Amniotic cavity infection syndrome

　　1. Etiology

　　1. Amniotic membrane rupture

　　Traditional obstetrics considers amniotic membrane rupture as a cause of IAIS, with the longer the rupture time, the higher the incidence of IAIS. Amniotic membrane rupture or premature rupture is just one of the causes of IAIS. Modern obstetrics has found that amniotic membrane rupture and IAIS are mutually causal, and IAIS may be the main cause of amniotic membrane rupture. The presence of IAIS caused by various reasons leads to amniotic membrane rupture, cervical dilation, and uterine contraction, resulting in further amniotic membrane rupture. The amniotic cavity is similar to the vagina, and as time goes by, the infection becomes more complex and severe.

　　2. Iatrogenic infections caused by obstetricians

　　It includes various amniocentesis techniques for diagnosis and treatment, fetal surgery or intrauterine surgery, amnioscopy and fetoscopy techniques, perinatal vaginal examinations, rectal examinations, and vaginal surgical procedures, etc.

　　3. Infections of the reproductive system during pregnancy and childbirth

　　It mainly refers to cervical and vaginal inflammation, such as common bacterial vaginosis, fungal vaginitis, and trichomoniasis vaginitis, etc. Bacteria in the cervix or vagina can ascend through a ruptured or unruptured amnion to reach the amniotic cavity, where they further reproduce, causing severe infection.

　　4. Amnionitis

　　Pregnant women usually have subclinical chronic endometritis before pregnancy, and the inflammatory process during pregnancy involves the placenta and amnion, further spreading to the amniotic sac and amniotic cavity.

　　二、发病机制

　　IAIS的特点是细菌性炎症或病原微生物引起的炎症，其致病机制和对母儿的影响均来自细菌和细菌引起的炎症反应过程。

　　1、细菌和细菌产物

　　细菌本身的不断生长、分裂和扩散，细菌因各种原因死亡裂解，细菌本身和细菌的各种裂解和代谢产物如内毒素或外毒素都能直接或间接对孕妇和胎儿造成各种损害。

　　2、炎症反应

　　(1)高热或发热：发热是各种炎症的重要特征，IAIS的发热除对孕妇产生各种影响外，不要忘记发热对胎儿的影响。发热甚至高热会引起胎儿严重的水电解质紊乱或严重的中枢神经系统损害。

　　(2)血管反应：炎症的定义是活体组织的血管对各种刺激的反应，血管反应是各种炎症的中心，包括血管壁本身和血管内的血液成分发生的各种反应。胎盘部位的血管反应对于妊娠的影响至关重要，直接涉及到胎盘功能。胎盘部位的血管反应主要有充血、水肿、渗出、出血、血栓形成，血栓和各种变性和坏死组织的机化、钙化、坏死、纤维化等。这些改变都能使胎盘的物质交换功能下降，造成胎儿窘迫。

　　(3)免疫功能异常：细菌性炎症可以激发人体的免疫系统，包括非特异性细胞和体液免疫，特异性细胞和体液免疫功能。免疫功能的适度增加主要为提高机体的抵抗力，但免疫机制的介导也是造成各种炎症损伤特别是胎盘损伤的重要机制。炎症细胞如白细胞释放的蛋白酶类物质如：MMP8和MMP9等可以破坏胎膜的正常组织结构，容易发生胎膜早破。另外免疫系统的细胞和细胞因子的变化是目前检测亚临床IAIS的重要方法，包括IL-6，IL-8，GCSF和TNF-α等。

　　(4)炎症介质：炎症反应过程中有激肽缓激肽系统、凝血和抗凝血系统以及花生四烯酸系统的参与，其中花生四烯酸系统产生的前列腺素对产科意义重大。近些年的研究发现PGE2和PGF2α可以引起强烈宫缩，子宫颈口扩张，宫缩抑制剂难以控制。

　　(5)细菌性炎症过程中的细菌，细菌代谢或裂解产物，炎症反应的细胞、因子和介质，可能通过胎儿的呼吸系统、消化系统、皮肤和脐带进入胎儿体内，引起各种反应。

　　1、炎症扩散到子宫肌层或伴有全身感染，则可以出现全身中毒症状，甚至休克或DIC，严重时可发生母儿死亡。

　　2、机体与病原菌相互作用中，由于机体的免疫功能薄弱，不能将病原菌限于局部，以致病原菌及其毒素向周围扩散，经淋巴道或直接侵入血流，引起全身感染。

　　The subclinical form of amniotic cavity infection syndrome may not present with any symptoms clinically, and only the clinical form of amniotic cavity infection syndrome has clinical symptoms. However, the symptoms are often non-specific and are often not paid much attention to by clinical physicians. The clinical manifestations of amniotic cavity infection caused by different pathogens are also different, but most cases have the following symptoms.

