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Objective World Health Organization recommends promoting breastfeeding without restricting its duration among HIV-positive women on lifelong antiretroviral treatment (ART). There is little data on breastfeeding duration and mother to child transmission (MTCT) beyond 24 months. We compared the duration of breastfeeding in HIV-exposed and HIV-unexposed children and we identified factors associated with postpartum-MTCT in a semi-rural population of Mozambique. Methods This cross-sectional assessment was conducted from October-2017 to April-2018. Mothers who had given birth within the previous 48-months in the Manhiça district were randomly selected to be surveyed and to receive an HIV-test along with their children. Postpartum MTCT was defined as children with an initial HIV positive result beyond 6 weeks of life who initiated breastfeeding if they had a first negative PCR result during the first 6 weeks of life or whose mother had an estimated date of infection after the child’s birth. Cumulative incidence accounting for right-censoring was used to compare breastfeeding duration in HIV-exposed and unexposed children. Fine-Gray regression was used to assess factors associated with postpartum-MTCT. Results Among the 5000 mother-child pairs selected, 69.7% (3486/5000) were located and enrolled. Among those, 27.7% (967/3486) children were HIV-exposed, 62.2% (2169/3486) were HIV-unexposed and for 10.0% (350/3486) HIV-exposure was unknown. Median duration of breastfeeding was 13.0 (95%CI:12.0–14.0) and 20.0 (95%CI:19.0–20.0) months among HIV-exposed and HIV-unexposed children, respectively (p<0.001). Of the 967 HIV-exposed children, 5.3% (51/967) were HIV-positive at the time of the survey. We estimated that 27.5% (14/51) of the MTCT occurred during pregnancy and delivery, 49.0% (2551) postpartum-MTCT and the period of MTCT remained unknown for 23.5% (12/51) of children. In multivariable analysis, mothers’ ART initiation after the date of childbirth was associated (aSHR:9.39 [95%CI:1.75–50.31], p = 0.001), however breastfeeding duration was not associated with postpartum-MTCT (aSHR:0.99 [95%CI:0.96–1.03], p = 0.707). Conclusion The risk for postpartum MTCT was nearly tenfold higher in women newly diagnosed and/or initiating ART postpartum. This highlights the importance of sustained HIV screening and prompt ART initiation in postpartum women in Sub-Saharan African countries. Under conditions where HIV-exposed infants born to mothers on ART receive adequate PMTCT, extending breastfeeding duration may be recommended.
The study was conducted within the Health and Demographic Surveillance System (HDSS) run by the Manhiça Research Health Center since 1996, which is located in Maputo Province, southern Mozambique [25]. The HDSS platform currently extends over the entire district of Manhiça, which has an area of 2,380 square kilometers and covers 46,441 households and 201,383 inhabitants, each one with a unique identification number. Every household is visited twice a year to collect data on vital events such as births, deaths, pregnancies and migrations [25]. Verbal autopsies are used to attribute a cause of death to all recorded death events, including those that occurred in the community, in accordance with WHO Verbal Autopsies Instrument Form 2016 [26]. The Manhiça District is served by fifteen health centers, one rural hospital and one referral district hospital. All public health facilities offer free access to HIV care and treatment. Routine patient-level HIV clinical data is recorded by providers in a paper-based system and prospectively entered into an electronic patient tracking system. At the time of the study, the B+ strategy was already implemented in all the health facilities which provided free ART to HIV-positive pregnant or breastfeeding mothers and 6 week Nevirapine prophylaxis for HIV-exposed children, regardless of both the feeding method and whether the mother’s diagnosis and ART initiation occurred during pregnancy or breastfeeding period [21, 27]. The ART regimen that most pregnant and lactating women received during the time period of this study was Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz (TDF+3TC+EFV) [21, 27]. Between October 2017 and April 2018, 5000 of the total children born alive in the previous 48 months within the HDSS were randomly selected to participate in this cross-sectional household survey. After informed consent was obtained, the survey was conducted with mothers, or in case of a mother’s absence, migration or death, with the child’s primary caregiver. Study HIV counselors administered a specific questionnaire designed to capture sociodemographic characteristics, HIV testing history and ART, antenatal care and duration of breastfeeding. For each individual mother and child, HIV-status was ascertained through documentation of previous testing, conducting age-appropriate testing with laboratory confirmation or verbal autopsy. Mothers who do not know their status or self-report being HIV-negative were tested at survey, as well as the HIV-exposed children. For children under 18 months of age, HIV diagnosis was determined with molecular testing through HIV DNA Polymerase Chain Reaction (PCR). Children 18 months or older and mothers were tested following the National HIV testing algorithm [21] which included two serial rapid diagnostic tests, Determine [28] and Unigold [29]. Documented known HIV-positive individuals were not re-tested, however for study purposes, all HIV positive participants (including those who