**Background:** Low birth weight (LBW) is a major risk factor for childhood mortality, morbidity, and lower cognitive outcomes, with over 20 million LBW infants born annually, most in sub-Saharan Africa and Southern Asia. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is a key intervention in malaria-endemic areas, and meta-analyses suggest three or more doses reduce LBW by approximately 20% compared with two doses. Previous results from the authors' trial in rural Malawi showed that adding azithromycin to monthly SP (AZI-SP) further reduced LBW prevalence and increased infant weight, length, and head circumference at 1 month of age, as well as reducing stunting and improving cognitive development. This secondary analysis aimed to determine whether these benefits were mediated through reduced maternal malaria parasitemia or through direct effects on fetal growth velocity.
**Methods:** Between December 2003 and October 2006, 1,320 pregnant women (gestational age 14–26 weeks) were enrolled in a single-center, randomized, partially placebo-controlled, outcome assessor–blinded trial in rural Malawi. Women were randomized to: (1) control group (n=436) receiving two doses of SP at enrollment and 28–34 weeks plus placebo for azithromycin; (2) monthly SP group (n=441) receiving SP monthly from enrollment until 37 weeks plus two doses of placebo; or (3) AZI-SP group (n=443) receiving monthly SP plus two doses of active azithromycin at enrollment and 28–34 weeks. Participants were seen every 4 weeks until 36 weeks, then weekly. Dried blood spots were collected at each visit for real-time PCR diagnosis of Plasmodium falciparum parasitemia. In a random subgroup of 341 women, fetal biparietal diameter and femur length were measured by ultrasound. Mixed-effects logistic regression was used for malaria outcomes, and mixed-effects linear regression for fetal growth, adjusting for baseline imbalances in parity and malaria prevalence.
**Key Results:** At enrollment, PCR-diagnosed malaria parasitemia prevalence was 43.2% in the control group, 38.2% in the monthly SP group, and 40.5% in the AZI-SP group. During follow-up, the overall proportion of positive DBS samples was 12.2% (177/1,447) in controls, 8.5% (126/1,489) in monthly SP, and 7.2% (108/1,497) in AZI-SP. For the entire follow-up period, the odds ratio (OR) for malaria parasitemia compared with control was 0.64 (95% CI: 0.42–0.98; p=0.040) for monthly SP and 0.50 (95% CI: 0.32–0.76; p=0.001) for AZI-SP. The marginal risk ratios were 0.75 (95% CI: 0.55–0.96) and 0.63 (95% CI: 0.45–0.81), respectively. In the second trimester, ORs were 0.79 (0.46–1.37; p=0.399) for monthly SP and 0.47 (0.26–0.84; p=0.012) for AZI-SP. In the third trimester, ORs were 0.58 (0.37–0.92; p=0.021) and 0.51 (0.32–0.81; p=0.004), respectively. Differences between AZI-SP and monthly SP were not statistically significant (OR 0.77, 95% CI: 0.49–1.20; p=0.248). No significant interactions were found with parity, HIV status, or bed net use, though the effect appeared larger among HIV-positive women (OR 0.24, 95% CI: 0.07–0.83) and primiparous women (OR 0.38, 95% CI: 0.16–0.90) in the AZI-SP group. For fetal growth, estimated mean biparietal diameter change per 4 weeks in the second trimester was 12.4 mm (control), 12.0 mm (monthly SP), and 11.9 mm (AZI-SP); in the third trimester, 7.1 mm, 7.0 mm, and 6.9 mm, respectively. Femur length change per 4 weeks in the second trimester was 9.4 mm, 9.9 mm, and 9.1 mm; in the third trimester, 6.7 mm, 6.0 mm, and 6.1 mm. None of the differences between groups were statistically significant (all global p>0.05). Sensitivity analyses excluding measurements at or after 38 weeks did not change the results.
**Clinical Implications:** Monthly SP with or without azithromycin significantly reduced maternal malaria parasitemia during pregnancy compared with two-dose SP, with the AZI-SP group showing a numerically greater but not statistically superior reduction. The lack of effect on fetal biparietal diameter and femur length growth velocity, combined with prior evidence that AZI-SP increased infant length and head circumference at 1 month, suggests that azithromycin's benefits on birth size are mediated primarily through extending pregnancy duration (mean 3 days longer) rather than increasing fetal growth velocity. Statistical modeling from prior work indicated approximately one-third of the birth weight difference was due to longer gestation and two-thirds to increased weight gain velocity, suggesting differential effects on weight versus linear growth. The findings imply that azithromycin's additional benefits likely operate through antibacterial or anti-inflammatory pathways rather than enhanced antimalarial activity. Limitations include the study being conducted 15–20 years ago, before current policies of monthly SP for all pregnant women, antiretroviral therapy for HIV-positive women, and co-trimoxazole prophylaxis, as well as concerns about increasing SP and antibiotic resistance. The study was not powered to detect small differences between monthly SP and AZI-SP groups or to make firm conclusions from subgroup analyses.