Coverage and effectiveness of intermittent preventive treatment in pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) on adverse pregnancy outcomes in the Mount Cameroon area, South West Cameroon

In sub-Saharan Africa, Plasmodium falciparum infection increases the risk of maternal anaemia and low birthweight, and prematurity in women and their neonates, respectively [1, 2]. It was estimated that without pregnancy-specific interventions, 9·5 million pregnant women were exposed to infection in 2010, leading to 750,000 low birthweight deliveries. Recommended malaria prophylactic treatment was estimated to prevent 128,000 low birthweight deliveries by 2015 [3]. Despite recent decline in malaria transmission in Africa, the burden of malaria in pregnancy (MiP) in the absence of adequate prevention remains substantial [3]. In geographical areas with high transmission, the impact of malaria on maternal health depends on age, gravidity, trimester of pregnancy, coinfection [1, 4] nutritional status [5] the intensity of malaria transmission (increased in rural populations), season, and use of malaria prevention [6].

In most African countries, SP remains the recommended drug for IPTp. SP provides intermittent clearance or suppression of existing asymptomatic infections from the placenta (the treatment effect) and may prevent new infections from occurring for several weeks by maintenance of suppressive drug levels (the post-treatment prophylactic effect) [7]. Based on the findings of multi-centre trials on the evaluation of IPTp-SP, three or more doses of IPTp-SP were associated with less placental malaria, higher mean birth weight and fewer LBW births compared with two doses [8]. Thus, the WHO policy on IPTp-SP was revised and recommends uptake of at least three SP doses with each dose administered at each scheduled antenatal care visit, at least 1 month apart up to the time of delivery and ideally by direct observed therapy [9]. Although there has been a fivefold increase in the percentage of women receiving the recommended three or more doses of IPTp in 20 African countries, coverage in Cameroon remains low (29%) [10].

The effectiveness of IPTp-SP is threatened by rising levels of parasite resistance to SP in several countries across Africa [11]. Emergence and successive acquisition of polymorphisms in both the P. falciparum dihydrofolate reductase/dihydropteroate synthetase (pfdhfr/pfdhps) genes are associated with a high-level of SP resistance and clinical treatment failure in several epidemiological settings. Parasites harbouring the K540E mutation, which is a proxy for the pfdhfr‐pfdhps quintuple mutant is strongly linked with resistance rendering SP ineffective to clear P. falciparum infections [12]. Sextuple mutant parasites (quintuple mutant plus the additional pfdhps A581G mutation) defined as super-resistant parasites [13] have been associated with a loss of IPTp-SP efficacy [14‐18]. Although resistance to SP reduces the parasitological efficacy of IPTp, beneficial associations between the use of IPTp-SP and low birthweight are still seen in areas where prevalence of parasites with quintuple mutations is > 90% [11, 12, 17]. IPTp-SP appears to protect against malaria as well as other non-malarial causes of LBW such as sexually transmitted and reproductive tract infections (STIs/RTIs). SP may exert its protection through antibacterial or anti-inflammatory actions [19, 20].

The wide spread of SP super-resistance in Africa is expected with continued SP use and may undermined anti-malarial policies [17]. In Yaoundé, Cameroon, highly resistant parasites (octuple mutation genes) to SP have been isolated from pregnant women with symptomatic P. falciparum infection [21]. Also, a high prevalence of P. falciparum SP resistant parasites among pregnant [22] and non-pregnant [23, 24] populations has been reported along the slope of Mount Cameroon. On this basis, continuous monitoring and evaluation of SP efficacy in Cameroon is crucial. Thus, this study determined the coverage of IPTp-SP since the transition from a 2-dose to 3-dose IPTp-SP policy in Cameroon in 2012. Secondly, the study ascertained whether 3 or more doses of SP to the 2-dose regimen for intermittent preventive therapy during pregnancy provide any additional benefits in reducing the risk of PM infection and LBW in some selected semi-rural and semi-urban settings in Mount Cameroon area, South West Region, Cameroon.

This study reports on the coverage of SP (doses) in the Mount Cameroon area since the transition from a 2-dose to 3-dose IPTp-SP policy in Cameroon in 2012. Given that the effectiveness of this strategy is being challenged by rising levels of parasite resistance, this study provide evidence on the extent at which ≥ 3 doses of SP compared with the 2-dose IPTp-SP regimen is effective against PM infection and LBW in the study area.

This study revealed an increased in the percentage of women receiving the recommended three or more doses of IPTp in the area consistent with World Malaria Report 2016 [38]. About two (47.0%) out of five women received the full WHO-recommended schedule which is higher than 29.3% from the National Demographic Health Survey (DHS) data collected in 2011 in Cameroon [10]. An overall prevalence of 29.5% for three doses of IPTp-SP was obtained from Malaria Indicator Surveys (MIS) conducted in Burkina Faso, Ghana, Mali, Malawi, Kenya, Nigeria, Sierra Leone, and Uganda with considerable inter- and intra-country variations in the adequate uptake of IPTp [39].

Comparatively, the coverage of IPTp (≥ 3) in the Mount Cameroon area appears to be better than in many other countries in sub-Saharan Africa, except for Ghana where a higher coverage of 60% has been reported [40]. Ten years after implementation of IPTp- SP in Cameroon, coverage with at least two doses in this part of the country has increased from 64.7% in 2009 [34] to 81.7% in 2017 as stipulated by the WHO previous policy on IPTp-SP [41]. Most women who did not take chemoprophylaxis during their pregnancy were from semi-rural setting, however the coverage of the IPTp-SP doses and ITN usage were similar in both semi-rural and urban areas. This observation highlights the positive contribution of malaria control programmes towards bridging disparities and inequities in accessing malaria health services between rural and urban women [10, 42]. Access to chemoprophylaxis and ITNs among pregnant women have become more equitable in Cameroon due to provision of IPTp-SP free of charge and affordable essential drug schemes which lower costs [10].