were diagnosed prior to or during the study visit) underwent confirmatory testing through Geenius HIV-1/2 Confirmatory Assay [30]. Clinical documentation was also used to obtain information about gestational age and infant antiretroviral prophylaxis. Verbal autopsy from HDSS database was used to ascertain HIV status in children and mothers who had died before the survey. Hospitalizations and outpatients’ visits were also obtained through the HDSS database. Information about maternal viral load and CD4 was extracted from the routinely collected data in the electronic patient tracking system, a Microsoft access database [31] co-managed by the Ministry of Health and other stakeholders, where each participant living with HIV had a unique numeric identifier that allows follow-up through the continuum of care [32]. HIV exposure was defined as follows: i) a child whose mother had a documented HIV-infection before birth or at the end of breastfeeding (confirmed exposure) and ii) a child born to a self-reported HIV-positive mother for whom the time of the mother’s infection could not be determined (probable exposure). Children born from HIV negative mothers were considered HIV-unexposed. If the mother was deceased and her HIV-status could not be confirmed, the child´s exposure was considered unknown and were excluded from the analysis. Date of HIV infection in the mother was estimated as follows: MTCT was assumed to occur during pregnancy and delivery if the child had a positive PCR result during the first 6 weeks of life [15, 33, 34]. Postpartum MTCT was defined for children with an initial HIV positive result beyond 6 weeks of life who initiated breastfeeding if 1) they had a first negative PCR during the first 6 weeks of life, or 2) did not have a prior negative PCR but whose mother had an estimated date of infection after the child’s birth. For children born to mothers with date of infection prior to child’s birth but without a DNA PCR by 6 weeks of age, the date of MTCT was considered unknown. Breastfeeding included any type of breastfeeding (exclusive, mixed and any breastfeeding after the introduction of complementary feeding) since birth. The mother or caregiver self-reported the total duration of any breastfeeding in months at the time of survey. Medians and interquartile ranges (IQR) were calculated to describe continuous variables and categorical variables were summarized using frequencies and its 95% confidence intervals. Comparisons between groups were made using Pearson chi-square or Fisher exact test and Kruskal Wallis tests, as applicable. In addition, we performed two analyses: First, we estimated breastfeeding duration in HIV-exposed and HIV-unexposed children with cumulative incidence of breastfeeding cessation, accounting for right censoring. Children who had not initiated breastfeeding were excluded from this analysis. HIV-exposure was evaluated as a factor associated with breastfeeding duration through Fine-Gray regression, using mortality as competing risk and adjusted for age and sex in a multivariable model. Second, among HIV-exposed children who had been breastfed at any time, we performed a Fine-Gray regression analysis to assess factors associated with postpartum MTCT, adjusting for age and sex and considering mortality a competing risk factor. Infants with MTCT during pregnancy and delivery and children in which it was not possible to establish whether MTCT was during pregnancy and delivery or postpartum were excluded from this analysis. A multivariable model was built including the variables with a p-value lower than 0.20 in the bivariate analysis and with less than 20% missing values. Time-varying covariates were handled by episode splitting. Variables age of the child, sex of the child, mother ART initiation and breastfeeding duration were forced-in covariates due to their clinical relevance. The variable ‘mother ART initiation’ was treated as a binary variable: ART initiation before delivery yes/no, and had more than 20% missing values. The missing data was addressed through multiple imputation using a logistic regression imputation method including our outcome variable and the other predictor variables. A total of 20 imputations were performed. Data was analyzed using Stata statistical software version 16 (Stata Corp., College Station, Texas, USA) [35]. We conducted a sensitivity analysis considering the time of infection of the mother as random date selected from a uniform distribution, a point at the quarter of the interval between the two dates considered at definition and a point at the three-quarters of the interval between the two dates specified above in definitions section. We conduct another two sensitivity analysis considering the 61 children HIV-exposed with unknown HIV serostatus as HIV-positive and the 12 children HIV-positive with no information on time of HIV acquisition as postpartum MTCT, respectively. This study was approved by the Mozambican National Bioethics Committee and the Barcelona Hospital Clinic Institutional Review Board. It was also reviewed in accordance with CDC human research protection procedures and was determined to be research, but CDC investigators did not interact with human subjects or have access to identifiable data or specimens for research purposes. Written informed consent was obtained from the mothers/caregivers of all children for the mothers/caregiver and children participation. In case of mothers between 14–16 years old, informed consent was provided by the legal representative of the young mother, after the mother’s consent.
