Tropical Medicine and International Health doi:10.1111/j.1365-3156.2011.02765.x volume 00 no 00

Systematic Review Intermittent preventive treatment of in pregnancy: at the crossroads of public health policy

R. Matthew Chico and Daniel Chandramohan

Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

Summary The intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) has been a key component of the focused antenatal care package for nearly a decade, reducing the burden of low birthweight attributable to malaria in sub-Saharan Africa. However, SP has lost parasite sensitivity in many sub-Saharan locations during the same period, rendering its beneficial effect in IPTp debatable. Malaria has also declined in some epidemiological settings. There is no evidence to suggest, however, that the risk of malaria in pregnancy without preventive measures has declined in the same locations. Thus, the urgency to identify efficacious drugs and ⁄ or new strategies to prevent malaria in pregnancy remains as great as ever. We summarise the results of recently published SP-IPTp studies from areas of high drug resistance and ⁄ or low malaria transmission. We also present the evidence for mefloquine and azithromycin-based combinations (ABCs), two leading drug options to replace SP in IPTp. We discuss optimal dosing for ABCs and their likely protection against several sexually transmitted and reproductive tract . We also summarise data from a diagnosis-based alternative to IPTp known as the intermittent screening and treatment (IST) for malaria. Clinical and operational research is urgently needed to compare birth outcomes achieved by IPTp with ABCs vs. IST using an efficacious antimalarial therapy.

keywords pregnancy, malaria, sexually transmitted infections, Africa south of the Sahara, antenatal care, intermittent preventive treatment of malaria in pregnancy

worldwide, of which 33 are in sub-Saharan Africa (WHO Introduction 2009). The unique burden of malaria in pregnancy was first The objective of SP-IPTp is to reduce the of described 75 years ago (Wickaramsuriya 1937). Several poor pregnancy outcomes. Of particular importance is chemoprophylaxes in pregnancy have been used in the protecting against low birthweight (<2.5 kg) attributable decades since. The intermittent preventive treatment of to malaria. Mortality rates rise sharply among infants born malaria in pregnancy (IPTp) was first tested in 1995 as a <2.5 kg (Kramer 1987), and malaria placental is single, observed, therapeutic course of sulphadoxine and a key risk factor for low birthweight that is preventable by pyrimethamine (SP; 500-mg sulphadoxine and 25-mg SP-IPTp (Steketee et al. 2001). Low birthweight babies pyrimethamine per tablet; three tablets total) provided as who survive infancy have more episodes of diarrhoeal part of antenatal consultations (Shulman et al. 1999). disease and respiratory infection than children born above WHO now recommends that pregnant women in areas of the 2.5 kg threshold (Mccormick 1985; Ashworth 1998). stable transmission receive 2–3 courses of SP-IPTp after the They are also more likely to have micro-vascular condi- onset of foetal movement with each course at least tions later in life (Godfrey & Barker 2000; Osmond & 1 month apart (WHO 2009). SP-IPTp was readily incor- Barker 2000; Eriksson et al. 2001; Barker 2004) and porated into the focused antenatal care package as women are at greater risk, when adults, of developing recommended by WHO (WHO Antenatal Care Trial pre-eclampsia and delivering low birthweight infants Research Group 2002) and is now policy in 37 countries themselves (Sibai et al. 2005). Thus, increasing birthweight

