Trimethoprim–Sulfamethoxazole in Pregnancy: No Impact on Birth Weight in a Zimbabwean RCT

Highlights

• Trimethoprim–sulfamethoxazole (TMP-SMX) prophylaxis during pregnancy did not significantly improve birth weight compared to placebo.
• The intervention was safe, with similar adverse event rates in both groups.
• The trial provides high-quality evidence to inform maternal infection prophylaxis guidelines in sub-Saharan Africa.

Clinical Background and Disease Burden

Maternal infections are a leading contributor to adverse birth outcomes, including low birth weight and preterm birth, especially in low- and middle-income countries. These outcomes are associated with increased neonatal morbidity and mortality, as well as long-term developmental sequelae. In sub-Saharan Africa, where the burden of infectious diseases is high, there is a pressing need for effective and safe interventions to improve maternal and neonatal outcomes. TMP-SMX is an antibiotic with broad-spectrum activity and is already used for prophylaxis in certain high-risk populations, such as people living with HIV. However, its impact on birth outcomes in the general obstetric population remained unclear until this trial.

Research Methodology

This double-blind, randomized, placebo-controlled trial was conducted in Zimbabwe and enrolled 993 pregnant women, including 131 with HIV infection. Participants were randomized to receive either TMP-SMX (960 mg daily) or matched placebo from at least 14 weeks’ gestation until delivery. The primary endpoint was infant birth weight, a robust surrogate for neonatal health. Secondary outcomes and safety were also assessed. The median gestational age at the start of intervention was 21.7 weeks (IQR, 17.3–26.4).

Key Findings

In the intention-to-treat analysis, mean (±SD) birth weights were 3040±460 g in the TMP-SMX group and 3019±526 g in the placebo group. The mean difference was 20 g (95% CI, −43 to 83; P=0.53), indicating no statistically significant benefit. The rates of adverse events, including maternal and neonatal complications, were similar between the two groups. These findings were consistent across prespecified subgroups, including women living with HIV.

The lack of significant difference suggests that TMP-SMX, as administered in this trial, does not translate to clinically meaningful improvements in birth weight in this population.

Mechanistic Insights and Biological Plausibility

TMP-SMX is known to reduce the incidence of certain bacterial infections and is recommended for HIV-positive pregnant women to reduce opportunistic infections. The hypothesis for this study was that broader prophylaxis against maternal infections might reduce subclinical infections linked to fetal growth restriction. However, the absence of benefit on birth weight implies either that the infectious etiologies most relevant for growth restriction are not effectively targeted by TMP-SMX, or that the background rate of preventable infections was too low for a measurable effect.

Controversies or Limitations

Several limitations must be considered. The median gestational age at intervention initiation was late in the first or early second trimester, possibly missing a window of maximal benefit. The study did not assess impacts on other important birth outcomes, such as stillbirth or neonatal sepsis, in detail. Generalizability may be limited to settings with similar infection epidemiology and healthcare infrastructure. Finally, the trial was powered to detect differences in birth weight, not rarer outcomes such as severe neonatal morbidity or mortality.

Conclusion

This rigorous, well-conducted trial demonstrates that TMP-SMX prophylaxis during pregnancy does not significantly improve birth weight in a Zimbabwean population, including both HIV-positive and HIV-negative women. These findings do not support broadening TMP-SMX use for birth weight improvement in similar settings. Further research may focus on alternative interventions or earlier prophylaxis. For now, TMP-SMX should remain targeted to established indications, such as prophylaxis in HIV-infected pregnant women.

References

Chasekwa B, Munhanzi F, Madhuyu L, et al. A Trial of Trimethoprim-Sulfamethoxazole in Pregnancy to Improve Birth Outcomes. N Engl J Med. 2025 Jun 5;392(21):2125-2134. doi: 10.1056/NEJMoa2408114. PMID: 40466066.