On the Pathway to Better Birth Outcomes?

A Systematic Review of Azithromycin and Curable Sexually Transmitted Infections

R Matthew Chico; Berkin B Hack; Melanie J Newport; Enesia Ngulube; Daniel Chandramohan


Expert Rev Anti Infect Ther. 2013;11(12):1303-1332. 

In This Article

Abstract and Introduction


The WHO recommends the administration of sulfadoxine-pyrimethamine (SP) to all pregnant women living in areas of moderate (stable) to high malaria transmission during scheduled antenatal visits, beginning in the second trimester and continuing to delivery. Malaria parasites have lost sensitivity to SP in many endemic areas, prompting the investigation of alternatives that include azithromycin-based combination (ABC) therapies. Use of ABC therapies may also confer protection against curable sexually transmitted infections and reproductive tract infections (STIs/RTIs). The magnitude of protection at the population level would depend on the efficacy of the azithromycin-based regimen used and the underlying prevalence of curable STIs/RTIs among pregnant women who receive preventive treatment. This systematic review summarizes the efficacy data of azithromycin against curable STIs/RTIs.


The WHO recommends the administration of sulfadoxine-pyrimethamine (SP) to all pregnant women who live in areas of moderate (stable) to high malaria transmission during scheduled antenatal care (ANC) visits, beginning in the second trimester and continuing to delivery.[1] This intervention, known as intermittent preventive treatment of malaria in pregnancy (IPTp), is national policy in 36 countries worldwide, 35 of which are in sub-Saharan Africa.[2] The objective of IPTp-SP is to reduce the incidence of low birthweight and maternal anemia attributable to malaria. In recent years, however, malaria parasites have developed resistance to SP such that IPTp no longer reduces the incidence of low birthweight in some epidemiological settings, particularly in East Africa.[3] Evidence suggests that in areas where parasites express the 581G dhps mutation that is associated with SP resistance, the administration of IPTp-SP may even harm fetal growth.[4–6] Thus, the urgency to replace SP has never been greater and azithromycin-based combination (ABC) therapies are among leading candidates to do so.

Azithromycin is a slow-acting analog of erythromycin in the macrolide (azalide) class of drugs, which targets the ribosomal subunit of susceptible microorganisms and causes cellular death by inhibiting protein synthesis.[7] It has in vitro and in vivo antimalarial properties[8] and can be safely administered during pregnancy.[9] Two human challenge studies have published results of azithromycin monotherapy treatment against Plasmodium falciparum infection. The first study reported a protective effect of 40% (n = 10; 95% CI: 12–74%) among immunologically naïve patients who received 250 mg azithromycin daily for 2 weeks prior to inoculation and for 1 week more following exposure.[10] When the same regimen was used for one additional week post-inoculation, treatment efficacy was 100% (n = 10).[11] Despite this finding, comparable results have not been replicated in endemic settings where patients often have mixed and multiple infections. However, in vitro evidence suggests that azithromycin may be combined with antimalarial partner drugs to prevent or to cure P. falciparum infection,[12] the malaria species most prevalent in sub-Saharan Africa and which uniquely adhere to the placenta of pregnant women. In addition to reducing the burden of malaria infection, ABC therapies may also protect against adverse birth outcomes attributable to curable sexually transmitted and reproductive tract infections (STIs/RTIs). This could offer considerable public health impact. A recent meta-analysis suggests that curable STIs/RTIs are as prevalent as malaria parasitemia, if not more so, among pregnant women who attend ANC facilities in sub-Saharan Africa.[13] Five curable STIs/RTIs – Treponema pallidum, Neisseria gonorrheae, Chlamydiatrachomatis, Trichomonas vaginalis and bacterial vaginosis – are associated with adverse birth outcomes that include spontaneous abortion,[14–18] stillbirth,[19–21] intrauterine growth retardation,[20,22,23] premature rupture of membranes,[24–26] preterm birth[17,22,23,26–33] and low birthweight (Table 1).[20,23,24,28,29,33–35] This paper summarizes azithromycin efficacy and sensitivity against these curable STIs/RTIs and highlights important issues for policymakers to consider while determining the potential use of ABC therapies in IPTp.