Preterm birth accounts for approximately 12% of all births in the United States and is a major contributor to perinatal morbidity and mortality (1,2). Despite progressive research within the field, the incidence of preterm birth has increased progressively from 1981 onwards to 38% (3). Premature rupture of membranes (PROM) is a complication that accounts for approximately one third of preterm births. There is a short delay between delivery and rupture of membranes, which increases the propensity for perinatal infection and intrauterine cord compression. Thus, both PROM and premature rupture of membranes before term can lead to significant perinatal morbidity and mortality. The optimal protocol for clinical evaluation and treatment of women with full-term and pre-term PROM is currently controversial. Management depends on pregnancy g and an assessment of the risk associated with preterm delivery and the relative risk of intrauterine infection, placental abruption and cord accidents that may occur during the expectancy process. The purpose of this literature is to provide an overview of the current understanding of these conditions, as well as to provide guidelines for management that have been validated based on appropriately managed outcome studies and also based on consensus and expert opinion. [Background] PROM is defined as rupture of fetal membranes occurring before labor initiation, and rupture of membranes occurring before 37 weeks of gestation is referred to as premature rupture of membranes at term (PPROM). Although full-term PROM is due to the normal physiological process of gradual decay of fetal membranes, pre-term PROM may be due to multiple pathological mechanisms acting alone or in combination (4). Gestational age and fetal status at the time of rupture of membranes have a significant impact on the etiology and consequences of PROM. Management may be determined by the presence or absence of significant intrauterine infection, progression of labor, or fetal compromise. When these factors are not present, especially in cases of uncomplicated PROM, obstetric management may significantly affect maternal and infant outcomes. Proper assessment of gestational age and knowledge of maternal, fetal, and neonatal risk domains are necessary for the appropriate evaluation, counseling, and care of patients with PROM. Etiology] A variety of factors may contribute to premature rupture of membranes. At full term, fetal membrane fragility may result from a combination of physiological changes and shear forces caused by uterine contractions (5-8). Intra-amniotic cavity infection has been shown to be frequently associated with uncomplicated PROM, especially when uncomplicated PROM occurs at an earlier gestational age (9). In addition, other factors such as low socioeconomic income, bleeding in mid- and late pregnancy, low body mass index (a number derived by dividing weight in kilograms by height in meters squared) less than 19.8, copper and ascorbic acid nutritional deficiencies, connective tissue disorders (e.g., hyperelastic skin syndrome), maternal smoking, cervical conization or cerclage, pulmonary disease during pregnancy, uterine hyperextension, and amniocentesis have been associated with the occurrence of uncomplicated PROM (10-19). The risk of recurrence of uncomplicated PROM ranges from 16% to 32% (20,21). In addition, women with a previous history of preterm labor (especially if the preterm labor was due to PROM), midterm pregnancy with cervical shortening (less than 25 mm) and current pregnancy with preterm labor or contractions all increase the risk of PROM (12,22). Although all these risk factors may act individually or in concert when causing PROM, there will be no recognized risk factors in many PROM cases. Therefore, identifying an effective treatment strategy for the prevention of PROM is difficult. Recent studies have shown that progestin therapy can reduce the risk of preterm labor or PROM due to recurrent spontaneous preterm labor (23,24). However, since most cases of PROM occur in women with no apparent risk factors, treatment after the onset of ruptured membranes is a pillar of care. Premature rupture of membranes in full-term pregnancies Complicating PROM at full term accounts for approximately 8% of all pregnancies and is often followed by rapidly initiated spontaneous labor and delivery. A large randomized trial showed that half of the women with PROM who underwent expectant treatment delivered within 5 hours and 95% delivered within 28 hours of rupture of membranes (25). The most notable maternal risk of full-term PROM is intrauterine infection, with an increased risk with duration of rupture of membranes (25-29), and fetal risks associated with full-term PROM include cord compression and episodic infection. Amniotic fluid leakage after amniocentesis The occurrence of amniotic fluid leakage after amniocentesis is associated with a better outcome than spontaneous uncomplicated PROM. The risk of PROM was found to be 1-1.2% in a study of women who underwent amniocentesis in midterm pregnancy due to prenatal diagnosis of a genetic disorder, and the rate of pregnancy loss due to this risk was 0.06% (30). In most patients, the membranes reseal and the amniotic volume returns to normal. Premature rupture of membranes at term Regardless of obstetric management or clinical presentation, delivery within one week is the most common outcome for any patient with preterm PROM who lacks adjuvant therapy. the earlier the PROM occurs in pregnancy, the longer the delay. With anticipatory