Matida, Luiza Harunari MD, PhD*; Santos, Naila Janilde Seabra MD, PhD*; Ramos, Alberto Novaes Jr MD, MPH†; Gianna, Maria Clara MD*; da Silva, Mariliza Henrique MD*; Domingues, Carmen Silvia Bruniera MD*; de Albuquerque Possas, Cristina PhD‡; Hearst, Norman MD, MPH§; for the Study Group of Vertical Transmission of HIV and Syphilis
HIV infection in children is an important public health problem in the world, mainly in poorer countries.1,2 An estimated 430,000 children were newly infected with HIV in 2008, 15.9% of total new cases. Of these children, approximately 90% were exposed to HIV through their mothers, emphasizing this important mode of transmission.2
In developed countries, where control actions reached satisfactory coverage with quality,3 the reduction in new cases of children infected by vertical transmission was substantial. In these countries, the rates of HIV transmission are <2%.1
Despite global inequities, similar epidemiological results are also seen in some developing countries, including Brazil,4-6 which has gained notoriety in the international setting due to its commitment and accountability in implementing actions to respond to HIV infection.7 The country was one of the first developing countries to guarantee universal and free access to highly active antiretroviral therapy to people living with HIV and to develop a national plan for reduction of HIV transmission.8
In Brazil, in 2006, an estimated 630,000 people were living with HIV, with 462,237 AIDS cases reported between 1980 and June of 2009. Of these, 13,012 (2.8%) were <13 years old. From 1997 to 2008, the total number of new cases in children was reduced 3.4 times, from 1128 to 337 cases. Since 1990, >90% of reported cases among children <13 years old resulted from vertical transmission, reaching nearly 93% in 2008.6,9 In São Paulo state, considering the period from 1997 to 2007, the number of reported AIDS cases due to vertical transmission decreased by 90.7%.
At the national level, the rate of vertical transmission was initially estimated at 16% between 1988 and 1993 in a study by Tess et al,10 including health services from 4 municipalities of São Paulo state, with 434 children exposed to HIV. Another relevant national study included 2924 children (57.1% from the southeastern region) at 63 health service locations in 20 states (including the Federal District), and it estimated transmission rates of 8.6% for 2000 and 7.1% for 2001.5
Combining these 2 studies, an average national decrease of approximately 55.6% can be estimated, despite regional inequalities. In developed countries, there was a substantial decrease during this period, with rates close to 1% in the United States.1
The state of São Paulo is responsible for 38.3% (176,946 cases) of total reported AIDS cases in Brazil from 1980 to June of 2009. Reported AIDS cases in children (<13 years of age) in São Paulo accounted for 36.5% (4744) of total AIDS cases among children in Brazil.9 São Paulo created, in 1983, the first STD/AIDS State Program in Brazil, implementing HIV infection control measures, including for vertical transmission of HIV.4 The zidovudine protocol11 was introduced in 1994 in São Paulo, while at the national level prevention guidelines were under development.
The elimination of HIV vertical transmission is a concrete possibility in Brazil,12 considering the national policies and the organization of health services and available scientific evidence, if all recommendations are followed. Interventions necessary for interrupting the vertical transmission of HIV are available in public health services (HIV testing, antiretroviral medications, lactation inhibitors, and infant feeding formula). Nonetheless, only half (52%) of the Brazilian pregnant women received antenatal interventions to prevent vertical transmission, and in São Paulo state, this coverage was 82%.4
The objectives of this study were to estimate the HIV vertical transmission rate in São Paulo state, by diagnosed and reported pregnant women in 2006, and to identify and discuss the main factors associated with progress and challenges for elimination of HIV vertical transmission.
This retrospective cross-sectional study used secondary data (hospital records and other specific tools) from patient visits to health services of São Paulo state. São Paulo state consists of 645 municipalities, with an estimated population of approximately 41 million inhabitants in 2006.
All municipalities that presented cases of pregnant women infected with HIV or children diagnosed with AIDS in 2006, registered in the Information System for Notifiable Diseases (SINAN, Sistema de Informação de Agravos de Notificação), were included. Since 1986, reporting of AIDS cases in adults and children has been mandatory in Brazil, and reporting of HIV infection in pregnant women and children exposed to HIV is also mandatory since 2000.
In total, data from 157 municipalities were analyzed from a total of 375 health service units, including primary health units, general and specialized ambulatory units, day hospitals, general and specialized hospitals (public, philanthropic, and private), maternities, and other services involved in the care and surveillance of sexually transmitted diseases and HIV/AIDS. Analysis of cases of pregnant women infected with HIV and exposed children considered aspects of antenatal, intrapartum, and postnatal periods, specific to occurrence of HIV vertical transmission. The SINAN database was converted to an Excel (Microsoft Office 2007) spreadsheet, and health services, which cared for pregnant women and exposed children, were identified.
