Obstetrics and Gynecology
Preterm Premature Rupture of the Fetal Membranes (pPROM)
1. What every clinician should know
Preterm premature rupture of the fetal membranes (pPROM) is defined as the onset of amniotic fluid leakage from the vagina before the onset of uterine contractions at less than 37 weeks' gestational age.
pPROM is responsible for 25-33% of preterm births. Fetal membrane rupture is a physiologic process at term, but results from abnormal structural weakening of the membranes in the region of the internal cervical os when it occurs preterm. The latent period from membrane rupture to delivery is typically brief after pPROM. With pPROM before 34 weeks’ gestation, more than 90% of women will deliver within 1 week. Near the limit of viability, about two-thirds of women will deliver within 1 week of membrane rupture, but one in five will achieve a latency of four weeks or more with expectant management. Spontaneous resealing of the membranes is uncommon after preterm PROM, except when fluid leakage occurs after amniocentesis where resealing is usual (86-94%).
pPROM results from accelerated membrane weakening that can occur through a number of pathways, including direct weakening by bacterial collagenases and proteases, and increased maternal cytokines or an imbalance in MMPs and TIMPs in response to microbial colonization, trauma, and uterine over-distension. Urogenital tract infections with genital tract pathogens such as Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and group B b-hemolytic streptococcus (GBS) have been associated with PROM. Clinical factors associated with pPROM include low socioeconomic status, poor nutrition (e.g. body mass index below 19.8 kg/m2, copper and ascorbic acid deficiencies), as well as prior cervical conization, maternal cigarette smoking, cervical cerclage, second- and third-trimester bleeding, acute pulmonary disease and prior episodes of preterm contractions.
In some cases, the factors leading to membrane rupture are subacute or chronic in nature. Women with a prior preterm birth are at increased risk for subsequent pPROM, as are asymptomatic women with a short cervical length (<25 mm) remote from delivery – indicating that some risk factors are present long before delivery, and even before pregnancy. Unfortunately, the cause of pPROM is often not apparent at the time of membrane rupture.
2. Diagnosis and differential diagnosis
The diagnosis of PROM can usually be made by clinical history, sterile speculum examination and laboratory evaluation for the presence of arborized crystals on a microscope slide of vaginal fluid (“ferning”) or a positive Nitrazine test (pH of amniotic fluid is usually 7.1-7.3 and will turn Nitrazine paper blue). At the time of sterile speculum examination, inspection for evident cervicitis, umbilical cord or fetal prolapse, and for visual assessment of cervical dilatation and effacement is helpful. Culture swabs for Neisseria gonorrhoeae,Chlamydia trachomatis, and GBS can be obtained as needed.
Digital cervical examination should be avoided unless delivery is considered imminent. If the diagnosis of pPROM remains unclear after initial evaluation, documentation of oligohydramnios by ultrasound is suggestive of membrane rupture, and amnioinfusion of indigo carmine dye (1 mL of dye in 9 mL of sterile normal saline) followed by observation for passage of blue fluid from the vagina onto a perineal pad is diagnostic of membrane rupture. Commercially available tests for detection of amniotic fluid in the vagina may be helpful if clinical examination is equivocal, but are not 100% sensitive or specific.
Potentially confounding factors in the diagnosis of pPROM include urine leakage, passage of the mucous plug, cervical infection and semen.
Management of pPROM balances the potential risks for perinatal complications with immediate delivery against the potential risks and benefits with expectant management. The risks of maternal morbidity should also be considered, especially when PROM occurs before the limit of fetal viability (currently 23 weeks gestation).
During initial assessment after pPROM, a best assessment of gestational age should be determined using earliest ultrasound information and menstrual or timed conception/IVF information as applicable. Fetal presentation, growth and residual amniotic fluid volume should be assessed by ultrasound, and the potential of fetal abnormalities should be considered. The patient should be evaluated for evidence of labor, abruption placentae, and clinical chorioamnionitis or other urogenital infections.
