W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
mBio. 2024 Feb 14;15(2):e0306523. doi: 10.1128/mbio.03065-23. Epub 2024 Jan 8.
Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1-, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2α. Treatment with 17-α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy.IMPORTANCEPregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. When outbred dams, with semi-allogenic fetuses, were infected with 2009 H1N1, in addition to pulmonary virus replication, lung damage, and inflammation, the placenta showed evidence of transient cell death and inflammation that was mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone were associated with detrimental effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment that is safe to use in pregnancy, prevented placental damage and inflammation and adverse fetal outcomes. This novel therapeutic option for the treatment of influenza during pregnancy should be explored clinically.
甲型流感病毒感染孕妇可导致母婴不良结局，但具体机制尚不清楚。2009 年 H1N1 病毒在胚胎第 10 天（E）感染异交系小鼠，导致母体发病率显著增加、胎盘组织损伤和炎症、胎儿生长受限以及通过断奶持续存在的发育迟缓。妊娠期间并未抑制肺部病毒复制，但感染的孕鼠循环和胎盘孕酮（P4）浓度受到抑制，这是由 H1N1 诱导的肺部环加氧酶（COX）-1 而非 COX-2 依赖性前列腺素（PG）F2α的合成和分泌增加所致。用 17-α-羟孕酮己酸酯（17-OHPC）治疗，一种在妊娠期间安全使用的合成孕激素，可改善 H1N1 感染的母婴不良结局，并预防胎盘细胞死亡和炎症。这些发现强调了孕激素治疗流感在妊娠期间的治疗潜力。
孕妇有患季节性和大流行性甲型流感病毒的严重风险。妊娠期间的流感感染与出生时的不良胎儿结局以及对成年后代的不良后果有关。当半同种异体胎儿的异交系孕鼠感染 2009 年 H1N1 时，除肺部病毒复制、肺损伤和炎症外，胎盘还显示出短暂细胞死亡和炎症的证据，这是由沿着花生四烯酸途径增加的活性介导的，导致循环孕酮抑制。胎盘损伤和孕酮抑制与围产期生长和后代发育迟缓的有害影响有关。用 17-OHPC 治疗 H1N1 感染的妊娠小鼠，17-OHPC 是一种在妊娠期间安全使用的合成孕激素治疗方法，可预防胎盘损伤和炎症以及不良胎儿结局。这是一种治疗妊娠期间流感的新的治疗选择，应在临床上进行探索。
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