Information was also obtained from other official sources, including epidemiological surveillance information on HIV/AIDS-related deaths—mortality information system (Sistema de Informações sobre Mortalidade); sources related to management of antiretroviral drugs—logistic control system of medicines (Sistema de Controle Logístico de Medicamentos); and information for the management of laboratory tests (quantification of circulating RNA from HIV plasma viral load and CD4+ T-cell count)—system for control of laboratory examinations (Sistema de Controle de Exames Laboratoriais). In Brazil, every HIV-infected citizen assisted by the National Unified Health System and who uses free laboratory tests or antiretrovirals is registered in these 3 systems.8 For data collection in health units, semistructured tools were developed by the research team and pretested. These health units provide care for women with HIV infection, prenatal care, birth, and perinatal care, and care for children exposed to HIV.
Trained technicians carried out data collection from patient records and other health registries. Professionals with management roles in regional health units were selected for this task to guarantee quality. All completed forms were systematically reviewed by technical supervisors of the São Paulo STD/AIDS State Program, and by researchers from the study team to verify completeness, consistency, and potential need for data review. The participation of professionals from clinical services was crucial for understanding data and for involving service providers in implementation of control strategies, including diagnosis, treatment, follow-up care, and reporting.
Data from forms were consolidated after double entry (in an Excel worksheet—Microsoft Office 2007) and systematically compared to detect inconsistencies. The final database was converted and analyzed in Stata (Stata Statistical Software: Release 11. College Station, TX: StataCorp LP).
To calculate the transmission rate, 185 children who did not have an available HIV status were maintained in the denominator (situation unknown). Despite potential misclassification, these children probably were uninfected or asymptomatic because they were not captured by health services at the time of study implementation. The HIV vertical transmission rate was calculated as a percentage with a 95% confidence interval. Categorical variables were expressed in absolute numbers and percentages. Numerical values were expressed as median values and grouped for subsequent analysis.
For univariate analysis, the outcome in exposed children (linked to pregnant women in the study) was the dependent variable and association between variables was verified by the chi-square test (significance at 0.05). Fisher exact test was used for variables with an expected frequency <5. Prevalence rates with respective 95% confidence intervals were calculated. The study was approved by the Research Ethics Committee of the Reference and Training Center of the STD/AIDS State Program, São Paulo.
There were 982 exposed children analyzed from mothers diagnosed in 2006. The transmission rate was 2.7% (1.86 to 3.94), corresponding to 27 children. In 185 cases (18.8%), the final HIV status was undefined for 132 live-born children lost to follow-up (13.4%), for 33 live-born children with only 1 undetectable viral load (3.4%), and in 20 cases of abortion/stillbirth (2%).
The average age of mothers was 28.7 (28.3-29.1) years, ranging from 14.4 to 46.3 years, at childbirth (among the 978 women with valid data). The average age of these women at time of HIV diagnosis was 24.9 (24.3-26.1) years, ranging from 14.0 to 44.8 years (among 964 women with valid data). Among 746 pregnant women who attended antenatal care (94.3% of 791 with this information), average time between start of antenatal care and pregnancy diagnosis was 2.4 months among a total of 835 women with valid data.
Tables 1 and 2 summarize main characteristics of pregnant women whose children received a final diagnosis. The majority of women reside in municipalities located in interior areas of the state (69.8%), had education less than or equal to the primary level (73.6%), and self-identified as having white skin color (56.3%). Among mothers of children infected with HIV, none were illiterate and a similar proportion of women had a high school level of education when compared with mothers who did not have a HIV-positive child. Regarding marital status, 73.6% had a partner or were married. The main reported mode of HIV exposure among pregnant women was sexual (95.6%). The majority (59.6%) were diagnosed with HIV before the antenatal period. Nonetheless, 35.2% were diagnosed during the antenatal period and 4.2% during delivery. The majority attended antenatal care (94.3%), usually outside of São Paulo city (70.6%). Regarding the number of antenatal consultations, 79% of pregnant women had ≥6 appointments, and the median number of consultations was 9 (954 women with valid data).
In 50.5% of cases, mothers presented with AIDS before pregnancy, according to the Brazilian definition criteria; among them, only 32.8% were taking antiretroviral drugs during pregnancy.
Among 94.2% of pregnant women who took prophylaxis at some point, 38.5% did so before 14 weeks and 21.7% began after 27 weeks. The majority had cesarean section (73%) and a single birth (96.1%); antiretroviral use during labor was 91.2%. Maternal deaths occurred in 2.8% (22 women) of this population.