　　1. Premature rupture of membranes, almost all patients have premature rupture of membranes. As the duration of membrane rupture extends, the possibility of amniotic cavity infection increases. Some authors believe that for those with premature rupture of membranes exceeding 24 hours, the incidence of amniotic cavity infection is over 30%.

　　2. As the scope of inflammation expands further, the body temperature of pregnant women increases. When the body temperature exceeds 37.5℃ during premature rupture of membranes and the cause cannot be found, it is necessary to consider the possibility of amniotic cavity infection. After the body temperature of pregnant women increases, accompanied by an increased heart rate, it should be noted that the heart rate of pregnant women can also be slightly faster under physiological conditions during pregnancy. However, when the heart rate is greater than 100 beats/min and no other cause can be found, it is necessary to consider the possibility of amniotic cavity infection. Some pregnant women may experience chest tightness and discomfort.

　　3. The white blood cell count in pregnant women may increase, but it should be noted that physiological changes during pregnancy can also cause an increase in white blood cell count. Additionally, there is a significant individual difference in white blood cell count, but it is generally within 20×109/L. Therefore, dynamic detection of the changes in white blood cell count can be adopted. If the white blood cell count increases progressively or is accompanied by nuclear left shift, it indicates amniotic cavity infection. If only nuclear left shift is present, it usually indicates severe infection.

　　4. Inflammation can not only involve the chorion and decidua but can also further invade the uterine muscle layer, leading to uterine tenderness. Inflammation that invades the placenta and amnion can produce endotoxins, causing edema in the chorionic villus space, and ischemic and hypoxic injuries to the fetus, which are manifested as an increased fetal heart rate, up to 160-180 beats/min. If the fetal heart rate exceeds 180 beats/min, it often indicates severe intrauterine infection in the fetus.

　　4. Before and after the onset of amniotic cavity infection syndrome, vaginal purulent discharge may occur. As the condition worsens, amniotic fluid gradually changes from clear to cloudy, and vaginal discharge also becomes purulent with a foul smell.

　　1. The main focus is on the prevention of high-risk factors that can cause amniotic cavity infection, which primarily involves the management of premature rupture of membranes. Currently, it is widely advocated to use prophylactic antibiotics if the membranes rupture within 12 hours, and some advocates suggest starting prophylactic antibiotic treatment as soon as there is a premature rupture of membranes. When premature rupture of membranes is estimated to indicate fetal maturity (the fetal lungs are considered mature for most pregnancies reaching 34 weeks), it is advisable to terminate the pregnancy early. Approximately 70% of pregnant women will naturally initiate labor within 24 hours after premature rupture of membranes. If there is still no uterine contraction after 24 hours, intravenous oxytocin infusion should be used to induce labor. Some people also advocate that if there is still no labor after 12 hours above the membrane rupture, misoprostol can be placed in the vaginal fornix to help initiate labor earlier without increasing the rate of cesarean sections or the use of oxytocin and the occurrence of amniotic cavity infection. If the gestational age at the time of membrane rupture

　　2、治疗无症状性菌尿无症状性菌尿是孕期常见的泌尿道感染，有3％～10％孕妇曾患过无症状性菌尿，其发生率与种族、孕产次及社会地位有关。无症状性菌尿患者有30％～50％发展为肾盂肾炎。新近有一项汇总分析表明，孕期无症状性菌尿患者发生早产及低体重儿的危险性较大。同时也发现无症状性菌尿与宫内感染有密切关系。因此，积极治疗无症状性菌尿可以减少宫内感染的发生。

　　3、积极处理滞产，产程中注意各种操作的消毒清洁工作，增强无菌意识产程中避免过多的肛查及阴道检查。通常在产程中肛查不要超过10次。

　　4、治疗孕妇全身感染性疾病有人报道，孕妇患肺炎链球菌性大叶性肺炎时，新生儿死亡后肺内虽无炎性病理改变，但肺组织培养出肺炎链球菌。通常，各种病原体血症可以经血行播散，传输到宫内，引起宫内感染，孕妇患感染性疾病时，包括各种特异性和非特异性感染，经积极治疗后可以降低胎儿宫内感染的机会。积极治疗孕期泌尿道感染，以减少相应并发症的发生。

