Of the 3,358 pregnant women whom we invited to participate in the study, 1,320 were randomized into the three intervention groups: control, monthly SP, and AZI-SP (). At enrollment, the three groups were comparable, except for small differences in the number of previous pregnancies and prevalence of malaria parasitemia (). The enrolled women and those not enrolled had approximately the same mean age (25 versus 26 years) and number of previous pregnancies (2.3 versus 2.5).
Figure 1. Participant flow in the study in Malawi in CONSORT recommended format.44
Baseline characteristics of participants at study enrollment, Malawi*
The mean (standard deviation, SD) number of scheduled SP treatments received was 2.0 (0.2) in the control group, 4.0 (1.0) in the monthly SP group, and 4.0 (0.9) in the AZI-SP group. Women in the AZI-SP group received a mean (SD) of 2.0 (0.2) azithromycin doses. Follow-up data were obtained from 99.7% of the participants for length of gestation, and from approximately 90% for birth weights within two days of delivery ().
The overall proportion of preterm delivery was 15.1%. Compared with the controls, participants in the monthly SP group had an RR (95% CI) 0.86 (0.64 to 1.16, P = 0.32) and an absolute risk reduction of 2.5% (−2.4 to 7.4%) for preterm delivery (). For women in the AZI-SP group, the corresponding RR was 0.66 (0.48 to 0.91, P = 0.01) and risk reduction was 6.1% (1.4 to 10.8%). Analyses adjusting for number of previous pregnancies and malaria at enrollment gave similar results.
Incidence of preterm delivery, very preterm delivery, and low birth weight with different definitions by study group, Malawi*
The mean (SD) duration of pregnancy was 38.4 (2.2) weeks in the control group, 38.5 (2.4) weeks in the monthly SP group, and 38.8 (2.1) weeks in the AZI-SP group (P = 0.03). Compared with the controls, the participants in the monthly SP group delivered on average (95% CI) 0.2 (−0.1 to 0.5, P = 0.25) gestation weeks later and those in the AZI-SP group delivered 0.4 (0.1 to 0.7, P < 0.01) gestation weeks later. The differences in gestational duration between the three groups concentrated in the lower half of the distribution (). A cumulative frequency plot demonstrates that more deliveries started to occur at 30–33 gestation weeks in the control and the monthly SP groups, but only after 35 gestation weeks in the AZI-SP group (P = 0.03, by log-rank test) (). Compared with controls, those in the AZI-SP group had an RR of 0.48 (95% CI) (0.26 to 0.89, P = 0.02) for delivery before 35 completed gestation weeks ().
Duration of pregnancy by percentile, by study group, Malawi*
Figure 2. Cumulative frequency plot showing timing (gestational weeks) of deliveries in each group, Malawi. This figure appears in color at www.ajtmh.org.
There was no statistically proven interaction on the incidence of preterm delivery between intervention group and either number of previous pregnancies (P = 0.25), maternal HIV status (P = 0.18), or bed net use at enrollment (P = 0.24). Stratified analyses suggested that monthly SP treatment was associated with a reduced incidence of preterm delivery mainly among women who were primigravida, HIV-infected, or did not use a bed net at enrollment (). In the AZI-SP group, the differences between those with and those without these risk factors were smaller. However, most of these subgroup results were statistically insignificant.
Stratified analysis of preterm delivery (< 37 gw) by study group based on number of previous pregnancies, maternal HIV status, and maternal bed net use at enrollment, Malawi*
The overall proportion of recorded LBW < 2,500 grams was 10.0%. Compared with the controls, babies in the AZI-SP group had a RR of 0.61 (95% CI) (0.40 to 0.93, P = 0.02) and absolute risk reduction of 5.1% (95% CI) (0.9 to 9.3%) for LBW, whereas babies in the monthly SP group did not differ significantly from the controls (). Analyses adjusting for baseline malaria and number of previous pregnancies gave similar results.
The overall proportion of maternal peripheral blood malaria parasitemia was 3.0% at approximately 32 gestation weeks and 2.9% at delivery (). Compared with the controls, participants in the monthly SP and AZI-SP groups had a lower prevalence of peripheral malaria parasitemia at 32 gestation weeks (RR = 0.45 and 0.34, respectively) and at delivery (RR = 0.40 and 0.35, respectively), but only the 32-week results reached statistical significance. For placental malaria, the inter-group differences were smaller (RR = 0.84 and 0.72, respectively, P > 0.05).
Secondary maternal outcomes, Malawi*
At post-natal visit, the prevalence of maternal vaginal Trichomonas infection was 14.3% whereas C. trachomatis and N. gonorrhoeae infections were uncommon. Compared with the controls, women in the AZI-SP group had a lower prevalence (RR = 0.65, P = 0.02) of T. vaginalis infection ().
During maternal follow-up, the mean (SD) number of non-scheduled outpatient visits to the research health center was 0.5 (0.8) in the control group, 0.6 (0.9) in the monthly SP group, and 0.4 (0.7) in the AZI-SP group (P < 0.01). The mean (SD) number of quinine doses given at these visits was 0.03 (0.18) for the control group, 0.02 (0.16) for the monthly SP group, and 0.01 (0.09) for the AZI-SP group (P = 0.10). Against the agreed practice, some SP doses were also given at the non-scheduled visits, but the number of these was small (mean = 0.008 doses), and there were no differences between the groups. Syphilis treatment during pregnancy was given to 19, 25, and 22 participants in the control, monthly SP and AZI-SP groups, respectively.
The overall perinatal mortality rate was 64/1,000 births and the neonatal mortality rate was 25/1,000 live births, and there were no major differences between the groups (P = 0.99 for perinatal deaths and P = 0.32 for neonatal deaths). We recorded 125 SAEs for infants (89 abortions, stillbirths, and infant deaths, 28 hospitalizations, and 8 congenital malformations): 44 in the control group, 48 in the monthly SP group, and 33 in the AZI-SP group (P = 0.18). Other types of neonate SAEs were evenly distributed between the groups, but significantly fewer (0.7%) neonates were hospitalized in the AZI-SP group than in the control group (2.7%) or monthly SP (2.9%) group (P = 0.02). For mothers, we observed 14 SAEs (1 death, 4 hospitalizations, and 9 cases of severe anemia): 3 in the control group, 5 in the monthly SP group, and 6 in the AZI-SP group (P = 0.71). Most SAEs were not considered related to trial interventions and no infant or mother had more than one SAE.