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has public health implications that are lifelong and inter- (Table 1) suggests that SP-IPTp protection is limited where generational. However, recent evidence suggests that the the risk of personal exposure has been reduced by sleeping protective effect of SP-IPTp against low birthweight has under insecticide-treated nets (ITNs). declined substantially in areas of high SP drug resistance. Two doses of SP-IPTp had no protective effect against Alternative drugs for IPTp and ⁄ or different strategies all low birthweight [relative risk (RR), 0.99; 95% CI: 0.70– together are urgently needed. 1.39] or placental infection (RR = 1.0; 95% CI: 0.88–1.13; Despite reductions in malaria transmission in some P = 0.964) in a randomised controlled trial in Mozam- locales of sub-Saharan Africa (O’meara et al. 2010), there bique. The trial was conducted 2003–2005 among 1030 is no evidence the risk of malaria in pregnancy has also women of all gravidae, 90% of whom used ITNs. SP-IPTp fallen without preventive measures in the same areas. did, however, confer some important benefits. Women Plasmodium falciparum is the most common form of given SP had 40% fewer clinical malaria cases (95% CI: malaria in the sub-Saharan region and is uniquely respon- 7.40–61.20; P = 0.020) and half the of periph- sible for placental infection. Primigravidae are most at risk eral parasitaemia (7.10% vs. 15.15%; P = 0.001). SP-IPTp because of their lack of anti-adhesion antibodies that provided greater protection than ITNs alone against prevent parasites from binding to placental chondroitin malaria parasitaemia (RR = 0.52; 95% CI: 0.27–0.99; sulphate A with semi-immunity acquired following P. fal- P = 0.044) in the first 8 weeks post-partum (Menendez ciparum infection in each successive pregnancy (Fried et al. 2008). Secondary analysis showed that SP-IPTp 1998). Thus, at the population level, it is possible that the reduced early neonatal mortality by 61.3% (95% CI: 7.4– risk of adverse events associated with P. falciparum 83.8; P = 0.024; 20 deaths overall; 15 placebo vs. exposure will remain constant (and potentially increase) 5 SP-IPTp; P = 0.039; Menendez et al. 2010). for an unknown period of time while malaria control and Another placebo-controlled trial of 1035 pregnant elimination measures are scaled up and multigravidae fail multigravidae conducted 2002–2004 in The Gambia to acquire immunity through exposure in prior pregnan- reported that SP-IPTp offers no greater protection against cies. low birthweight than ITNs alone (effect difference = 28 g; We summarise results of recently published SP-IPTp 95% CI: 11–67; P = 0.16; Mbaye et al. 2006). Self- studies from areas of high SP resistance and ⁄ or low reported ITN use was 78% in both groups, although nets malaria transmission and present efficacy and safety data were not study-issued. for mefloquine and azithromycin-based combinations A lack of protective effect of SP-IPTp was observed in an (ABCs), two leading drug options to replace SP in IPTp. un-blinded randomised trial carried out from 2004 to 2007 We discuss optimal dosing for ABCs and the secondary among 5775 women of all gravidae in a low transmission benefits they would offer: clearing and ⁄ or preventing area of Uganda. No difference in the percentage of low several sexually transmitted and reproductive tract infec- birthweight infants was seen across the three intervention tions (STI ⁄ RTIs) in pregnancy. We present evidence from a groups: SP-IPTp alone (6.48%), ITNs alone (6.28%) and diagnosis-based alternative to IPTp that relies on inter- SP-IPTp plus ITNs (6.85%); P = 0.80 (Ndyomugyenyi mittent screening and treatment (IST) for malaria delivered et al. 2010). within a focused antenatal care package. Finally, we Alarming evidence comes from another cross-sectional discuss current coverage rates of antenatal care, the study in Tanzania with data from 2002 to 2005. Placental growing use of point-of-care diagnostic tools for HIV and parasitaemia was significantly higher in women given any syphilis, and the implications of incorporating a rapid dose of SP-IPTp than in women who received none [84% malaria tests alongside them as part of IST of malaria. (87 of 104) vs. 16% (17 of 104); P = 0.03]. Bed-net use was lowest among those who received no SP-IPTp doses (23.5%) in contrast to women given treatment early in IPTp with sulphadoxine-pyrimethamine pregnancy (36%) or shortly before delivery (30%) (Har- Meta-analysis has shown that two courses of SP-IPTp rington et al. 2009). The increase in placental parasitaemia administered in areas of high malaria transmission where among women given SP-IPTp was likely the result of parasites are sensitive to the drug combination increases extreme drug resistance. A study conducted in a nearby the mean birthweight of children born to paucigravidae by area reported a day-28 SP treatment failure rate of 82% 121 g [95% confidence interval (CI): 61–180] (Garner & among children under 5 years of age with a parasite Gulmezoglu 2006). SP-IPTp has less effect on the neonatal population that exhibited near saturation of the dhfr ⁄ dhps birthweight of multigravidae because they are better able quintuple mutation and mutation along dhps gene at codon to manage parasite densities (Rogerson et al. 2007). 581 (Gesase et al. 2009). Parasites resistant to pyrimeth- However, evidence from recently published studies amine may also be able to repopulate a human more

2 ª 2011 Blackwell Publishing Ltd ª Table 1 Low birthweight and parasitaemia (peripheral and placental) outcomes from recently published studies of sulphadoxine-pyrimethamine intermittent preventive Chandramohan D. & Chico M. R. Health International and Medicine Tropical 01BakelPbihn Ltd Publishing Blackwell 2011 treatment of malaria in pregnancy (SP-IPTp) in sub-Saharan Africa

Placebo (with ITNs) SP (2 courses without ITNs) SP (2 courses with ITNs)

Parasitaemia Parasitaemia Parasitaemia Malaria Location transmission (reference) Gravidae LBW Peripheral PlacentalLBW Peripheral PlacentalLBW Peripheral Placental and ITN coverage Key findings

