Abstract

The aim of this research was to analyze pregnancy incidence and associated factors in a cohort of 753 women living with HIV/AIDS (WLWHA) in Rio de Janeiro, Brazil, from 1996 to 2016. Women aged 18-49 years who were not on menopause (surgical or natural) and did not have a tubal ligation were eligible for the study. Data were collected by medical professionals during initial and follow-up visits. Person-time pregnancy incidence rates were calculated throughout the follow-up period. Pregnancy incidence-associated factors were investigated by univariate and multiple analyzes, using an extension of the Cox survival model. Follow-up visits recorded 194 pregnancies, with an incidence rate of 4.01/100 person-years (95% CI: 3.47; 4.60). A higher pregnancy incidence was associated with CD4 nadir ≥ 350 cells/mm³, use of an antiretroviral regimen not containing Efavirenz, and prior teenage pregnancy. In turn, women with a viral load ≥ 50 copies/mL, age ≥ 35 years old, with two or more children and using a highly effective contraceptive method showed a lower incidence. Results showed a significant reduction in pregnancy incidence after 2006, a significant reduction in female sterilization from 1996 to 2016, and a high rate of cesarean sections. The association found between pregnancy incidence and the use of contraceptive methods and virological control markers suggests a good integration between HIV/AIDS and reproductive health services. The high rate of cesarean section delivery indicates the need to improve childbirth care.

Keywords:
Pregnancy; HIV Infections; Cohort Studies

Resumo

O objetivo deste estudo foi analisar a incidência de gravidez e fatores associados em uma coorte de mulheres vivendo com HIV/aids (MVHA) no Rio de Janeiro, Brasil. Foi realizada uma coorte clínica com 753 MVHA entre 1996 e 2016. Mulheres com idade entre 18-49 anos que não estavam na menopausa natural ou cirúrgica e que não tinham laqueadura tubária foram elegíveis para o estudo. Os dados foram coletados durante as consultas iniciais e de acompanhamento por profissionais médicos. As taxas de incidência por pessoa-tempo foram calculadas durante todo o período de acompanhamento. Análises univariadas e múltiplas foram realizadas para investigar fatores associados à incidência de gravidez, utilizando uma extensão do modelo de sobrevida de Cox. Foram registradas 194 gestações durante as consultas de acompanhamento, com uma taxa de incidência de 4,01/100 pessoas-ano (IC95%: 3,47-4,60). Uma maior incidência de gravidez foi associada a nadir CD4 ≥ 350 células/mm³, terapia antirretroviral sem Efavirenz e gravidez anterior na adolescência, enquanto uma menor incidência foi observada em mulheres com carga viral ≥ 50 cópias/mL, idade ≥ 35 anos, com dois ou mais filhos e que usavam um método contraceptivo altamente eficaz. Houve uma redução significativa na incidência de gestações após 2006, uma redução significativa na esterilização feminina entre 1996 e 2016 e uma alta taxa de cesarianas. A associação entre a incidência de gestações e o uso de métodos contraceptivos e marcadores de controle virológico sugere uma boa integração entre HIV/aids e serviços de saúde reprodutiva. A alta taxa de cesarianas indica a necessidade de melhoria na assistência ao parto.

Palavras-chave:
Gravidez; Infecções por HIV; Estudos de Coortes

Resumen

El objetivo de este estudio fue analizar la incidencia del embarazo y los factores asociados en una cohorte de mujeres que viven con VIH/SIDA (MVHA) en Río de Janeiro, Brasil. Se realizó una cohorte clínica con 753 MVHA entre 1996 y 2016. Las mujeres de 18-49 años que no estaban en la menopausia natural o quirúrgica y que no tenían ligadura de trompas fueron elegibles para el estudio. Los datos se recopilaron durante las consultas iniciales y de seguimiento por parte de profesionales médicos. Las tasas de incidencia por persona-tiempo se calcularon durante todo el período de seguimiento. Se realizaron análisis univariados y múltiples para investigar los factores asociados con la incidencia del embarazo utilizando una extensión del modelo de supervivencia de Cox. Se registraron 194 embarazos durante las consultas de seguimiento, con una tasa de incidencia de 4,01/100 personas-año (IC95%: 3,47-4,60). Una mayor incidencia de embarazo se asoció con nadir CD4 ≥ 350 células/mm³, terapia antirretroviral sin Efavirenz y embarazo previo en la adolescencia, mientras que una menor incidencia se observó en mujeres con carga viral ≥ 50 copias/mL, edad ≥ 35 años, con dos o más hijos y que usaban un método anticonceptivo muy eficaz. Hubo una reducción significativa en la incidencia de embarazos después de 2006, una reducción significativa en la esterilización femenina entre 1996 y 2016 y una alta tasa de cesáreas. La asociación entre la incidencia de embarazos y el uso de métodos anticonceptivos y marcadores de control virológico sugiere una buena integración entre el VIH/SIDA y los servicios de salud reproductiva. La alta tasa de cesáreas indica la necesidad de mejorar la asistencia al parto.

