Defining the combined benefit of intermittent preventive malaria treatment in pregnancy
Authors: Sam Salman, Tim M E Davis, Brioni Moore
Journal: The Lancet Global Health (2020)

WHO has included intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine as an important malaria intervention since 2012.1WHOWHO policy brief for the implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP). World Health Organization, Geneva2013Google Scholar Although other candidate therapies remain under investigation and despite waning sulfadoxine-pyrimethamine antimalarial efficacy due to increasing parasite resistance, IPTp with sulfadoxine-pyrimethamine remains a key component of the management of pregnant women in malaria-endemic areas. In areas of high-grade parasite resistance, the use of IPTp with sulfadoxine-pyrimethamine is associated with improved birthweight, suggesting that there are benefits of beyond antimalarial efficacy. In The Lancet Global Health, Michelle Roh and colleagues2Roh ME ter Kuile FO Rerolle F et al.Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.Lancet Glob Health. 2020; 8: e942-e953Google Scholar did a mediation analysis with individual-level patient data drawn from three IPTp trials from Uganda and Kenya, in which sulfadoxine-pyrimethamine was compared with dihydroartemisinin-piperaquine. Their primary aim was to identify the relative benefits afforded through antimalarial versus other drug effects. Although dihydroartemisinin-piperaquine is one of the most promising IPTp candidates to replace sulfadoxine-pyrimethamine should its efficacy wane substantially, this analysis showed that the non-malarial effects of sulfadoxine-pyrimethamine on birthweight (suggested as being primarily due to antibiotic activity against reproductive tract infections) outweighed the more potent antimalarial effects of dihydroartemisinin-piperaquine.2Roh ME ter Kuile FO Rerolle F et al.Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.Lancet Glob Health. 2020; 8: e942-e953Google Scholar These findings support the proposition that the success of IPTp cannot be gauged from its antimalarial effects alone. Roh and colleagues2Roh ME ter Kuile FO Rerolle F et al.Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.Lancet Glob Health. 2020; 8: e942-e953Google Scholar recommend that future ITPp regimens should consider combinations of sulfadoxine-pyrimethamine with dihydroartemisinin-piperaquine, rather than dihydroartemisinin-piperaquine alone, so that both a reduction in maternal malaria and improved birthweight outcomes are achieved. However, we suggest that alternative antimicrobial partners for dihydroartemisinin-piperaquine might be preferable. The need for dihydroartemisinin-piperaquine partners other than sulfadoxine-pyrimethamine is highlighted by the contraindication to sulfadoxine-pyrimethamine use in HIV-positive women receiving concomitant co-trimoxazole therapy, a consideration that complicates the widespread deployment of IPTp with sulfadoxine-pyrimethamine in sub-Saharan Africa. Azithromycin is one such candidate that has been investigated when combined with sulfadoxine-pyrimethamine in two IPTp trials in Malawi3Luntamo M Kulmala T Mbewe B Cheung YB Maleta K Ashorn P Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial.Am J Trop Med Hyg. 2010; 83: 1212-1220Crossref PubMed Scopus (69) Google Scholar and Papua New Guinea.4Unger HW Ome-Kaius M Wangnapi RA et al.Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial.BMC Med. 2015; 13: 9Crossref PubMed Scopus (42) Google Scholar Although azithromycin has only modest antimalarial activity in its own right,5Gingras BA Jensen JB Activity of azithromycin (CP-62,993) and erythromycin against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.Am J Trop Med Hyg. 1992; 47: 378-382Crossref PubMed Scopus (47) Google Scholar it is an efficacious addition to sulfadoxine-pyrimethamine because of activity against sexually transmitted infections (STIs). The association between STIs and adverse birth outcomes is well established and an estimated 25–30% of pregnant women in low-income and middle-income countries are infected with Neisseria gonorrhoea, Chlamydia trachomatis, or Trichomonas vaginalas.6Joseph Davey DL Nyemba DC Gomba Y et al.Prevalence and correlates of sexually transmitted infections in pregnancy in HIV-infected and- uninfected women in Cape Town, South Africa.PLoS One. 2019; 14e0218349Crossref Scopus (16) Google Scholar Azithromycin is recommended for treatment of N gonorrhoea and C trachomatis in pregnancy,7WHOWHO guidelines for the treatment of Chlamydia trachomatis. World Health Organization, Geneva2016Google Scholar, 8WHOWHO guidelines for the treatment of Neisseria gonorrhoeae. World Health Organization, Geneva2016Google Scholar whereas sulfadoxine-pyrimethamine has a more limited spectrum of activity, primarily against Gram-positive bacteria.9Capan M Mombo-Ngoma G Makristathis A Ramharter M Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin.Malar J. 2010; 9: 303Crossref PubMed Scopus (28) Google Scholar In a study of pregnant Melanesian women,10Moore BR Benjamin JM Tobe R et al.A randomized open-label evaluation of the antimalarial prophylactic efficacy of azithromycin-piperaquine versus sulfadoxine-pyrimethamine in pregnant Papua New Guinean women.Antimicrob Agents Chemother. 2019; 63: 63Crossref Scopus (2) Google Scholar those allocated to azithromycin plus piperaquine delivered much higher birthweight babies than women receiving sulfadoxine-pyrimethamine alone.10Moore BR Benjamin JM Tobe R et al.A randomized open-label evaluation of the antimalarial prophylactic efficacy of azithromycin-piperaquine versus sulfadoxine-pyrimethamine in pregnant Papua New Guinean women.Antimicrob Agents Chemother. 2019; 63: 63Crossref Scopus (2) Google Scholar The outcomes of the IMPROVE trial (NCT03208179), in which IPTp with sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and dihydroartemisinin-piperaquine plus azithromycin will be compared, will be of great interest and could provide a key opportunity to show the non-malarial benefits of azithromycin. Metronidazole is another antimicrobial candidate under investigation for addition to IPTp regimens. Metronidazole has activity against T vaginalis and bacterial vaginosis while azithromycin does not. In the ASPIRE trial (NCT04189744), IPTp with sulfadoxine-pyrimethamine, IPTp with sulfadoxine-pyrimethamine plus metronidazole, and IPTp with dihydroartemisinin-piperaquine plus metronidazole are being compared. Unlike azithromycin, metronidazole has no antimalarial efficacy and all its associated pregnancy benefits will be non-malarial. A similar mediation analysis to that used by Roh and colleagues2Roh ME ter Kuile FO Rerolle F et al.Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.Lancet Glob Health. 2020; 8: e942-e953Google Scholar could show the relative benefit sulfadoxine-pyrimethamine has specifically for bacterial vaginosis and T vaginalis in the ASPIRE trial. IPTp with sulfadoxine-pyrimethamine remains one of the key components of strategies to reduce the burden of malaria in pregnancy. Although Roh and colleagues' findings2Roh ME ter Kuile FO Rerolle F et al.Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.Lancet Glob Health. 2020; 8: e942-e953Google Scholar were not unexpected, given the known continuing benefits of IPTp with sulfadoxine-pyrimethamine even in areas of high parasite resistance, the novel use of mediation analysis to determine the non-malarial contributions of sulfadoxine-pyrimethamine provides a framework for similar analyses in future IPTp studies. Additionally, this study suggests that the success of sulfadoxine-pyrimethamine when first introduced as IPTp was probably due to both malarial and non-malarial effects. In searching for a replacement, the ideal candidate regimen should address the effects of both malarial and non-malarial infections on adverse pregnancy outcomes. We declare no competing interests. Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysisIPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight. Full-Text PDF Open Access