Supplementary Material for: INTRAUTERINE TREATMENT IN TWO FETUSES AFFECTED BY CYSTIC FIBROSIS.TO WHOM AND SINCE WHEN?REPORT OF CASES.

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease asociated to low survival disease into adulthood. The appearance of the cystic fibrosis transmembrane conductance regulator (CFTR) therapy has revolutionized the management and the prognosis of this patients with an improvement in the pancreatic and lung function with a much better quality of life. More women with CF are considering being mothers. Other clinical scenario is the prenatal diagnosis of fetus with CF. Three cases reports have been published suggesting that CFTR therapy during pregnancy in fetuses affected by CF might prevent prenatal meconium ileous (MI), which are the one who have a higher risk of gastrointestinal morbidity and long-term complications. Case presentation: We present two cases reports in which the diagnosis of CF occurred during intrauterine life and treatment with CFTR therapy was administered to healthy pregnant women in order to reduce the risk MI in their fetuses. In both cases the diagnosis suspicion was by ultrasound findings with a genetic confirmed diagnosis by amniocentesis. In the first case, the mother received the CTFR therapy during five weeks and MI was not developed by the newborn. In the second one, the mother received the treatment only for a week and MI could not be avoided. Conclusion: This clinical situation has special ethical considerations, since a drug is being administered through compassionate use to a women who does not need it. The fundamental reason is the lack of authorization for the use of these drugs in newborns but in adults. We hope that these two clinical cases, together with those already published, will increase the knowledge and experience of using this drug in this context helping with the management of pregnant women with fetuses affected by CF in order to reduce associated complications.

引言：囊性纤维化（Cystic Fibrosis, CF）是一种常染色体隐性遗传病，患者成年后生存率偏低。囊性纤维化跨膜传导调节因子（CFTR）治疗的问世，彻底革新了这类患者的临床管理模式与预后结局，可改善胰腺与肺功能，大幅提升患者生活质量。如今，愈来愈多CF女性患者有生育意愿。另一临床场景为胎儿囊性纤维化的产前诊断。已有3篇病例报告显示，妊娠期间对受累胎儿给予CFTR治疗，或可预防产前胎粪性肠梗阻（Meconium Ileus, MI）——此类患儿发生胃肠道并发症与远期不良事件的风险显著升高。

病例报告：本文报告2例病例：均为宫内确诊CF，临床对健康孕妇给予CFTR治疗，以降低其胎儿发生胎粪性肠梗阻的风险。两例均通过超声检查发现疑似征象，并经羊膜穿刺术完成遗传学确诊。第一例中，孕妇接受了为期5周的CFTR治疗，新生儿未出现胎粪性肠梗阻。第二例中，孕妇仅接受了1周的治疗，最终未能避免胎粪性肠梗阻的发生。

结论：该临床场景存在特殊的伦理争议：此类药物通过同情性用药途径，被给予并无用药指征的孕妇。究其根本，此类药物目前仅获批用于成人患者，尚未获得新生儿人群的用药许可。我们期望，本研究的两例病例结合已发表的相关报告，能够增进该临床场景下CFTR治疗的认知与实践经验，助力囊性纤维化受累胎儿孕妇的临床管理，从而降低相关并发症的发生风险。