Palabras-clave:
Embarazo; Infecciones por HIV; Estudios de Cohortes

Introduction

Highly active antiretroviral therapy (HAART) has affected the reproductive pattern of women living with HIV/AIDS (WLWHA) by increasing women’s survival and quality of life and reducing mother-to-child HIV infection transmission. While research conducted in the 1990s showed a lower pregnancy incidence and a higher rate of pregnancy terminations in WLWHA ¹1. Kline A, Strickler J, Kempf J. Factors associated with pregnancy and pregnancy resolution in HIV seropositive women. Soc Sci Med 1995; 40:1539-47.^,22. Van Benthem BH, de Vincenzi I, Delmas MC, Larsen C, van den Hoek A, Prins M. Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women. AIDS 2000; 14:2171-8.^,33. Bongain A, Berrebi A, Mariné-Barjoan E, Dunais B, Thene M, Pradier C, et al. Changing trends in pregnancy outcome among HIV-infected women between 1985 and 1997 in two southern French university hospitals. Eur J Obstet Gynecol Reprod Biol 2002; 104:124-8.^,44. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6., more recent studies report an increased number of births in this population ⁵5. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Trends in management and outcome of pregnancies in HIV-infected women in the UK and Ireland, 1990-2006. BJOG 2008; 115:1078-86., with rates similar to those observed in the general population ⁶6. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,77. Salters K, Loutfy M, de Pokomandy A, Money D, Pick N, Wang L, et al. Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada. PLoS One 2017; 12:e0180524.. But the proportions of unplanned pregnancies and induced abortions remain high, stressing the importance of greater integration between clinical care and reproductive health services ⁸8. Gómez-Suárez M, Mello MB, Gonzalez MA, Ghidinelli M, Pérez F. Access to sexual and reproductive health services for women living with HIV in Latin America and the Caribbean: systematic review of the literature. J Int AIDS Soc 2019; 22:e25273..

Brazil is a continental country with an estimated population of 200 million inhabitants and a concentrated HIV epidemic. Although HIV/AIDS detection rate in women showed a 50% reduction in the period 2010-2020 ⁹9. Secretaria de Vigilância em Saúde, Ministério da Saúde. Boletim Epidemiológico HIV/Aids 2021; Número Especial. file:///home/carolina/Downloads/boletim_aids_2021_internet.pdf (accessed on 19/Jun/2022).
file:///home/carolina/Downloads/boletim_... , the HIV detection rate in pregnant women increased by 30.5%, going from 2.1 cases/1,000 live births in 2010 to 2.7 cases/1,000 live births in 2020. This finding may be explained by the greater diagnosis of HIV infection during prenatal care and improved surveillance of mother-to-child transmission ⁹9. Secretaria de Vigilância em Saúde, Ministério da Saúde. Boletim Epidemiológico HIV/Aids 2021; Número Especial. file:///home/carolina/Downloads/boletim_aids_2021_internet.pdf (accessed on 19/Jun/2022).
file:///home/carolina/Downloads/boletim_... . Clinical guidelines for preventing mother-to-child transmission have been available in Brazil since the 1990s, and despite reports of implementation flaws of these protocols ¹⁰10. Araujo ESP, Friedman RK, Camacho LAB, Derrico M, Moreira RI, Calvet GA, et al. Cascade of access to interventions to prevent HIV mother to child transmission in the metropolitan area of Rio de Janeiro, Brazil. Braz J Infect Dis 2014; 18:252-60.^,1111. Miranda AE, Pereira GF, Araujo MA, Silveira MF, Tavares LL, Silva LC, et al. Avaliação da cascata de cuidado na prevenção da transmissão vertical do HIV no Brasil. Cad Saúde Pública 2016; 32:e00118215.^,1212. Lovero KL, Oliveira TRD, Cosme EM, Cabrera NB, Guimarães MF, Avelar JG, et al. Retrospective analysis of risk factors and gaps in prevention strategies for mother-to-child HIV transmission in Rio de Janeiro, Brazil. BMC Public Health 2018; 18:1110., the mother-to-child transmission rate decreased in the country, being estimated at 2% in 2011-2012 ¹³13. Domingues RMSM, Saraceni V, Leal MDC. Mother to child transmission of HIV in Brazil: data from the "Birth in Brazil study", a national hospital-based study. PLoS One 2018; 13:e0192985., with a 69.7% reduction in the AIDS detection rate in children under 5 in the period 2010-2020 ⁹9. Secretaria de Vigilância em Saúde, Ministério da Saúde. Boletim Epidemiológico HIV/Aids 2021; Número Especial. file:///home/carolina/Downloads/boletim_aids_2021_internet.pdf (accessed on 19/Jun/2022).
file:///home/carolina/Downloads/boletim_... .

Research on pregnancy incidence in WLWHA in Brazil are scarce. A previous study conducted with data from a cohort of women followed at the Evandro Chagas Brazilian National Institute of Infectious Diseases, Oswaldo Cruz Foundation (INI/Fiocruz), from 1996 to 2003, found a pregnancy rate of 6.9/100 WLWHA, 2.1/100 of induced abortions, and 33.3% of repeat pregnancies ¹⁴14. Friedman RK, Bastos FI, Leite IC, Veloso VG, Moreira RI, Cardoso SW, et al. Pregnancy rates and predictors in women with HIV/AIDS in Rio de Janeiro, Southeastern Brazil. Rev Saúde Pública 2011; 45:373-81.. The authors observed higher pregnancy rates in younger women and in women living with a partner, while highly educated WLWHA using antiretroviral (ART) showed lower rates. Thus, this study sought to analyze pregnancy incidence, outcomes and associated factors during a 20-year follow-up period in the INI/Fiocruz women cohort.

