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

As in most Sub-Saharan countries, Cameroon experienced a generalized HIV epidemic. The prevalence was estimated in 2011 to be 4.3% among adults aged 15–49 years with 550,000 people living with HIV and 32,800 deaths in a population of 20 million inhabitants [18]. The use of antiretroviral multitherapy has dramatically reduced mortality, transforming HIV infection from an acute to a chronic disease. One consequence is that any action intended for caring people living with HIV needs their motivation, making compliance to follow-up a key for success. We took advantage of the Pediacam cohort, launched in 2007, constituted of HIV-exposed and HIV-unexposed infants included in the first week of life and followed for five years. We used this cohort to evaluate the proportion of infants who did not return for follow-up after inclusion in the first phase of the study, and identified factors associated with this loss to follow-up (LTFU).

The overall LTFU rate was 23.2% [CI95% 22.2-24.8], and was significantly lower for HIV-infected mother-infant pairs (9.8%) than HIV-uninfected mother-infant pairs (36.7%). Few relevant studies that have addressed the problem of LTFU included a control group. In a nested case control study including 594 HIV-uninfected and 456 HIV-infected mothers in Zimbabwe [19], dropout at 9 months was 19%; the higher LTFU rate in HIV-uninfected mother-infant pairs (23.1%) is similar to our observation that LTFU among infants born to HIV-infected mothers was about 3 times higher than among infants born to HIV-uninfected mothers. The failure of HIV-uninfected mother-child pairs to return for visits might reflect their concern about stigmatization. Indeed, involving HIV-uninfected mothers in a study concerning HIV-infected mothers is a real challenge because of the possible misinterpretation that involvement indicates HIV positivity [20]. Despite the existence of information, education and communication (IEC) activities, stigma within the community is still an important reality [21]. Also, for many HIV-infected mothers, the participation in such studies is reinforced by their desire to help their infant or to facilitate their access to ART. This factor is not relevant to HIV-uninfected mothers [22]. Therefore, motivation and direct benefits associated with participation in this type of study are not equal for different groups of infants. The failure of HIV-infected mother-child pairs to return for scheduled clinical visits (9.6%) in this study was lower than reported in other African studies, including those conducted in PMTCT programmes. In Mozambique, Ethiopia, Angola, and Cameroon, LTFU rates of 75.17% [23], 47.96% [24] , 19.27% [9], and 17.55% [25], respectively, have been reported for infants by the age of 3 months. In general, LTFU tends to be lower in cohort studies than routine PMTCT programs [11]. In a cohort study conducted in South Africa, 78% of participants attended their scheduled 12-month visit whereas only 18% returned in the routine PMTCT programme [26]. The high follow-up rate in the Pediacam study may be due to the reminders by telephone, reimbursement of transport fees, provision of child care and free vaccines, and strong coordination.

The factors associated with LTFU differed according to maternal HIV status. HIV-uninfected mothers aged ≤ 35 years (<25 years and 25–35 years) more likely than those >35 years old to be LTFU. Similarly, Kaplan et al. [27] reported that younger patients were at greater risk of LTFU with an adjusted odds ratio of 2.2 [95% CI 1.30-3.60]. Recent evidence suggests that social factors, such as stability (income, education, occupation), are associated with LTFU [28]. In Africa, both social and economic stability increases with age. Most women aged 35 years and above are in marital relationships (89.9% of women >35 years old live with a partner versus 72% of women <25 years old). The probability of being employed is substantially greater at old than young ages (younger women are more likely to be in education. The same reasons may explain why younger mothers are more likely to be LTFU. Young participants may be geographically more mobile [29]. Lower maternal education level was also independently associated with LTFU, but only among infants born to HIV-uninfected mothers. This observation contrasts with others studies which report a higher risk of LTFU among HIV-exposed infants born to less educated mothers [30]. In India, women with graduate level education were less likely than women with less than graduate level education to be LTFU [31]. The direct benefits of HIV-study participation are not shared by HIV-uninfected mothers, their motivation to participate may be associated to their ability to understand the potential benefits of the study, such as new scientific information about HIV and its treatment; this may have a larger effect on educated participants. More than 90% of the HIV-uninfected women enrolled in this study had at least a secondary school level education.