　　5、预防胎儿宫内感染TORCH，做好卫生宣教工作必要时进行育龄妇女相应的预防接种。

　　6、治疗细菌性阴道病细菌性阴道病时，阴道分泌物性质发生改变，阴道内乳酸杆菌减少，而与细菌性阴道病有关的细菌增加，革兰阴性细菌及厌氧菌如加德纳菌、动弯杆菌及消化链球菌和支原体及衣原体等。孕期细菌性阴道病的发生率估计在16％左右，是孕妇阴道分泌物异常的常见原因。但也有近一半细菌性阴道病患者无症状。有很多研究都提示细菌性阴道病与宫内感染有密切关系。甚至有人认为下生殖道的细菌感染是上生殖道感染的一个标志。引起细菌性阴道病的病原体可以穿过宫颈管的黏液栓，穿过完整的胎膜引起羊膜腔感染。细菌性阴道病患者阴道内细菌内毒素及蛋白溶解酶、黏蛋白酶、唾液酸酶、IgA蛋白溶解酶和磷脂酶均增加。这些细胞因子的增加均与宫内感染的发生有密切关系。有人发现有细菌性阴道病病史的患者，剖宫产时发生的绒毛膜羊膜炎及产后子宫内膜炎的发生率，较无细菌性阴道病病史的患者要高4倍。因此，积极治疗孕期细菌性阴道病对于减少宫内感染的发生有重要意义。

　　Firstly, maternal blood determination

　　1. Erythrocyte sedimentation rate:

　　It is a non-specific method to check for infection. Any infection is accompanied by an acceleration of erythrocyte sedimentation rate, including autoimmune diseases such as systemic lupus erythematosus (SLE). During normal pregnancy, erythrocyte sedimentation rate will also accelerate. If it is greater than 60mm/h, the sensitivity for diagnosing amniotic cavity infection syndrome is 65%, and the specificity is 100%. Due to the poor sensitivity of erythrocyte sedimentation rate in diagnosing amniotic cavity infection syndrome, it limits its clinical application.

　　2. White blood cell count:

　　Leukocyte elevation is the gold standard for infection, but it lacks specificity. As a diagnostic method for amniotic cavity infection syndrome, the positive predictive value or negative predictive value is 40% to 75% and 52% to 89% respectively. As for how much leukocytes should increase to diagnose amniotic cavity infection syndrome, it is indeterminate. Leukocytes have a high specificity for diagnosing obvious infections, but their sensitivity and positive predictive value are low for histological chorioamnionitis, simple amniotic fluid culture positivity, and mild clinical infections.

　　3. Maternal blood C-reactive protein (CRP):

　　CRP is a reaction result of the body after infection, produced by the liver, and is also non-specific, which is induced by IL-6. Currently, many studies evaluate the value of CRP in diagnosing asymptomatic intrauterine infection, but the positive predictive value and negative predictive value vary greatly among researchers (40% to 90%). False elevation may occur when uterine contractions exceed 6 hours or when other infectious diseases are present. However, if there is a significant increase, or if it starts low and then increases, it has certain diagnostic value. If the increase is more than 30%, it has a significant predictive value for intrauterine infection. Studies have shown that if CRP increases 12 hours before delivery, the positive predictive value for predicting intrauterine infection can reach 100%. The increase in CRP is not only related to intrauterine infection but also has a certain correlation with neonatal infection. In general, CRP is not very sensitive, which limits its clinical application.

　　4. Detection of cytokines:

　　The value of IL-6 in the diagnosis of amniotic fluid infection syndrome, many scholars have tried to detect cytokines in maternal blood to diagnose amniotic fluid infection syndrome. Lewis et al. detected the level of IL-6 in the blood of 57 pregnant women with premature rupture of membranes at 24 to 35 weeks of gestation before delivery. In 35 cases, the level of IL-6 was elevated, and in 27 cases, at least one complication in newborns occurred (including neonatal respiratory distress syndrome, neonatal necrotizing enterocolitis, intraventricular hemorrhage, neonatal sepsis, and congenital pneumonia). Among them, 24 cases had an IL-6 level higher than normal, and among the 30 cases without neonatal complications, only 11 had an IL-6 level higher than normal (OR=13.8, 95% CI, 2.93-74.7). Among the 13 pregnant women with neonatal complications who used corticosteroids before delivery, 10 had an IL-6 level higher than normal. Among the 32 pregnant women with amniotic fluid infection syndrome, 24 (75%) had an IL-6 level higher than normal, and among the 25 pregnant women without amniotic fluid infection syndrome, only 11 (44%) had an IL-6 level higher than normal (P≤0.03, OR 3.82, 95% CI, 1.09-13.0). Murtha found that when IL-6>8ng/L (8pg/ml), amniotic fluid infection can be diagnosed [positive predictive value (PPV)=96%, negative predictive value (NPV)=95%]. As a cytokine, IL-6 has high specificity in the diagnosis of infectious diseases and is released early in the inflammatory process. Additionally, due to the convenience of specimen collection, it is more convenient for clinical use. However, further prospective studies are needed to assess its value as a diagnostic tool for amniotic fluid infection syndrome.

