This study reports on HEI mortality and attributable causes and predictors in rural North-Central Nigeria. VA remains an important approach for reporting causes of death in resource-limited and/or unstable settings where mortality records may be absent or poorly maintained (14–16). Among the modest number of published reports on specific causes of mortality among African HEI, few have been from the post-ART/-PMTCT scale up era, and fewer still from rural settings where VA may be most applicable for data collection (27–38). To date, there is little available data on causes of death, determined by VA or otherwise, among HEI in Nigeria.
The 12-month infant mortality risk among HEI in our study (88.7/1,000) was higher than the national infant mortality rate of 65/1,000 (2). Our study was unable to tease out whether transmitted HIV infection or the state of being HIV-exposed were direct causes or contributing factors to in- and ex utero deaths, however we postulate a high likelihood that this is the case: prior studies report higher mortality rates among HIV-exposed uninfected infants compared to non-HIV exposed infants (35,39–42). The mortality risk results should however be interpreted with caution given our relatively small sample size. Additionally, we were unable to confirm HIV status among 20 of 35 live-born infants who died; availability of those results could have influenced our conclusions with respect to contribution of HIV infection to mortality in our cohort.
In utero deaths accounted for slightly more than half of infant deaths (53.3%) in our cohort. However, due to constraints in availability of sophisticated diagnostics and our VA approach, causes of intra-uterine death could not be ascertained. That being said, the lack of relatively simple routine prenatal syphilis testing for pregnant women in our cohort was a major missed opportunity, as syphilis is a significant cause of stillbirth globally (43). Dual HIV-syphilis testing and subsequent treatment for women found positive for one or both conditions is important for disease control and infant survival, particularly in sub-Saharan Africa (44). Birth asphyxia and sepsis were the most common attributable causes of neonatal and post-neonatal death respectively. Infectious and respiratory diseases have been reported as the major causes of death among HEI in low-resource, high-burden countries (45). Specifically, pneumonia, diarrhea, septicemia and malnutrition have been reported as the most common causes of death among HEI in sub-Saharan Africa (27–39). Our study agrees with previous HEI mortality studies, which report diarrhea, birth asphyxia/perinatal conditions and sepsis as major causes of death among HIV-exposed infants and children under 24 months (28,35,46,47). These studies also cite acute respiratory infection and malnutrition as major causes of HEI death, however our VA approach was unable to determine these outcomes for our cohort.
Bivariate analysis correlated the following with HEI mortality: non-facility delivery, new maternal HIV diagnosis, maternal efavirenz-based regimen assisted delivery, unskilled birth attendant, post-postpartum maternal death and infant’s non-receipt of nevirapine prophylaxis within 72 hours of life. Several studies support our findings of non-facility delivery, new maternal HIV diagnosis, maternal efavirenz, non-vaginal delivery, unskilled birth attendant, post-postpartum maternal death as correlates of HEI mortality (32,34,38,48). In our study however, only non-receipt of infant nevirapine within 72 hours persisted as a correlate of HEI mortality in multivariate analysis.
The independent predictive value of non-/or late receipt of nevirapine prophylaxis and infant mortality in our study is not unexpected. Timely receipt within 72 hours of birth and completion of at least 6 weeks of infant antiretroviral prophylaxis has been shown to reduce HIV transmission to HEI during gestation, delivery and breastfeeding (49–53). This evidence is reflected in the WHO (54) and Nigerian guidelines (55) for infant antiretroviral prophylaxis in PMTCT. As such, infants who did not receive prophylaxis or received it later than recommended will be at higher risk for HIV transmission and subsequently, mortality, particularly if ART initiation is delayed or missed. However, given that some of the deceased infants were HIV-free, the correlation of late/non-receipt of infant prophylaxis with mortality may point to more global issues in the HEI’s life or family/environment, such as poor health-seeking behavior, poverty, poor knowledge, or concurrent but unmeasured risks of mortality related or unrelated to maternal and/or infant HIV infection. Unfortunately, there are currently few published studies specifically investigating or reporting on non-/late receipt of antiretroviral prophylaxis as a predictor of HEI mortality.
Our study showed no significant association between the MoMent study’s structured mentor mother support intervention and infant survival. While there is ample evidence on the positive impact of maternal peer support on maternal PMTCT retention, adherence and viral suppression, EID timeliness/uptake, and rate of vertical transmission in Nigeria (20,21) and in sub-Saharan Africa and globally (56–62), few studies explicitly report on its direct impact on HEI mortality. This may be due largely to sample size constraints; studies conducted so far-including ours- may not have been powered enough to investigate this.
A robust PMTCT program should be comprehensive and integrated with maternal, neonatal and child healthcare and goals. This should include dual antenatal HIV/syphilis testing of pregnant women, maternal access to facility delivery, timely initiation of maternal treatment and infant prophylaxis where relevant, early diagnosis and treatment of infant HIV and other perinatal and infectious diseases such as birth asphyxia, sepsis and pneumonia, that contribute to early infant mortality. Simplified VA approaches combined with strengthened monitoring and evaluation could improve the availability and quality of data on HEI mortality and contribute to feasible and sustainable approaches to management reducing mortality among HEI in high HIV-burden, resource-limited settings.
Study Limitations
Our study is not without limitations. The generalizability of our VA approach in determining cause of death is not confirmed. This is partly due to lack of prior comparative data (VA or otherwise) and an unavailable “gold standard” such as clinical/laboratory diagnosis for determining cause of death among HEI in our largely rural study setting. Thus, bias is introduced by inaccuracies from wrong reporting, wrong causes of death ascribed, and absence of an established diagnosis reflected by the high number of “not otherwise specified“ cases.
Unfortunately, the unavailability of complete data on HIV test results limited the analysis of HIV-positive status as a predictor of (in- or ex-utero) infant mortality. Malaria is a significant cause of infant mortality in our study setting (12,13,63); our VA approach may have underestimated malaria-related mortality in our cohort.
Another limitation is non-collection of data on infant feeding status at time of death to analyze as a predictor of mortality. A study conducted in India among HIV-exposed infant found that mixed feeding and animal milk substitute are important factors responsible for high rates of gastroenteritis, which in turn contributed to infectious hospitalization and in-hospital mortality (64). As previously mentioned, the non-availability of maternal syphilis testing was a missed opportunity for infant mortality analysis, specifically for stillbirths.