Once considered potentially viable, fetal well-being can be ascertained by fetal heart rate monitoring. GBS carrier status should be known based on culture results within 6 weeks or a positive urine culture in pregnancy; alternatively, an anovaginal culture should be obtained if there is not such history or documentation. Absent a recent anovaginal GBS culture or a history of positive urine culture, a risk factor-based approach for prevention of vertical GBS transmission should be used. Expectantly managed patients with pPROM should be cared for in a facility with the ability to provide emergent delivery and neonatal intensive care. Maternal transfer to such a facility, if needed, should be performed early in the course of management. Outpatient management is not recommended when PROM occurs after the limit of viability.
Infants born at 34-36 weeks’ gestation ( late preterm birth) have a higher risk of complications than term infants, but severe acute morbidities and mortality are uncommon. Expectant management of PROM occurring in this gestational age range is not recommended because latency is typically too short to enhance fetal maturation, antenatal corticosteroids for fetal maturation are not typically recommended in this gestational age range, and expectant management increases the risk of chorioamnionitis.
If fetal pulmonary maturity is documented at 32 weeks gestation or more, the likelihood of serious acute morbidities is low and antenatal corticosteroids would not be given. These considerations, combined with the risks of conservative management, suggest that these patients should be delivered for PROM at 32-33 weeks if fetal pulmonary maturity has been documented. The lecithin-to-sphingomyelin ratio (L/S ratio) and the phosphatidylglycerol (PG) test are predictive of pulmonary maturity when performed on vaginal pool specimens or at amniocentesis.
The lamellar body count can be performed from amniocentesis specimens, but mucous in a vaginal pool specimen may interfere with function of the lab analyzer for this test. If amniotic fluid testing reveals an immature result or cannot be accomplished at 32-33 weeks gestation, expectant management with antenatal corticosteroid administration for fetal maturation and concurrent antibiotic treatment to reduce the risk of intrauterine infection is appropriate. If extended latency (greater than or equal to 1 week) is not anticipated after completion of antenatal corticosteroid treatment, then delivery at this time is prudent.
With pPROM between the limit of viability and 31 weeks gestation, delivery is associated with a high likelihood of perinatal complications for the newborn and a high risk of serious long-term complications. In the absence of clinical evidence of intrauterine infection, suspected placental abruption, advanced labor or a non-reassuring fetal heart rate pattern, expectant management is encouraged. During this time, continued inpatient observation is recommended, with serial clinical assessment for maternal or fetal indications for delivery (e.g. progressive labor, abruption placentae, chorioamnionitis and evidence of umbilical cord compression).
If the diagnosis of chorioamnionitis is equivocal, amniocentesis can be performed for glucose assessment (concentration less than 16 mg/dL suggestive of infection), Gram’s stain, culture and sensitivity. Leukocytes alone in amniotic fluid are not well correlated with intrauterine infection after PROM. Antenatal corticosteroid administration (e.g. betamethasone 12 mg I.M. q24h x 2 doses or dexamethasone 12 mg I.M q12h x 4 doses) for fetal maturation should be performed if this has not been done previously, as such treatment significantly reduces newborn complications, including RDS, IVH and NEC, without increasing the risks of maternal or newborn infections.
Broad spectrum antibiotics to prevent infection and prolong pregnancy should be given during expectant management of pPROM remote from term. Such treatment significantly prolongs latency from membrane rupture to delivery and reduces both gestational range and infectious newborn complications. One such regimen includes: initial broad spectrum intravenous therapy for 48 hours (2 g of ampicillin IV every 6 hours and 250 mg of erythromycin IV every 6 hours) followed by oral therapy for 5 days (250 mg of amoxicillin PO every 8 hours and 333 mg of enteric-coated erythromycin base PO every 8 hours). Oral amoxicillin-clavulanic acid treatment is not recommended after pPROM because one large study found more frequent NEC with this treatment. Current evidence does not support that prophylactic or therapeutic tocolytic therapy during expectant management of pPROM will delay delivery adequately to improve newborn outcomes, and this treatment is not recommended for routine use.
