Premature rupture of membranes
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# Overview
Premature rupture of membranes (PROM) (referred to as pre-labor rupture of membranes for simplicity in this article) is a condition which occurs in pregnancy when the amniotic sac ruptures before the onset of labor. A related term is pPROM which stands for preterm premature rupture of the membranes which occurs when the rupture happens before 37 weeks gestation. Risk factors include maternal vaginal infections which ascend to the amniotic membrane, vaginal bleeding during pregnancy and maternal stature, among others.

# PPROM
Preterm prelabor rupture of membranes (PPROM) is a condition where the amniotic sac leaks fluid before 37 weeks of gestation. This can be caused by a bacterial infection or by a defect in the structure of the amniotic sac, uterus, or cervix. In some cases, the leak can spontaneously heal, but in most cases of PPROM, labor begins within 48 hours of membrane rupture. When this occurs, it is necessary that the mother receive treatment to avoid possible infection in the newborn.

# Classification
Prelabor rupture of membranes may be classified according to gestational age at which the rupture occurs. If more than 18 hours have passed after the rupture of membranes without the onset of labor it is termed as prolonged PROM. If rupture occurs before age of viability (37 weeks) it is termed as preterm prelabor rupture of membranes (pPROM). If the gestational age is between 20 0/7 weeks to 25 6/7 it is considered as "periviable PROM". Other types of rupture of membranes are artificial rupture of membranes (AROM), spontaneous rupture of membranes (SROM).

# Pathophysiology
Membrane strength is dependent on extracellular proteins including but not limited to collagen, fibronectin and laminin. Matrix metalloproteases (MMPs) degrade collagen which reduces membrane strength. These are inhibited by metalloproteinase inhibitors. The balance between these proteins maintains membrane integrity. It is thought that PROM and pPROM can be caused by a combination of events that lead to membrane weakening via direct damage or reduction of supporting elements.  Up to a third of PROM cases are linked to amniotic fluid positive for bacteria. These infections may be asymptomatic until presentation. In case of an altered flora of the vaginal canal, some invasive species of bacteria produce collagenases, proteases, which directly degrade the amniotic membranes, in addition to the inflammatory effect and subsequent damage to the membranes by the host immune system. 
Hypoxic stress to the fetus and placenta are linked to a three to seven times likelihood of PROM. This stress can be due to maternal hypertension, preeclampsia/eclampsia and problems with the umbilical cord. This stress causes release of fetal corticotropin releasing hormone (CRH), leading to inhibition of transcription in decidual cells (via the glucocorticoid and progesterone receptor ligand), leading to a state of progesterone resistance and consequent weakening of membranes.
Fetal ACTH release also results in a downstream increase of androgens, which are converted by the placenta into estrones. These estrones act on the myometrium to increase gap junctions and receptors for pro-contractile hormones. Coupled with the anti-progesterone effects of fetal CRH, this pathway results in an excitable and procontractile myometrium.

# Differentiating PROM from other Diseases
Other disorders causing abnormal vaginal wetness are:
- Urinary incontinence
- Excessive discharge
- Urinary tract infection
- bacterial vaginosis
- cervical mucus
The diagnosis of PROM is done via careful history and physical examination, ultrasound is employed to confirm oligohydramnios. These tests can also be done to rule out the differentials listed.

# Epidemiology and Demographics
PROM complicates 3% of preterm pregnancies and occurs in 5% to 10% of term pregnancies. 60% to 80% cases of PROM occur in term pregnancies.
Pregnant females of all age groups may develop PROM, however there is a higher chance of adolescent pregnancies progressing towards PROM and pPROM.
African american females are more likely to experience PROM.

# Risk Factors
Common risk factors in the development of PROM include important maternal risk factors such as chorioamnionitis, sepsis, previous history of PROM. Additional factors are similar to those for preterm birth such as abnormal bleeding during the second trimester or late in the pregnancy, low BMI, reduced cervical length, smoking and drug abuse. Low socioeconomic status and deficiency of copper or vitamin C, along with connective tissue disorders are also linked to increased risk of PROM. Fetal factors include prematurity, infection, cord prolapse, or malpresentation. 

# Screening
There is insufficient evidence to recommend routine screening for PROM. In women with positive vaginal-rectal group B strep (GBS) cultures within the past 5 weeks, antibiotic prophylaxis is recommended intrapartum by the CDC. If the patient is not in labor, antibiotics are to be continued for 48 hours and cultures to be repeated. If repeat cultures are positive, intrapartum antibiotics are recommended. For cases of PPROM, fetal nonstress testing is done to monitor status.

# Natural History, Complications, and Prognosis
The majority of pregnancies progress to delivery within one week of membrane rupture, the common cause of induced or spontaneous labor is chorioamnionitis, which complicates up to 60% of PROM cases. In usual cases of PROM, labor is induced as soon as possible if pregnancy is viable. If expectant management is practiced, the patient is at increased risk of infection, abruptio placentae, and umbilical cord accident as well as complications linked to residual oligohydramnios. The risk of long term neurodevelopmental problems however, is not affected. PROM and PPROM are the most common cause of premature delivery, neonatal respiratory distress syndrome and neonatal death.

