Maternal characteristics in HAART-unexposed and exposed women
The cohort comprised 1630 women, with a mean age of 30.1 years (sd 5.1) and median CD4 count of 159 cells/mm3 (IQR 105-200). Women who declined study participation were not included in the data base. Fourteen percent of included women (n = 233) were HAART unexposed. In the remainder (n = 1397) who received HAART during pregnancy, duration of therapy was known for 70%, with 54.5% of these (n = 533) initiating HAART before 28 weeks ("early HAART") and 427 at ≥ 28 weeks ("late HAART"; Figure ).
Figure 1 Flow diagram of study population. HAART - highly active antiretroviral treatment; early HAART was defined as initiation before 28 weeks of pregnancy and late HAART as initiation at ≥28 weeks of pregnancy; PI-based HAART - protease inhibitor-based (more ...)
Compared with unexposed women (Table ), HAART-exposed women were older (30.3 vs. 28.9, p < 0.001), had a lower median CD4 count (154 cells/mm3 vs. 191 cells/mm3, p < 0.001), and a lower rate of anaemia (46% [416/912] vs. 57% [57/100], p = 0.03). However, no differences were detected between these groups for other risk factors for LBW or preterm birth, such as gravidity, hypertension, alcohol use, smoking, syphilis and previous miscarriage. Of note, diabetes requiring treatment with medication (oral hypoglycaemics or insulin) was uncommon, with only four women in the cohort meeting these criteria. Positive syphilis serology (rapid plasma reagin) was detected in 3.8% (38/1001) of women.
Demographics and maternal health status in women exposed and unexposed to antiretroviral treatment and by duration of exposure
Characteristics of women by clinic site and MTCT rates
Compared with women at RHM, those at CMJH were less frequently primigravidas (10% [49/487] vs. 16% at RHM [77/467], p = 0.005), more likely to have advanced WHO HIV disease (46% stage 1 [165/359] vs. 73% [281/385], p < 0.001) and more likely to have had previous miscarriages (22% [67/305] vs. 14% [63/450], p = 0.002). Information on TB was not available from RHM and was only available for 33% (466/1397) of women at CMJH, with 17% (80/466) of these having either current or prior TB.
A total of 1019 infants attended their scheduled visit for HIV DNA PCR testing at six weeks. Risks of MTCT were 3.6-fold higher in the non-HAART than HAART group (19% [37/191] versus 5% [45/828], p < 0.001), with the largest reduction in transmission among the early HAART group (2% [8/350] versus 10% [31/316] in the late group, p < 0.001).
Maternal characteristics in early versus late HAART initiators
The median duration from HAART initiation to childbirth was 18.4 weeks (IQR 12.1-42.6) for the early HAART group and 5.8 weeks (IQR 3.3-8.5) for the late group (p < 0.001). Women in the early group more commonly received NVP-based HAART (46%, 254/553), while those in the late group were more likely to receive protease inhibitor-based HAART (68%, 290/427; Figure ). No differences were detected between the early and late HAART groups in terms of baseline CD4 count, previous preterm birth rates, syphilis prevalence and smoking. However, women in the early HAART group had higher rates of previous miscarriage than the late HAART group (22% [70/313] vs.12% [38/310], p = 0.001).
Infant outcomes: low birth weight
The mean birth weight for infants in the cohort was 2.88 kg, with 22.4% (275/1228) having LBW. Among infants with known HIV status, LBW was more common in HIV-positive than negative infants (33% [24/73] vs. 22% [173/804], p = 0.04). In HAART-unexposed infants, 27% (60/224) were LBW compared with 23% (90/388) of early HAART-exposed and 19% (76/407) of late HAART-exposed infants (p = 0.05). No differences, however, were detected when comparing rates of LBW in HAART-unexposed versus HAART-exposed infants (27% [60/224] vs. 21% [215/1004], p = 0.08), or between the early and late HAART groups (23% [90/388] vs. 19% [76/407], p = 0.12). Among women with early HAART-exposure, higher rates of LBW were observed in women receiving efavirenz-based regimens (38% [36/95]) compared with nevirapine (20% [31/158]) and protease inhibitor-based regimens (17%, [23/135]; p < 0.001). There were no differences in rates of LBW by regimen in the late HAART group (Table ).