Alternatively, magnesium sulfate for neuroprotection was demonstrated to reduce moderate-severe cerebral palsy in a large multicenter North American study involving mostly women with pPROM before 32 weeks gestation; this finding is consistent with other similar studies in women at high risk for preterm birth. As such, intrapartum magnesium sulfate (e.g., a 6 gram bolus followed by 2 grams per hour) is recommended for women presenting with pPROM before 32 weeks regardless of whether expectant management is attempted.
Preterm PROM complicates about one fourth of pregnancies with a cervical cerclage and one half of pregnancies requiring an emergent cerclage. Retrospective studies have not demonstrated reductions in newborn morbidities with cerclage retention after pPROM, and one study has suggested more infectious morbidities if the stitch is left in after pPROM. Because of this, cerclage removal is recommended when the patient arrives with pPROM and with a cervical stitch in place.
The patient with pPROM before the limit of viability should be given a realistic appraisal of potential fetal and neonatal outcomes with previable and periviable birth. In addition to the maternal risks of conservative management delineated above, prolonged bed rest may result in muscle wasting, bone demineralization, deep venous thrombosis, and significant financial and social hardships.
If the patient requests delivery after counseling, this can usually be accomplished with vaginal prostaglandin E2oral or vaginal prostaglandin E1 (i.e., misoprostol), high-dose intravenous oxytocin infusion, or by dilatation and evacuation. The optimal approach will depend on clinical findings (e.g. gestational age, chorioamnionitis and presence of a uterine scar), patient preferences, and physician experience with these alternatives. If expectant management is pursued, ultrasound evaluation of fetal lung growth has been used by some to estimate the risk of lethal pulmonary hypoplasia (indicated by a lack of increase in the size of the fetal lung or chest circumference over time). With pPROM before 20 weeks, persistent and severe oligohydramnios is a strong predictor of subsequent lethal pulmonary hypoplasia. Amnioinfusion to restore the amniotic fluid volume and treatments to seal the membrane defect after pPROM have not been adequately evaluated and are not recommended in routine clinical practice.
The most common maternal complication after pPROM is chorioamnionitis (13-60%). Expectant management provides time for subclinical deciduitis to progress to overt infection and for ascending infection. Fortunately, maternal sepsis (0.8%) leading to death (0.14%) is uncommon. Premature separation of the placenta (abruptio placentae) is diagnosed in 4-12% of cases. After pPROM, the fetus is at risk for complications from intrauterine infection, umbilical cord compression and placental abruption. Umbilical cord prolapse can occur, particularly with fetal malpresentation.
Expectant management is associated with a 1-2% risk of fetal death. When the amniotic fluid volume is severely decreased after early pPROM, particularly with prolonged oligohydramnios after pPROM before 20 weeks gestation, the fetus is at risk for restriction deformities and pulmonary hypoplasia. For the liveborn infant, gestational age at delivery is the key determinant of newborn complications and survival. RDS, NEC, IVH and sepsis are the most common of serious acute newborn complications. Newborn sepsis is two-fold more common after pPROM. Early preterm birth can also lead to long-term complications such as chronic lung disease, blindness, deafness, developmental and motor delay and cerebral palsy.
5. Prognosis and outcome
The optimal way to prevent complications from pPROM is to prevent its occurrence. Potentially modifiable risk factors include cigarette smoking, poor nutrition, urinary tract and sexually transmitted infections, acute pulmonary diseases and severe hydramnios. Other than treatment of infections, it is unknown whether correction of these factors can prevent pPROM. However, knowledge of risk can help to focus counseling for at-risk women about suspicious symptoms and about the importance of timely evaluation if pPROM is suspected.