Methods

Study design

Clinical WLWHA cohort assisted at INI/Fiocruz, located in Rio de Janeiro, Brazil. The cohort began in 1996 and was paused in December 2016. Inclusion criteria for participation in the cohort consisted of being female at birth, being over 18 years old and having a confirmed HIV infection diagnosis ¹⁵15. Grinsztejn B, Bastos FI, Veloso VG, Friedman RK, Pilotto JH, Schechter M, et al. Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil. Int J STD AIDS 2006; 17:473-8..

Inclusion criteria

All women with at least two visits (initial consultation and one follow-up visit) and who, at the initial visit, were under 50 years old and were not on natural menopause (period of no menstrual cycles for more than one year), surgical menopause (total or subtotal hysterectomy and/or bilateral oophorectomy), or had not undergone tubal ligation surgery were eligible.

Data collection

A team comprising clinicians and gynecologists regularly (annual or biannual consultations) monitored all women, using standardized instruments to collect gynecological and behavioral data. All medical professionals underwent training to standardize data collection ¹⁵15. Grinsztejn B, Bastos FI, Veloso VG, Friedman RK, Pilotto JH, Schechter M, et al. Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil. Int J STD AIDS 2006; 17:473-8..

Self-reported race/ethnicity, schooling years, lifetime drug use, age at onset of sexual activity, lifetime number of partners and obstetric history, including teenage pregnancy (under 20 years old), were collected at the initial consultation and analyzed as baseline predictors. Information on age, number of children, domestic violence, sexual violence, smoking, alcohol use, viral load, CD4 nadir, ART use and diagnosis of opportunistic disease ¹⁶16. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41(RR-17):1-19. were obtained at the first visit and updated at follow-up. Data regarding marital status and contraceptive use (“no use”; “low efficacy” - natural, male condom, female condom, diaphragm, withdrawal; “high efficacy” - oral hormones, injectable hormonal, IUD; “combined” - high efficacy associated with a barrier method) were collected exclusively at follow-up visits. All data updated during follow-up were analyzed as time-dependent predictors.

As INI/Fiocruz does not provide obstetric care, we collected outcomes of new pregnancies and dates during cohort visits and/or HIV and gynecological routine care after the event. Outcomes were classified into vaginal delivery, cesarean section, spontaneous abortion (including tubal pregnancies) and voluntary termination of pregnancy (induced abortion). Data on natural or surgical menopause and tubal ligation was also verified during follow-up.

Observation of these women began from their inclusion in the cohort, or from the date of termination of pregnancy for those who were pregnant at the initial consultation. During follow-up, new observation periods began after a new pregnancy ended. Follow-up lasted until their final gynecological appointment on December 31, 2016, or when they had natural or surgical menopause, tubal ligation surgery, or turned 50.

Data analysis

First, we described the women’s social, demographic, clinical and laboratory characteristics at the beginning of follow-up using frequencies and summary measures.

We then described the outcomes of all pregnancies, including those existing at the initial visit, divided into four periods: 1996-2000, 2001-2006, 2007-2010 and 2011-2016. Chi-square test of tendency, with a 0.05 significance level, was used to verify whether there was a change in the type of outcome during these follow-up periods.

Pregnancy incidence during follow-up was estimated by calculating person-time incidence rates (per 100 person-years) throughout the follow-up period and over the four periods defined for the cohort. Changes in the pregnancy incidence rate over the follow-up periods when compared to the 1996-2001 period was estimated by Wald test, with a 0.05 significance level.

Finally, factors associated with the outcome “pregnancy incidence” were investigated using an extension of the Cox survival model ¹⁷17. Carvalho MS, Andreozzi VL, Codeço CT, Campos DP, Barbosa MTS, Shimakura SE. Análise de sobrevivência: teoria e aplicações em saúde. Rio de Janeiro: Editora Fiocruz; 2019., which allows for the inclusion of time-dependent variables, identifying each patient as a cluster (inclusion of more than one pregnancy per patient) and stratifying the baseline incidence curve by the total number of pregnancies over time. Time-dependent variables used the record closest to the outcome (pregnancy), considering a maximum window of one year. The univariate and multiple analyzes performed used the free software R version 4.0.5 (http://www.r-project.org).

The cohort study of WLWHA at INI/Fiocruz was approved by the institution’s Ethics Research Committee. All data confidentiality procedures were adopted and all participants signed an informed consent form upon joining the cohort.

Results

From 1996 to December 2016, a total of 1,383 WLWHA joined the INI/Fiocruz gynecological cohort. Of these, we selected 753 for the present analysis. Figure 1 describes the reasons for exclusion.

Most of the study sample joined the cohort after 2006. Mean age was 33.4 years (standard deviation - SD = 7.8), most reported being mixed race and had more than 8 years of schooling. Nearly 20% were smokers, 38.3% reported consumption of alcoholic beverages and 16.8% the use of some other drug. Almost a third of the women reported past experiences of domestic violence and 13.4% suffered sexual violence. Of the study sample, 18.7% (median age = 16.5 years, interquartile range - IQR: 15; 18) reported onset of sexual activity under the age of 15 and most had more than 5 sexual partners in their lifetime. More than 80% of the women reported a previous pregnancy, 47.1% of which had their first pregnancy in adolescence. Mean number of children was 1.4 (SD = 1.3) and almost half of the sample had a previous abortion. Almost half of the women lived with a partner and used low efficacy contraceptive methods. Most were exposed to HIV through sexual contact, and one woman was exposed by vertical transmission. At initial consultation, 61.4% reported a HIV infection diagnosis of less than 2 years, 24% had already been diagnosed with an opportunistic disease, 62.9% had a viral load ≥ 50 copies/mL, 45.8% CD4 nadir < 200 cells/m³, and 41.8% did not use antiretroviral therapy (Table 1).