# Diagnosis
Assessment of PROM involves taking a focused medical history, a physical examination with a sterile speculum, ultrasound and other commercial tests if a diagnosis is not reached prior.

## Diagnostic Study of Choice
The diagnosis of PROM is made according to characteristic findings on history and physical examination. Usual cases present as a woman in late trimester pregnancy complaining of leakage of fluid. The gold standard for diagnosis per speculum is pooling of fluid in the posterior vaginal vault. If there is no pooling observed, the patient is told to bear down or apply fundal pressure in order to increase the outflow of amniotic fluid and get visual confirmation of leakage. There may still be no pooling observed, in which case diagnostic testing is employed in the form of ultrasound to gauge the amniotic fluid volume. Ultrasound is also useful to assess fetal wellbeing. If oligohydramnios is detected, the diagnosis of PROM is confirmed. In cases of low-normal or normal amniotic fluid volume, other tests can be done to confirm PROM/PPROM.

## History and Symptoms
The hallmark of PROM is pooling of fluid. A history of leakage of clear fluid from the vagina is suggestive of PROM.

## Physical Examination
Patients with PROM usually appear well, some may be in active labor. Physical examination of patients is usually remarkable for leakage of clear or yellow fluid from the vagina, which may be a sudden gush or a slow leak that is evident by wetting of clothes. Fetal position is determined using Leopold's maneuver. For women in active labor, sterile speculum examination is recommended to confirm pooling of amniotic fluid, as digital examination has been shown to increase the risk of infection and early labor (also called latency). Fever, foul-smelling vaginal discharge, fetal tachycardia (especially more than expected due to maternal temperature), and abdominal pain are highly indicative of infection.

## Laboratory Findings
PROM is a clinical diagnosis, however in cases where membrane rupture is unclear or pooling is not visible in the vagina, bedside dipstick or strip based testing for specific amniotic fluid proteins has shown to be highly sensitive and specific for detecting PROM. An elevated concentration of vaginal fluid placental alpha microglobulin-1 protein is highly suggestive of PROM (Amnisure Test). IGFBP-1, or placental protein 12 (PP12) is another protein found in high concentrations in amniotic fluid and is the target of dipstick tests to detect PROM.
Less sensitive tests include the nitrazine and fern tests. A nitrazine paper test strip is used to test the pH of vaginal fluid. normal vaginal pH  is from 3.8 to 4.2, the pH of urine, which is typically <6.0 but may be higher, amniotic fluid usually has a pH range of 7.0 to 7.3. False negatives can occur if the leaking sporadic or if the amniotic fluid is diluted by other vaginal fluids. False positives can be attributed to alkaline fluids in the vagina, like blood, seminal fluid, urine or soap. Urinary tract infections can also raise the urine pH.
Amniotic fluid forms a "ferning" pattern when allowed to dry on a slide. Fluid collected from the posterior fornix is dried on a glass slide for 10 minutes. Amniotic fluid produces a delicate ferning pattern, while dried cervival mucus forms a thicker, wider pattern. Well-estrogenized cervical mucus or a fingerprint  on the microscope slide may cause a false positive fern test. False negatives may be because of the slide being prepared with inadequate amniotic fluid or contamination with vaginal discharge or blood.

## Electrocardiogram
There are no ECG findings associated with PROM.

## X-ray
There are no x-ray findings associated with PROM.

## Ultrasound
Echocardiography/ultrasound  may be helpful in the diagnosis of PROM/pPROM. Findings on an ultrasound diagnostic of PROM include:
- four quadrants amniotic fluid index (AFI): <5 cm
- two diameter pocket method: <1 x 1 cm or <15 cm2
- maximum vertical pocket depth: <2 cm
It is also used to determine fetal presentation and position.

## CT scan
There are no CT scan findings associated with PROM.

## Other Imaging Findings
There are no other imaging findings associated with PROM.

## Other Diagnostic Studies
Other Studies are done if there is no clear evidence of PROM. Indigo carmine dye is injected into the amniotic sac under ultrasound guidance. Leakage of the blue dye into the vagina indicates rupture of membranes. Diamine Oxidase may also be used.

