Safety of Daily Co-Trimoxazole in Pregnancy in an Area of Changing Malaria Epidemiology: A Phase 3b Randomized Controlled Clinical Trial

IntroductionAntibiotic therapy during pregnancy may be beneficial and impacts positively on the reduction of adverse pregnancy outcomes. No studies have been done so far on the effects of daily Co-trimoxazole (CTX) prophylaxis on birth outcomes. A phase 3b randomized trial was conducted to establish that daily CTX in pregnancy is not inferior to SP intermittent preventive treatment (IPT) in reducing placental malaria; preventing peripheral parasitaemia; preventing perinatal mortality and also improving birth weight. To establish its safety on the offspring by measuring the gestational age and birth weight at delivery, and compare the safety and efficacy profile of CTX to that of SP.MethodsPregnant women (HIV infected and uninfected) attending antenatal clinic were randomized to receive either daily CTX or sulfadoxine-pyrimethamine as per routine IPT. Safety was assessed using standard and pregnancy specific measurements. Women were followed up monthly until delivery and then with their offspring up to six weeks after delivery.ResultsData from 346 pregnant women (CTX = 190; SP = 156) and 311 newborns (CTX = 166 and SP = 145) showed that preterm deliveries (CTX 3.6%; SP 3.0%); still births (CTX 3.0%; SP 2.1%), neonatal deaths (CTX 0%; SP 1.4%), and spontaneous abortions (CTX 0.6%; SP 0%) were similar between study arms. The low birth weight rates were 9% for CTX and 13% for SP. There were no birth defects reported. Both drug exposure groups had full term deliveries with similar birth weights (mean of 3.1 Kg). The incidence and severity of AEs in the two groups were comparable.ConclusionExposure to daily CTX in pregnancy may not be associated with particular safety risks in terms of birth outcomes such as preterm deliveries, still births, neonatal deaths and spontaneous abortions compared to SP. However, more data are required on CTX use in pregnant women both among HIV infected and un-infected individuals.Trial RegistrationClinicaltrials.gov NCT00711906.

引言
妊娠期抗生素治疗或可获益，并对改善不良妊娠结局具有积极作用。目前尚无关于每日复方新诺明（Co-trimoxazole, CTX）预防性给药对妊娠结局影响的相关研究。本研究开展一项3b期随机试验，旨在证实妊娠期每日服用CTX在降低胎盘疟疾发生率、预防外周虫血症、减少围产期死亡及提高出生体重方面，不劣于磺胺多辛-乙胺嘧啶（Sulfadoxine-Pyrimethamine, SP）间歇预防性治疗（Intermittent Preventive Treatment, IPT）。此外，本研究通过测量分娩时的孕龄与出生体重，评估CTX对子代的安全性，并对比CTX与SP的安全性及有效性特征。

方法
将就诊于产前门诊的妊娠妇女（包括HIV感染及未感染者）随机分组，分别接受每日CTX或常规SP间歇预防性给药治疗。采用标准化及妊娠特异性指标评估安全性。对受试者进行每月随访直至分娩，随后对其所娩新生儿随访至产后6周。

结果
本研究共纳入346名妊娠妇女（CTX组190例，SP组156例）及311名新生儿（CTX组166例，SP组145例）。两组的早产发生率（CTX组3.6%，SP组3.0%）、死胎发生率（CTX组3.0%，SP组2.1%）、新生儿死亡率（CTX组0%，SP组1.4%）及自然流产率（CTX组0.6%，SP组0%）均无统计学差异。CTX组低出生体重率为9%，SP组为13%。本研究未报道任何出生缺陷病例。两组受试者均为足月分娩，平均出生体重均为3.1kg。两组的不良事件（Adverse Events, AEs）发生率与严重程度均无统计学差异。

结论
与SP相比，妊娠期每日暴露于CTX未显示出与早产、死胎、新生儿死亡及自然流产等妊娠结局相关的特定安全性风险。但仍需更多数据来评估CTX在HIV感染及未感染妊娠妇女中的应用情况。

试验注册
ClinicalTrials.gov NCT00711906