　　Secondly, amniotic fluid examination

　　Amniocentesis is often used as a diagnostic method for amniotic fluid infection syndrome. Currently, the gold standard for the diagnosis of amniotic fluid infection syndrome is amniotic fluid culture, but its drawback is that the results take a long time to come out. In cases of premature rupture of membranes, nearly 80% of those with positive amniotic fluid cultures will develop obvious clinical infections, while only 10% of those with negative cultures will develop obvious clinical infections. Therefore, when diagnosing neonatal infections and clinical chorioamnionitis, its positive predictive value (PPV) is 67%, and its negative predictive value (NPV) is 95%. Amniotic fluid culture cannot clearly determine the site of infection, and this method has limited diagnostic value for mycoplasma and chlamydia infections.

　　1. Gram staining examination of amniotic fluid:

　　Gram staining of amniotic fluid smears is an ancient and widely used method due to its simple and convenient operation, especially suitable for those with ruptured membranes. The smear is used to find white blood cells and bacteria, both of which suggest the presence of amniotic cavity infection syndrome. The sensitivity of this examination method is 23% to 60%, and the specificity is 76% to 100%. The negative predictive value can reach 63% to 100%. Therefore, the value of this examination lies in the fact that if the examination is negative, it can basically exclude the presence of intrauterine infection. However, for those without ruptured membranes, amniocentesis is required, which limits its clinical application.

　　2. Measurement of glucose concentration in amniotic fluid:

　　Many studies believe that low glucose concentration in amniotic fluid is one of the manifestations of amniotic cavity infection syndrome. Gauthier tested the glucose concentration in amniotic fluid of 91 pregnant women and found that the concentration of amniotic fluid glucose

　　3. Other examinations:

　　The white blood cell count in amniotic fluid smears, with a count of 20×106/L (20/mm3) or more as the diagnostic criterion, results in a sensitivity of 80% for diagnosing intrauterine infection and a specificity of 90%. The positive predictive value and negative predictive value are 96% and 85%, respectively. Detection of bacterial 16srDNA in amniotic fluid using PCR methods has a sensitivity of 100%, but this method requires special equipment and is time-consuming. The detection of catalase in amniotic fluid as a diagnostic method for intrauterine infection has a positive predictive value and negative predictive value of 95% and 88%, respectively. This method is expected to be a better method for diagnosing amniotic cavity infection syndrome.

　　4. Cytokines:

　　Currently, the diagnosis of intrauterine infection focuses on the use of inflammatory cytokines. Cytokines are small molecular glycoproteins produced by different types of cells, especially those involved in immune responses. Studies have shown that the placenta can produce these inflammatory factors during intrauterine infection. The levels of two types of cytokines (IL-1β, IL-6) in amniotic fluid are significantly increased during intrauterine infection, which has greater value in diagnosing amniotic cavity infection syndrome than amniotic fluid staining smears and detecting glucose concentration in amniotic fluid. Taking amniotic fluid IL-6 exceeding 7.9μg/L (7.9ng/ml) as the standard for diagnosing abnormal amniotic fluid culture, its positive predictive value and negative predictive value are 67% and 86%, respectively. In the case of preterm premature rupture of membranes with infection, IL-6 is significantly elevated. However, there is currently no clear standard value to distinguish the presence or absence of intrauterine infection. The value of IL-1β in umbilical cord blood of infected individuals is not significantly correlated with the length of latency, and the relationship between IL-1β and perinatal prognosis is not yet clear.

　　All the above-mentioned examination methods require the collection of amniotic fluid, and the success rate of amniocentesis is 45% to 97%, with certain complications. It is not recommended to use the above methods to diagnose amniotic cavity infection syndrome in all cases, but for cases with premature rupture of membranes, the above methods have significant advantages.