treatment, 2.8-13% of women can anticipate cessation of amniotic fluid leakage and are able to return to normal amniotic fluid volume. The incidence of clinically significant amniotic cavity infection in women with unterm PROM is 13-60%, and the incidence of postpartum infection is 2-13% (33-37). The incidence of infection increases with decreasing gestational age at rupture of membranes (38, 39) and increases with vaginal fingering (40). Fetal previa abnormalities increase uncomplicated PROM, with placental abruption occurring in 4-12% of uncomplicated PROMs (41, 42), but severe maternal sequelae are uncommon (35, 43). The most important risk for the fetus after an unfull-term PROM is the complication of preterm birth, and respiratory distress has been reported as the most common complication in preterm infants of all gestational ages before full term (4, 44). The incidence of other serious conditions including neonatal infections, intraventricular hemorrhage, and necrotizing small bowel colitis are also associated with preterm birth, but these complications become less common the closer to term. Unfull-term PROM and exposure to intrauterine inflammation are associated with an increased risk of impaired neurodevelopment (9, 45). After validation of corticosteroid use, prolonged intervals, gestational age at delivery, and birth weight, ruptured membranes at earlier gestational ages were also associated with an increased risk of neonatal white matter damage (P<0.001) (46). However, there are no data recommendations showing that delivery immediately after prom avoids these risks. The presence of maternal infection contributes to the additional risk of neonatal infection. The 1-2% prenatal fetal death in utero after uncomplicated prom is attributed to infection, umbilical cord accidents and other factors. Premature rupture of membranes in nonviable fetuses The reported fetal survival rate after PROM at 24-26 weeks of gestation is approximately 57% (47). A recent systematic review involving 201 patients from 11 studies showed a perinatal survival rate of 21% for patients with viable preterm fetuses expecting treatment after PROM (48). Survival data may vary by study site. Most studies of midterm pregnancy and nonviable fetuses with PROM use a retrospective analysis and include only those patients who are suitable and receive prospective treatment, which may prolong the waiting time and significantly improve outcomes. A small number of patients with PROM in nonviable fetuses will have an extended waiting period. A review of 12 studies evaluated patients with midtrimester PROM with a mean prolonged period ranging from 10.6 to 21.5 days (47), with 57% of patients delivering within a week and 22% continuing for a month or more. The incidence of PROM followed by stillbirth at 16-28 gestational weeks ranged from 3.8% to 22% (11, 33, 49), compared to 0-2% at 30-36 gestational weeks (50, 51). The increased mortality can be explained by increased susceptibility to cord compression or fetal susceptibility to hypoxia and intrauterine infection. This result reflects the fact that no intervention for a viable preterm fetus with impaired fetus is also an option. Serious maternal complications following PROM in midterm pregnancies and nonviable fetuses include intra-amniotic cavity infection, endometritis, placental abruption, retained placenta, and postpartum hemorrhage. Maternal sepsis is a rare but serious complication that occurs in approximately 1% of cases, and there are individual reports of maternal death due to infection in this setting (52). The outcome of survivors of premature rupture of membranes at term depends on gestational age, symptoms of infection, prolonged duration and other complications for the mother and fetus. Various conditions of fetal lung compression or low amniotic fluid or both may lead to pulmonary insufficiency. The risk of fetal pulmonary insufficiency after PROM at 16-26 weeks of gestation has been reported to vary from <1% to 27% (37, 52). Fatal pulmonary insufficiency secondary to ruptured membranes after 24 weeks of gestation rarely occurs, presumably because alveolar growth has occurred sufficiently to support postnatal development (53, 54). Earlier midtrimester fetal membrane rupture, severe amniotic fluid hypohydramnios and duration of rupture lasting more than 14 days are all major determinants of the risk of pulmonary insufficiency (55, 56). Long-lasting hypohydramnios have also been associated with in utero deformities, including facial anomalies (e.g., low ears and medial canthus), limb contractures, and other postural abnormalities. [Clinical considerations and recommendations] How to diagnose premature rupture of membranes? Most cases of PROM can be diagnosed based on the patient's medical history and physical examination. In particular, examination before full term should be performed in such a way that the risk of causing infection is minimized. Because cervical speculum examination increases the risk of infection and the use of a speculum does not provide valid information, it should be avoided unless the patient is in labor or planning to deliver (49, 57-59). Sterilized speculum examination can be used to detect cervicitis and cord or fetal prolapse, to assess the chances of cervical dilation and accommodation, and to obtain a culture of secretions, as appropriate. The diagnosis of ruptured membranes can be established by visualizing the fluid flowing from the cervical canal. If the diagnosis is still in doubt, the pH of the fluid in the lateral vaginal wall