Manhic¸a, Primiravidae 20.7% 23.6% 52.3% – – – 21.8% 13.5% 52.1% Perennial SP was as Mozambique (25 ⁄ 121) (30 ⁄ 127) (219 ⁄ 419) (29 ⁄ 133) (18 ⁄ 133) (222 ⁄ 426) transmission with effective as (Menendez 1–3 pregnancies 6.7% 16.1% 10.3% 6.3% seasonal variation; placebo et al. 2008) (13 ⁄ 195) (31 ⁄ 193) (20 ⁄ 194) (12 ⁄ 192) Self-reported use of ‡4 pregnancies 11.7% 8.0% 5.4% 30.4% ITNs was 90% in (21 ⁄ 180) (14 ⁄ 175) (9 ⁄ 167) (51 ⁄ 168) both treatment nemtetpeetv ramn fmlrai pregnancy in malaria of treatment preventive Intermittent groups

Farafenni, Secundigravidae and 6.9% 3.3% – – – – 5.5% 9.0% – Perennial SP was as The Gambia Multigravidae (63 ⁄ 917) (34 ⁄ 1035) (51 ⁄ 931) (91 ⁄ 1010) transmission with effective as (Mbaye seasonal variation; placebo et al. 2006) Self-reported ITN use was 78% in both groups

Kabale, Primigravidae 5.5% 12.9% 2.6% 5.1% 14.6% 4.3% 8.1% 15.3% 3.1% Low and unstable ITNs alone, Uganda (18 ⁄ 329) (201 ⁄ 1559) (16 ⁄ 622) (16 ⁄ 313) (231 ⁄ 1580) (28 ⁄ 651) (27 ⁄ 333) (231 ⁄ 1510) (19 ⁄ 613) transmission; SP-IPTp (Ndyomugyenyi Secundigravidae 5.8% 7.7% 5.1% Women in placebo alone, and et al. 2010) (16 ⁄ 277) (22 ⁄ 287) (14 ⁄ 276) and SP-IPTp plus ITNs plus 2–4 previous 5.9% 6.6% 7.2% ITNs group were SP-IPTp pregnancies (37 ⁄ 631) (40 ⁄ 610) (44 ⁄ 614) given treated nets; were ‡5 pregnancies 8.3% 6.1% 6.7% 97.0% used them. non-inferior (27 ⁄ 325) (21 ⁄ 347) (21 ⁄ 315) Women in SP-IPTp to each other group were not given ITNs and just 6.0% used their own Muheza, Primigravidae – – 35.3%* – – 45.5% – – 50.0%à Perennial Placebo Tanzania (6 ⁄ 17) (35 ⁄ 77) (5 ⁄ 10) transmission; ITN represents (Harrington Secundigravidae 41.2%* 28.6% 40.0%à use summarised women who et al. 2009) (7 ⁄ 17) (22 ⁄ 77) (4 ⁄ 10) among asterisks. received no Multigravidae 23.5%* 26.0% 10%à IPTp in this (4 ⁄ 17) (20 ⁄ 77) (1 ⁄ 10) cross- sectional study; SP use increased the risk of placental parasitaemia oue0 o00 no 00 volume

SP, sulphadoxine-pyrimethamine; ITNs, insecticide treated bed-nets; LBW, low birthweight. *Women who never received any SP-IPTp during the antenatal period; (0% used ITNs). Women who received SP-IPTp early in pregnancy (positive medical report ⁄ record but undetectable drug level; 14% used ITNs). àWomen who received recent SP-IPTp recipient (positive report ⁄ record and detectable drug level; 30% used ITNs). 3 Tropical Medicine and International Health volume 00 no 00