　　Some studies have detected the relationship between IL-8 in urine and intrauterine infection, finding that the positive predictive value and negative predictive value of elevated IL-8 in urine as a diagnostic indicator for amniotic cavity infection syndrome are 71% and 82% respectively. This method is simple and practical, but its value still needs to be further evaluated.

　　5. Enzymes:

　　Due to premature rupture of membranes or amniotic cavity infection syndrome, the extracellular matrix of amniotic cells has a common manifestation, that is, the degradation of extracellular matrix. Matrix metalloproteinases (MMPs) are the key enzymes in this process. The activity of this enzyme is enhanced in this pathological process. The inhibitors of matrix metalloproteinases (TIMPs) can covalently bind to MMPs, reducing their activity. The MMPs that degrade human amniotic membranes are MMP-2, and its corresponding inhibitor is TIMP-2. Maymon found that in cases of premature rupture of membranes or amniotic cavity infection syndrome, there is no significant correlation between the concentration of MMP-2 in amniotic fluid and gestational age; there is no significant difference in the concentration of MMP-2 in amniotic fluid between those with premature rupture of membranes and those with intact membranes. Conversely, compared with pregnant women who have not yet gone into labor, pregnant women with spontaneous labor have a significantly lower concentration of TIMP-2 in amniotic fluid. In cases with amniotic cavity infection syndrome accompanied by premature rupture of membranes, whether it is preterm or term delivery, the concentration of TIMP-2 in amniotic fluid is also significantly lower. Therefore, TIMP-2 in amniotic fluid can be used as a diagnostic indicator for amniotic cavity infection syndrome.

　　Three, fetal biophysical behavior detection for the diagnosis of amniotic cavity infection syndrome

　　After the onset of intrauterine infection, the level of prostaglandin (PG) in amniotic fluid increases, which can change the biological behavior of the fetus. At the same time, intrauterine infection can cause edema of the chorionic villus space and constriction of the umbilical vessels, thereby increasing the resistance of placental blood vessels, affecting the oxygen supply to the fetus, and subsequently changing the fetal heart rate and fetal movement. Through fetal heart monitoring and B-ultrasound examination, it is possible to determine whether there is intrauterine infection in the fetus.

　　1. Amniotic fluid measurement:

　　In cases of premature rupture of membranes, there is a correlation between amniotic fluid volume and amniotic cavity infection syndrome. Vintzileos divided premature rupture of membranes into three groups according to the size of amniotic fluid level, and found that those with oligohydramnios (referring to the maximum amniotic fluid level)

　　2. NST examination:

　　Using non-reactive NST as an index to predict amniotic cavity infection syndrome, the sensitivity for predicting positive amniotic fluid culture is 86%, and the specificity is 70%. The positive predictive value and negative predictive value are 75% and 82% respectively. For predicting clinical and subclinical chorioamnionitis, the sensitivity and specificity are 78% and 86% respectively, and the positive predictive value and negative predictive value are 68% and 92% respectively. There are also reports that non-reactive NST cannot predict the occurrence of intrauterine infection and neonatal sepsis. However, overall, most research results suggest that non-reactive NST and tachycardia are significantly correlated with intrauterine infection. It is also believed that this test is best performed within 24 hours before delivery, when its predictive value is the highest. If the time exceeds 24 hours before delivery, its predictive value will significantly decrease. Currently, there is no evidence to show what relationship the pregnancy prognosis of preterm premature rupture of membranes has after the results of NST are processed.

　　3. Fetal biophysical profile (BPP):

　　It is a method of using ultrasound to observe the fetal activity in utero in real time, including five indicators: amniotic fluid volume (AF), fetal respiratory-like movement (FBM), fetal movement (FM), muscle tone (FT), and fetal heart rate (FHR) reactivity. BPP was initially used mainly for assessing the fetal intrauterine health status in high-risk pregnancies. After Vintzileos first used BPP scoring to diagnose intrauterine infection in 1985, many studies have conducted in-depth research on the value of BPP in diagnosing intrauterine infection. Gauthier performed BPP checks on 111 cases with premature rupture of membranes and found a close correlation between BPP scoring and intrauterine infection. Flemming found that low BPP scoring within 24 hours before delivery was closely correlated with histological chorioamnionitis. Vintzileos found that BPP scoring

