Preterm Premature Rupture of Membranes (PPROM) Case File

Preterm Premature Rupture of Membranes (PPROM) Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 41

A 32-year-old G2P0010 African American woman at 28 weeks’ gestation comes into the obstetrical triage unit complaining of leakage of fluid per vagina approximately 4 hours previously. She denied uterine contractions or vaginal bleeding. Her prenatal course has been unremarkable. She had a miscarriage at 8 weeks’ gestation previously. On examination, her BP is 100/78 mm Hg, HR 82 beats per minute, RR 18 breaths/min, and temperature 98.3°F. Her heart and lung examinations are normal. The abdomen is soft and nontender. The uterus is nontender with a fundal height of 27 cm. The fetal heart tones are in the 140 bpm range. A speculum examination reveals gross pooling of fluid in the vagina, and the cervix appears to be visually closed.

➤ What is the most likely diagnosis?

➤ What are your next steps?

➤ How would you manage the patient if she went into labor?

ANSWERS TO CASE 41:

Preterm Premature Rupture of Membranes (PPROM)

Summary: A 32-year-old G2P0010 African American woman at 28 weeks’ gestation has symptoms of vaginal leakage of fluid 4 hours previously. She is afebrile. The fetal heart tones are in the 140 bpm range. A speculum examination reveals gross pooling of fluid in the vagina, and the cervix appears to be visually closed.

➤ Most likely diagnosis: Preterm premature rupture of membranes (PPROM).

➤ Next steps:

1. Confirm the diagnosis: ferning test; pH testing (nitrazine paper) on vaginal fluid.

2. Baseline assessment of maternal and fetal well-being:

    a. CBC, urinalysis, comprehensive metabolic panel

    b. GBS culture. Consider an assay for gonorrhea and chlamydia

    c. Consider a urine drug screen

    d. Obstetric ultrasound

    e. Electronic fetal monitoring (if fetus is viable) and monitoring for contractions

3. Broad-spectrum antibiotics.

4. Corticosteroids for fetal lung maturation.

5. Consider pros and cons of expectant management.

6. Stabilization and transfer to a perinatal center where the fetus can be managed (if appropriate).

➤ Managing the patient if she went into labor:

➤ Assessment of maternal vital signs.

➤ Sterile speculum examination before digital examination.

➤ Assessment of the presentation and residual amniotic fluid volume by ultrasound.

➤ Penicillin for GBS prophylaxis (unless a recent GBS culture [within 5 weeks] is available with negative results).

➤ Intrapartum fetal heart rate monitoring.

➤ Consider the placement of an intrauterine pressure catheter for amnioinfusion if a vaginal delivery is an option and decelerations are noted.

➤ Consider intravenous magnesium sulfate for neuroprotection.

ANALYSIS

Objectives

1. Be able to describe the risk factors of PPROM.
2. Be able to describe the management of PPROM.
3. Be able to describe the complications of PPROM including early secondtrimester PPROM.

Considerations

This is a 32-year-old G2P0010 African American woman at 28 weeks’ gestation that presented with PPROM. Any pregnant patient that presents to a labor and delivery unit with complaints of leaking fluid requires prompt and thorough evaluation to rule in or out the possibility of PPROM. Maternal evaluation for signs of infection or sepsis (clinical assessment, vitals and labs) is important as infection is clinically evident in 13% to 60% of PPROM patients. Fetal assessment is initiated with external fetal monitors to evaluate fetal heart tones and uterine activity. PPROM is ruled in or out primarily on sterile speculum examination (positive nitrazine, pooling on Valsalva maneuver, and visualized ferning on microscopy). False positives may result from intravaginal semen, cervical mucus, blood, Trichomonas, and some antiseptics. Additionally, the patients described loss of fluid may be related to the intermittent loss of urine. During a speculum examination, cultures must be obtained for evaluation of infectious etiology (gonorrhea/Chlamydia probe, wet mount) and GBS carrier status (with culture and sensitivities for penicillin-sensitive patients). Cervical dilation is assessed visually and digital manipulation is avoided as it has been shown to increase infection rates. Intrauterine evaluation is continued with ultrasound to assess for the gestational age, fetal weight, presentation, placental location, and amniotic fluid index. Laboratory investigation includes CBC, type and screen, comprehensive metabolic panel (CMP), and urinalysis. If there is concern for illegal drug use it is reasonable to obtain urine toxicology. The treatment plan is then determined once fetal and maternal status, gestational age, and labor status have been appropriately assessed.