R. M. Chico & D. Chandramohan Intermittent preventive treatment of malaria in pregnancy

rapidly than less-fit ones when placed under drug pressure, IPTp with azithromycin-based combinations thereby increasing in vivo parasite densities following treatment (De Roode et al. 2005; Mockenhaupt et al. Azithromycin is a slow-acting macrolide that produces 2007). delayed-death in malaria parasites by causing the progeny Despite these reports, ecological studies have shown that of exposed parasites to inherit an apicoplast incapable of SP-IPTp continues to reduce the risk of low birthweight in protein synthesis (Retsema & Fu 2001; Schlu¨ nzen et al. areas where day-14 treatment failure rates in children have 2003; Dahl & Rosenthal 2008). A 3-day treatment regimen been as high as 40% (Ter Kuile et al. 2007) and WHO of azithromycin is optimal against P. falciparum with continues to encourage SP-IPTp use (WHO 2011). dosing no <1 g ⁄ day (Chico et al. 2008). However, azi- thromycin needs a partner compound and not all antima- larial drugs are pharmacologically compatible. Leading drugs and strategies to replace SP-IPTp Several ABCs may be considered for IPTp. Azithromycin plus chloroquine has demonstrated an additive-to-syner- IPTp with mefloquine gistic effect in vitro against P. falciparum (Nakornchai & Mefloquine is a slowly eliminated 4-quinoline-methanol Konthiang 2006). Additive effect has been reported against that acts against the asexual stages of the malaria parasite. chloroquine-sensitive strains while synergy has been A randomised controlled trial from 1987 to 1990 involving observed with chloroquine-resistant parasites. Although 4187 pregnant women in Malawi compared a treatment not well understood, chloroquine resistance is reversible dose of mefloquine (750 mg) administered at enrolment with calcium channel blockers that inhibit p-glycoprotein- followed by weekly chemoprophylaxis (250 mg) with three mediated efflux (Martin et al. 1987; Bray et al. 1994). chloroquine chemoprophylaxis regimens. Data from 1766 Because azithromycin is a p-glycoprotein substrate (Pachot mothers followed to delivery showed that women given et al. 2003), it may serve as a metabolic catalyst for mefloquine had fewer low birthweight infants than all reversing chloroquine resistance when the combination is chloroquine groups combined (12.5% vs. 15.5%; used against chloroquine-resistant strains. P = 0.05; Steketee et al. 1996a) and fewer cases of break- Synergy was seen in vivo within a multi-stage trial in India through parasitaemia [3.3% (13 of 394) vs. 17.7% (237 of (Dunne et al. 2005). In the first-stage, azithromycin (1 g 1077); Steketee et al. 1996c]. Adverse events were reported daily for 3 days) eliminated parasites in 19% (3 of 16) of by 60% of women in both treatment groups, decreasing to non-pregnant adults by day 28 while chloroquine cured 25% after the final course. One woman given mefloquine 27% (4 of 15) of cases. In the second-stage, co-adminis- developed severe neuropsychiatric symptoms which re- tration of azithromycin plus chloroquine using the same solved within 2 weeks (Steketee et al. 1996b). daily-doses cleared parasites in 97% (61 of 63) of patients Another randomised controlled trial in Benin from 2005 by day 28. These results are particularly noteworthy in the to 2008 tested SP-IPTp against mefloquine-IPTp among discussion of IPTp given that high sensitivity to chloroquine 1601 women (Table 2). At enrolment, 53% of patients in has returned in vitro (Djimde et al. 2001; Takechi et al. both groups reported sleeping under ITNs the previous 2001) and in vivo (Kublin et al. 2003; Laufer et al. 2006) in night. Mefloquine was more efficacious than SP in Malawi and, to a lesser extent, in Kenya (Mwai et al. 2009). preventing placental malaria (1.7% vs. 4.4%; P = 0.005) Azithromycin could be combined with piperaquine and clinical episodes (26 cases vs. 68 cases ⁄ 10 000 person- which is probably better tolerated than chloroquine (Davis months; P = 0.007). However, there was no difference in et al. 2005). Azithromycin has an additive effect with the percentage of low birthweight babies born to women either mefloquine or pyronaridine (Nakornchai & Kon- who received mefloquine and SP (8% vs. 9.8%; differ- thiang 2006). Artesunate and azithromycin, in contrast, ence = )1.8%; 95% CI: )4.8 to 1.1; Briand et al. 2009). have demonstrated antagonism against fresh P. falciparum After the first course of IPTp, there were significantly samples (Nakornchai & Konthiang 2006), a confirmation higher rates of adverse events in the mefloquine group of earlier observations from clones and culture-adapted compared to SP (78% vs. 32%; P = 0.001). Of these malaria parasites (Ohrt et al. 2002). Antagonism may women, 28% given mefloquine sought medical attention partially explain why a recent paediatric trial suspended for their reaction while only 5% did from the SP group. treatment using azithromycin plus artesunate (Sykes et al. Following the second course of IPTp, side effects declined 2009), although two studies of semi-immune adults have to 39% and 13% in the mefloquine and SP groups, shown efficacious results (Noedl et al. 2006; Thriemer respectively. As in Malawi, one subject had severe neuro- et al. 2010). Additive-to-synergistic in vitro effect has been psychiatric symptoms caused by mefloquine, resolving reported between azithromycin and dihydroartemisinin spontaneously within 3 days. (Noedl et al. 2007). Azithromycin could also be added to

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Table 2 Low birthweight, placental parasitaemia and preterm delivery outcomes in recently published intermittent preventive treatment of malaria in pregnancy studies involving azithromycin and mefloquine in sub-Saharan Africa