　　4. Doppler examination:

　　Some people believe that an increased S/D ratio in umbilical blood flow indicates the presence of intrauterine infection. Flemming conducted daily umbilical blood flow S/D ratio tests and BPP checks on cases with premature rupture of membranes, and found that the S/D ratio of patients with chorioamnionitis was abnormal. If an increase of 15% in the S/D ratio is considered abnormal, the positive and negative predictive values of histological chorioamnionitis are 71% and 61% respectively. Yucal compared the relationship between the S/D ratio and placental pathological examination, and found that the proportion of elevated S/D ratios in patients with histological chorioamnionitis was twice as high as that in pregnant women without chorioamnionitis. However, some authors reported that the abnormality of the S/D ratio is not significantly related to chorioamnionitis. Therefore, the value of using the umbilical blood flow S/D ratio to diagnose intrauterine infection still needs further study.

　　Patients with amniotic cavity infection syndrome should pay attention to the following points in diet: 1. Eat light and nutritious food, pay attention to dietary balance, and eat more fresh fruits and vegetables. 2. Avoid spicy and刺激性 food.

　　First, treatment

　　1. Application of antibiotics:

　　Antibiotics sensitive to the bacteria should be selected according to the results of bacterial culture, but before using antibiotics, various factors such as the safety of various antibacterial drugs during pregnancy and pharmacological changes should be considered. Low-toxicity, broad-spectrum antibiotics that are easy to cross the placenta can be selected if the culture results are not yet available, and anaerobic bacterial infections should also be considered, such as ampicillin, lincomycin, clindamycin, and metronidazole. Antibiotics can help with fewer neonatal infections, but whether they can improve the prognosis of neonates with amniotic cavity infection is yet to be determined.

　　2. Timely termination of pregnancy:

　　Amniotic cavity infections occurring after 34 weeks of gestation should be terminated as soon as possible, and sufficient antibiotic therapy should be provided during the implementation of the termination of pregnancy plan. As for amniotic cavity infection syndrome occurring before 34 weeks, it is also advisable to terminate pregnancy early. The longer the time of intrauterine infection, the greater the risk of intrauterine fetal death, neonatal sepsis after birth, and maternal puerperal infection. However, if the gestational age is too small and the fetus is not easy to survive, conservative treatment can be applied, and antibiotics should be administered while closely observing the fetal heart rate and the changes in the white blood cell count and classification of the pregnant woman. If there is a possibility of threatening the safety of the mother and child, pregnancy should be terminated in a timely manner. The method of termination of pregnancy should be selected based on whether there are obstetric indications. If it is not possible to deliver vaginally in the short term, cesarean section should be performed. During vaginal delivery, attention should be paid to changes in fetal heart rate during labor, and whether there is fetal heart rate intrauterine infection or distress. Currently, with the use of antibiotics, the complications of extraperitoneal cesarean section are not lower than those of routine cesarean section, so it is not recommended to use it routinely.

　　3. Post-treatment:

　　After the amniotic cavity infection, the newborn should be given throat swabs, external ear swabs, nasal swabs, and umbilical cord blood cultures to enable early treatment of possible neonatal sepsis. Eye drops containing antibiotics should be used to prevent or treat ophthalmia. Appropriate anti-infection treatment should be given for pelvic inflammatory disease and urinary tract infection in pregnant women.

　　4. Treatment of clinical IAIS:

　　The treatment of IAIS is very complex, and it is necessary to combine factors such as gestational age, the scope of infection, the type of infection, the general condition of the pregnant woman, the general condition of the fetus, placental function, the medical conditions and level of the hospital where the patient is treated, and other various factors. In short, the treatment of IAIS should follow the principle of individualization.

　　The application of antibiotics has been confirmed, and the principle is early, sensitive, able to cross the placenta, low toxicity to the fetus, and sensitive antibiotics. Penicillin is usually preferred, and aminoglycoside antibiotics can be added; cephalosporin antibiotics can be selected according to circumstances; erythromycin and clindamycin can also be selected; the systemic application of metronidazole has not yet been determined regarding its toxic and side effects on the fetus, and it can be used short-term if necessary; tetracycline, streptomycin, and chloramphenicol are contraindicated.

　　If cesarean section is needed, there are different opinions on the surgical technique for cesarean section, and it is best to perform extraperitoneal cesarean section.

　　5. Subclinical IAIS:

　　The treatment plan for subclinical IAIS is usually a conservative treatment plan based on antibiotic therapy, and oxytocin inhibitors can be added if necessary.