APPROACH TO

Preterm Premature Rupture of Membranes (PPROM)

Premature rupture of membranes (PROM) is defined as the ROM prior to the onset of labor. Preterm PROM (PPROM) is the ROM that occurs prior to 37 0/7 weeks. Approximately 3% of all pregnancies are complicated by PPROM and is the underlying etiology of one-third of preterm births.1 Normal fetal membranes are biologically very strong in preterm pregnancies. The weakening mechanism is likely multifactorial. Studies have shown PPROM to be associated with intrinsic (intrauterine stretch/strain from polyhydramnios and multifetal pregnancies, cervical incompetence) and extrinsic factors (ascending bacterial infections that release proteases and metalloproteinase).2 There is evidence demonstrating an association between ascending infection from the lower genital tract and PPROM. In women with PPROM about one-third of pregnancies have positive amniotic fluid cultures3,4 and studies have shown that bacteria have the ability to cross intact membranes.5,6 Other risk factors include smoking, placental abruption, prior PPROM, cocaine, previous cervical lacerations/surgeries, short cervical length (< 25 mm), trauma, and positive fetal fibronectin (see Table 41–1). A study by Lee et al showed a recurrence rate of 16.7% in patients with prior pregnancy complicated by PPROM.7

PPROM is associated with significant maternal and fetal morbidity and mortality. The time from rupture of membranes to delivery is known as “latency.” The latency period is inversely proportional to the gestational age at PPROM. Latency period of 1 week or less is present in 50% to 60% of PPROM patients.8 During this period amnionitis occurs in 13% to 60%, and abruptio placentae occurs in 4% to 12%.8 Maternal and fetal complications decrease with increasing gestational age at the time of PPROM. Multiple complications have been associated with PPROM (see Table 41–2).

The primary maternal morbidity is chorioamnionitis. Incidence varies with population and gestational age at PPROM, with reported frequency from 15% to 40%.2 Women with intrauterine infection deliver earlier than noninfected women.9 Chorioamnionitis typically precedes fetal infection but this is not always the case, and therefore close clinical monitoring is required. Fetal morbidity and mortality varies with gestational age, the treatment rendered and the presence of comorbidities, particularly infection. The most common complication is respiratory distress syndrome (RDS). Other serious fetal complications include necrotizing enterocolitis, intraventricular hemorrhage, and

Table 41–1 RISK FACTORS FOR PPROM
MATERNAL	FETAL
Collagen disease	Polyhydramnios
Cervical insufficiency	Congenital anomalies
Smoking	Multiple gestations
Cocaine use
Cervical infections (gonorrhea; chlamydia)
COPD

Table 41–2 COMPLICATIONS OF PPROM
MATERNAL	FETAL
Chorioamnionitis	Prematurity
Endometritis	Pulmonary hypoplasia
Sepsis	Deformities/contractures
Postpartum hemorrhage	Neonatal sepsis
	IVH
	NEC

sepsis. The three causes of neonatal death associated with PPROM are prematurity, sepsis, and pulmonary hypoplasia. Preterm infants born with sepsis have a mortality rate four times higher than those without sepsis.9

Making the Diagnosis

Management of PPROM starts with initial evaluation and diagnosis of rupture of membranes. The patient typically complains of a “gush” of fluid but some patients will report persistent leakage of fluid. This patient history of rupture of membranes is accurate in 90% of cases.10 Diagnosis is established on sterile speculum evaluation. Confirmatory findings include pooling of amniotic fluid in posterior fornix and/or leakage of fluid on Valsalva; positive nitrazine test of fluid (vaginal pH 4.5-6.0, amniotic fluid pH 7.1-7.3, nitrazine turns dark blue above 6.0-6.5); amniotic fluid ferning on microscopy. Friedman and McElin found that two positive findings had an accuracy of 93.1%.10 More recently, other tests have been evaluated in the diagnosis of ruptured membranes and fetal fibronectin and elevated insulin-like growth factor binding protein-1 in cervico-vaginal secretions have reported sensitivities of 94% and 75% and specificities of 97%, respectively.11,12

Should the initial tests be ambiguous or negative, in the face of continued clinical suspicion other diagnostic modalities can be utilized. The ultrasound finding of oligohydramnios is usually confirmatory. Occasionally for cases when the history of PROM is suspicious and other physical tests are negative, the transabdominal intraamniotic injection of indigo-carmine (1-2 mL in 4-9 mL sterile saline) needs to be considered. In these cases the presence of blue dye on a vaginal pad after ambulation would confirm the leaking of amniotic fluid.

At the time of the initial evaluation, the patient’s cervical os should be visually assessed for dilatation and possible prolapse of umbilical cord or fetal limb. Brown et al found visual estimation of cervical dilation had a positive predictive value of 86.5% and negative predictive value of 100%.13 Digital evaluation of cervix should be avoided; Lewis et al found that in PPROM patients gestational ages 24 to 35 weeks, who underwent digital vaginal examination, had a significantly decreased mean latency period (2.1 vs 11.3 days).14 Ultrasound evaluation of the gestational age, fetal weight, fetal presentation, placental location, and assessment of amniotic fluid index (AFI) are vital for treatment planning. A low AFI (< 5.0 cm) and low maximum vertical fluid pocket (< 2.0 cm) at the time of initial assessment is associated with shorter latency, increased RDS, and increased composite morbidity (death or RDS, early sepsis, stage 2-3 necrotizing enterocolitis, and/or grade III-IV intraventricular hemorrhage).15

Management

Patients diagnosed with PPROM would benefit from an admission to the hospital in all likelihood until delivery.