SP (2 courses SP (2 courses SP (monthly SP (monthly with MQ (2 courses without ITNs) with ITNs) with ITNs) AZ twice and ITNs) with ITNs) Malaria Location Parasitaemia Parasitaemia transmission (reference) Gravidae LBW Preterm LBW Preterm placental LBW Preterm LBW Preterm LBW placental and ITN use Key findings

Ouidah, Primigravidae – – 18% –– –––– 15%– Perennial MQ was as Benin (35 ⁄ 195) (29 ⁄ 193) transmission protective as (Briand Multigravidae 6.9% 5.5% with seasonal SP but 78% pregnancy in malaria of treatment preventive Intermittent et al. (37 ⁄ 535) (30 ⁄ 542) variation; of women had 2009) All 9.8% 4.4% 8.0% 1.7% Self-reported adverse gravidae (72 ⁄ 730) (29 ⁄ 656) (59 ⁄ 735) (11 ⁄ 663) net-use events. Of previous night these women, was 53% in 28% sought both treatment medical groups attention for their reaction to MQ Mangochi, 0 previous – – – 30.0% – – 18.7% – 14.6% – – Holoendemic- Monthly SP Malawi pregnancies (33 ⁄ 110) (20 ⁄ 107) (13 ⁄ 89) transmission; plus AZ twice (Luntamo 1 previous 17.4% 24.4% 18.8% Self-reported during et al. pregnancy (15 ⁄ 86) (19 ⁄ 78) (15 ⁄ 80) net-use previous antenatal 2010) 2 previous 12.6% 11.3% 8.9% night ranged period was pregnancies (30 ⁄ 239) (29 ⁄ 256) (24 ⁄ 271) between 59.4% significantly All gravidae 12.9% 17.9% 9.1% 15.4% 7.9% 11.88% and 61.0% more (52 ⁄ 402) (78 ⁄ 435) (36 ⁄ 394) (68 ⁄ 441) (32 ⁄ 406) (52 ⁄ 440) across groups protective (data not than SP alone collected on or monthly SP net treatment) Southern All Mean 17.4% – – – – Mean 16.8% – – Malaria AZ offered no Malawi gravidae 2.99 kg (189 ⁄ 1.087) 3.03 kg (184 ⁄ 1096) transmission additional (Van Broek (n = 769) (n = 739) not reported; protection Den et al. Net use not above SP 2009) reported alone, but therapy for syphilis (7.4% prevalence in both groups) was not

curative and 00 no 00 volume may have diluted effect

SP, sulphadoxine-pyrimethamine; ITNs, insecticide treated bed-nets; LBW, low birthweight; AZ, azithromycin. 5 Tropical Medicine and International Health volume 00 no 00