We recorded 225 pregnancies in total, 31 at the initial visit and 194 at follow-up. We observed a significant reduced proportion of women who joined the cohort while pregnant: 11.2% in the first period to less than 3% in subsequent periods (p < 0.01). Of the 178 women who had a pregnancy, 20% were repeat pregnancies (5% with 3 or more pregnancies). Delivery (68%) was the most frequent pregnancy outcome, with 16.9% vaginal deliveries and 48.9% cesarean sections. We recorded 71 early fetal losses (12.4% spontaneous abortion, 14.7% induced abortion, 4.4% ectopic pregnancy). We found no significant differences in pregnancy outcomes during the analyzed periods (Table 2). Ectopic pregnancies increased in 2006-2010, reaching 8.5% of the total outcomes. Half of the ectopic pregnancies were repeat pregnancies, occurring in only two women. Delivery by cesarean section increased in 2000-2006, with subsequent stabilization in the periods 2006-2010 and 2011-2016. Performance of tubal ligation surgery at the time of delivery showed a significant reduction during the analysis period (Table 2).

The 194 pregnancies observed during follow-up were recorded among 4,841,149 person-years, resulting in a pregnancy incidence rate of 4.01/100 person-years (95% confidence interval - 95%CI: 3.47; 4.60). We found a non-significant difference in the pregnancy incidence rate between the periods 1996-2000 (6.59) and 2001-2005 (3.11, p = 0.342), but a significant reduction to 2.17 in 2006-2010 (p = 0.018) and to 1.49 in 2011-2016 (p = 0.027). The main factors associated with a higher pregnancy incidence rate were CD4 nadir ≥ 350, use of an ARV regimen without Efavirenz, and adolescent pregnancy. Women ≥ 35 years old, with two or more children, who had a viral load ≥ 50 copies/mL, and used a highly effective contraceptive method showed a lower incidence rate (Table 3).

Discussion

Results of this study, which evaluated a WLWHA cohort followed at the largest service for HIV/AIDS care and prevention in Rio de Janeiro, over 20 years (1996-2016), show a pregnancy incidence of 4.01/100 person-years, with a significant reduction after 2006.

Studies conducted from 1996 to 2016 ⁴4. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.^,66. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,1818. Choi H, Kim MH, Lee SJ, Kim EJ, Lee W, Jeong W, et al. Pregnancy rates and outcomes of HIV-infected women in Korea. J Korean Med Sci 2018; 33:e296.^,1919. Burgos-Soto J, Balestre E, Minga A, Ajayi S, Sawadogo A, Zannou MD, et al. Incidence of pregnancy after antiretroviral therapy initiation and associated factors in 8 West African countries. J Acquir Immune Defic Syndr 2014; 67:e45-54.^,2020. Poda A, Hema A, Konaté A, Kaboré F, Zoungrana J, Kamboulé E, et al. Pregnancy rate and birth outcomes among women receiving antiretroviral therapy in Burkina Faso: a retrospective cohort study. Pan Afr Med J 2016; 23:105.^,2121. Lancaster KE, Kwok C, Rinaldi A, Byamugisha J, Magwali T, Nyamapfeni P, et al. Incident pregnancy and pregnancy outcomes among HIV-infected women in Uganda and Zimbabwe. Int J Gynaecol Obstet 2015; 131:255-9. reported pregnancy incidence ranging from 2.9 per 100 person-years ¹⁹19. Burgos-Soto J, Balestre E, Minga A, Ajayi S, Sawadogo A, Zannou MD, et al. Incidence of pregnancy after antiretroviral therapy initiation and associated factors in 8 West African countries. J Acquir Immune Defic Syndr 2014; 67:e45-54. to 10.1/100 person-years ²¹21. Lancaster KE, Kwok C, Rinaldi A, Byamugisha J, Magwali T, Nyamapfeni P, et al. Incident pregnancy and pregnancy outcomes among HIV-infected women in Uganda and Zimbabwe. Int J Gynaecol Obstet 2015; 131:255-9.. Contrary to our findings, Haddad et al. ⁶6. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16., in a study conducted in 9 U.S. centers, reported a non-significant increase in pregnancy incidence in WLWHA and a significant increase in live births (from 2.85 to 7.27/100 person-years) in the periods 1994-1997 to 2006-2012, with similar values in WLWHA and in women not living with HIV/AIDS (WNLWHA) in more recent periods. Studies in Canada ⁷7. Salters K, Loutfy M, de Pokomandy A, Money D, Pick N, Wang L, et al. Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada. PLoS One 2017; 12:e0180524. and Europe ²²22. Kowalska JD, Pelchen-Matthews A, Ryom L, Losso MH, Trofimova T, Mitsura VM, et al. Prevalence and outcomes of pregnancies in women with HIV over a 20-year period. AIDS 2021; 35:2025-33. also report an increased number of pregnancies in WLWHA after the years 2000-2002. One study in Burkina-Faso ²⁰20. Poda A, Hema A, Konaté A, Kaboré F, Zoungrana J, Kamboulé E, et al. Pregnancy rate and birth outcomes among women receiving antiretroviral therapy in Burkina Faso: a retrospective cohort study. Pan Afr Med J 2016; 23:105. showed an increase in pregnancy incidence in women using ART for longer periods. Moreover, United Kingdom and Ireland ²³23. French CE, Cortina-Borja M, Thorne C, Tookey PA. Incidence, patterns, and predictors of repeat pregnancies among HIV-infected women in the United Kingdom and Ireland, 1990-2009. J Acquir Immune Defic Syndr 2012; 59:287-93. reported an increase in repeat pregnancies and an increase in repeat pregnancies in women on ART was observed in Latin America and the Caribbean ²⁴24. Kreitchmann R, Megazzini K, Melo VH, Fernandes Coelho D, Watts DH, Krauss M, et al. Repeat pregnancy in women with HIV infection in Latin America and the Caribbean. AIDS Care 2015; 27:1289-97..

