BACKGROUND: Malaria 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 FINDINGS: Using 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. CONCLUSIONS: Despite 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.