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SP where there is low to moderate prevalence of dhfr ⁄ dhps ASAQ. The risk of low birthweight among paucigravidae mutation. A trial in Malawi between 2003 and 2004 found did not differ significantly between groups. Of all gravidae recrudescent episodes to be less frequent among asymp- who had low birthweight newborns, 11.3%, 11.3% and tomatic parasitaemic pregnant women who received azi- 11.0% were in the SP-IPTp, IST-SP and IST-ASAQ groups, thromycin (1 g daily for 2 days) plus SP compared to SP respectively. Rates among primigravidae were also similar: alone (hazard ratio = 0.19; 95% CI: 0.06–0.63; Kalilani 16.1%, 17.2% and 17.0%, respectively (Tagbor et al. et al. 2007). 2010). A separate study of 109 pregnant women conducted Two preventive treatment studies using azithromycin in the same location 6 months later showed SP to have an plus SP have produced contrasting results (Table 2). The adequate parasite clearance rate of 85% (uncorrected) at first was a three-arm study conducted between 2003 and day-42 (unpublished observation cited by Tagbor et al. 2006 in Malawi that compared two courses of SP-IPTp to 2010). Thus, within this malaria-transmission setting and monthly SP-IPTp and monthly SP-IPTp plus 1 g azithro- parasite sensitivity to SP, a strategy of IST may be a mycin administered two times during the antenatal period; reasonable alternative to SP-IPTp (Table 2). low birthweight prevalence was 12.9% (52 of 402), 9.1% (36 of 394) and 7.9% (32 of 406), respectively. As would Antenatal care: coverage of components and evolution be expected, paucigravidae were protected most by of the package preventive therapy (Luntamo et al. 2010). In contrast, the ‘APPLe’ study (azithromycin for the prevention of pre-term An estimated 71% of women in sub-Saharan Africa have at labour) conducted in Malawi between 2004 and 2005 least one antenatal visit, while 44% benefit from four or showed no difference in birthweight and the prevalence of more consultations (Kinney et al. 2010). Despite these pre-term delivery among the 2297 women given either two contacts with the health system, consistent delivery of all courses of 1 g of azithromycin or placebo (Van Broek Den components of the antenatal care package remains a et al. 2009). These results need to be interpreted with challenge. Only 15% of HIV-infected pregnant women caution. Inadequate syphilis treatment, 1 g of benzyl receive antiretroviral therapy to prevent vertical penicillin, was provided to women in both groups who had transmission of the human immunodeficiency virus (HIV); positive test results. The WHO recommends benzyl pen- just 29% are informed of signs of pregnancy complica- icillin in higher doses for individuals with neurosyphilis tions; 60% are given iron tables or syrup; 60% have their (WHO 2001); antenatal therapy usually involves 2.4 MU blood pressure measured; 78% receive tetanus toxoid of benzathine penicillin G, the regimen for early to late (Kinney et al. 2010); 39% of women have latent syphilis (WHO 2005). Azithromycin is active against blood drawn and tested for syphilis (Peeling et al. 2006); maternal syphilis but does not perfuse the placenta and, only 25% receive any SP from any source while 14% of all therefore, has not been found to cure congenital syphilis women are given two or more courses of SP-IPTp (Van Eijk (Zhou et al. 2007). Thus, penicillin therapy unlikely cured et al. 2011). congenital syphilis and the azithromycin dose was sub- optimal for maternal syphilis, both are consequential HIV screening points as 7.1% of women in both groups were diagnosed as positive with venereal disease research laboratory assays. Rapid point-of-care (PoC) tests for HIV have revolution- As a result, the protective effect of azithromycin may well ised voluntary counselling and testing (Harries et al. 2010) have been higher had 2.4 MU of benzathine penicillin G and are now used in some antenatal settings. A randomised been administered (Table 2). clinical trial of 1282 pregnant women in Nairobi, Kenya, illustrates their value. Of participants allocated to the PoC group, 96% (575 of 599) received same-day results Intermittent screening and treatment of malaria in including 96% of the sero-positive women (76 of 79). This pregnancy was in contrast to an 11-day wait for women in the ELISA Rapid diagnostic tests for malaria have been used to group of which only 73% (333 of 456) returned for test conduct IST for malaria during antenatal visits and may outcomes. Among sero-positive women, only 65% (53 of represent a viable alternative to IPTp in some epidemio- 82) learned their positive status (Malonza et al. 2003). logical settings. A three-arm trial from 2007 to 2008 in Obtaining rapid results during the same visit is important Ghana, of 3333 women, compared SP-IPTp with IST for the provision of antiretroviral therapy to as many HIV- against SP and IST using artesunate-amodiaquine (ASAQ). positive women as possible. Delivering voluntary counsel- Women in the two IST groups were screened with a rapid ling and testing for HIV patients at home increases service diagnostic test and, if positive, provided either SP or coverage (Jaffar et al. 2009; Lugada et al. 2010). In the

