Severity of Maternal HIV Disease and Adverse Birth Outcomes
Characteristics of HIV-Positive Participants Who Delivered Live, Singleton Infants in the Malaria and HIV-1 in Pregnancy Study, Malawi
Among the HIV-infected women in the parent Malaria and HIV-1 in Pregnancy (MHP) cohort, 809 live singleton deliveries occurred, 80% via vaginal delivery. Participant's median age at enrollment was 24 years (interquartile range: 21–28 years), and the median gravidity was 2 (interquartile range: 1–4 pregnancies) (Table 1). A majority of the participants had attended primary school (91%), were unemployed (75%), and lived in an urban setting (76%). At the time of delivery, 56% of the participants had anemia, 26% had histological evidence of chorioamnionitis, and 7% were syphilis seropositive. One quarter of the participants were primigravid. Most (86%) participants took iron–folate supplements during the pregnancy, and 93% received at least 1 dose of intermittent preventative therapy for malaria during pregnancy for malaria (Table 1). With regard to malaria, 10 of the women were peripheral blood smear positive, 8% were placental blood smear positive, and 18% had histological evidence of malaria in a placental biopsy. Because all HIV-positive women in the MHP study received their HIV-1 diagnosis at enrollment, all participants were antiretroviral treatment naive; 95% of the HIV-infected participants received single-dose nevirapine to prevent HIV-1 mother-to-child transmission.
In this cohort of HIV-infected women, 21% of participants delivered a LBW infant and 16% delivered preterm. Age, malaria status, and gravidity were not associated with prevalence of LBW or PTD (Table 2). Anemia was more common among women with infants with LBW (68%) and PTD (68%) compared with women with normal weight term infants (52%). Chorioamnionitis was also more commonly observed in the LBW (33%) and PTD (37%) groups compared with the normal weight term delivery group (23%). Female sex was more prevalent among LBW infants (57%) compared with normal weight term infants (46%). Finally, syphilis seropositivity was more common among mothers of PTD infants (11%) than normal weight term infants (6%) (Table 2).
Maternal peripheral HIV-1 viral load was inversely correlated with continuous infant birthweight (correlation coefficient = -0.08, P = 0.06), but not with continuous duration of gestation (correlation coefficient = -0.05, P = 0.5) (Figs. 1A, C). HIV-1 concentration in the placenta was inversely correlated with both birthweight (correlation coefficient = -0.15, P = 0.01) and duration of gestation (correlation coefficient = -0.20, P = 0.0008) (Figs. 1B, D).
(Enlarge Image)
Figure 1.
Correlation between viral load and continuous birthweight or gestational age. Birthweight is inversely correlated with HIV-1 concentration in peripheral plasma (A) and placental plasma (B). Gestational age does not correlate with HIV-1 concentration in peripheral plasma (C) but is inversely correlated with HIV-1 concentration in placental plasma (D). P values were calculated by pairwise correlation. Horizontal black dotted lines indicate the cutoff for low birthweight (<2500 g) or preterm birth (<37 weeks).
The effect of HIV-1 disease severity on prevalence of LBW differed meaningfully by maternal malaria status. Residence, education level, primigravid status, and anemia were retained as confounders in adjusted multivariable models. Among women with malaria, we observed no significant association between any measure of HIV-1 disease severity and prevalence of LBW in unadjusted or adjusted analyses (Table 3). Among malaria-negative women, for all measures of HIV-1 disease severity, more severe HIV-1 disease was significantly associated with increased prevalence of LBW in both unadjusted and adjusted models. The adjusted PR for a 1-log increase in placental HIV-1 viral load was 1.22 (95% CI: 1.00 to 1.48); for a 1-log increase in peripheral HIV-1, viral load was 1.38 (95% CI: 1.08 to 1.77); and for a 100-cell per microliter decrease in CD4 T cells was 1.12 (95% CI: 1.05 to 1.21) (Table 3).
The effect of HIV-1 disease severity on prevalence of PTD also differed by maternal malaria status (Table 4). Among malaria-positive women, neither placental viral load nor CD4 T-cell count were significantly associated with PTD in unadjusted or adjusted analyses, but a 1-log increase in peripheral viral load was significantly protective against PTD in adjusted analyses (PR: 0.56, 95% CI: 0.47 to 0.85). Among women without malaria, higher placental viral load and lower CD4 T-cell count were both significantly associated with increased prevalence of PTD (adjusted PR for a 1-log increase in placental viral load: 1.29, 95% CI: 1.02 to 1.63; adjusted PR for 100-cell per microliter decrease in CD4 T cells: 1.16, 95% CI: 1.05 to 1.28). Increases in peripheral HIV-1 viral load did not significantly increase prevalence of PTD in malaria-negative women (Table 4).