Although we did not assess pregnancy incidence in WNLWHA, to verify whether this outcome would differ between these groups of women, the fertility rates of Brazilian women faced a significant decrease, especially after the 2000s, reaching an average of 1.7 children per woman in 2010-2015 ²⁵25. Fundo de População das Nações Unidas. Fecundidade e dinâmica da população brasileira. https://brazil.unfpa.org/pt-br/publications/fecundidade-e-dinamica-da-populacao-brasileira-folder (accessed on 07/Jul/2022).
https://brazil.unfpa.org/pt-br/publicati... . The significant reduction in pregnancy incidence observed after 2006 may simply mirror the fertility pattern of the country, with a marked reduction in the South and Southeast regions, where our service is located.

The rate of repeated pregnancies observed was intermediate between that reported by French et al. ²³23. French CE, Cortina-Borja M, Thorne C, Tookey PA. Incidence, patterns, and predictors of repeat pregnancies among HIV-infected women in the United Kingdom and Ireland, 1990-2009. J Acquir Immune Defic Syndr 2012; 59:287-93., in a U.K. study conducted in 1990-2009 (25.9%), and that reported by Floridia et al. ²⁶26. Floridia M, Tamburrini E, Masuelli G, Martinelli P, Spinillo A, Liuzzi G, et al. Rate, correlates and outcomes of repeat pregnancy in HIV-infected women. HIV Med 2017; 18:440-3., in Italy, in the period 2011-2016 (16%). In the latter, women with repeated pregnancies presented more negative outcomes in the first pregnancy than those who did not have a repeat pregnancy. Similarly, we observed that 50% of ectopic pregnancies occurred in only two women, in repeat pregnancies.

Although data on reproductive planning and intention to become pregnant were not available for analysis, the lower pregnancy incidence observed in women who used more effective contraceptive methods and in women with unfavorable viral infection control parameters, such as viral load ≥ 50 copies/mL and nadir of CD4 < 200 cells/mm³, suggest planned pregnancies, considering the reproductive intention and clinical condition of each woman. The higher rate of pregnancies in women taking ART without Efavirenz supports this hypothesis, suggesting the lower prescription of ART regimens with this drug for women who expressed the intention of becoming pregnant, since efavirenz can cause neurological defects in the newborn.

We observed a higher proportion of pregnant women at the initial consultation in the first follow-up period (1996-2000). Information about the time of diagnosis of the infection, whether it occurred during pregnancy or before, is unavailable, and our hypotesis for the higher proportion of pregnant women in the period 1996-2000 is HIV infection diagnosis during prenatal care. Although Brazil had restricted access to serological HIV testing in the late 1990s, the Brazilian Ministry of Health’s guidelines recommended offering HIV testing to all pregnant women during prenatal care since the 1990s. Thus, in a context of limited HIV testing, prenatal care became an opportunity for performing HIV infection diagnosis.

Limited access to testing also explains the late HIV infection diagnosis during the first periods of our cohort: a quarter of the women already had a diagnosis of opportunistic disease when joining and almost 50% had a CD4 nadir below 200 cells/mm³. An analysis including the total number of WLWHA assisted at the INI/Fiocruz cohort identified improved parameters related to HIV infection - such as higher CD4 counts, lower viral load and use of antiretroviral therapy - in more recent years of entry, which the authors attribute to successful national HIV/AIDS control policies ²⁷27. Zachek CM, Coelho LE, Domingues RMSM, Clark JL, De Boni RB, Luz PM, et al. The intersection of HIV, social vulnerability, and reproductive health: analysis of women living with HIV in Rio de Janeiro, Brazil from 1996 to 2016. AIDS Behav 2019; 23:1541-51..