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same way, community health workers have doubled the Management of malaria in pregnancy among number of women who receive SP-IPTp (Msyamboza et al. HIV-positive women 2009). Thus, integration of antenatal interventions could occur at the facility or community level. Three courses of SP-IPTp are recommended for HIV- positive women until their CD4 count drops below 350 cells ⁄ ll or is considered to have progressed to the Syphilis screening WHO clinical stage three or four with any CD4 level. Antenatal screening and treatment of syphilis is a standard Thereafter, co-trimoxazole chemoprophylaxis has been policy throughout sub-Saharan Africa, but diagnostic recommended by the WHO against opportunistic infec- coverage rates with rapid plasma reagin (RPR) assay have tions (Menendez et al. 2007). This guideline may need to been low, in part, because of the complexity of testing and be revisited in the light of observations in Malawi showing infrastructure requirements. In addition, the time required co-trimoxazole alone to be more protective against para- for laboratory processing means that RPR results are not sitaemia among HIV-positive pregnancy women than SP often available during the same consultation (Peeling et al. alone (Kapito-Tembo et al. 2011). 2006). Thus, rapid PoC tests for syphilis have been developed to facilitate same-day results and prompt treat- Mefloquine and antiretroviral therapy ment (Peeling 2003; Peeling & Ye 2004). While not yet in widespread use, they have a diagnostic sensitivity ranging In the presence of antiretroviral drugs darunavir ⁄ ritonavir, from 93.7% to 100% and specificity 94.1% to 100% (Lien serum concentrations of mefloquine are likely to increase et al. 2000; Sato et al. 2003; WHO 2003; Diaz et al. 2004) and decrease with etravirine. Limited clinical data suggest and are important tools the campaign to eradicate that ritonavir co-administration may not significantly congenital syphilis (WHO & Special Programme for affect mefloquine serum concentrations (Dooley et al. Research and Training in Tropical Diseases 2006). 2008); however, mefloquine lowers ritonavir concentra- tions at steady state (Khaliq et al. 2001). Curable STI ⁄ RTIs (excluding syphilis) Azithromycin and antiretroviral therapy With the exception of syphilis, antenatal care does not include screening for curable STI ⁄ RTIs. Rather a diagnos- The antiretroviral drug nelfinavir increases the peak and tic algorithm is used to identify women who present with a total area under the curve concentrations of azithromycin symptomatic infection. The method, however, has poor by more than 100% (Amsden et al. 2000). Dose reductions sensitivity (30–80%) and specificity (40–80%) with the may not be required given the safety profile of azithromy- sum of the two rarely exceeding 120% (Vuylsteke et al. cin, but close monitoring of patients using nelfinavir and 1993; Alary et al. 1998; Daly et al. 1998; Mayaud et al. azithromycin is warranted. A placebo-control trial among 1998). Meta-analysis suggests that infection rates of HIV-positive non-pregnant patients reported gastrointesti- malaria and curable STI ⁄ RTIs are comparable among nal disturbances among 78.9% (67 of 85) of azithromycin pregnant women attending antenatal facilities in sub- recipients as compared to 27.5% (24 of 89) who received Saharan Africa (Chico 2010). Thus, a considerable burden placebo. Patients were using various combinations of of STI ⁄ RTIs in pregnancy is unattended. zidovudine, didanosine, zalcitabine and stavudine during STI ⁄ RTIs contribute to low birthweight, spontaneous the study as well as three other chemoprophylaxes for abortion, stillbirth, newborn morbidity and mortality pneumocystis infection (Oldfield et al. 1998). It is not (Mullick et al. 2005). ABC regimens for IPTp containing known whether any of these compounds potentiated two or more grams of azithromycin would eliminate absorption of azithromycin, thereby producing gastro- maternal syphilis (Kiddugavu et al. 2005; Riedner et al. intestinal side effects. 2005), Neisseria gonorrhoeae (Handsfield et al. 1994) and Chlamydia trachomatis (Rahangdale et al. 2006). Azithro- Discussion mycin also offers chemoprophylactic protection against Trichomonas vaginalis (Kaul et al. 2004; Luntamo et al. Relatively few SP-IPTp efficacy studies have been con- 2010). ABCs may also protect against bacterial vaginosis if ducted in areas with high SP resistance and ⁄ or low administered early in pregnancy. Meta-analysis has shown transmission, all of which have some methodological that treatment prior to gestational-week 20 limitations including the lack of blinding, subjective significantly decreases the risk of pre-term birth (Peto odds measures of ITN use, and ⁄ or inadequate power to deter- ratio = 0.63, 95% CI: 0.48–0.84; Mcdonald et al. 2005). mine various secondary benefits of SP-IPTp. Nevertheless,

