Trimethoprim-sulfamethoxazole during pregnancy does not reduce risk of prematurity

1. In this randomized controlled trial, prophylactic treatment with trimethoprim-sulfamethoxazole (TMP-SMX) was not associated with a reduction in the incidence of prematurity or small-for-gestational-age (SGA) births.

2. TMP-SMX treatment was not associated with a higher incidence of adverse events of congenital anomalies.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Prematurity and SGA status, defined as a birth weight below the 10th percentile, are major contributors to neonatal mortality. HIV infection induces inflammatory responses in both the mother and neonate, which have been associated with these adverse pregnancy outcomes. As such, antibiotics have been proposed as a potential intervention to mitigate these effects by reducing inflammation. TMP-SMX is widely used among individuals with HIV in sub-Saharan Africa, but its role as a prophylactic treatment during pregnancy remains underexplored. This study aimed to assess whether TMP-SMX could reduce the incidence of prematurity and SGA births among individuals with HIV. The findings indicated that TMP-SMX treatment did not significantly increase birth weight. Similarly, there were no significant differences in the secondary outcomes, including the incidence of low birth weight, SGA status, maternal hospitalization or death, fetal loss, or neonatal hospitalization or death. While TMP-SMX treatment was associated with a slightly longer gestation and fewer preterm births, these differences were not statistically significant. Rates of adverse events and congenital anomalies were also comparable between groups. Study limitations included that 7.7% of randomized participants never initiated treatment, and among those who did, the median gestational age at initiation was 22 weeks. Furthermore, the study was underpowered to detect differences in congenital anomalies, and lower-than-expected postnatal follow-up limited assessment of neonatal growth trajectories. Overall, prophylactic treatment with TMP-SMX was not associated with a reduction in the incidence of prematurity and SGA births.

Click here to read the study in NEJM

Relevant Reading: Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention

In-Depth [randomized controlled trial]: This randomized controlled trial evaluated the efficacy of prophylactic TMP-SMX in reducing the incidence of prematurity and SGA births, with the goal of improving neonatal outcomes. Eligible participants had a positive urine pregnancy test, known HIV status (HIV-positive individuals were included if their CD4 count was >350 cells/μL), were not previously taking TMP-SMX, had no contraindications to the drug, and were able to receive prenatal care at the study site. Exclusion criteria were not explicitly stated. A total of 993 participants were randomized: 495 to TMP-SMX and 498 to placebo. The first dose of TMP-SMX was administered at a median gestational age of 21.7 weeks. Mean birth weight was 3040 ± 460 g in the TMP-SMX group and 3019 ± 526 g in the placebo group (95% Confidence Interval [CI], –43 to 83; p=0.53). In a subgroup analysis of participants with HIV, there was limited evidence suggesting a slight increase in birth weight with TMP-SMX treatment. Secondary outcomes were generally comparable between groups. The incidence of low birth weight was 10.0% in the TMP-SMX group and 11.6% in the placebo group (Relative Risk [RR], 0.86; 95% CI, 0.60 to 1.24). Preterm birth occurred in 6.9% vs. 11.5% (RR, 0.60; 95% CI, 0.39 to 0.91), while SGA births occurred in 20.3% vs. 17.7% (RR, 1.15; 95% CI, 0.88 to 1.50). Fetal loss was reported in 4.2% vs. 3.3% (RR, 1.27; 95% CI, 0.66 to 2.43). The mean gestational duration was 39.3 ± 1.7 weeks in the TMP-SMX group and 38.6 ± 2.6 weeks in the placebo group (95% CI, 0.2 to 0.7). Head circumference-for-age at six weeks was slightly higher in the TMP-SMX group (0.27 ± 1.18 vs. 0.19 ± 1.23; 95% CI, –0.11 to 0.26). Maternal hospitalization or death occurred in 4.2% vs. 5.0%, and neonatal hospitalization or death in 3.1% vs. 2.6%. Adverse events (114 vs. 110) and congenital anomalies (5 vs. 4) were similar between groups. In summary, TMP-SMX treatment was not associated with significant improvements in gestational age, birth weight, or neonatal outcomes.

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