　　Currently, there are many related studies, but the conclusions are inconsistent, the effects are uncertain, and there is no unified approach at present.

　　Two, Prognosis

　　In recent years, there has been a considerable amount of research on the impact of amniotic cavity infection syndrome on both mothers and infants. According to the presence or absence of clinical symptoms, amniotic cavity infection syndrome can be divided into clinical amniotic cavity infection syndrome and subclinical amniotic cavity infection syndrome. The latter refers to the presence of histological evidence, or bacteriological evidence indicating chorioamnionitis, or positive amniotic fluid bacterial culture, but without obvious clinical symptoms. deFelice et al. studied 483 pregnant women with amniotic cavity infection syndrome and found that even in the subclinical form of amniotic cavity infection syndrome, compared to normal pregnant women, the probability of neonates developing intracranial lesions (such as intracranial hemorrhage, ventriculomalacia, etc.) is 2.7 to 3.5 times higher, and the risk of neonates experiencing seizures is 2.3 times higher. Rao et al. found that pregnant women with acute chorioamnionitis have a higher risk of fetal meconium aspiration syndrome compared to those without chorioamnionitis, and the likelihood of neonatal hyaline membrane disease (also known as neonatal respiratory distress syndrome), neonatal sepsis, and the need for neonatal intensive care unit admission also increases. The severity of the harm to the fetus from amniotic cavity infection syndrome may vary depending on the gestational age, with earlier onset usually resulting in more severe harm. The severity of this harm is closely related to the presence of various cytokines produced by various bacteria in the amniotic fluid. Hitti et al. found that if amniotic cavity infection syndrome is accompanied by elevated tumor necrosis factor and IL-6 in the amniotic fluid, the risk of fetal intrauterine death is higher than that in those with amniotic cavity infection syndrome without elevated cytokines. At the same time, the risk of neonates developing pulmonary hyaline membrane disease, intraventricular hemorrhage, neonatal necrotizing enterocolitis, and multiple organ dysfunction is 2 to 3 times higher than that of normal neonates. After intrauterine infection, monocytes release IL-1β and TNF, and the increase in these two factors can lead to an increase in bacterial products such as endotoxins and other cytokines, increasing the permeability of the fetal blood-brain barrier. Further, it leads to the production of IL-1β, IL-6, and TNF-α by fetal glial cells. TNF-α has a direct cytotoxic effect on oligodendrocytes. Some studies have found that up to 80% of patients with ventriculomalacia have elevated levels of IL-1β, IL-6, and TNF-α in their blood, while only 18% of patients without ventriculomalacia have elevated levels of these factors. In addition, patients with amniotic cavity infection syndrome also have a higher chance of preterm birth, especially if they have amniotic cavity infection syndrome before 30 weeks of gestation, which makes preterm birth and even miscarriage more likely. Consequently, the incidence of neonatal pulmonary hypoplasia leading to neonatal hyaline membrane disease increases. Jobe believes that after the occurrence of amniotic cavity infection syndrome, the inflammatory mediators in the amniotic fluid, such as interleukin-1 and bacterial endotoxins, increase, which can increase the incidence of fetal pneumonia on one hand, but also promote the maturation of fetal lung development. This is because the fetal lung is also a target organ for inflammatory mediators, and therefore, postpartum brain damage and other inflammatory injuries can eventually lead to maldevelopment of the bronchi and lungs. On the other hand, certain inflammatory mediators in the uterus can promote fetal lung development,This is because the IL-1α in amniotic fluid can increase the expression of surfactant protein mRNA, increase the synthesis of surfactant substances on the alveolar surface, and at the same time increase surfactant lipids, improving the pressure-volume curve of the lungs in preterm infants.

　　1. The relationship between preterm birth and amniotic cavity infection syndrome:

　　Normal cervical mucus contains IgG, which constitutes the first line of defense against ascending infections of the lower genital tract. The shorter the cervical length, the closer the cervical external os is to the amnion, and at this time, the amount of cervical mucus is also less, making ascending infections of the lower genital tract more likely to occur. Some studies have shown that the combination of cervical length and fetal fibronectin (FFN) in cervical mucus can accurately predict the occurrence of spontaneous preterm birth and also has good predictive value for puerperal infection. It is also closely related to chorioamnionitis and neonatal sepsis. This suggests that preterm birth is closely related to infection itself.