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the evidence suggests that (i) combining SP-IPTp with ITNs weight and neonatal survival attributable to preventive offers little or no added protection over ITNs alone in low antibiotic treatment appear to have been independent of transmission areas; and (ii) in areas where SP resistance is malaria infection and could, therefore, be even better with very high, SP-IPTp may actually be harmful. an ABC regimen that is also active against malaria. Mefloquine is a potential candidate to replace SP, but its The non-inferiority of IST-SP and IST-ASAQ observed tolerability remains an issue. The studies in Malawi and on birthweight compared to SP-IPTp in the Ghana study Benin each had at least one woman experience a serious was likely the result of SP being quite efficacious at that neurologic reaction to treatment. A recent Cochrane study site. Indeed, the PCR-corrected parasitological fail- Review of malaria chemoprophylaxis found that poor ure on day 28 was only 5.6% (95% CI: 1.6–13.8) among tolerability of mefloquine may impact patient safety. the 71 pregnant women who were parasitaemic at enrol- Mefloquine has been implicated in the deaths of 22 ment and administered SP-IPTp. Transmission was high in travellers, including five suicides, who were using the drug the study area with 29.6% of primigravidae and 10.2% at recommended dosages (Jacquerioz & Croft 2009). multigravidae having peripheral parasitaemia at enrol- Several potential ABCs can be considered for IPTp but ment. One major limitation of this study was that the risk there is limited empirical evidence on their beneficial effects of placental malaria was not determined and thus the against malaria in pregnancy. The likely protection of possibility that IST with SP or ASAQ is not as efficacious as ABCs against STI ⁄ RTIs makes them attractive because SP-IPT in preventing placental infection cannot be most pregnant women in the region who have STI ⁄ RTIs excluded. Nevertheless, these data suggest that IST may be are neither diagnosed nor treated (Mayaud et al. 1995; a potential alternative to IPTp in certain epidemiological Peeling 2003). An estimated 30% of all adverse foetal settings. outcomes can be averted if syphilis, gonorrhoea and The availability of rapid tests for syphilis and HIV makes chlamydia are treated (Gray et al. 2001). As noted, syphilis it possible to offer integrated screening for malaria, syphilis testing and treatment is already part of the antenatal and HIV within a focused antenatal care package. Clinical package and rapid tests have the potential to increase studies are needed to compare the use of syphilis and HIV coverage (Peeling et al. 2006). Use of ABCs would cure rapid tests alongside either ABCs in IPTp or IST with maternal syphilis but the prevention of vertical transmis- hypothesis being that the inadequacies of the syndromic sion would still require intramuscular injection of 2.4 MU management of STI ⁄ RTIs may be overcome by using benzathine-penicillin G (Chico et al. 2008). An ABC ABCs. Operations research must simultaneously characte- regimen containing 3 g of azithromycin would prevent and rise the capacity required by health systems to implement cure gonorrhoea, chlamydia, trichomoniasis and, poten- these approaches at national scale within a focused tially, bacterial vaginosis. Thus, ABCs could have a antenatal care package. Greater health system capacity transformative effect on maternal, foetal and newborn may be required at the facility level, for example, to health and could be rolled out alongside use of rapid tests provide routine IST compared to IPTp. This is because a for HIV and syphilis. well-functioning supply chain would be needed to ensure An ABC that contains 3 g of azithromycin per course rapid diagnostic tests for malaria are consistently available would represent 6–9 g over the antenatal period (2–3 and that test results actually guide treatment. In addition, courses) which would likely yield results comparable to a health care providers would still be reliant on using a randomised controlled trial that tested 3 g of antibiotic in suboptimal diagnostic algorithm to identify and treat cases Uganda. Between 1994 and 1998, 4033 pregnant women of gonorrhoea, chlamydia, trichomoniasis and bacterial received either a one-time course of 1-g azithromycin with vaginosis. In contrast, depending upon the timing of 2-g metronidazole and 400 mg of cefixime, or iron ⁄ folate treatment, IPTp-ABC could simply prevent and ⁄ or clear and low-dose multivitamins. Children born to mothers malaria and the curable STI ⁄ RTIs noted. However, more who received were 32% less likely to have low capacity may be needed at the community level if house- birthweight than children born to mothers receiving hold visitation is involved in the delivery of multi-day ABC iron ⁄ folate and multivitamins (RR = 0.68; 95% CI: 0.53– regimens. 0.86). Neonatal morality was 17% (RR = 0.83; 95% CI: 0.71–0.97) lower in the antibiotic group than in the control Conclusions group. Conducted prior to the SP-IPTp era, no malaria chemoprophylaxis was provided and malaria symptoms The future of SP-IPTp is at the crossroads of public health were similar between groups: 15.5% (303 of 1958) in the policy. Despite declines in malaria transmission in some antibiotic group vs. 17.8% (324 of 1816) among the locales there is no evidence to suggest the risk of malaria in controls (Gray et al. 2001). Thus, improvements in birth- pregnancy without preventive measures is lower in the

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same settings. At the same time, the protective effect of scoring system for the management of women presenting with SP-IPTp is compromised in many areas and a change of vaginal discharge in Malawi. Sexually Transmitted Infections drug and ⁄ or strategy is urgently needed. IPTp with 74, S50–S58. mefloquine or azithromycin-based combinations are lead- Davis TM, Hung TY, Sim IK, Karunajeewa HA & Ilett KF (2005) ing contenders to replace SP. Azithromycin may also cure Piperaquine: a resurgent antimalarial drug. Drugs 65, 75–87. De Roode JC, Helinski ME, Anwar MA & Read AF (2005) and prevent several STI ⁄ RTIs that affect pregnant women Dynamics of multiple infection and within-host competition in in the sub-Saharan region, reduce the dual-burden of genetically diverse malaria infections. The American Naturalist malaria and STI ⁄ RTIs in pregnancy and, potentially, 166, 531–542. transform maternal, foetal and neonatal health. 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Corresponding Author R. Matthew Chico, Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. E-mail: [email protected]

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