DISCUSSION
LBW, stunting, malaria, parasitemia, weight gain, PCR-diagnosed malaria parasitemia
MALARIA, PRETERM BIRTH, PARASITEMIA
The aim of this study was to determine the impact of antenatal monthly SP with or without two doses of azithromycin on maternal PCR-diagnosed malaria parasitemia and fetal biparietal diameter and femur length growth velocity in the second and third trimesters of pregnancy compared with two doses of SP. In a sample of 1,320 rural Malawian women, the odds of malaria parasitemia during the second and third trimesters separately or combined were up to 50% lower among participants treated with monthly SP or AZI-SP compared with those in the control group. There were no statistically significant interactions between malaria parasitemia and maternal HIV status, parity, or bed net use. However, the odds of malaria parasitemia were 50–76% lower among HIV-positive and primiparous women in the monthly SP and AZI-SP groups compared with those in the control group, with statistically significant differences among primiparous women in both intervention groups compared with the control. There were no differences between the groups in the growth velocity of biparietal diameter or femur length.The strengths of this trial include random group allocation, broad inclusion criteria, a large sample size, comprehensive follow-up, and blinding of the outcome assessors. Internal validity could have been compromised by variation in the timing of DBS collection in terms of 1) gestational weeks and ultrasound measurements during pregnancy, 2) the small baseline differences in the prevalence of maternal malaria parasitemia and number of previous pregnancies between the intervention groups, and 3) that the study was not powered to detect small differences between the monthly SP and the AZI-SP groups or find interactions for the outcomes. However, we used all available malaria parasitemia and ultrasound measurements as outcomes, regardless of the timing, using mixed effect models that allowed this. All the models adjusted for variables with imbalance at baseline. Thus, we believe these factors did not bias our conclusions, and we consider the findings indicative of a causal association between the antenatal monthly SP and AZI-SP interventions and reduced maternal malaria parasitemia prevalence during pregnancy. The impact may have been larger among primiparous or HIV-positive women than among multiparous or HIV-negative women, but the study was not sufficiently powered to make firm conclusions from the subgroup analyses. In contrast, the findings do not provide support for a hypothesis that either of the interventions would affect biparietal diameter or femur length growth velocity.Our results are in line with other studies that have shown a positive impact of monthly SP on maternal malaria during pregnancy compared with the two-dose SP regimen.Although maternal malaria has been shown to have a negative impact on fetal and newborn head size and length,Because we did not measure fetal abdominal circumference in this study, we could not use ultrasound assessment to calculate fetal weight gain during pregnancy in the way we assessed gains in length. However, we have previously reported that infants born to mothers in the AZI-SP group had about 40% lower incidence of LBW and 140 g higher mean birth weight than infants born to mothers in the control group.Earlier results from this trial have shown that antenatal AZI-SP treatment reduced the incidence of preterm birth, LBW, and incidence of stunting during the first 5 years of a child’s life compared with two doses of SP.After the implementation of our study 15–20 years ago, the recommendation for IPTp has changed from two doses to monthly dosing with SP.In conclusion, results from this study support the hypothesis that monthly SP with or without two doses of azithromycin reduced maternal malaria parasitemia during pregnancy in Malawi. In contrast, the study findings did not provide evidence that the same interventions would affect growth velocity of fetal biparietal diameter and femur length. When combined with earlier results on birth size, the findings suggest that the AZI-SP intervention increased mean infant length at 1 month of age mainly by extending the duration of pregnancy and increased birth weight also by increasing the speed of fetal weight gain. The addition of azithromycin to monthly SP did not greatly improve the antimalarial effect of the IPTp regimen but further improved birth outcomes through other mechanisms, probably through antibacterial and anti-inflammatory pathways.