# Treatment

## Medical Therapy
Initial evaluation by a physician guides the management of PROM. The risks of neonatal immaturity are weighed against the risk for infection and fetal health. In a term pregnancy where premature rupture of membranes has occurred, spontaneous labour should be permitted. Current obstetrical management includes an induction of labour at approximately 6 hours if it has not already begun, and Group B Streptococcal prophylaxis at 18 hours. Some hospitals, birth centers and private midwives do not induce labor at any point after PROM, but rather watch carefully for any signs of infection and ensure that nothing is introduced into the vagina after the PROM, including sterile vaginal exams. If the pregnancy is at term or if there are signs of neonatal distress it is recommended to induce labor as soon as possible unless contraindicated, in which case delivery via caesarean section is performed. Expectant management is practiced according to the patients wishes and the assessment of the clinician. Studies have shown early induction to reduce maternal and fetal complications such as infection and cord prolapse when compared to expectant management of PROM. If management options remain unclear, fetal assessment is done for lung maturity via testing the amniotic fluid for surfactant. This helps gauge whether expectant management is viable and whether or not steroids are to be administered.    
In premature birth premature rupture of membranes, antibiotic therapy should be given to decrease the risk of sepsis. Ampicillin or erythromycin should be administered for 7 days, and antenatal steroids if the gestational age is less than 30 weeks. Tocolysis may be used, although controversial, to reduce the risk of prematurity related complications in the fetus. The mother should be admitted to hospital and put under careful surveillance for preterm labour and chorioamnionitis. Induction of labour should happen at around 36 weeks.
One study showed that the frequency of cesarean delivery, endometritis and perinatal mortality did not differ between the groups, however, there was a higher risk of infection and fetal morbidity in the expectant managed group. 
Expectant management
- For women who meet the following criteria, it is considered safe to opt for expectant management.
No signs of intrauterine infection
Cephalic presentation of the fetus
Encouraging fetal ECG
Amniotic fluid pocket on ultrasound at least 2 by 2 cm
Patient safety at home and access to hospital
Patient is educated with regards to charting blood pressure and temperature at home every 6 hours and when to present to the hospital.
Daily fetal kick counts
Daily nonstress test and leukocyte count
- No signs of intrauterine infection
- Cephalic presentation of the fetus
- Encouraging fetal ECG
- Amniotic fluid pocket on ultrasound at least 2 by 2 cm
- Patient safety at home and access to hospital
- Patient is educated with regards to charting blood pressure and temperature at home every 6 hours and when to present to the hospital.
- Daily fetal kick counts
- Daily nonstress test and leukocyte count
- The womans activity is limited to modified bed rest and complete pelvic rest. Vitals must be charted 3 times daily.
- Antibiotics (usually 48 hours of IV ampicillin and erythromycin, followed by 5 days of oral amoxicillin and erythromycin) have been shown to lengthen the latency period and reduce risk of neonatal morbidity.
- If pregnancies are periviable (>24 but <34 weeks) corticosteroids are given to facilitate lung maturity. Another course of corticosteroids may be given if the following criteria are met:
The pregnancy is < 34 weeks.
Women are at risk of delivering within 7 days.
The last course was given  14 days prior.  Corticosteroids should also be considered in the following circumstances:
At gestational age 34 weeks 0 days to 36 weeks 6 days if women are at risk of delivering within 7 days and no prior corticosteroids have been given. Starting at gestational age 23 weeks 0 days if there is a risk of preterm delivery within 7 days.  IV magnesium sulfate should be considered in pregnancies < 32 weeks; in utero exposure to this drug has shown to reduce the risk of severe neurologic dysfunction (eg, due to intraventricular hemorrhage), including cerebral palsy, in neonates.  Tocolytic use remain controversial, and must be decided on a case basis. "Prelabor Rupture of Membranes (PROM)"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- The pregnancy is < 34 weeks.
- Women are at risk of delivering within 7 days.
- The last course was given  14 days prior.  Corticosteroids should also be considered in the following circumstances:
- At gestational age 34 weeks 0 days to 36 weeks 6 days if women are at risk of delivering within 7 days and no prior corticosteroids have been given. Starting at gestational age 23 weeks 0 days if there is a risk of preterm delivery within 7 days.  IV magnesium sulfate should be considered in pregnancies < 32 weeks; in utero exposure to this drug has shown to reduce the risk of severe neurologic dysfunction (eg, due to intraventricular hemorrhage), including cerebral palsy, in neonates.  Tocolytic use remain controversial, and must be decided on a case basis. "Prelabor Rupture of Membranes (PROM)"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
It is prudent to note that many studies have linked prolonged rupture of membranes to unfavorable outcomes with regards to fetal and maternal mortality. 
Active Management
In women with known vaginal Group B streptococcus (GBS) colonization, prophylactic antibiotics and early induction of labor is recommended.
Multiple studies suggest oxytocin as the drug of choice to induce labor in women with PROM.  Oral misoprostol (100ug for up to two doses six hours apart) for induction of labor in women with term PROM was not found to be more effective. Classic management of labor induction with only oxytocin has however shown an increase in maternal as well as perinatal morbidity compared to studies with prostaglandins in patients with PROM with a unsuitable cervix (Bishop score of less than 6).
The maternal and fetal/neonatal hazards from induction of labor include failed induction leading to increased latency, uterine hyperstimulation, uterine hypotony, abruptio placentae, uterine rupture, inadvertent preterm delivery, fetal distress, electrolyte disturbances (hyponatremia), hyperbilirubinemia and postpartum hemorrhage.

## Surgery
Surgery is not the first-line treatment option for patients with PROM. Surgery is usually reserved for patients with either contraindications for vaginal delivery or labor, or cases that have been complicated with chorioamnionitis. 

## Primary Prevention
There are no established measures for the primary prevention of PROM.

## Secondary Prevention
There are no established measures for the secondary prevention of PROM.
Algorithm for PROM at term