Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model.
Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model.
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DOI：
10.1371/journal.pmed.1002243
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发表时间：
2017-02
期刊：
影响因子：
15.8
通讯作者：
Cairns M
中科院分区：
文献类型：
--
作者：
Walker PG;Floyd J;Ter Kuile F;Cairns M
疟疾传播在21世纪已大幅下降，但持续传播地区的孕妇仍然需要保护，以防止与妊娠期疟疾相关的不良妊娠和分娩结果。最近发出了一项行动呼吁，以解决妊娠期疟疾间歇预防性治疗（IPTp）的覆盖率仍然很低的问题。然而，这一呼吁受到了一些人的质疑，部分原因是担心对磺胺嘧啶-乙胺嘧啶（SP）的耐药性，SP是目前唯一推荐用于IPTp的药物。利用现有的MiP数学模型，我们将非洲各地疟疾流行变化的估计值与SP耐药性突变图以及非洲各地产前获取和IPTp与SP （IPTp-SP）的当前覆盖范围相结合。利用SP抗性突变与妊娠期间SP的寄生虫学功效之间的关系，我们估计了IPTp-SP在非洲各地的不同影响，以及提高IPTp-SP摄取以匹配当前产前保健（ANC）覆盖率的增量价值。2000年至2015年，在撒哈拉以南非洲流行地区，无保护妊娠（即未使用驱虫蚊帐）中MiP和疟疾所致低出生体重导致活产的风险分别下降了37%（33%-41% 95%可信区间[crI]）和31%（27%-34% 95%可信区间[crI]）。然而，这些成果是脆弱的，覆盖范围远未达到最佳。2015年，如果不采取干预措施，这些地区3060万例妊娠中仍有950万例（830万- 1040万，95% crI）会感染恶性疟原虫，导致75万例（39万- 110万，95% crI）产妇分娩。在这950万例（69.3%）感染风险妊娠中（53.4%[1630万/ 3060万]），总共有660万例（560万- 730万，95% crI）发生在根据最新耐药性估计，SP疗效接近完美的环境中（bb0 99%）。这些孕妇中有44%（占所有孕妇的23%）没有接受任何IPTp-SP，尽管进行了≥3次产前检查，代表160,000 （94,000-236,000 95% crI）可预防的低出生体重（LBW）分娩。只有4%（140万）的怀孕发生在与SP有效性受损相关的六胞胎单倍型患病率为10%的环境中。42%的怀孕发生在五倍dhfr/dhps单倍型已经建立的环境中，但体内疗效数据表明SP在清除感染方面保持了大部分有效性。如果不考虑怀孕期间使用ITNs的保护，将IPTp-SP扩展到非洲所有产前检查≥3次的妇女，可以防止额外的21.5万例（12.8万- 31.8万例95% crI） LBW分娩。在26个国家中，有足够的近期数据来估计ITN的影响（基于人口的ITN使用数据，可以按出生率分层），我们估计，主要由于初产妇使用ITN的情况较低，通过扩大IPTp-SP来预防的潜在低出生婴儿出生实际上只有16.5%可以通过使用ITN来预防。我们的分析还强调了在估计针对寄生虫终点（如分娩时胎盘感染）的干预措施的有效性与包括出生体重在内的健康结果之间的关系时存在的困难，这也是由一系列不相关因素决定的。我们也没有捕获疟疾负担的其他方面，如临床疟疾、孕产妇和新生儿贫血以及流产，所有这些都增加了有效预防策略的总体重要性，但它们与传播强度、胎次和SP耐药性有自己的关系。尽管非洲的疟疾传播最近有所下降，但在缺乏适当预防的情况下，疟疾感染的负担仍然很大。即使考虑到SP耐药性，将IPTp-SP扩大到所有参加非洲国民大会的妇女，以及针对首次母亲的长效驱虫蚊帐分发，也将对撒哈拉以南非洲几乎所有疟疾流行环境中的孕产妇和婴儿健康产生重大影响。普遍获得用磺胺嘧啶-乙胺嘧啶（IPTp-SP）药物对妊娠期疟疾进行间歇性预防性治疗是预防妊娠期疟疾的基石。基于其高度安全性、可接受性、有效性和成本效益，遏制疟疾伙伴关系发起了一项全球行动呼吁。在一些地区，疟原虫产生了耐药性——尤其是一连串的六种突变，可能严重影响药物的疗效——以及最近疟疾传播的下降，导致一些人质疑这种行动呼吁是否明智。我们使用一个数学模型，将妊娠期疟疾的当前风险图与非洲各地的耐药性水平图结合起来，以估计扩大IPTp-SP的可能影响，同时考虑到耐药性的影响。我们发现，在非洲疟疾持续传播地区的绝大多数怀孕中，IPTp-SP可能在怀孕期间对疟疾保持实质性的有效性，受六联体突变影响的地区只占这些怀孕的一小部分。我们发现，即使考虑到最近疟疾传播的下降，在非洲许多地区提供IPTp-SP的好处仍然很大，但尽管许多国家产前诊所的出诊人数大幅增加，但干预措施的使用率仍然很低。总的来说，这些调查结果支持这样一种建议，即如果成功，增加IPTp-SP使用的努力将对孕产妇和新生儿健康产生重大影响，而且鉴于大多数妇女已经获得产前保健，这将具有很高的成本效益。尽管截至2010年，六联体突变仅局限于非洲的一小部分地区，但在非洲的大部分地区（五分之一的育龄高危妇女居住在这些地区），五联体突变（六联体突变的直接前兆）已达到饱和，这突出表明需要仔细监测耐药性的传播，也突出表明，如果六联体突变传播，研究替代策略是有益的。
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. 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. 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. Universal access to intermittent preventive treatment of malaria in pregnancy with the drug sulphadoxine-pyrimethamine (IPTp-SP) has been a cornerstone of prevention of malaria in pregnancy, and a Global Call to Action has been launched by the Roll Back Malaria Partnership based upon its high safety, acceptability, effectiveness, and cost-effectiveness. The development of resistance by the parasite in some regions—particularly a sequential chain of six mutations that may severely compromise the efficacy of the drug—and recent falls in malaria transmission have led some to question the wisdom of this call to action. Using a mathematical model, we combined maps of the current risk of malaria in pregnancy with maps of the level of drug resistance across Africa to estimate the likely impact of scaling up IPTp-SP, taking into account the effects of resistance. We found that in the large majority of pregnancies in areas of sustained malaria transmission in Africa, IPTp-SP is likely to retain substantial effectiveness against malaria in pregnancy, with areas affected by the sextuple mutation representing a small proportion of these pregnancies. We found that, even accounting for recent declines in malaria transmission, the benefits of providing IPTp-SP in lots of areas of Africa remain substantial, but uptake of the intervention remains low despite large increases in antenatal clinic attendance in many countries. In general, these findings support the suggestion that, if successful, the drive to increase IPTp-SP use will have a substantial and, given that the majority of women already access antenatal care, highly cost-effective impact upon maternal and neonatal health. Although the sextuple mutation was confined to only a small proportion of areas in Africa as of 2010, there are large areas of Africa (one in five women of childbearing age at risk reside in such areas) where the quintuple mutation (the immediate precursor to having the sextuple mutation) has reached saturation, which highlights the need for careful monitoring of the spread of resistance and also highlights the benefits of research into alternative strategies if the sextuple mutation spreads.