Discussion
fetal loss, nausea, malaria, vomiting, dizziness, infection, weight gain, reinfection, malaria infection, chlamydia
MALARIA, ADVERSE EVENTS, STIS, INFECTION, CHLAMYDIA INFECTION, REINFECTION, BACTERIAL VAGINOSIS, PRETERM DELIVERY
In this trial, which compared standard of care with monthly IPTp with sulfadoxine–pyrimethamine with monthly IPTp with dihydroartemisinin–piperaquine and monthly IPTp with dihydroartemisinin–piperaquine plus azithromycin, the use of dihydroartemisinin–piperaquine was associated with reductions in clinical malaria, malaria infection detected by microscopy during pregnancy, and placental malaria at the time of birth. However, despite these reductions in malaria, the risk of adverse pregnancy outcomes (composite primary endpoint) was significantly lower in the sulfadoxine–pyrimethamine group than in both dihydroartemisinin–piperaquine groups. Newborn babies in the sulfadoxine–pyrimethamine group had a lower risk of low birthweight and of being small for gestational age compared with the dihydroartemisinin–piperaquine groups. Birthweight for gestational age Z scores at birth, a marker of fetal growth, were higher in the sulfadoxine–pyrimethamine group, as were Z scores for estimated fetal weight obtained by ultrasound. No statistical differences were reported in mean gestational age at birth, preterm delivery, fetal loss, or neonatal mortality. The results were similar in all three countries, including northeastern Tanzania, where 40% of parasites carried the highly resistant sextuple In a previous meta-analysisThe observed 31% lower risk of low birthweight with sulfadoxine–pyrimethamine versus dihydroartemisinin–piperaquine (the reciprocal of the 44% increase in risk, relative to sulfadoxine–pyrimethamine) and 25% lower risk versus dihydroartemisinin–piperaquine plus azithromycin (the reciprocal of the 33% increase in risk, relative to sulfadoxine–pyrimethamine) are similar to the 18% reduction in low birthweight associated with daily iron supplementation in high-quality trials,The mechanisms by which sulfadoxine–pyrimethamine might stimulate fetal growth are not fully understood. A potent non-malarial effect of sulfadoxine–pyrimethamine might exist that outweighed any improvements in birthweight associated with better malaria prevention in the dihydroartemisinin–piperaquine group.The number of serious adverse events was similar across all three groups in mothers and infants. IPTp with dihydroartemisinin–piperaquine was well tolerated, which is essential for drugs used for chemoprevention when most recipients are asymptomatic. Although dizziness, vomiting, and nausea were more frequently reported in the dihydroartemisinin–piperaquine groups than in the sulfadoxine–pyrimethamine group, these adverse events were reported by less than 5% of participants and did not affect adherence or dropouts. However, the addition of azithromycin resulted in significantly more vomiting than with dihydroartemisinin–piperaquine alone.Furthermore, adding azithromycin to dihydroartemisinin–piperaquine was not associated with a reduction in the composite primary endpoint of adverse pregnancy outcomes, any of the individual components of the composite primary endpoint, or a reduction in STIs and bacterial vaginosis. The high prevalence of curable STIs and bacterial vaginosis at enrolment (16·9%) in this study, which is similar to that reported in a meta-analysis,We considered more frequent doses of azithromycin during pregnancy at the design stage. However, after discussion with WHO, this idea was disregarded in favour of a single dose of azithromycin because of concerns about the potential effect of azithromycin on macrolide resistance when given presumptively several times in pregnancy to all pregnant women even when asymptomatic. None of the pregnancy studies summarised, including our trial, involved partner screening and treatment for STIs; therefore, reinfection cannot be ruled out. The risk of reinfection is an important consideration, which might explain the superior effect of sulfadoxine–pyrimethamine on chlamydia infection. Women in the dihydroartemisinin–piperaquine plus azithromycin group received 2 g of azithromycin at the enrolment visit, double the WHO-recommended first-line treatment for chlamydia (1 g on 1 day). By contrast, participants in the IPTp with sulfadoxine–pyrimethamine group received a median of five courses of 1·5 g of sulfadoxine throughout pregnancy. Sulfadoxine is a sulfonamide derivative. Sulfisoxazole, another sulfonamide, which inhibits Because both dihydroartemisinin–piperaquine and azithromycin can cause QT prolongation,The strengths of this trial are that it was powered to detect differences in the composite primary endpoint of adverse pregnancy outcomes and used ultrasound to determine gestational age for the accurate assessment of preterm delivery, small for gestational age, and estimated fetal weight gain during pregnancy. It also contained serial measures of gestational weight and assessment of malaria infection and common STIs and bacterial vaginosis. Furthermore, adherence to the follow-up schedule was good, with 91% of scheduled visits attended and 92% of participants included in the primary analysis, and the trial was done in areas with both high and very high sulfadoxine–pyrimethamine resistance.A limitation of this study is that only the first-day dose of each course was given as directly observed therapy in the clinic: although all sulfadoxine–pyrimethamine courses were given under direct supervision, the second and third day doses of the 3-day dihydroartemisinin–piperaquine course and the second day dose of the 2-day azithromycin course were self-administered at home. Even though the self-reported adherence to all doses of dihydroartemisinin–piperaquine exceeded 97·5%, this was verified in less than 10% of IPTp courses by unannounced home visits. Furthermore, 9% of monthly courses were skipped. Incomplete adherence or spacing beyond 1 month between some of the courses could have resulted in inadequate piperaquine drug concentrations,In conclusion, replacing IPTp with sulfadoxine–pyrimethamine with dihydroartemisinin–piperaquine will probably result in marked and clinically relevant reductions in clinical malaria and maternal malaria infection during pregnancy in areas with high sulfadoxine–pyrimethamine resistance. However, countries that choose to do so need to be aware that replacing sulfadoxine–pyrimethamine with dihydroartemisinin–piperaquine might increase the absolute number of adverse pregnancy outcomes compared with IPTp with sulfadoxine–pyrimethamine, even in areas with very high sulfadoxine–pyrimethamine resistance. We hypothesise that in these high resistance areas, sulfadoxine–pyrimethamine is likely to continue to provide benefits through malaria-independent effects on fetal growth, which might have masked any reductions in malaria-associated adverse pregnancy outcomes with dihydroartemisinin–piperaquine. Combining the superior antimalarial effects of dihydroartemisinin–piperaquine and the non-malarial effect of sulfadoxine–pyrimethamine on fetal growth merits future investigation. Further studies of how IPTp with sulfadoxine–pyrimethamine promotes gestational weight gain and fetal growth are also warranted.