Table 3 presents the main characteristics of HIV-exposed children with an established diagnosis. The majority were given antiretroviral prophylaxis (98.3%), although 41.3% received it late (between 6 and 24 hours); 56.7% had prophylaxis in the first 6 hours (32.4% within 2 hours of birth and 24.3% between 2 and 6 hours). Ninety-eight percent did not breastfeed, and 99.7% did not receive donated breast milk. Duration of antiretroviral prophylaxis was 6 weeks in 91.5% of cases. Forty-nine children (7.0%) had siblings infected with HIV.
Variables related to mothers, such as divorced or separated, age <16 years, injection drug use, lack of antenatal care, diagnosis at delivery (with antenatal care as a protective factor), and progression to death, were more common in women whose children were HIV infected, although differences did not reach statistical significance.
In univariate analysis, children at greater risk for HIV infection had the following characteristics: mother exposed to HIV by blood transfusion, <6 antenatal visits, not receiving antiretroviral prophylaxis at any point (pregnancy, birth, or newborn), mother not using antiretrovirals at time of birth, child not taking prophylaxis or taking prophylaxis for <6 six weeks, and breastfeeding.
This study indicates a decreasing trend of HIV vertical transmission in Sao Paulo with levels approaching elimination, which seems to be associated with antiretroviral policy and interruption of breastfeeding. However, we still identified associated factors with this mode of transmission related to serious operational issues in implementation of these interventions.
The analysis of the epidemiological and operational profile of Sao Paulo state provides lessons for responding to vertical transmission in the country as a whole, despite epidemiological and operational differences. Considering the main national-level studies as a reference,5,10 the rate of vertical HIV transmission in the state has progressed to levels suggestive of control. According to the definition by the Pan American Health Organization, “elimination” corresponds to ≤2 HIV-positive children per 100 HIV-positive mothers.13
In Brazil, there was a decline from 1988-2003 of 16%10 to 2.7% in 2006, with a relative reduction of 83.1%. Internationally, this performance is inferior to many developed countries, some of which have reached levels <2%,1,14 but it is excellent in comparison with other developing countries.15,16 For example, from a transmission rate of 25% in 1991, the United States reached a transmission rate of <2% during 1999-20001; in 2004, it was estimated that <100 children were diagnosed annually as new cases of HIV infection.1
Reductions of varying proportions have also been reported by other studies in other Brazilian states, all in the southeastern region, highlighting the impact of interventions to prevent vertical HIV transmission.13,17-20 Brazil still presents major social, economic, and cultural inequalities, and there are multiple levels of quality of health services in terms of prenatal care and the adoption of measures to prevent vertical transmission of HIV.21 Attention should be given to continued surveillance and routine care, especially in places with social inequalities, even in Brazil's southeastern region and Sao Paulo state.
Concerning exposed children, lack of prophylaxis (or receipt for <6 weeks) and maternal breastfeeding are associated with increased vulnerability and are fundamental for vertical transmission.22 In our study, in 94% of cases, mothers of infected children received prenatal care, and the main variables associated with vertical transmission were related to operational issues. This situation demonstrates that, beyond access to prenatal care, it is necessary to expand the quality of health services.23 Besides these operational issues, factors such as urban poverty, race/color, and low educational level were identified as determinants of vertical transmission of HIV, even in more developed areas of the country.6,24 In our study, none of the demographic and socioeconomic variables were significantly associated with vertical transmission; although these variables did not present statistical significance, there is a suggestion of increased infection when the mother was divorced or separated, was of age <16 years, was an injection drug user, lacked antenatal care, was diagnosed at delivery, and progressed to death.
Although this is a cross-sectional study based on secondary data, the search for information from different sources, together with a better national database (SINAN), allowed for more and higher quality data than previous studies in Brazil. Additionally, the present study defines the transmission rate based on HIV-infected mothers and their exposed children in the health services of all of São Paulo state, instead of only selected reference centers, better approximating the actual situation.
Interestingly, if we define HIV-exposed children with only 1 undetectable viral load and subsequently lost to follow-up as actually noninfected, the total noninfected would be 803 (81.8%). The initial result indicating noninfection in children, when reported to family members as an undetectable viral load result, may have created a presumption of safety, and this may have been why they did not return for additional follow-up. This reinforces the need to contextualize posttest counseling in these situations and to strengthen active case identification.
Our study has limitations besides those related to database quality and quality of medical registries. Pregnant women with HIV not captured by the current reporting system may be influencing the results, biasing the observed rate of transmission; however, considering the structural network of health services in São Paulo state, infected children who progress to AIDS had a high probability to be identified by the health system. We were not able to examine other potential factors that might be associated with vertical transmission, including sociodemographic, behavioral, and economic factors. For example, sexual transmission may be associated with injecting drug use behavior of a partner that may be strongly underreported. Nevertheless, our results suggest that women who use drugs or whose partners use drugs should be the focus of greater attention for HIV testing services, family planning, and prenatal care. This issue is one of the main challenges for Brazil, especially in less developed regions.25 Another challenge is to improve procedures to assure that prenatal services receive timely laboratory results, including new technologies such as the use of rapid HIV diagnostic tests in maternity hospitals.
