993-9
https://doi.org/10.1016/S0140-6736(13)60... .

In view of the aforementioned aspects and considering the relevant and persistent gaps in studies on prematurity by CS, this paper seeks to analyze the factors associated with prematurity in CS reported cases in Fortaleza, Ceará, Brazil.

METHODS

This cross-sectional study, which analyzed the prevalence and the factors associated with prematurity in pregnant women with syphilis, used data from all ten public maternity hospitals in Fortaleza, capital of Ceará, Brazil.

The city has about 2.5 million inhabitants, gross domestic product of R$ 41.2 billion, and human development index of 0.754¹⁴14. Instituto Brasileiro de Geografia e Estatística IBGE. Panorama Fortaleza. Rio de Janeiro: IBGE; c2017 [cited 2020 Dec 21]. Available from: https://cidades.ibge.gov.br/brasil/ce/fortaleza/panorama.
https://cidades.ibge.gov.br/brasil/ce/fo... . The coverage of the Brazilian Family Health Strategy (FHS) is 57.6%, and the coverage of prenatal care is 95% (unpublished data, provided by the Municipal Health Department).

All CS reported cases in 2015 were included in the study, considering children who were born alive, i.e., deliveries in which there was expulsion or complete extraction of the fetus, regardless of the mother’s gestational age, of the product of conception and of any sign of life (heartbeat, breathing or even umbilical cord pulsation) after maternal separation. To define CS, the following criteria were considered, established by the Brazilian Ministry of Health¹⁵15. Ministério da Saúde (BR). Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis. Brasilia, DF: Ministério da Saúde; 2015. (p. 26):

• Child whose mother had, during prenatal care or at delivery, reactive (with any titration) non-treponemal tests and reactive treponemal test, and who has not been treated or has received inadequate treatment.

• Child whose mother was not diagnosed with syphilis during pregnancy and, given the impossibility of the maternity hospital to take the treponemal test on her, presented reactive (with any titration) non-treponemal test at delivery.

• Child whose mother was not diagnosed with syphilis during pregnancy and, given the impossibility of the maternity hospital to take the treponemal test on her, presented reactive treponemal test at delivery.

• Child whose mother presented reactive treponemal test and non-reactive non-treponemal test at the time of delivery, without prior treatment.

Cases of abortions and stillbirths were excluded, due to the unavailability of information for many of the variables included in this study, which would impair the analysis. In addition, were also excluded the cases of ectopic pregnancy, molar pregnancy or abortion, and cases in which pregnant women had heart diseases, severe lung diseases, severe nephropathies, endocrinopathies, hematological diseases and chronic arterial hypertension, neurological diseases, psychiatric diseases requiring follow-up, autoimmune diseases, genetic alterations, history of deep vein thrombosis or pulmonary embolism, gynecological diseases, Hansen’s disease, tuberculosis or any clinical pathology requiring specialized follow-up, as well as cases of patients using antihypertensive (BP > 140/90mmHg before 20 weeks of gestational age – GI). The exclusion of these diseases occurred because they were related to prematurity risk⁶6. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Boletim epidemiológico sífilis. Brasília, DF: Ministério da Saúde; 2019.^–88. Cardoso ARP, Araújo MAL, Cavalcante MS, Frota MA, De Melo SP. Análise dos casos de sífilis gestacional e congênita nos anos de 2008 a 2010 em Fortaleza, Ceará, Brasil. Cienc Saude Colet. 2018;23(2):563-74. https://doi.org/10.1590/1413-81232018232.01772016
https://doi.org/10.1590/1413-81232018232... , possibly acting as a confounding factor for prematurity by CS.

Data were collected between June and September 2018. All cases of CS reported in 2015 in the Sistema de Informação de Agravos de Notificação (SINAN – Notifiable Diseases Information System) were surveyed. Data were collected from the notification forms and, later, from the medical records of the mother and baby and from the pregnant woman prenatal card. It is noteworthy that maternity hospitals attach a copy of the card to the medical record. When there were divergences between the sources, the data from the medical records were considered valid.