Similar to other studies, the factors associated with pregnancy incidence were related both to sociodemographic characteristics, such as age ¹1. Kline A, Strickler J, Kempf J. Factors associated with pregnancy and pregnancy resolution in HIV seropositive women. Soc Sci Med 1995; 40:1539-47.^,22. Van Benthem BH, de Vincenzi I, Delmas MC, Larsen C, van den Hoek A, Prins M. Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women. AIDS 2000; 14:2171-8.^,44. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.^,66. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,2222. Kowalska JD, Pelchen-Matthews A, Ryom L, Losso MH, Trofimova T, Mitsura VM, et al. Prevalence and outcomes of pregnancies in women with HIV over a 20-year period. AIDS 2021; 35:2025-33.^,2828. Sharma A, Feldman JG, Golub ET, Schmidt J, Silver S, Robison E, et al. Live birth patterns among human immunodeficiency virus-infected women before and after the availability of highly active antiretroviral therapy. Am J Obstet Gynecol 2007; 196:541.e1-6.^,2929. Bedimo AL, Bessinger R, Kissinger P. Reproductive choices among HIV-positive women. Soc Sci Med 1998; 46:171-9.^,3030. Linas BS, Minkoff H, Cohen MH, Karim R, Coham D, Wright RL, et al. Relative time to pregnancy among HIV-infected and uninfected women in the Women's Interagency HIV Study, 2002-2009. AIDS 2011; 25:707-11., number of children ¹1. Kline A, Strickler J, Kempf J. Factors associated with pregnancy and pregnancy resolution in HIV seropositive women. Soc Sci Med 1995; 40:1539-47., and use of contraceptive methods ⁶6. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16., and to HIV infection characteristic, such as CD4 nadir ²2. Van Benthem BH, de Vincenzi I, Delmas MC, Larsen C, van den Hoek A, Prins M. Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women. AIDS 2000; 14:2171-8.^,66. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,2222. Kowalska JD, Pelchen-Matthews A, Ryom L, Losso MH, Trofimova T, Mitsura VM, et al. Prevalence and outcomes of pregnancies in women with HIV over a 20-year period. AIDS 2021; 35:2025-33.^,2929. Bedimo AL, Bessinger R, Kissinger P. Reproductive choices among HIV-positive women. Soc Sci Med 1998; 46:171-9., viral load ⁴4. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6., and use of ART medication ⁴4. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.^,77. Salters K, Loutfy M, de Pokomandy A, Money D, Pick N, Wang L, et al. Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada. PLoS One 2017; 12:e0180524.^,3131. Johnson LF, Mutemaringa T, Heekes A, Boulle A. Effect of HIV infection and antiretroviral treatment on pregnancy rates in the Western Cape Province of South Africa. J Infect Dis 2020; 221:1953-62.. These findings are in line with previous studies with WLWHA, which reveal that reproductive decisions are complex and not solely determined by HIV infection aspects ¹1. Kline A, Strickler J, Kempf J. Factors associated with pregnancy and pregnancy resolution in HIV seropositive women. Soc Sci Med 1995; 40:1539-47.^,66. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,3232. MacCarthy S, Rasanathan JJ, Crawford-Roberts A, Dourado I, Gruskin S. Contemplating abortion: HIV-positive women's decision to terminate pregnancy. Cult Health Sex 2014; 16:190-201..

The higher incidence of pregnancies in women with a history of adolescent pregnancy is consistent with the fertility profile observed in Brazil. Although the total fertility rate is decreasing, fertility in youth under 20 years of age remains high, especially among groups with lower income and schooling, reaching a maximum value in the 20-24 age group. Rather than expressing a desire to have children at this age, this high fertility results from the lack of access to reproductive health services and contraceptive methods ²⁵25. Fundo de População das Nações Unidas. Fecundidade e dinâmica da população brasileira. https://brazil.unfpa.org/pt-br/publications/fecundidade-e-dinamica-da-populacao-brasileira-folder (accessed on 07/Jul/2022).
https://brazil.unfpa.org/pt-br/publicati... . Early pregnancy can limit achieving a higher educational level and entering and remaining in the labor market, turning motherhood into a strategy of social recognition or even a possible life project in a society with limited possibilities ³³33. Menezes G, Aquino EML, Silva D. Induced abortion during youth: social inequalities in the outcome of the first pregnancy. Cad Saúde Pública 2006; 22:1431-46.^,3434. Singh S, Darroch JE, Frost JJ. Socioeconomic disadvantage and adolescent women's sexual and reproductive behavior: the case of five developed countries. Fam Plann Perspect 2003; 33:251-8.. Adolescent pregnancy also affects other Latin American countries, where 20% of births is by adolescent mothers. Reducing adolescent fertility is one of the Pan-American Health Organization’s (PAHO) goals for sustainable development in the period 2018-2030 ³⁵35. Organização Pan-Americana da Saúde. Agenda de Saúde Sustentável para as Américas 2018-2030: um chamado à ação para a saúde e o bem estar na região. https://iris.paho.org/bitstream/handle/10665.2/49172/CSP296-por.pdf?sequence=1&isAllowed=y (accessed on 12/Oct/2022).
https://iris.paho.org/bitstream/handle/1... .

The ectopic pregnancy prevalence observed was higher than that reported by Stringer et al. ³⁶36. Stringer EM, Kendall MA, Lockman S, Campbell TB, Nielsen-Saines K, Sawe F, et al. Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy. PLoS One 2018; 13:e0199555. in Africa (1%), but similar to that observed by research in China (3.4%) ³⁷37. Wu M, Yan Y, Zou S, Wu S, Feng L, Liy Y, et al. Adverse pregnancy outcomes among pregnant women living with HIV in Hubei province, China: prevalence and risk factors. AIDS Care 2023; 35:351-8. and the U.S.A. (5%) ⁴4. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.. We found a proportion of induced abortions lower than that reported by other studies ²2. Van Benthem BH, de Vincenzi I, Delmas MC, Larsen C, van den Hoek A, Prins M. Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women. AIDS 2000; 14:2171-8.^,33. Bongain A, Berrebi A, Mariné-Barjoan E, Dunais B, Thene M, Pradier C, et al. Changing trends in pregnancy outcome among HIV-infected women between 1985 and 1997 in two southern French university hospitals. Eur J Obstet Gynecol Reprod Biol 2002; 104:124-8.^,44. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.^,66. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16.^,77. Salters K, Loutfy M, de Pokomandy A, Money D, Pick N, Wang L, et al. Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada. PLoS One 2017; 12:e0180524.^,2222. Kowalska JD, Pelchen-Matthews A, Ryom L, Losso MH, Trofimova T, Mitsura VM, et al. Prevalence and outcomes of pregnancies in women with HIV over a 20-year period. AIDS 2021; 35:2025-33.^,2929. Bedimo AL, Bessinger R, Kissinger P. Reproductive choices among HIV-positive women. Soc Sci Med 1998; 46:171-9. and without a significant reduction in the 20-year period analyzed. Studies conducted in the U.S. and in European countries report a significant reduction in the frequency of induced abortions with the advancement of ART ²2. Van Benthem BH, de Vincenzi I, Delmas MC, Larsen C, van den Hoek A, Prins M. Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women. AIDS 2000; 14:2171-8.^,33. Bongain A, Berrebi A, Mariné-Barjoan E, Dunais B, Thene M, Pradier C, et al. Changing trends in pregnancy outcome among HIV-infected women between 1985 and 1997 in two southern French university hospitals. Eur J Obstet Gynecol Reprod Biol 2002; 104:124-8.^,44. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281-6.^,55. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Trends in management and outcome of pregnancies in HIV-infected women in the UK and Ireland, 1990-2006. BJOG 2008; 115:1078-86.. However, a U.S. study with a WLWHA cohort found no evidence of a reduction in induced abortions or its association with aspects related to infection control, indicating the need for greater integration with contraception services ⁶6. Haddad LB, Wall KM, Mehta CC, Golub ET, Rahangdale L, Kempf MC, et al. Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women. Am J Obstet Gynecol 2017; 216:71.e1-71.e16..