or posterior vaginal vault is tested for evaluation. Vaginal secretions usually have a pH of 4.5-6.0, whereas amniotic fluid usually has a pH of 7.1-7.3. False-positive results often occur in the presence of blood or semen contamination, alkaline antiseptics, or bacterial vaginosis. False-negative results may occur when amniotic fluid leakage persists for a long time and when the amount of residual amniotic fluid is extremely low. Secondary information can also be obtained by swabbing the posterior vaginal fornix (avoiding cervical mucus) and placing a dried microscopic intercept of the vaginal fluid, which is visible as dendritic branches (fern-like changes) under the microscope, further indicating rupture of the fetal membranes. Ultrasound examination of the amniotic fluid volume to document low amniotic fluid may be a useful adjunct, but it is not diagnostic. When the clinical history and physical examination are inconclusive, ultrasound-guided transabdominal injection of indigo carmine dye (1 mL in 9 mL of sterile saline) followed by observation of blue vaginal fluid can definitively diagnose ruptured membranes. What is the initial treatment once PROM is diagnosed? For all patients with PROM, gestational age, fetal position and fetal health should be determined. In patients of any gestational age with significant intrauterine infection, placental abruption, or evidence of fetal compromise, the best treatment is prompt delivery. In the absence of an indication for immediate delivery, a laboratory test of cervical secretions for Chlamydia trachomatis and Neisseria gonorrhoeae may be obtained if available to make a diagnosis. The need for group B streptococcal prophylaxis in the event of an uncomplicated PROM delivery is well established (60). In patients with uncomplicated PROM, electronic fetal heartbeat and contraction monitoring can provide the opportunity to identify occult cord compression and assess asymptomatic contractions. One study showed variable decelerations in 32% of women with an unfull-term PROM (61). Patients with a biophysical score of Q6 and delivery within 24 hours were shown to be associated with positive amniotic fluid cultures and perinatal infections, and their association was confirmed by at least eight studies (62), most of which assessed the fetus daily in patients after an uncomplicated PROM. Abnormal test results should reassess the clinical status and may lead to a decision to proceed to delivery. It is important to remember that the possibility of nonresponsive results in fetal heart rate tests less than 32 gestational weeks is due to the fact that the immature fetus is actually healthy; however, once a responsive result has been obtained, a subsequent nonresponsive result should be considered suspicious. There is no consensus among experts on the optimal frequency and mode of fetal monitoring in the face of PROM. What is the best way to start treatment in patients with premature rupture of membranes at term? Fetal heart rate monitoring should be used to evaluate the fetal status. The standard dates should be re-verified to assess gestational age, since in fact, all aspects of subsequent treatment depend on this information. Because it is considered that the best outcome for group B streptococcal prophylaxis is within 4 hours before delivery, when the decision to deliver is made, group B streptococcal prophylaxis should be given based on the results of the previous culture or if the patient at risk was not originally tested for culture (60). One of the largest randomized studies to date found that induction of labor with contractions reduced the interval between PROM and delivery and not only did not increase cesarean delivery or neonatal infections, but also reduced the incidence of chorioamnionitis, the prevalence of postpartum fever, and neonatal antibiotic therapy (25). These data suggest that for women with full-term PROM, labor should be induced at the time of manifest rupture of membranes, often using contractin drips to allow for prodromal labor to reduce the risk of chorioamnionitis. Allowing sufficient time for progression of the incubation period for delivery. When is delivery recommended for premature rupture of membranes in preterm fetuses? The timing of delivery depends on gestational age and fetal status (see Table 1), and there is variation between institutions regarding the optimal time of delivery. At 32-33 full gestational weeks, the risk of serious complications of preterm delivery is low if the maturity of the fetal lungs is confirmed by amniotic fluid specimens collected by vaginal or amniocentesis (51). Therefore, if fetal lung maturity is established, induction of labor should be considered. If fetal lung maturity cannot be established, expectant treatment may be beneficial. The efficacy of corticosteroids, recommended by some experts in women with PROM at 32-33 full gestational weeks, is not specifically described. Because of the risk of elevated chorioamnionitis (63, 64) and the fact that antenatal corticosteroids are not recommended after 34 gestational weeks to promote fetal lung maturation, delivery is recommended when PROM occurs at ≥34 gestational weeks. Those patients with PROM occurring between 24 and 31 full weeks of gestation should be treated expectantly until 33 full weeks of gestation if no maternal or pediatric contraindications exist. Extended expectancy with prophylactic antibiotics and a course of antenatal corticosteroids can help to reduce the risk of infection and neonatal morbidity associated with gestational age.