Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase III double-blind randomized clinical trial

虽然产妇和新生儿健康是国际发展的高度优先领域，但全世界每年有100万产妇和400万新生儿死亡，其中一半发生在撒哈拉以南非洲。细菌感染，即败血症，是撒哈拉以南非洲孕产妇和新生儿死亡的主要原因。新生儿可能在分娩过程中--通过产道时--以及生命的头几天/几周内被感染，这是因为与母亲有密切的身体接触，当母亲携带细菌时，即使她没有表现出任何症状。由于母亲是细菌传播给新生儿的重要来源，在分娩期间使用抗生素治疗母亲应该会减少新生儿严重细菌疾病的发生和死亡率。在许多高收入国家，孕妇在怀孕期间会接受B组链球菌阴道携带的筛查，这种细菌是发达国家新生儿败血症的主要原因。如果妇女是携带者，她们在分娩期间接受静脉注射抗生素治疗，以减少传播和随后对其后代产生严重疾病的风险。虽然这种干预措施在发达国家取得了成功，但撒哈拉以南非洲等地区的基础设施和资源限制阻碍了静脉注射抗生素的筛查和使用。此外，在撒哈拉以南非洲，几种细菌病原体是导致新生儿败血症的原因，而抗生素要有效，需要覆盖广泛的细菌。我们建议在冈比亚和布基纳法索进行一项大型试验，以确定在分娩期间给妇女服用单剂口服抗生素是否会降低新生儿死亡率。这项试验还将评估服用抗生素是否会减少母亲及其新生儿在出生后头几周的住院率。我们将使用一种抗生素(阿奇霉素)，这种抗生素已经在撒哈拉以南非洲用于消除其他疾病，如沙眼(感染导致失明的最重要原因)，并有可能消除该地区通常导致严重疾病的大多数细菌。在撒哈拉以南非洲地区使用这种抗生素的一个好处是，它可以在室温下储存，而不需要冰箱。重要的是，由于这种抗生素在撒哈拉以南非洲的临床护理中没有广泛使用，使用抗生素导致的任何暂时的耐药性增加对临床护理的影响都很小。我们在冈比亚进行的一项较小规模的试验(招募了829名妇女)中产生了关于干预效果的强有力的初步数据。我们发现，在分娩期间服用这种抗生素的母亲所生的婴儿不太可能携带可能导致严重疾病的细菌。此外，这些婴儿也不太可能患有细菌性皮肤和脐带感染，这两种情况在撒哈拉以南非洲的新生儿中都很常见。在服用阿奇霉素的母亲中，发烧和乳房炎(两者在分娩后都很常见)的发生率较低。初步数据证实了我们的假设，即阿奇霉素可以用于减少细菌传播，但它太小，无法评估抗生素对死亡率和住院的影响。如果我们发现阿奇霉素可以预防母亲和新生儿的严重细菌感染，那么它可能是一种有效的干预措施，因为它价格便宜，管理简单。

Though maternal and neonatal health are high priority areas for international development, worldwide there are 1 million maternal and 4 million neonatal deaths every year and half of them occur in sub-Saharan Africa. Bacterial infections, namely sepsis, are a leading cause of maternal and neonatal deaths in sub-Saharan Africa. Newborns can be infected during labour - when passing through the birth canal - and also during the first days/weeks of life, as a consequence of the close physical contact with the mother, when the latter carriers bacteria even when she does not show any symptoms. As the mother is an important source of bacterial transmission to the newborn, treating mothers with antibiotics during labour should reduce the occurrence of severe bacterial disease and mortality in the newborn. In many high-income countries, pregnant women are screened during pregnancy for vaginal carriage of Group B Streptococcus, the bacteria responsible for the vast majority of neonatal sepsis in the developed world. If women are carriers, they are treated with intravenous antibiotics during labour to reduce transmission and subsequent risk of severe disease to their off-spring. Although this intervention has been successful in developed countries, infrastructure and resource limitations in regions like sub-Saharan Africa prevent both screening and use of intravenous antibiotics. Also, in sub-Saharan Africa several bacterial pathogens are responsible for neonatal sepsis and antibiotics, to be effective, would need to cover a wide range of bacteria. We propose to conduct a large trial in The Gambia and Burkina Faso to determine if a single dose of an oral antibiotic given to women during labour decreases newborn mortality. The trial will also assess whether giving the antibiotic reduces hospitalisations in mothers and their newborns during the first few weeks after birth. We will use an antibiotic (azithromycin) that has already been used to eliminate other diseases in sub-Saharan Africa, such as trachoma (the most important cause of blindness caused by infection), and has the potential to eliminate most of the bacteria commonly causing severe disease in the region. An advantage of using this antibiotic in sub-Saharan Africa is that it can be stored at room temperature without the need of a fridge. Importantly, since this antibiotic is not widely used in clinical care in sub-Saharan Africa, any temporary increase in resistance, as a result of using the antibiotic, will have small impact on clinical care.We have generated robust preliminary data on the effect of the intervention in a smaller trial conducted in The Gambia (829 women recruited). We found that, babies born to mothers who had taken this antibiotic during labour were less likely to carry bacteria that can cause severe disease. Furthermore, these babies were also less likely to have bacterial skin and umbilical infections, both of which are common among newborns in sub-Saharan Africa. And in mothers who had taken azithromycin, fevers and mastitis (both common after giving birth) were less frequent. The preliminary data confirm our hypothesis that azithromycin can be used to reduce bacterial transmission but it was too small to assess the effect of the antibiotic on mortality and hospitalizations. If we find that azithromycin prevents severe bacterial infections in mothers and newborns, then it could be an effective intervention since it is cheap and simple to administer.