The analyzed outcome was prematurity (when the child is born with less than 37 full weeks of gestation). The following maternal variables were analyzed: sociodemographic (age, marital status, education, occupation) and related to prenatal care (attendance to prenatal care, number of consultations, beginning of follow-up, examinations for syphilis, number of tests for syphilis, results of the first and second tests for syphilis, titration of the VDRL test in prenatal care, time of syphilis diagnosis, treatment in prenatal care, treatment of the partner and titration of the VDRL test at delivery) and use of illicit drugs.

Data were analyzed in the statistical software SPSS (Statistical Package for the Social Sciences, version 23, IBM, USA) and in the Stata, version 10.0 (Stata Corp., USA), by Stepwise method for multiple logistic regression. For the bivariate analysis, Pearson’s chi-squared and Fisher’s exact tests were used, considering p < 0.05. The adjusted analysis included the variables with p < 0.20, remaining those with p < 0.05. As a measure of effect, the odds ratio (OR) and the 95% confidence interval were used.

This study was approved by the Research Ethics Committee of the Universidade de Fortaleza (Unifor), Opinion No. 2,110,189, and is part of a larger study entitled Manifestações Clínicas e Complicações em Crianças com Sífilis Congênita (Clinical Manifestations and Complications in Children with Congenital Syphilis).

RESULTS

In 2015, 674 cases of CS were reported in Fortaleza, of which 478 were considered eligible. We excluded 196 cases (31 abortions, 39 stillborns and 126 pregnant women who presented other risk problems for prematurity). A total of 73 children (15.3%) were born premature.

Table 1 shows the sociodemographic and obstetric profile of the pregnant women with syphilis who had premature babies. The mean age was 24.9 years (SD = 6.3), and most were between 20 and 29; 54 (74%) completed elementary school and 26 (35.6%) reported the use of some illicit drug. A number of 52 women attended prenatal care (71.2%); of these, 37 (71.1%) were tested at least once for syphilis; and 11 (21.2%) underwent treatment with at least one dose of benzathine penicillin. At delivery, 32 (43.8%) presented titration > 1:8 on the VDRL test (Table 1).

Table 2 describes the data from pregnant women whose VDRL titration was > 1:8 at delivery. Among pregnant women with syphilis who had premature babies, 24 (75%) attended prenatal care; of these, 9 (37.5%) were never tested for syphilis. All those with reactive results in prenatal care had titration > 1:8. The cases of prematurity occurred in pregnant women who underwent incomplete treatment and, mainly, who were not treated or received some drug other than penicillin.

In the bivariate analysis, the following situations were associated with the outcome of prematurity: illicit drug use (p = 0.001; OR: 2.39; 95%CI: 1.39–4.11), not having attended prenatal care (p = 0.004; OR: 2.28; 95%CI: 1.28–4.05), having been diagnosed with syphilis at delivery (p < 0.001; OR: 3.29; 95%CI: 1.93–5.61), and having presented VDRL titration at delivery > 1:8 (p = 0.001; OR: 2.31; 95%CI: 1.38–3.87) (Table 3).

When analyzing only pregnant women who attended prenatal care, prematurity was associated with: having attended less than six consultations (p = 0.005; OR: 2.35%; 95%CI: 1.28–4.33), never been tested for syphilis (p = 0.008; OR: 2.44%; 95%CI: 1.24–4.77), having not been treated or having received treatment with some drug other than benzathine penicillin (p < 0.001; OR: 3.59; 95%CI:1.79–7.23) (Table 4).

Table 5 shows the analysis of multiple logistic regression, adjusted, of sociodemographic, prenatal care and deliveries aspects of pregnant women with syphilis associated with the outcome of prematurity. We found that women who had VDRL titration > 1:8 at delivery and those who were not treated or received treatment with some drug other than penicillin were 2.46 (95%CI: 1.33–4.53; p = 0.004) and 3.52 (95%CI: 1.74–7.13; p< 0.001) times more likely to have premature babies, respectively.