The increased proportion of cesarean sections from 2001 to 2005 is consistent with existing recommendations at the time of performing cesarean section to reduce the mother-to-child transmission rate ³⁸38. International Perinatal HIV Group; Andiman W, Bryson Y, Martino M, Fowler M, Harris D, et al. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1 - a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999; 340:977-87^,3939. Halpern MT, Read JS, Ganoczy DA, Harris DR. Cost-effectiveness of cesarean section delivery to prevent mother-to-child transmission of HIV-1. AIDS 2000; 14:691-700.. Later studies, however, started recommending elective cesarean section only for women with high viral load after the 34th gestational week ⁴⁰40. Briand N, Jasseron C, Sibiude J, Azria E, Pollet J, Hammou Y, et al. Cesarean section for HIV-infected women in the combination antiretroviral therapies era, 2000-2010. Am J Obstet Gynecol 2013; 209:335.e1-e12.^,4141. Kennedy C, Yeh PT, Pandey S, Betran AP, Narasimhan M. Elective cesarean section for women living with HIV: a systematic review of risks and benefits. AIDS 2017; 31:1579-91.. Such recommendation was not followed by a reduction in the cesarean section rate in more recent periods of our cohort, which remained stable and above 70%. In the U.K., the highest cesarean section rates in WLWHA were observed in 1999, with a significant increase in vaginal deliveries in the period 1999-2006 ⁵5. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Trends in management and outcome of pregnancies in HIV-infected women in the UK and Ireland, 1990-2006. BJOG 2008; 115:1078-86.. Similarly, France saw an increase from 25% in 2000 to 53% in 2010 in the rate of vaginal births in WLWHA ⁴⁰40. Briand N, Jasseron C, Sibiude J, Azria E, Pollet J, Hammou Y, et al. Cesarean section for HIV-infected women in the combination antiretroviral therapies era, 2000-2010. Am J Obstet Gynecol 2013; 209:335.e1-e12.. Brazil is one of the countries with the highest cesarean rate worldwide, largely determined by non-clinical factors ⁴²42. Nakamura-Pereira M, do Carmo Leal M, Esteves-Pereira AP, Domingues RM, Torres JA, Dias MA, et al. Use of Robson classification to assess cesarean section rate in Brazil: the role of source of payment for childbirth. Reprod Health 2016; 13 Suppl 3:128.. The high cesarean section rate observed in this WLWHA cohort may reflect the existing care model, with great flexibility in indicating cesarean sections or even little familiarity with the most recent guidelines on the best mode of delivery for WLWHA. Difficulty in accessing viral load tests may be another explanation. A national, hospital-based study conducted in 2011-2012 showed that 45% of pregnant WLWHA had an undiagnosed viral load at delivery ¹³13. Domingues RMSM, Saraceni V, Leal MDC. Mother to child transmission of HIV in Brazil: data from the "Birth in Brazil study", a national hospital-based study. PLoS One 2018; 13:e0192985..

We observed a significant reduction in the proportion of tubal ligation surgery performed during follow-up in the cohort, from 53.8% to 20%, a trend also observed countrywide. Brazil saw a reduction in female sterilization among married women (aged 15-44 years) from 38.5% to 25.9% in the period 1996-2006 ⁴³43. Centro Brasileiro de Análise e Planejamento, Ministério da Saúde. Pesquisa Nacional de Demografia e Saúde da Criança e da Mulher - PNDS 2006: dimensões do processo reprodutivo e da saúde da criança. Brasília: Ministério da Saúde; 2009. (Série G. Estatística e Informação em Saúde).. Sterilization had become the second most frequent contraceptive method in the country, although mostly used by women with lower education and from lower economic classes. In the 2013 Brazilian National Health Survey, 25.9% of sexually active women aged 18-49 years reported using surgical methods (male and female), especially women with less education and no health insurance ⁴⁴44. Trindade RE, Siqueira BB, Paula TF, Felisbino-Mendes MS. Contraception use and family planning inequalities among Brazilian women. Ciênc Saúde Colet 2021; 26 Suppl 2:3493-504..