The Association Between HIV-1 and LBW Remains After Exclusion of PTD and HIV-Infected Infants
When the data set was restricted to include only infants born after 37 weeks' gestation (n = 662), the associations between HIV-1 severity and prevalence of LBW among women with malaria were strengthened, but remained not statistically significant: the adjusted PR for a 1-log10 increase in placental viral load was 1.64 (95% CI: 0.98 to 2.74) compared with 1.26 (95% CI: 0.87 to 1.83) in the primary analysis (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A445). The PR for LBW for a 1-log10 increase in peripheral HIV-1 viral load was 1.66 (95% CI: 0.80 to 3.47) compared with 0.88 (95% CI: 0.57 to 1.35) in the primary analysis. However, excluding these observations had almost no affect on the magnitude of the associations between HIV-1 severity and prevalence of LBW in women without malaria. Given the reduced sample size, many of the PRs are no longer statistically significant, but the strength of the associations was essentially unchanged (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A445).
When the data set was restricted only to observations with infants known to be HIV negative at birth (n = 686), we observed no meaningful changes in the associations between HIV-1 severity and prevalence of LBW or PTD for malaria-positive or malaria-negative women (see Table S2 and S3, Supplemental Digital Content, http://links.lww.com/QAI/A445). Thus, the observed associations in our primary analysis between HIV-1 severity and LBW or PTD are unlikely to be explained by infant HIV-1 status at birth.
Our primary analysis established that most associations between HIV-1 severity and birth outcomes were meaningfully different by malaria status. Our final sensitivity analysis assessed whether our findings were robust to the method of malaria diagnosis; in other words, was the same pattern observed for women with malaria diagnosed by peripheral blood smear, placental blood smear, and placental histology? For both LBW and PTD, the patterns observed in the primary analysis were repeated in the sensitivity analysis, with no meaningful differences by method of malaria diagnosis (see Table S4 and S5, Supplemental Digital Content, http://links.lww.com/QAI/A445).
Results
Characteristics of HIV-Positive Participants Who Delivered Live, Singleton Infants in the Malaria and HIV-1 in Pregnancy Study, Malawi
Among the HIV-infected women in the parent Malaria and HIV-1 in Pregnancy (MHP) cohort, 809 live singleton deliveries occurred, 80% via vaginal delivery. Participant's median age at enrollment was 24 years (interquartile range: 21–28 years), and the median gravidity was 2 (interquartile range: 1–4 pregnancies) (Table 1). A majority of the participants had attended primary school (91%), were unemployed (75%), and lived in an urban setting (76%). At the time of delivery, 56% of the participants had anemia, 26% had histological evidence of chorioamnionitis, and 7% were syphilis seropositive. One quarter of the participants were primigravid. Most (86%) participants took iron–folate supplements during the pregnancy, and 93% received at least 1 dose of intermittent preventative therapy for malaria during pregnancy for malaria (Table 1). With regard to malaria, 10 of the women were peripheral blood smear positive, 8% were placental blood smear positive, and 18% had histological evidence of malaria in a placental biopsy. Because all HIV-positive women in the MHP study received their HIV-1 diagnosis at enrollment, all participants were antiretroviral treatment naive; 95% of the HIV-infected participants received single-dose nevirapine to prevent HIV-1 mother-to-child transmission.
LBW and PTD Are Common in Malawi
In this cohort of HIV-infected women, 21% of participants delivered a LBW infant and 16% delivered preterm. Age, malaria status, and gravidity were not associated with prevalence of LBW or PTD (Table 2). Anemia was more common among women with infants with LBW (68%) and PTD (68%) compared with women with normal weight term infants (52%). Chorioamnionitis was also more commonly observed in the LBW (33%) and PTD (37%) groups compared with the normal weight term delivery group (23%). Female sex was more prevalent among LBW infants (57%) compared with normal weight term infants (46%). Finally, syphilis seropositivity was more common among mothers of PTD infants (11%) than normal weight term infants (6%) (Table 2).
Placental Viral Load Correlates With Birthweight and Gestational Age
Maternal peripheral HIV-1 viral load was inversely correlated with continuous infant birthweight (correlation coefficient = -0.08, P = 0.06), but not with continuous duration of gestation (correlation coefficient = -0.05, P = 0.5) (Figs. 1A, C). HIV-1 concentration in the placenta was inversely correlated with both birthweight (correlation coefficient = -0.15, P = 0.01) and duration of gestation (correlation coefficient = -0.20, P = 0.0008) (Figs. 1B, D).
