Different factors associated with loss to follow-up of infants born to HIV-infected or uninfected mothers: Observations from the ANRS 12140-PEDIACAM study in Cameroon

Background: Loss to follow-up (LTFU) is a cause of potential bias in clinical studies. Differing LTFU between study groups may affect internal validity and generalizability of the results. Understanding reasons for LTFU could help improve follow-up in clinical studies and thereby contribute to goals for prevention, treatment, or research being achieved. We explored factors associated with LTFU of mother-child pairs after inclusion in the ANRS 12140-Pediacam study. Methods: From November 2007 to October 2010, 4104 infants including 2053 born to HIV-infected mothers and 2051 born to HIV-uninfected mothers matched individually on gender and study site were enrolled during the first week of life in three referral hospitals in Cameroon and scheduled for visits at 6, 10 and 14 weeks of age. Visits were designated 1, 2 and 3, in chronological order, irrespective of the child’s age at the time of the visit. Mother-child pairs were considered lost to follow-up if they never returned for a clinical visit within the first six months after inclusion. Uni- and multivariable logistic regression were adjusted on matching variables to identify factors associated with LTFU according to maternal HIV status. Results: LTFU among HIV-unexposed infants was four times higher than among HIV-exposed infants (36.7% vs 9.8%, p∈<∈0.001). Emergency caesarean section (adjusted Odds Ratio (aOR)∈=∈2.46 95% Confidence Interval (CI) [1.47-4.13]), young maternal age (aOR∈=∈2.29, 95% CI [1.18-4.46]), and absence of antiretroviral treatment for prophylaxis (aOR∈=∈3.45, 95% CI [2.30-5.19]) were independently associated with LTFU among HIV-exposed infants. Factors associated with LTFU among HIV-unexposed infants included young maternal age (aOR∈=∈1.96, 95% CI [1.36-2.81]), low maternal education level (aOR∈=∈2.77, 95% CI [1.95-3.95]) and housewife/unemployed mothers (aOR∈=∈1.56, 95% CI [1.16-2.11]). Conclusion: Failure to return for at least one scheduled clinical visit is a problem especially among HIV-unexposed infants included in studies involving HIV-exposed infants. Factors associated with this type of LTFU included maternal characteristics, socio-economic status, quality of antenatal care and obstetrical context of delivery. Enhanced counselling in antenatal and intrapartum services is required for mothers at high risk of failure to return for follow-up visits. Data used in this analysis were obtained from the ANRS-Pediacam cohort based in three referral hospitals in Cameroon (The Maternity of the Central hospital/Mother and Child Center of the Chantal Biya Foundation (MCH/MCC-CBF), Essos Hospital Center in Yaoundé (EHC) and the Laquintinie Hospital in Douala (LH)) and coordinated by the Centre Pasteur of Cameroon. The ANRS 12140-Pediacam study was designed to assess the feasibility of early diagnosis of HIV and early antiretroviral multitherapy in HIV-infected infants, and to evaluate the humoral response of these children to vaccines of the Expanded Program on Immunization (EPI). The ANRS 12140-Pediacam is an ongoing prospective cohort study involving two consecutive phases. The first phase of the study included all infants born live to HIV-infected mothers with documented serostatus (group 1) identified before the 8th day of life from November 2007 to October 2010 and an equivalent number of infants born to HIV-uninfected mothers matched individually on gender and recruitment site. All newborns were expected to attend a clinical visit, according to the Cameroon National EPI calendar, at ages 6, 10 and 14 weeks for routine vaccination. Infant follow-up in the first phase was scheduled to coincide with this EPI timetable to minimise the number of visits to the hospital required. However, visits (follow-up visits) are designated hereafter as the first, second and third, independent of the age of the child. Samples for HIV virological testing were collected from HIV-exposed infants at the first follow-up visit (scheduled for 6 weeks), as previously described [13,14]. HIV test results were provided at the second visit (scheduled for 10 weeks). During the second visit, all parents/caregivers who received a negative result for their infants were counselled about how to avoid practises favouring HIV transmission to their infant. For breastfed infants whose first HIV test was negative were retested if they became symptomatic or six weeks after weaning if asymptomatic. For infants with a positive or indeterminate result from the first test, a blood sample was collected at the second visit for confirmatory testing. The results were announced at the third clinical visit (scheduled for 14 weeks). Incentives, including free medical support for consultation, biological analysis, additional vaccines and reimbursement of transport costs, were provided to parents/caregivers by the project during follow-up visits. All HIV-infected children and control groups of HIV-uninfected infants followed since birth, born to either HIV-infected or non-infected mothers were eligible for the second phase of the Pediacam project planned from 14 weeks to 5 years. This phase is not described here as it is not relevant to this study. Socioeconomic and demographic characteristics of the families and obstetrical characteristics were collected at enrolment by questionnaire-based interview with mothers and examination of their hospital booklets. Questionnaires were also used subsequently to collect data on infant vital status, pathologies, vaccinations and HIV testing process as appropriate. Reminder phone calls were made to families who did not return for a follow-up visit within one week of the planned date. The ANRS 12140- Pediacam study has received ethical approval in Cameroon from the National Ethic Committee and in France from the Biomedical Research Committee of the Pasteur Institute of Paris. An administrative authorization was also delivered by the Cameroonian Ministry of Public Health. Written informed consent was obtained from parents or guardians prior to inclusion of infants into the research project. All infants born live to HIV-infected mothers and infants born to HIV-uninfected mothers matched on gender and recruitment site, enrolled from November 2007 to October 2010 into the first phase of the ANRS-Pediacam study planned from the first to 14th week of life were eligible for this analysis. The main outcome was loss to follow-up (LTFU) or “failed to return for at least one scheduled clinical visit” defined as mother-child pairs who never returned for a clinical visit during the first 6 months of age after inclusion in the ANRS-Pediacam study. Those who attended clinical visits, even if only once, were not considered to be lost to follow-up. The threshold of six months was chosen because several studies indicate that knowing the HIV status of the child before age 6 months favours early initiation of HAART [15,16]. Returning for a clinical visit at least once within six months was perceived as having the willingness to comply with the study schedule; failure to attend subsequently may indicate loss of motivation due to constraints associated with the health system. The covariables considered included variables pertaining to infant’s characteristics at birth (gender, prematurity, birth weight, APGAR, hospitalization at birth), maternal characteristics and socio-economic status (HIV serological status, marital status, level of education, socio-professional activity, monthly income, presence of a functional fridge at home, access to electricity, access to tap water), quality of antenatal care and obstetrical context of delivery (primigravid, mode of delivery, place of birth, number of antenatal visits, ART prophylaxis for PMTCT and disclosure of HIV status) and paternal characteristics (age, level of education and socio-professional activity). Maternal and infant characteristics are described using frequencies for categorical variables, medians and interquartile ranges for continuous variables. Their relation to LTFU was evaluated in each group defined by maternal HIV serostatus because of the differences observed between the two groups. For multiple births, only the first infant was included in the analysis. To examine covariables associated with LTFU, logistic regression models were adjusted on site and gender (matching variables) as appropriate for the matched study design [17]. The initial multivariable logistic regression model included those non collinear covariables found by univariable analysis to be associated with LTFU (as the dependent variable) with a p-value ≤ 0.25. The final model was obtained by successively removing variables not associated at a p-value <0.05 only if the odds ratios for the remaining variables were unchanged and taking interactions into account. The following known risk factors were maintained in the final model: low birth weight, prematurity and maternal educational level and socio-professional activity (as a surrogate for economic status). We performed a sensitivity analysis where we imputed missing data as a category for each variable. All statistical analyses were performed using R 2.15 software.