As of March 5, 2008, 1402 women had been enrolled in the P1025 cohort, of whom 1,196 were eligible for this study. Of these, 22 women were excluded from all analyses due to no reported ARV use during pregnancy or unknown antiretroviral history, and 397 women were excluded from primary analyses due to current or recent ARV use at conception, leaving 777 women in the primary study population.
Demographic and clinical characteristics of the 777 women in the study population are provided in . More than half of the women were older than 25 years, 58% were black, 55% were diagnosed with HIV prior to conception, and 13% had prior preterm births. While no women were on ARV at conception by study design, half were on ARVs for more than 20 weeks during pregnancy and the majority (87%) initiated ARVs in the first or second trimester. Only 15% of women had a documented CD4+ cell count <200 cells/ml, 16% had a viral load >30,000 copies/ml, and 8% had symptomatic HIV disease (CDC category C excluding CD4+ cell count criteria) during pregnancy. There were also few co-morbid diagnoses during pregnancy. These included gestational diabetes (1%), gestational hypertension (3%), hepatitis C infection (4%), and sexually transmitted infections (19%).
Demographic and clinical characteristics of the all preterm births study population (N=777) according to use of combination therapy with protease inhibitors (PI) during pregnancy
Of the 777 women in the study population, 558 (72%) received combination ARV with PI. The most common regimens in this group were zidovudine plus lamivudine with nelfinavir (47%) and zidovudine plus lamivudine with lopinavir/ritonavir (22%). Two hundred and two women (26%) received combination ARV without PI; the most common regimens were zidovudine plus lamivudine plus abacavir, (61%) and zidovudine plus lamivudine with nevirapine (30%). Eleven women (1%) received two agents during pregnancy; 10 received zidovudine plus lamivudine and 1 received emtricitabine plus tenofovir. Six women (1%) received only zidovudine during pregnancy.
There were significant differences between women who received ARV with and without PI (). Women who were on ARV with PI during pregnancy were more likely to have CD4+ cell counts < 200 cells/mL (18% vs. 10%), viral load > 30,000 copies/mL (20% vs. 6%), and symptomatic clinical disease (10% vs. 3%). They also were more likely to have enrolled into P1025 in their second trimester (34% vs. 24%) and have delivered in the later years of the study, 2007-2008 (22% vs. 14%).
Seventeen percent (130/777) of all births in the study population were preterm. Of the 558 women who received ARV with PI, 102 (18%) delivered preterm. Of the 219 women who received ARV without PI, 28 (13%) delivered preterm. After outcomes review of the 130 preterm births, 58% were classified as spontaneous preterm births, 21% as possibly related preterm births, and 21% as unrelated preterm births (). There were several diagnoses associated with the possibly related preterm births (). The majority of the unrelated preterm births were elective cesarean sections or inductions.
shows the frequency distributions of gestational ages at delivery according to ARV use for the spontaneous preterm birth study population () and all preterm birth study population (). Comparison of the two frequency distributions reveals that the majority (67%) of the twelve very preterm births in women who took ARV with PI during pregnancy had identifiable causes of preterm delivery that may not be associated with ARV use during pregnancy. Three were associated with non-reassuring fetal heart rate tracing, one in a woman with gestational hypertension, and one in a woman with active HSV infection. Two of the very preterm births were intrauterine fetal demises and two were associated with placental abruption. One very preterm birth was associated with pre-eclampsia. Although, there was a significant trend toward a higher risk of preterm birth, particularly very preterm birth (< 32 weeks gestation) among women using ARV with PI in the all-preterm birth study population (p-value: 0.04), no significant difference in the risk was detected in the spontaneous preterm birth study population (p-value: 0.56) or combined spontaneous and possibly related preterm birth study population (p-value: 0.14).
Frequency distribution of gestational age at delivery by preterm birth study population and antiretroviral therapy use during pregnancy
In a multivariable logistic regression analysis of spontaneous preterm birth, no significant association was observed between risk of spontaneous preterm birth and use of ARV with PI compared to ARV without PI (Odds ratio (OR): 1.22, 95% confidence interval (CI): 0.70, 2.12) (). Similarly, no significant association was observed between use of ARV with PI and risk of combined spontaneous and possibly-related preterm birth or all preterm birth. The outcomes review and exclusion of possibly-related and unrelated preterm births increased the univariable p-values of several known predictors of preterm birth to > 0.10 so that they were not included in the multivariable model of spontaneous preterm birth. Sensitivity analyses including the 397 women who were initially excluded due to ARV use prior to pregnancy also did not detect a significant association between ARV with PI and risk of spontaneous preterm birth (OR: 1.34, 95% CI: 0.84, 2.16). Finally, in further sensitivity analyses re-classifying women who took tocolytic therapy at less than 37 weeks as delivering ‘preterm,’ no significant association between ARV with PI and all preterm birth was detected (OR: 1.25, 95% CI: 0.80, 1.96).
Risks of preterm birth and low birth weight according to the use of combination therapy with protease inhibitors (PI) during pregnancy
Fourteen percent (110/760) of infants with birth weight available had low birth weight. No significant association was observed between ARV with PI use and risk of low birth weight in the low birth weight study population (OR: 1.36, 95% CI: 0.76, 2.44) (). Sensitivity analyses including women who were initially excluded due to prior ARV use also did not detect a significant association between ARV with PI use and low birth weight (OR: 1.38, 95% CI: 0.83, 2.28).