(Enlarge Image)
Figure 1.
Correlation between viral load and continuous birthweight or gestational age. Birthweight is inversely correlated with HIV-1 concentration in peripheral plasma (A) and placental plasma (B). Gestational age does not correlate with HIV-1 concentration in peripheral plasma (C) but is inversely correlated with HIV-1 concentration in placental plasma (D). P values were calculated by pairwise correlation. Horizontal black dotted lines indicate the cutoff for low birthweight (<2500 g) or preterm birth (<37 weeks).
Low Birthweight
The effect of HIV-1 disease severity on prevalence of LBW differed meaningfully by maternal malaria status. Residence, education level, primigravid status, and anemia were retained as confounders in adjusted multivariable models. Among women with malaria, we observed no significant association between any measure of HIV-1 disease severity and prevalence of LBW in unadjusted or adjusted analyses (Table 3). Among malaria-negative women, for all measures of HIV-1 disease severity, more severe HIV-1 disease was significantly associated with increased prevalence of LBW in both unadjusted and adjusted models. The adjusted PR for a 1-log increase in placental HIV-1 viral load was 1.22 (95% CI: 1.00 to 1.48); for a 1-log increase in peripheral HIV-1, viral load was 1.38 (95% CI: 1.08 to 1.77); and for a 100-cell per microliter decrease in CD4 T cells was 1.12 (95% CI: 1.05 to 1.21) (Table 3).
Preterm Delivery
The effect of HIV-1 disease severity on prevalence of PTD also differed by maternal malaria status (Table 4). Among malaria-positive women, neither placental viral load nor CD4 T-cell count were significantly associated with PTD in unadjusted or adjusted analyses, but a 1-log increase in peripheral viral load was significantly protective against PTD in adjusted analyses (PR: 0.56, 95% CI: 0.47 to 0.85). Among women without malaria, higher placental viral load and lower CD4 T-cell count were both significantly associated with increased prevalence of PTD (adjusted PR for a 1-log increase in placental viral load: 1.29, 95% CI: 1.02 to 1.63; adjusted PR for 100-cell per microliter decrease in CD4 T cells: 1.16, 95% CI: 1.05 to 1.28). Increases in peripheral HIV-1 viral load did not significantly increase prevalence of PTD in malaria-negative women (Table 4).
The Association Between HIV-1 and LBW Remains After Exclusion of PTD and HIV-Infected Infants
When the data set was restricted to include only infants born after 37 weeks' gestation (n = 662), the associations between HIV-1 severity and prevalence of LBW among women with malaria were strengthened, but remained not statistically significant: the adjusted PR for a 1-log10 increase in placental viral load was 1.64 (95% CI: 0.98 to 2.74) compared with 1.26 (95% CI: 0.87 to 1.83) in the primary analysis (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A445). The PR for LBW for a 1-log10 increase in peripheral HIV-1 viral load was 1.66 (95% CI: 0.80 to 3.47) compared with 0.88 (95% CI: 0.57 to 1.35) in the primary analysis. However, excluding these observations had almost no affect on the magnitude of the associations between HIV-1 severity and prevalence of LBW in women without malaria. Given the reduced sample size, many of the PRs are no longer statistically significant, but the strength of the associations was essentially unchanged (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A445).
When the data set was restricted only to observations with infants known to be HIV negative at birth (n = 686), we observed no meaningful changes in the associations between HIV-1 severity and prevalence of LBW or PTD for malaria-positive or malaria-negative women (see Table S2 and S3, Supplemental Digital Content, http://links.lww.com/QAI/A445). Thus, the observed associations in our primary analysis between HIV-1 severity and LBW or PTD are unlikely to be explained by infant HIV-1 status at birth.
Our primary analysis established that most associations between HIV-1 severity and birth outcomes were meaningfully different by malaria status. Our final sensitivity analysis assessed whether our findings were robust to the method of malaria diagnosis; in other words, was the same pattern observed for women with malaria diagnosed by peripheral blood smear, placental blood smear, and placental histology? For both LBW and PTD, the patterns observed in the primary analysis were repeated in the sensitivity analysis, with no meaningful differences by method of malaria diagnosis (see Table S4 and S5, Supplemental Digital Content, http://links.lww.com/QAI/A445).
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