This study documents that women with advanced HIV disease are not only more likely to transmit HIV but also have an increased risk of miscarriage and stillbirth and infants born to these mothers have an increased risk of neonatal and early mortality. High rates of neonatal and early mortality are primarily attributable to low birth weight and preterm birth, both also increased among women with advanced disease. It is only after the neonatal period that the infant’s HIV status begins to make a significant contribution to excess mortality.
In this study, the risks of miscarriage and stillbirth were 31 and 26 per 1000 live-born births, respectively. From another cohort study in Lusaka, Zambia, the estimated rate of stillbirth was 21 per 1000 live-born births where 75.2% of the participating women were HIV-uninfected [30
]. We found that among HIV-infected women, miscarriage was associated with CD4 cell counts <350 cells/mm3
. This result is similar to other studies [31
]. In a South African cohort study, women with CD4 cell counts <250 cells/mm3
had a two-fold increased risk of the adverse outcome (antenatal heath, miscarriage or stillbirth) compared to those with CD4 cell counts >500 cells/mm3
]. Another study in India reported that symptomatic women had a significantly increased rate of miscarriage, compared to asymptomatic women [32
In our study, high plasma viral load was significantly associated with stillbirth among HIV-infected women. Many studies have reported increased risk of stillbirth in HIV-infected women compared to HIV-negative women [2
], but only two studies have examined risk factors associated with stillbirth among HIV-infected pregnant women [3
]. A study in Tanzania found that elevated CD3 count, but not other markers such as CD4 or CD8 counts, was associated with stillbirth [33
]. In the cohort conducted in four cities in sub-Saharan Africa, the risk of stillbirth was correlated with decreasing CD4 count [3
] but not with plasma viral load categorized into ≥100,000 copies/ml or less. In our analysis, the mean baseline plasma viral load of mothers who delivered stillbirths was significantly higher (median value 76,560 vs. 39,783 copies/ml, p
0.01) thus fitting it as a continuous variable (log scale) seemed to be more accurate. Furthermore, symptomatic women had a more than a three-fold increased risk of stillbirth compared to asymptomatic women, suggesting that maternal disease progression may play an important role in perinatal outcomes.
Some previous studies have tried to document HIV status of pregnancy losses [34
]. One study which did so by in situ
hybridization showed that 60% of the spontaneous fetal losses (6/10) were associated with HIV transmission to the fetus [35
]. It is possible that advanced maternal disease might have increased pregnancy losses via intrauterine transmission [37
] but we could not directly examine such mechanism. Since ART only became available towards the end of the study, 52 out of 66 women (79%) who had miscarriages or stillbirths should have received ART under the current WHO guidelines but did not. Although certain ART regimens may increase the risk of adverse pregnancy outcomes [39
], it also reduces the risk of perinatal transmission and improves maternal health [41
]. Timely ART for HIV-infected pregnant women may result in a net improvement in these perinatal outcomes.
Our data indicate that HIV infection acquired during pregnancy begins to contribute to excess mortality as early as 70 days but mostly only after the neonatal period, independent of LBW and early cessation of breastfeeding. After the neonatal period, IU-infected infants had more than a six-fold increased risk of mortality compared to NI infants through 70 days. Prior studies have not as precisely considered the timing of early mortality of infected infants [19
] nor separated IU transmission from IP/ePP transmission [21
]. Some studies have found IU-infected infants to have onset of symptoms in first few months of life and faster disease progression than those infected at delivery or later [15
]. Despite recent scale-up, only 15% of HIV-exposed infants had access to early infant diagnosis and one-third of infants diagnosed of HIV did not receive appropriate antiretroviral treatment in 2011 [44
]. Our results re-emphasize the crucial role of early infant diagnosis in order to initiate therapy for infected infants given their rapid progression [45
LBW was previously associated with infant death between 8 weeks and 6 months of life [9
], post-neonatal death (29–365 days) and infant mortality [21
] among HIV-infected children as well as among HIV-exposed uninfected [22
]. Among perinatally-infected infants, the effect of LBW on infant survival dominates the neonatal period but persists thereafter even once HIV-related disease contributes to infant mortality. In our study, high maternal viral load and low hemoglobin were the most significant predictors of LBW and preterm birth as observed in other studies [4
]. Advanced maternal disease seems to indirectly affect early infant survival via the risk of LBW and premature birth. Thus to complement antiretroviral interventions, other interventions such as providing cotrimoxazole [27
] or multivitamin supplements during pregnancy [48
] may need to be considered to improve overall birth outcomes.
Early breastfeeding cessation was a significant risk factor for both neonatal and early mortality. Breastfeeding has a significant role in infant survival for all infants including those born to HIV-infected women [20
]. Maternal death was also related to infant mortality and is closely related to cessation of breastfeeding. However, we found breastfeeding to be a strong protector of infant survival independent of confounding effects of maternal health and survival.
Some social factors significantly affected infant survival. Infants with more than one sibling aged 5–16 years had decreased rates of early mortality. This may reflect families with greater birth spacing or substantial care provided by an older sibling. Teenage pregnancy was associated with an increased risk of neonatal and early mortality. In the general population, some studies have reported adverse associations between teenage pregnancy and perinatal mortality, largely attributable to preterm birth [49
], while others have not [52
]. In our study, maternal age <20 years was associated with neonatal mortality independent of preterm birth.
The study has several limitations. First, most of study participants were enrolled into the study during second or third trimester thus miscarriages and stillbirths occurring in earlier gestational ages are excluded resulting in underestimated rates of these outcomes. Our study thus has limited capacity to comment on the predictors of early pregnancy loss. However, most early pregnancy loss is due to chromosomal abnormalities and is unlikely to be influenced by maternal HIV status [53
]. Second, distinguishing between miscarriage and stillbirth is difficult particularly with inaccuracies in estimates of gestational age. Nevertheless, similar factors were associated with both of these adverse outcomes hence the consequence of misclassification seems to be limited. Third, HIV status could not be determined for some infants. However, we examined the extent of bias in sensitivity analyses which suggested that these exclusions did not appreciably affect the results. Finally, the cut-off of 70 days might have been too early to see any adverse effects of IP/ePP infection but this analysis aimed to examine how rapidly intrauterine and perinatally-acquired HIV infection affect infant survival.