Our data reveal program shortcomings and also reveal areas of significant improvement, such as substantial (albeit not perfect) incorporation of prevention strategies in health services. This new scenario indicates other new challenges to include in the policy agenda and in national strategic planning: the large number of noninfected children exposed to antiretrovirals, HIV resistance to antiretrovirals used, and the increased survival of infected children, which demands new forms of care by health professionals.1,12
In conclusion, the study reinforces previous findings of advances toward elimination of HIV vertical transmission in São Paulo state. This trend is a result of different strategies used in the past 25 years, especially the introduction of antiretroviral treatment and nonuse of breastfeeding. Data on HIV vertical transmission in São Paulo state are comparable with those of many developed countries. Although serious operational issues remain, conditions exist to respond effectively. São Paulo state demonstrates that it is possible to achieve advanced levels of control for this preventable mode of HIV transmission.
Research team: Alberto Novaes Ramos, Jr (Federal University of Ceará), Ângela Tayra (STD/AIDS State Program, São Paulo), Arachu Castro (Harvard University); Carmen Silvia Bruniera Domingues (STD/AIDS State Program, São Paulo), Cristina Possas (Department of STD, AIDS and Viral Hepatitis), Ivone Aparecida de Paula (STD/AIDS State Program, São Paulo), Luiza Harunari Matida (research coordinator, STD/AIDS State Program, São Paulo), Maria Clara Gianna (coordinator of STD/AIDS State Program, São Paulo), Mariliza Henrique da Silva (STD/AIDS State Program, São Paulo), Marina Aragão Wahlbuhl Gonçalves (STD/AIDS Municipality Program, São Paulo), Marizélia Moreira (National Agency of Health), Naila Janilde Seabra Santos (STD/AIDS State Program, São Paulo), Paulo Roberto Teixeira (Secretary of Health, São Paulo State), Sandra Regina de Souza (Secretary of Health, São Paulo State); Arachu Castro (Harvard University, EUA); and the Department of STD, AIDS and Viral Hepatitis, Data collection and supervision team: Adélia Araujo Bispo, Ana Maria Rodrigues, Ana Silvia da Paixão Gibbons, Analice de Oliveira, Angela Mattos Marchesini, Aparecida Massako Nakae, Beatriz Scanavelli, Benedita Maria de Castro, Cândida Maria dos Santos, Carlos Roberto de Oliveira, Carmenm Silvia Bruniera Domingues, Celsis de Jesus Pereira, Clara Alice Franco de Almeida Carvalho, Dagmar Maia Kistemann, Eliana Mara Pessoa, Eliane Monteiro, Filomena Maria do Carmo Nicoletti Chudek, Francisco Vanin Pascalicchio, Gisele Gutierres Carvalho Ciciliato, Ione Aquemi Guibu, Ivone Aparecida de Paula, Kezia Paiva Martins, Kimie Therezinha Nishimura Turuta, Laura Brzeski, Lilian Andrade Grimm, Lucia Aparecida Dourado Shiguematsu, Lucille Mary Loureiro Soares, Luiza Harunari Matida, Marcia Polon do Carmo, Marcia Regina Pacola, Marco Antonio Ribas, Maria Angela Silva Landroni, Maria Aparecida da Silva, Maria Aparecida Ferreira Fernandes, Maria Cecilia Rossi de Almeida, Maria Clara Neves da Costa, Maria Cristina Covolan Bachiega, Maria da Conceição Pinto, Maria de Fatima Jorge, Maria do Carmo Ferreira, Marina Aragão Wahlbuhl Gonçalves, Marisdalva Viegas Stump, Mariza Vono Tancredi, Marli Prado, Monica de Arruda Rocha, Naila Janilde Seabra Santos, Nivania Fuin Zavith, Olinda Keiko Mizuta, Patricia Helena Vaquero Marques, Rejane Alves Fraissat, Rosa Maria Alves Seixas, Ruth Nogueira Cordeiro de Moraes Jardim, Saloa Abdelnour Hoeppner, Sheila Maria Figueira Jacintho da Cruz, Silvia Karina Favinha Campassi Falzoni, Sonia Aparecida Fioratti, Sueli Bellini Garcia, Teresa Maria Isaac Nishimoto, Viviane da Rocha Sousa, Wedja Sparinger, and finally, the Grupo de Estudo de Transmissão Vertical do HIV e da Sífilis do Estado de São Paulo.
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