Placental inflammation in high risk pregnancies: a novel therapeutic target to prevent stillbirth?

死产是指怀孕24周后婴儿出生前死亡。在英国，每220名孕妇中就有1人会出现这种情况；2012年，英国有3696名死产婴儿。死产率的下降速度比出生后婴儿死亡率的下降速度慢得多。英国的死产率比欧洲邻国高。专家们呼吁像我们这样的国家到2020年将死产数量减半。在英国，与死产相关的最常见情况是胎儿生长受限（FGR）；这个词描述的是没有达到预期尺寸的婴儿。超过40%的死产与FGR有关，FGR婴儿死产的可能性是其17倍。为了防止死产，患有FGR的婴儿可能会过早分娩，使他们因出生前和出生后遭受脑损伤而残疾的风险增加。与出生体重健康的婴儿相比，他们在以后的生活中患肥胖、糖尿病和高血压的可能性也更高。因此，该项目侧重于需要解决的临床条件。胎盘（胎儿）对健康怀孕至关重要。超过65%的死产与胎盘异常有关。胎盘异常包括来自母体的血流量减少和炎症或感染造成的损害。尽管怀孕期间的炎症是妊娠并发症和存活婴儿终身问题的主要原因，但我们不明白炎症是如何导致这些不良结果的。因此，我们无法识别怀孕期间的炎症，也没有任何治疗方法来预防不良后果。我们已经证明，人类和动物的胎盘会因炎症而受损，使其无法正常运作。我们发现，在死产风险较高的孕妇中，胎盘和母亲血液中的炎症因子水平较高。重要的是，在怀孕期间炎症的动物模型中，用一种新的抗炎药物治疗可以防止胎盘损伤和对后代生长和生存的不利影响。这为针对胎盘的抗炎治疗提供了希望，可以预防人类妊娠中的FGR和死胎。目前对孕妇进行这些抗炎治疗还为时过早；然而，目前的研究将为炎症在胎盘损伤和FGR/死产中的作用提供进一步的证据。我们将对人类高危妊娠进行详细的研究，并测试增加胎盘炎症的血液检查是否可以改善目前检测死产风险最高的婴儿的方法。为此，我们将使用健康妊娠以及FGR和死产的人类胎盘和母体血液样本来了解炎症与不良妊娠结局之间的联系。我们已经从高危妊娠的母亲那里收集了1000多份血液样本，并提供了母亲和婴儿的详细临床信息。我们将研究炎症因子如何导致胎盘损伤，并在人类和动物妊娠中测试抗炎治疗。这些实验将提供进一步的证据，证明治疗炎症可以保护胎盘免受损害，减少FGR和死产的发生率。我们的目标是开发新的治疗方法，防止婴儿死亡或出生时患有严重残疾，这些研究是至关重要的第一步，并将促进人体临床试验。

Stillbirth describes the death of a baby before birth after 24 weeks of pregnancy. This occurs in approximately 1 in 220 pregnancies in the UK; in 2012 there were 3,696 stillborn babies in the UK. The rate of stillbirth has decreased much more slowly than deaths of babies after birth. The UK has a higher stillbirth rate than neighbouring countries in Europe. Experts have called upon countries such as ours to halve the number of stillbirths by 2020.In the UK, the most common condition associated with stillbirth is fetal growth restriction (FGR); this describes a baby that does not reach their expected size. Over 40% of stillbirths are associated with FGR, and FGR babies are 17 times more likely to be stillborn. To prevent stillbirths, babies with FGR may be delivered prematurely, placing them at an increased risk of disability due to brain damage sustained before and after birth. They also have a higher likelihood of becoming obese, diabetic and having higher blood pressure in later life than babies of a healthy birthweight. This project therefore focuses on clinical conditions that need to be addressed.The placenta (afterbirth) is essential for a healthy pregnancy. Over 65% of stillbirths are associated with abnormalities of the placenta. Abnormalities in the placenta include reduction in blood flow from the mother and damage from inflammation or infection. Although inflammation during pregnancy is a major cause of pregnancy complications and lifelong problems for surviving babies, we do not understood how inflammation leads to these poor outcomes. As a result, we cannot identify inflammation during pregnancy and do not have any treatments to prevent poor outcomes. We have shown in humans and animals that the placenta is damaged by inflammation making it unable to function normally. We found higher levels of inflammatory factors in the placenta and mothers' blood in pregnancies at high risk of stillbirth. Importantly, in an animal model of inflammation during pregnancy, treatment with a new anti-inflammatory drug prevented placental damage and the adverse effects on growth and survival of the offspring. This provides hope that anti-inflammatory treatment targeting the placenta could prevent FGR and stillbirth in human pregnancies.It is currently too early to give these anti-inflammatory treatments to pregnant women; however, the current study will provide further evidence of the role of inflammation in placental damage and FGR/stillbirth. We will perform detailed studies of human high risk pregnancies and test whether addition of a blood test for placental inflammation can improve current methods to detect babies at greatest risk of stillbirth. To do thus, we will use human placental and maternal blood samples from healthy pregnancies and those with FGR and stillbirth to understand the link between inflammation and adverse pregnancy outcomes. We have already collected over 1,000 blood samples from mothers with high risk pregnancies, with detailed clinical information on mothers and babies. We will study how inflammatory factors cause placental damage and test anti-inflammatory treatments in human and animal pregnancies. These experiments will provide further evidence that treating inflammation can protect the placenta from damage and reduce the incidence of FGR and stillbirth. These studies are essential first steps in our goal to develop new treatments to prevent babies from dying or being born with serious disabilities and will facilitate human clinical trials.