DISCUSSION

In this study, we found the outcome of prematurity in 15.3% of the cases of CS, a percentage higher than the estimated rates for pregnant women in general, described in a Brazilian study: between 7.7%¹⁶16. Leal MDC, Esteves-Pereira AP, Viellas EF, Domingues RMSM, Gama SGND. Prenatal care in the Brazilian public health services. Rev Saude Publica. 2020;54:8. https://doi.org/10.11606/s1518-8787.2020054001458
https://doi.org/10.11606/s1518-8787.2020... and 11.1%¹⁷17. Leal MC, Szwarcwald CL, Almeida PVB, Aquino EML, Barreto ML, Barros F, et al. Reproductive, maternal, neonatal and child health in the 30 years since the creation of the Unified Health System (SUS). Cienc Saude Colet. 2018;23(6):1915-28. https://doi.org/10.1590/1413-81232018236.03942018
https://doi.org/10.1590/1413-81232018236... . Pregnant women who were not treated or treated with drugs other than benzathine penicillin during prenatal care, as well as those who had high VDRL titers at delivery, had more outcomes of prematurity.

We can observe that a significant number of pregnant women with syphilis who had premature babies attended prenatal care. However, many opportunities to prevent CS were lost, a situation also evidenced in another study conducted in six Brazilian capitals¹⁸18. Saraceni V, Pereira GFM, Silveira MF, Araújo MAL, Miranda AE. Vigilância epidemiológica da transmissão vertical da sífilis: dados de seis unidades federativas no Brasil. Rev Panam Salud Publica. Journal of Public Health. 2017;41:e44. https://doi.org/10.26633/RPSP.2017.44
https://doi.org/10.26633/RPSP.2017.44... . Prenatal care can positively impact the health of pregnant women and avoid infant mortality¹⁹19. Lima JC, Mingarelli AM, Segri NJ, Zavala AAZ, Takano AO. Estudo de base populacional sobre mortalidade infantil. Cienc Saude Colet. 2017;22(3):931-9. https://doi.org/10.1590/1413-81232017223.12742016
https://doi.org/10.1590/1413-81232017223... , and it is an important predictor to prevent unfavorable outcomes related to syphilis during pregnancy, provided it is conducted with quality²⁰20. Plotzker RE, Murphy RD, Stoltey JE. Congenital syphilis prevention: strategies, evidence, and future directions. Sex Transm Dis. 2018;45 9S Suppl 1:29-37. https://doi.org/10.1097/OLQ.0000000000000846
https://doi.org/10.1097/OLQ.000000000000... ^,2121. Benzaken AS, Pereira GFM, Cunha ARCD, Souza FMA, Saraceni V. Adequacy of prenatal care, diagnosis and treatment of syphilis in pregnancy: a study with open data from Brazilian state capitals. Cad Saude Publica. 2019;36(1):e00057219. https://doi.org/10.1590/0102-311x00057219
https://doi.org/10.1590/0102-311x0005721... .

Among the lost opportunities, we highlight the lack of diagnosis and failures in the treatment of pregnant women. A meta-analysis study showed that prenatal interventions significantly reduce the risk of pregnant women having an adverse result due to syphilis²²22. Hawkes SJ, Gomez GB, Broutet N. Early antenatal care: does it make a difference to outcomes of pregnancy associated with syphilis? A systematic review and meta-analysis. PLoS One. 2013;8(2):e56713. https://doi.org/10.1371/journal.pone.0056713
https://doi.org/10.1371/journal.pone.005... . However, during the period of this study, the routine examination requested to the pregnant women was the VDRL test, there was no daily blood collection in the units, and the results were available only 15 days after collection, hindering the diagnosis. In addition, the rapid testing (RT) was being implemented.

The RT for syphilis is a strategy that can increase the coverage of testing in pregnant women, especially when conducted at the first consultation, enabling immediate treatment. Considering that most pregnant women attended two or more consultations and started prenatal care before the end of the second trimester of pregnancy, there would be time for adequate treatment if they had undergone RT.

However, during the period of this study, Brazil experienced a severe penicillin scarcity²³23. Ministério da Saúde (BR). Nota Informativa Conjunta nº 109/2015/GAB/SVS/MS, GAB/SCTIE/MS. Orienta a respeito da priorização da penicilina benzatina para sífilis em gestantes e penicilina cristalina para sífilis congênita no país e alternativas para o tratamento da sífilis. Brasília, DF: Ministério da Saúde; 2015., contributing to many pregnant women not being treated or receiving drugs other than benzathine penicillin. These pregnant women were 3.52 times more likely to have premature babies, a situation also evidenced in studies conducted in China, which identified higher chances of prematurity and other outcomes in pregnant women with untreated or inadequately treated syphilis²⁴24. Zhang XH, Xu J, Chen D, Guo L, Qiu L. Effectiveness of treatment to improve pregnancy outcomes among women with syphilis in Zhejiang. Sex Transm Infect. 2016;92(7):537-41. https://doi.org/10.1136/sextrans-2015-052363
https://doi.org/10.1136/sextrans-2015-05... ^,2525. Qin JB, Feng TJ, Yang TB, Hong FC, Lan LN, Zhang CL, et al. Synthesized prevention and control of one decade for mother-to-child transmission of syphilis and determinants associated with congenital syphilis and adverse pregnancy outcomes in Shenzhen, South China. Eur J Clin Microbiol Infect Dis. 2014;33(12):2183-98. https://doi.org/10.1007/s10096-014-2186-8
https://doi.org/10.1007/s10096-014-2186-... .