Despite the decline in female sterilization in this group, WLWHA still have certain reproductive health needs unmet ⁸8. Gómez-Suárez M, Mello MB, Gonzalez MA, Ghidinelli M, Pérez F. Access to sexual and reproductive health services for women living with HIV in Latin America and the Caribbean: systematic review of the literature. J Int AIDS Soc 2019; 22:e25273.^,4545. MacCarthy S, Rasanathan JJK, Ferguson L, Gruskin S. The pregnancy decisions of HIV-positive women: the state of knowledge and way forward. Reprod Health Matters 2012; 20(39 Suppl):119-40., including reports of coercive sterilization ⁴⁵45. MacCarthy S, Rasanathan JJK, Ferguson L, Gruskin S. The pregnancy decisions of HIV-positive women: the state of knowledge and way forward. Reprod Health Matters 2012; 20(39 Suppl):119-40.^,4646. Kendall T, Albert C. Experiences of coercion to sterilize and forced sterilization among women living with HIV in Latin America. J Int AIDS Soc 2015; 18:19462., frequently at childbirth ⁸8. Gómez-Suárez M, Mello MB, Gonzalez MA, Ghidinelli M, Pérez F. Access to sexual and reproductive health services for women living with HIV in Latin America and the Caribbean: systematic review of the literature. J Int AIDS Soc 2019; 22:e25273.^,4646. Kendall T, Albert C. Experiences of coercion to sterilize and forced sterilization among women living with HIV in Latin America. J Int AIDS Soc 2015; 18:19462.^,4747. Oliveira F, Kerr L, Frota A, Nóbrega A, Bruno Z, Leitão T, et al. HIV-positive women in northeast Brazil: tubal sterilization, medical recommendation and reproductive rights. AIDS Care 2007; 19:1258-65.^,4848. Barbosa RM, Cabral CS, Lago TG, Pinho AA. Differences in the Access to Sterilization between Women Living and Not Living with HIV: results from the GENIH Study, Brazil. PLoS One 2016; 11:e0164887., and a high rate of regret ⁴⁹49. Raziano VT, Smoots AN, Haddad LB, Wall KM. Factors associated with sterilization among HIV-positive US women in an urban outpatient clinic. AIDS Care 2017; 29:612-7.^,5050. Badell ML, Lathrop E, Haddad LB, Goedken P, Nguyen ML, Cwiak CA. Reproductive healthcare needs and desires in a cohort of HIV-positive women. Infect Dis Obstet Gynecol 2012; 2012:107878.. A study comparing WLWHA and WNLWHA in the state of São Paulo, in 2013-2014, found no difference in the risk of sterilization between the two groups after adjusting for schooling, race/ethnicity and number of children, but observed a higher probability of sterilization of WLWHA at the time of delivery ⁴⁸48. Barbosa RM, Cabral CS, Lago TG, Pinho AA. Differences in the Access to Sterilization between Women Living and Not Living with HIV: results from the GENIH Study, Brazil. PLoS One 2016; 11:e0164887.. A U.S. study with WLWHA found a low preference (3%) for sterilization in the post-HAART era, associated with a reduction in the mother-to-child transmission rate ⁵¹51. Ezeanolue EE, Stumpf PG, Soliman E, Fernandez G, Jack I. Contraception choices in a cohort of HIV+ women in the era of highly active antiretroviral therapy. Contraception 2011; 84:94-7.. Integrating sexual and reproductive health services and HIV services ⁵²52. Milford C, Beksinska M, Greener R, Pienaar J, Greener LR, Mabude Z, et al. Fertility desires of people living with HIV: does the implementation of a sexual and reproductive health and HIV integration model change healthcare providers' attitudes and clients' desires? BMC Health Serv Res 2021; 21:509., removing institutional and structural barriers, and reducing stigma and discrimination are essential to free WLWHA’s reproductive choices from violence and coercion ⁸8. Gómez-Suárez M, Mello MB, Gonzalez MA, Ghidinelli M, Pérez F. Access to sexual and reproductive health services for women living with HIV in Latin America and the Caribbean: systematic review of the literature. J Int AIDS Soc 2019; 22:e25273.^,4646. Kendall T, Albert C. Experiences of coercion to sterilize and forced sterilization among women living with HIV in Latin America. J Int AIDS Soc 2015; 18:19462..

Some limitations must be highlighted. As pregnant women are not followed-up at INI/Fiocruz, information on perinatal outcome and mother-to-child transmission rate is unavailable. Besides, we had loss of information about the outcome in 6 (2.7%) participants. Absence of data on the intention to become pregnant, adequacy of method use, marital status at the time of pregnancy, and partner and family support limited assessing these factors. Finally, we were unable to assess the use of Dolutegravir (DTG) and its effect on pregnancy outcomes because DTG implementation became a 1st-line regimen in Brazil only in 2017 ⁵³53. Pereira GFM, Kim A, Jalil EM, Fonseca FF, Shepherd BE, Veloso VG, et al. National Cohort Study of Dolutegravir and Pregnancy Outcomes in Brazil. Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study. Lancet HIV 2021; 8:e33-e41..

Conclusion

We observed a significant reduction in pregnancy incidence in WLWHA after 2006, with a high rate of cesarean sections and a reduction in female sterilization. The association between pregnancy incidence and use of contraceptive methods and virological control markers suggests good integration between HIV/AIDS care services and sexual and reproductive health services. Conversely, the high rate of cesarean section delivery indicates the need to improve childbirth care.

References

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History