Women suffering pPROM are at increased risk for preterm birth and pPROM in future pregnancies. A history of preterm birth after PROM confers a three-fold increased risk for recurrent preterm birth due to recurrent P (13.5% versus 4.1%; P < .01). A short cervical length on transvaginal ultrasound is also associated with an increased risk of subsequent pPROM and preterm birth.
Unfortunately, only a small fraction of women destined to deliver preterm can be predicted. Most preterm births occur in women considered to be at low-risk. However, for those with a prior preterm birth due to preterm labor or PROM, weekly intramuscular progesterone has been shown to reduce the risk of recurrent preterm birth.
6. What is the evidence for specific management and treatment recommendations
Gauthier, DW, Meyer, WJ. "Comparison of gram stain, leukocyte esterase activity, and amniotic fluid glucose concentration in predicting amniotic fluid culture results in preterm premature rupture of membranes". Am J Obstet Gynecol. vol. 167. 1992. pp. 1092-5.(Value of amniotic fluid assessment for clinical chorioamnionitis when the diagnosis is unclearclinically.)
Waters, TP, Mercer, BM. "The management of preterm premature rupture of the membranes near the limit of fetal viability". Am J Obstet Gynecol. vol. 201. 2009. pp. 230.(Outcomes after pPROM near and before the limit of viability.)
Neerhof, MG, Cravello, C, Haney, EI, Silver, RK. "Timing of labor induction after premature rupture of membranes between 32 and 36 weeks’ gestation". Am J Obstet Gynecol. vol. 180. 1999. pp. 349-52.(Impact of expectant management of pPROM near term.)
Mercer, BM, Crocker, L, Boe, N, Sibai, B. "Induction vs. expectant management in PROM with mature amniotic fluid at 32-36 weeks: A randomized trial". Am J Obstet Gynecol. vol. 82. 1993. pp. 775-82.(Randomized controlled trial of expectant management of PROM with documented fetal pulmonary maturity near term.)
Mercer, B, Miodovnik, M, Thurnau, G. "for the NICHD-MFMU Network: Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: A randomized controlled trial". JAMA. vol. 278. 1997. pp. 989-95.(U.S. multicenter trial of antibiotic treatment during conservative management of pPROM before 32 weeks gestation.)
Kenyon, SL, Taylor, DJ, Tarnow-Mordi, W. "for the Oracle Collaborative Group: Broad spectrum antibiotics for preterm, prelabor rupture of fetal membranes: The ORACLE I Randomized trial". Lancet. vol. 357. 2001. pp. 979-88.(European multicenter trial of antibiotic treatment during conservative management of pPROM.)
Harding, JE, Pang, J, Knight, DB, Liggins, GC. "Do antenatal corticosteroids help in the setting of preterm rupture of membranes". Am J Obstet Gynecol. vol. 184. 2001. pp. 131-9.(Meta-analysis of the impact of antenatal corticosteroid administration on newborn outcomes after pPROM.)
Rouse, DJ, Hirtz, DG, Thom, E, Varner, MW, Spong, CY, Mercer, BM. "A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. Eunice Kennedy Shriver NICHD Maternal – Fetal Medicine Units Network". N Engl J Med. vol. 359. 2008. pp. 895-905.(U.S. Multicenter trial of magnesium sulfate for neuroprotection before anticipated early preterm birth in a population of predominantly complicated by pPROM.)
Mercer, BM, Goldenberg, RL, Moawad, AH. "for the National Institutes of Child Health and Human Development Maternal Fetal Medicine Units (NICHD-MFMU) Network: The preterm prediction study: Effect of gestational age and cause of preterm birth on subsequent obstetric outcome". Am J Obstet Gynecol. vol. 181. 1999. pp. 1216-21.(Observational multicenter study of risk factors for preterm birth and recurrent preterm birth.)
Meis, PJ, Klebanoff, M, Thom, E. "for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network: Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate". N Engl J Med. vol. 348. 2003. pp. 2379-85.(U.S. multicenter trial of weekly intramuscular progesterone treatment to prevent recurrent preterm birth.)
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