Infant outcomes according to maternal antiretroviral regimens and duration of treatment in pregnancy
Given that this initial analysis showed higher rates of LBW in women receiving efavirenz-based regimens from early in pregnancy, we compared characteristics of women in this group with women taking other regimens. Women taking early HAART and receiving efavirenz had higher rates of TB compared with those on nevirapine and protease inhibitor-based therapy (28% [25/88] vs. 14% [25/183] and 10% [1/10] respectively, p = 0.01), lower median CD4 counts (138 cells/mm3 vs. 155.5 cells/mm3 vs. 164 cells/mm3 respectively, p = 0.03), and longer median weeks on HAART (62.7 [IQR 33.1-86.4] vs.15.6 [IQR 10.7-25.8] and 17.1 [IQR 13.7-23.1] respectively, p < 0.001).
Overall, only 2% (26/1228) of all infants in the cohort were classified as very low birth weight (VLBW). More HAART-unexposed than exposed infants were VLBW (4% [10/224] vs. 2% [16/1004], p = 0.01). The mean CD4 cell count of the VLBW group did not differ from the remainder of the cohort (148 cells/mm3 vs. 153 cells/mm3, p = 0.65). Rates of VLBW infants were similar in the early and late HAART groups and for all HAART regimens. Seven of the infants had known maternal risk factors for VLBW, including maternal history of previous miscarriage, previous preterm delivery, or hypertension. One infant in this group was HIV infected.
Predictors of low birth weight
In univariate analysis evaluating associations between HAART and LBW, including both HIV-positive and HIV-negative infants, no significant associations were detected in the late HAART group (Table ). However, in the early HAART group, receipt of an efavirenz-containing regimen, lower CD4 cell count, and maternal hypertension were associated with LBW. Although rates were low, neither smoking nor alcohol use was associated with LBW. In multivariate analysis, large effects of immunological status remained, with each 50 cells/mm3 increase in CD4 cell count associated with a 57% reduction in the odds of LBW (95% CI 0.45-0.71, p < 0.001). There was a trend towards hypertension being associated with increased odds of LBW (AOR 2.1, 95% CI 0.92-4.82; p = 0.08). In multivariate analysis, the effect of efavirenz exposure was removed (AOR 1.02, 95% CI 0.46-2.25), and unexpectedly, nevirapine-based HAART was associated with a reduced odds of LBW compared with HAART-unexposed women (AOR 0.38, 95% CI 0.18-0.81, p = 0.01). Similar results were found in multivariate analysis of associations between HAART groups and LBW when modelling was restricted to only HIV-negative infants (data not shown).
Multivariate logistic regression showing risk factors for LBW in HAART-exposed women irrespective of infant HIV status
Infant outcomes: preterm birth
The overall rate of preterm birth in the cohort was 13.3% (145/1093). Rates were higher among women exposed to HAART during pregnancy than those unexposed (15% [138/946] vs. 5% [7/147], p = 0.002). In the analysis of early versus late HAART, infants whose mothers initiated treatment before 28 weeks had a higher rate of preterm birth compared with after 28 weeks (21% [81/389] vs. 5% [21/427], p < 0.001). HAART exposure was not associated with increased rate of extremely premature birth (6% [58/946] vs. 4% in unexposed women [6/147], p = 0.43).
Predictors of preterm birth
In univariate analysis evaluating predictors of preterm birth in all infants (regardless of HIV status), in the early HAART group, every 50 cells/mm3 rise in maternal CD4 cell count was associated with a 31% decrease in the odds of preterm birth (95% CI 0.58-0.83, p < 0.001, Table ). This association remained significant in multivariate analysis (AOR 0.68, 95% CI 0.55-0.85, p = 0.001). In the multivariate analysis of specific HAART regimens, early exposure to any regimen was associated with preterm birth compared with HAART-unexposed infants, with receipt of early efavirenz and nevirapine associated with the higher odds of preterm birth (AOR 5.6, 95% CI 2.1-15.2, p = 0.001, and AOR 5.4, 95% CI 2.1-13.7, p < 0.001, respectively), than protease inhibitor-containing regimens (AOR 3.0, 95% CI 1.1-8.4, p = 0.04). Neither smoking nor alcohol use was associated with preterm birth in this analysis. Drug regimen was not associated with preterm birth in the late HAART group.
Multivariate logistic regression showing risk factors for preterm birth in HAART-exposed women irrespective of infant HIV status