Ioannidis et al. reported an association in Malawi between LTFU and teaching/student occupations: infants born to HIV-infected mothers who were teachers or students were less likely to attend follow-up visits. This might have been due to concerns about stigmatization from being identified as HIV positive. Our analysis indicated that HIV-unexposed infants born to employed mothers were more likely to be LTFU possibly because they do not have enough time off from work to attend visits. In US, Krishnan et al. reported that activities such as work or school prevent participants from adhering to follow-up [29].

LTFU of HIV-infected mother-infant pairs was also significantly and independently associated with the absence of ART prophylaxis. This observation is consistent with findings in Uganda presented by Ahoua et al. [32]; they reported a higher risk of LTFU for patients with incomplete or no ARV prophylaxis. A study in the USA reported a slightly lower LTFU rate in ARV-experienced than ARV-naïve mothers, probably due to familiarity with health-care system and a better understanding of the importance of follow-up.

We found an association between LTFU and emergency caesarean section, and this contrasts with a study in Malawi where this factor was not reported to be associated with LTFU [30]. However, our finding is similar to observations in the Pediacam study concerning factors associated to incomplete infant HIV diagnosis process. It may be because many of these women are referred from primary antenatal care settings to the hospitals participating in the Pediacam survey because of complications of labour/delivery; these women may prefer to return to their local health centres for infant follow-up after delivery [14].

A study in Malawi identified low birth weight as a significant factor influencing return to follow-up visits [30]. This was attributed to high mortality rate among low birth weight infants. In our analysis, low birth weight tended to be associated with LTFU, and was not significant in multivariable analysis. Other factors, notably hospitalization at birth and pre-term, presented the same characteristics.

In this study, 67 HIV-infected mother-infant pairs who were LTFU were traced: 26 of the infants were deceased (Figure 1).

Previous studies identified poor socio-economic conditions as a reason for LTFU. For example, HIV-infected women in India staying in families with higher economic status were found to be less likely than women living at a lower economic status to be LTFU both before and after delivery [31]. A study in South Africa identified financial difficulty as the major obstacle to attending follow-up visits for patients on antiretroviral therapy [33]. In rural Malawi, inability to afford transport costs related to the long distances to hospitals has been cited as impeding the ability to comply with protocol [21]. We did not find any such factors in our study. This divergence of results may be a consequence of the different ways that socio economic factors were assessed in these studies. In our study, we used monthly income, access to electricity at home, presence of a functional fridge at home, access to tap water at home and socio-professional activity as surrogates of economic status. We assumed that reimbursement of transport fees, and free milk, vaccines and biological exam provided by the study minimized the effects of economic status; also Pediacam operates in urban areas, where there are fewer socioeconomically disadvantaged people than in rural areas.

The factors associated with LTFU in the HIV-infected mothers group pertained to antenatal care and the obstetrical context of delivery; those associated with LTFU in the HIV-uninfected mothers group were largely relevant to socioeconomic status. For both groups of maternal HIV status, young maternal age was associated with LTFU.

One of the strengths of this study is its multicentre design including three referral hospitals with different working practices and recruitments, reflecting the diversity of practical management of PMTCT programmes. Moreover, these centres are located in two large cities of Cameroon with heterogeneous populations, albeit mostly living in urban areas. In contrast, recruitment of HIV-infected and HIV-uninfected women in the same health centres may have affected the acceptability to, and follow-up of, HIV-uninfected women, ad this is a limitation of the study. In addition, the low rate of LTFU among HIV-infected mother-child pairs, relative to other sub-Saharan Africa studies, could have reduced the power of the study to identify factors associated with LTFU.