Research Article: Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model

Date Published: February 28, 2017

Publisher: Public Library of Science

Author(s): Patrick G. T. Walker, Jessica Floyd, Feiko ter Kuile, Matt Cairns, Ivo Mueller

Abstract: BackgroundMalaria transmission has declined substantially in the 21st century, but pregnant women in areas of sustained transmission still require protection to prevent the adverse pregnancy and birth outcomes associated with malaria in pregnancy (MiP). A recent call to action has been issued to address the continuing low coverage of intermittent preventive treatment of malaria in pregnancy (IPTp). This call has, however, been questioned by some, in part due to concerns about resistance to sulphadoxine-pyrimethamine (SP), the only drug currently recommended for IPTp.Methods and findingsUsing an existing mathematical model of MiP, we combined estimates of the changing endemicity of malaria across Africa with maps of SP resistance mutations and current coverage of antenatal access and IPTp with SP (IPTp-SP) across Africa. Using estimates of the relationship between SP resistance mutations and the parasitological efficacy of SP during pregnancy, we estimated the varying impact of IPTp-SP across Africa and the incremental value of enhancing IPTp-SP uptake to match current antenatal care (ANC) coverage.The risks of MiP and malaria-attributable low birthweight (mLBW) in unprotected pregnancies (i.e., those not using insecticide-treated nets [ITNs]) leading to live births fell by 37% (33%–41% 95% credible interval [crI]) and 31% (27%–34% 95% crI), respectively, from 2000 to 2015 across endemic areas in sub-Saharan Africa. However, these gains are fragile, and coverage is far from optimal. In 2015, 9.5 million (8.3 million–10.4 million 95% crI) of 30.6 million pregnancies in these areas would still have been infected with Plasmodium falciparum without intervention, leading to 750,000 (390,000–1.1 million 95% crI) mLBW deliveries. In all, 6.6 million (5.6 million–7.3 million 95% crI) of these 9.5 million (69.3%) pregnancies at risk of infection (and 53.4% [16.3 million/30.6 million] of all pregnancies) occurred in settings with near-perfect SP curative efficacy (>99%) based on the most recent estimates of resistance. Forty-four percent of these pregnancies (23% of all pregnancies) were not receiving any IPTp-SP despite making ≥3 ANC visits, representing 160,000 (94,000–236,000 95% crI) preventable low birthweight (LBW) deliveries. Only 4% (1.4 million) of pregnancies occurred in settings with >10% prevalence of the sextuple haplotype associated with compromised SP effectiveness. Forty-two percent of all pregnancies occurred in settings where the quintuple dhfr/dhps haplotype had become established but where in vivo efficacy data suggest SP maintains the majority of its effectiveness in clearing infections.Not accounting for protection from the use of ITNs during pregnancy, expanding IPTp-SP to all women with ≥3 ANC visits in Africa could prevent an additional 215,000 (128,000–318,000 95% crI) LBW deliveries. In 26 countries with sufficient recent data to estimate ITN impact (population-based ITN usage data that can be stratified by gravidity), we estimate that, due primarily to low ITN use by primigravidae, only 16.5% of the potential LBW births prevented by scaling up IPTp-SP would in fact have already have been prevented through ITN use.Our analysis also highlights the difficulties associated with estimating the relationship between the effectiveness of interventions against parasitological endpoints such as placental infection at delivery and health outcomes including birthweight, which is also determined by a wide range of unrelated factors. We also did not capture other aspects of malaria burden such as clinical malaria, maternal and neonatal anaemia, and miscarriage, all of which increase the overall importance of effective preventative strategies but have their own relationship with transmission intensity, parity, and SP resistance.ConclusionsDespite recent declines in malaria transmission in Africa, the burden of MiP in the absence of adequate prevention remains substantial. Even accounting for SP resistance, extending IPTp-SP to all women attending ANC, as well as long-lasting insecticidal net distribution targeted towards first-time mothers, would have a sizeable impact upon maternal and infant health in almost all malaria-endemic settings in sub-Saharan Africa.

Partial Text: Malaria in pregnancy (MiP) has long been understood to have a devastating impact on mother and child. Prior to the unprecedented investment in malaria control that has occurred in the 21st century [1], it had been estimated that nearly 20% of low birthweight (LBW) deliveries (35% of those that were preventable) were caused by malaria [2,3], leading to an estimated 11.4% of neonatal deaths and causing 5.7% of infant deaths in malaria-endemic areas of Africa [4]. The prevalence and burden of malaria have declined markedly in the 21st century [5], primarily due to the dramatic increase in the coverage of malaria interventions, with the usage of insecticide-treated nets (ITNs) increasing from <2% in 2000 to 55% in 2015 and the proportion of malaria cases adequately treated increasing from <1% in 2005 to 16% in 2014 [6]. However, in areas of sustained transmission, women of childbearing age infected with malaria parasites remain at high risk of adverse outcomes such as malaria, anaemia, maternal mortality, stillbirth, preterm delivery, and having a LBW baby in the event they become pregnant [7]. Our estimates of the changing risk and burden of MiP across malaria-endemic sub-Saharan Africa support the notion that the observed declines in transmission in the 21st century coincided with reductions in the likelihood that women experienced malaria infection in pregnancy. However, our previous modelling suggested that, as transmission falls, among those who become infected, the average severity of MiP, and the risk of LBW, is likely to increase due to lower levels of immunity to placental infection [44]. This effect has recently been observed in data [45], and we estimate that proportional reductions in the burden of adverse outcomes due to MiP in terms of mLBW are likely to lag behind proportional reductions in the prevalence of infection in pregnancy [5]. As a result, MiP remains a substantial public health issue to address within most transmission settings and—because parity-dependent immunity means the first experience of MiP is substantially more severe than subsequent experiences—is likely to remain so until transmission is sufficiently low to ensure that women can live through their entire reproductive life without experiencing malaria during pregnancy at all. Source:


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