The possibility of a new penicillin scarcity²⁶26. Nurse-Findlay S, Taylor MM, Savage M, Mello MB, Saliyou M, Lavayen M, et al. Shortages of benzathine penicilina for prevention of mother-to-child transmission of syphilis: Na evaluation from multi-country surveys and stakeholder interviews. PLoS Med. 2017;14(12):e1002473. https://doi.org/10.1371/journal.pmed.1002473
https://doi.org/10.1371/journal.pmed.100... is worrisome, since benzathine penicillin is the drug of choice for the treatment of syphilis in pregnant women, as it is the only one that crosses the transplacental barrier and treats the baby²³23. Ministério da Saúde (BR). Nota Informativa Conjunta nº 109/2015/GAB/SVS/MS, GAB/SCTIE/MS. Orienta a respeito da priorização da penicilina benzatina para sífilis em gestantes e penicilina cristalina para sífilis congênita no país e alternativas para o tratamento da sífilis. Brasília, DF: Ministério da Saúde; 2015.. For this reason, it is necessary to develop studies evaluating the efficacy of alternative drugs²⁷27. Taylor MM, Kara EO, Araujo MAL, Silveira MS, Miranda AE, Coelho ICB, et al. Phase II trial evaluating the clinical efficacy of cefixime for treatment of active syphilis in non-pregnant women in Brazil (CeBra). BMC Infect Dis. 2020;20:405. https://doi.org/10.1186/s12879-020-04980-1
https://doi.org/10.1186/s12879-020-04980... .

In this study, we also identified a higher chance of prematurity in pregnant women whose VDRL titration was > 1:8 at delivery. High VDRL titers in pregnant women during prenatal care and at delivery may represent active syphilis, a condition associated with severe CS outcomes, including prematurity³3. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, et al. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396. https://doi.org/10.1371/journal.pmed.1001396
https://doi.org/10.1371/journal.pmed.100... ^,2828. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Temmerman M, Broutet N, et al. Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study. Lancet Glob Health. 2016;4(8):e525-33. https://doi.org/10.1016/S2214-109X(16)30135-8
https://doi.org/10.1016/S2214-109X(16)30... . For this reason, after treatment, the cure control of syphilis in pregnant women should occur monthly, by monitoring the decrease of VDRL titers¹⁵15. Ministério da Saúde (BR). Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis. Brasilia, DF: Ministério da Saúde; 2015..

A detailed analysis of the cases of pregnant women who had high VDRL titers at delivery showed that no woman who received complete treatment (three doses of benzathine penicillin) had a premature baby, reinforcing the importance of timely diagnosing and treating pregnant women with syphilis, thus preventing serious outcomes, such as prematurity due to CS.

This study has, as limitation, the analysis of secondary data, considering that lack of registration or low-quality data are common. Including the collection in different data sources (notification forms and medical records) contributed greatly to minimize the problem. Moreover, the exclusion of stillborns, due to the lack of registration of important variables, and the exclusion of pregnant women who presented injuries that could interfere in the outcome of prematurity by CS, may have underestimated the number of premature infants.

The findings of this study show that prematurity due to CS is preventable, provided that pregnant women with syphilis are treated appropriately. We also identified that weaknesses in prenatal care are associated with this outcome, which highlights the importance of implementing public policies to improve the quality of prenatal care.

In this sense, primary health care has an indispensable role to detect syphilis in pregnant women and ensure the testing and treatment. These efforts to prevent prematurity by CS can avoid severe consequences for the baby, the family and the health system.

REFERENCES

Publication Dates

History