　　Although considerable progress has been made in perinatal medicine in recent years, more than 70% of perinatal deaths are still related to preterm birth, and the incidence of preterm birth is high, ranging from 7% to 11%. Among them, cases with premature rupture of membranes account for 80%, and the remaining 20% are caused by other maternal and fetal reasons. As early as 1940, it was noted that injecting bacterial endotoxins into pregnant animals could cause abortion and preterm birth. Clinically or subclinically, chorioamnionitis, whether or not there is growth of pathogens in amniotic fluid culture, the level of IL-6 in amniotic fluid increases. Therefore, some people believe that amniotic cavity infection syndrome is a cause of preterm birth. Studies have shown that 10% to 40% of preterm births have positive amniotic cavity cultures (with an average of 13%), and the pathogens isolated are mostly from the genus Bacteroides. The cause of preterm birth in amniotic cavity infection syndrome may be related to inflammatory cell infiltration in the amnion and chorion during amniotic cavity infection syndrome, as well as the endotoxins produced by various pathogens, which can stimulate inflammatory cells to produce various cytokines. For example, cytokines produced by monocytes can increase the levels of IL-6 and TNF in amniotic fluid, and high levels of IL-6 and TNF can further stimulate the release of prostaglandins by human chorion and decidua, thus triggering labor. This also indicates that IL-6 and TNF can serve as markers for the presence or absence of intrauterine infection. Some researchers conducted amniocentesis on 269 women undergoing elective cesarean section and found that the level of IL-6 in amniotic fluid of women who delivered naturally was more than 7 times higher than that of women who underwent elective cesarean section. Other researchers also found that the level of IL-6 in amniotic fluid of women with spontaneous preterm birth was higher, and the lower the gestational age, the higher the IL-6 level. Additionally, IL-6 can directly promote the synthesis of prostaglandins by uterine smooth muscle cells, thus triggering labor. Moreover, due to inflammatory reactions, the amniotic membranes in amniotic cavity infection syndrome are prone to premature rupture, leading to preterm birth. This indicates that preterm birth and amniotic cavity infection syndrome may be mutually causal. The source of infection can be from the lower genital tract, such as pathogens in the cervix and vagina, or from direct infection within the uterus, such as various aerobic and anaerobic bacteria, chlamydia trachomatis, mycoplasma, cytomegalovirus, and rubella virus, etc.

　　2. The Relationship Between Premature Rupture of Membranes and Amniotic Cavity Infection Syndrome:

　　After the occurrence of amniotic cavity infection syndrome, there is an inflammatory reaction in the intrauterine embryo tissue, and inflammatory cells secrete inflammatory mediators that cause premature delivery, and can also produce various enzymes, such as elastase of leukocyte elastin and metalloproteinases, which have digestive and solubilizing effects on the collagen components of the amnion, so it is easy to have premature rupture of membranes when the amniotic cavity infection syndrome occurs. Conversely, after the occurrence of premature rupture of membranes, bacteria in the lower genital tract can easily pass through the cervical mucus plug and ascend to cause intrauterine infection. In summary, there is also a causal relationship between amniotic cavity infection syndrome and premature rupture of membranes.

　　3. Miscarriage and Intrauterine Fetal Death:

　　Severe intrauterine infection causing labor is relatively understandable. Some researchers have found that even mild or chronic infections have a higher risk of miscarriage and intrauterine fetal death than normal pregnancy. Boyd and his colleagues studied 45 cases with pathological examination and no genetic defects from two hospitals from 1993 to 2000, and found that 31 were early pregnancy, 23 had chronic amnionitis; 5 were mid-pregnancy, 3 had chronic amnionitis; 9 were late pregnancy, 5 had chronic amnionitis. The total perinatal mortality rate was 770‰, and only 18% of the cases reached full term gestation; among them, 19 patients had recurrent abortion of 3 times or more; 5 had severe intrauterine growth restriction. Segal reported a case of a patient with an intrauterine ring pregnancy and a candidal infection, resulting in intrauterine fetal death at 18 weeks of gestation.

　　4. Intrauterine Growth Retardation of Fetus:

　　Willians et al. studied 2579 pregnant women and parturients with histological evidence of amnionitis, and 7732 pregnant women without evidence of amniotic cavity infection as a control group, and found that pregnant women with amniotic cavity infection syndrome had poorer fetal and neonatal growth and development than normal pregnant women, especially at 28-32 weeks of gestation, when the difference was the greatest. The ratio of fetal birth weight to placental weight was also lower in those with amniotic cavity infection syndrome. Some researchers have found that the fetal weight of those who deliver naturally