In conformity with reports of several studies, ANC initiation in the first trimester or earlier in the second trimester as well as frequent ANC visits made before delivery allowed for more SP doses to be taken [34, 43, 44]. Uptake of ≥ 3 doses was also associated with type of health care facility where MDH had the highest coverage (72%). In Cameroon, the health district is the implementer unit of the health system and thus it not uncommon for the availability of SP at MDH to form the basis for high IPTp-SP coverage among pregnant women attending ANC in this facility. The relatively low uptake of SP at the level of the health centres may be due to unavailability of SP as a result of stock outs. During stock outs, IPTp is suspended until stocks are replenished or women are asked to buy SP from local drug vendors. Stock outs may be related to drug shortage at the central unit or challenges in supply chain management programs [45]. Periodic shortage of SP in rural health facilities has been reported as a major barrier to the implementation of IPTp-SP programme in some malaria endemic countries [46, 47].

Earlier studies of IPTp in Cameroon demonstrated a clear reduction in placental parasitaemia following receipt of SP [32, 48]. Also, data from a meta-analysis showed that ≥ 3 doses was associated with less placental malaria [8]. Contrarily, our study did not show prophylactic effectiveness of IPTp-SP in reducing PM infection. The risk of placental parasitaemia increased by 42% among delivery women having taken ≥ 3 doses. Although, PM parasitaemia was generally scarce as reported in previous studies [32], increase parasite load was noted mainly among women from urban areas who had adequate SP doses. The ineffectiveness of IPTp-SP on PM infection was noteworthy among primiparae. It is well known that in areas of intense transmission, primigravidae have higher vulnerability to malaria infection and its adverse consequences [1]. Thus, the effect of IPTp-SP against malaria should be more profound in these individuals than in secundi- and multigravidae as suggested by Valea et al. [49]. The lack of prophylactic effect of IPTp-SP in the prevention of malaria parasitaemia observed may be due to the presence of highly drug resistant P. falciparum parasites among infected pregnant women in south-western Cameroon. Agbor and Apinjoh [22] provide evidence of a high prevalence (51.1%) of pfdhps A581G mutation among pregnant women along the slope of mount Cameroon. Also, Chauvin et al. [21] reported pfdhfr/pfdhps octuple mutant alleles with A581G and A613S mutations among parasites isolated from pregnant women with symptomatic P. falciparum infection in Yaoundé, Cameroon. Although pfdhps K540E mutation was not observed in the study area [22], its presence, though rare, was confirmed in studies in Yaoundé [21]. In several countries in East Africa, SP resistance linked to vast predominance of highly resistant strains of pfdhps 540E and pfdhps 581G mutations in these populations has been associated with in vivo therapeutic failure to SP [11, 14‐18, 50, 51]. IPTp use in areas with 581G mutation facilitate increase in parasite density whereby these highly resistant parasites out-compete the wild type populations and overgrow under drug pressure [14]. This may partly explain the increase placenta parasite load seen among women especially those from high IPTp-SP coverage areas, such as Muyuka. In line with reports from Benin by Moussiliou et al. [52], which highlight the inability of SP to ensure optimal antiplasmodial protection in late pregnancy, these present findings further suggest that SP is potentially failing in Central-West Africa. Future studies in the mount Cameroon area to link SP drug resistance molecular markers and efficacy of IPTp-SP are crucial taking into consideration the WHO recommendation to discontinue IPTp-SP in areas with A581G mutation > 10% [53].

Although ineffective in reducing PM infection, IPTp-SP showed improvement of infant outcomes in the area. Chemoprophylaxis with IPTp –SP (≥ 3 doses) was associated with reduced odds of LBW by 22%. From this study, the association between timing of ANC initiation and dosage frequency suggests that earlier dosing reduces odds of PM infection and thus improves birth weight outcome than late dosing which is linked to late antenatal enrolment. Comparable with reports from Burkina Faso [49], increased number of doses from 2 to ≥ 3 doses did not confer additional protection from LBW nor significantly increase birth weight. Gutman et al. [50] suggested that under conditions of resistance, more doses would be required to achieve the same benefit seen with only 2 doses in areas without resistance. SP resistance increases the minimum inhibitory concentration, leading to a shorter duration of prophylaxis. Interestingly, particularly among primiparae, adequate doses of SP was seen associated with improved birth weight outcome despite evidence of no parasitological response in clearance of placental infection. This is consistent with extensive reports on beneficial associations between the use of IPTp-SP and low birthweight still seen in areas where the efficacy of SP to clear parasitaemia has clearly decreased [11, 12]. Besides its anti-malarial activity, IPTp-SP appears to confer benefit through yet undefined pathways [19, 20, 54]. Sulfadoxine is a broad-spectrum antibiotic that possibly exerts an inhibitory effect against non-malaria causes of LBW and preterm birth [55]. Its antibacterial activity can lead to maternal and infant weight gain through changes in gut and vagina bacteria flora associated with indirect metabolic benefits and reduction in the impact of urogenital tract infections [56, 57], respectively. SP exposure inhibits (immunomodulatory role) maternal inflammatory responses to infections that are known to trigger preterm delivery [58].