Once PPROM is verified, the treatment plan must balance the maternal, fetal, neonatal risks/benefits of prolonged pregnancy or expeditious delivery and possible inclusion of medical intervention. Many studies have demonstrated benefits in conservative management for gestations of less than 34 weeks, whereas the management of pregnancies complicated by PPROM between 34 and 37 weeks of gestation continues to be controversial.16

A retrospective series examining neonatal outcome following cases with PPROM between 32 weeks and 36 weeks showed that the specific gestation for reduced morbidity was 34 weeks.17 The incidence of respiratory distress syndrome and the length of hospital stay were reduced in infants delivered after 34 weeks of gestation. The incidence of RDS was 22.5% and 5.8% at 33 and 34 weeks, respectively. Although the incidence beyond 34 weeks was relatively low, the condition affected infants into the 36th week, with incidences of 10.4% to 1.5% at 35 and 36 weeks, respectively.

• PPROM at 34 0/7 to 36 6/7 weeks:

Naef et al showed that conservative management at this gestational age range lead to increased risk of maternal amnionitis (16% vs 2%), prolonged maternal length of stay (5.2 vs 2.6 days), and lower mean cord pH (7.25 vs 7.35).16 Additionally, there is increase of umbilical cord compression/prolapse and placental abruption. In addition the risk of severe morbidity and mortality to the fetus in this age range is low. Thus, expeditious delivery in this gestational age range is most reasonable. If GBS status is not verifiable or a patient has risk factors, GBS prophylaxis should be given. In this gestational age range, there is no significant data to support corticosteroids for fetal lung maturity.

• PPROM at 32 0/7 to 33 6/7 weeks:

In this gestational age range there remains a significant risk for RDS, approximately 35%. Therefore, an attempt to determine fetal lung maturity (FLM) can be considered. FLM can be determined from vaginal pooling sample to assess phosphatidylglycerol (PG) levels. In most cases the risk-benefit ratio does not justify an amniocentesis in this clinical setting.

• PPROM under 32 weeks:

In the absence of clinical signs of labor, abruption, or maternal or fetal signs of infection most patients in this gestational age will benefit from an expectant management with daily assessment of the maternal and fetal well-being.

1. Antenatal assessment:

a. Maternal: The criteria for the diagnosis of clinical chorioamnionitis include maternal pyrexia, tachycardia, leukocytosis, uterine tenderness, malodorous vaginal discharge, and fetal tachycardia. During inpatient observation, the woman should be regularly examined for such signs of intrauterine infection and an abnormal parameter or a combination of them may indicate intrauterine infection. The frequency of maternal and fetal assessments (temperature, pulse, and fetal heart rate auscultation) should be between 4 and 8 hours.18,19,20

Maternal fever (above 38.0°C) in the absence of other sources of infection, offensive vaginal discharge, and fetal tachycardia (rate above 160 bpm) indicate clinical chorioamnionitis. There is a variation in the literature regarding the accuracy of the laboratory tests of leukocytosis and raised C-reactive protein in the prediction of chorioamnionitis. The sensitivities and false-positive rates for leukocytosis in the detection of clinical chorioamnionitis range from 29% to 47% and 5% to 18%, respectively.18,20 The specificity of C-reactive protein is 38% to 55%.18,20,21 The presence of leukocytosis may be useful clinically in cases where there is doubt about the diagnosis of chorioamnionitis.

b. Fetal: Electronic fetal heart rate tracing is useful because fetal tachycardia may represent a sign of fetal infection and is frequently used in the clinical definition of chorioamnionitis in some studies. Fetal tachycardia predicts 20% to 40% of cases of intrauterine infection with a falsepositive rate of about 3%.18,22,23 There are no randomized controlled trials to support the use of frequent biophysical or Doppler assessment. The disparity in the literature evaluating these tests of fetal well-being suggests that, although some studies have shown benefit, overall the tests are of limited value in differentiating between fetuses with and without infection.24

2. Use of corticosteroids: A meta-analysis of 15 randomized controlled trials involving more than 1400 women with preterm rupture of the membranes demonstrated that antenatal corticosteroids reduced the risks of respiratory distress syndrome (RR 0.56; 95% confidence interval [CI] 0.46-0.70), intraventricular hemorrhage (RR 0.47; 95% CI 0.31-0.70), and necrotizing enterocolitis (RR 0.21; 95% CI 0.05-0.82).25 They do not appear to increase the risk of infection in either mother (RR 0.86; 95% CI 0.61- 1.20) or baby (RR 1.05; 95% CI 0.66-1.68).25 

3. Use of antibiotics: Twenty-two trials involving over 6000 women with PPROM before 37 weeks were included in a meta-analysis.26 The use of antibiotics following PPROM was associated with a statistically significant reduction in chorioamnionitis (RR 0.57; 95% CI 0.37-0.86). There was a

significant reduction in the numbers of babies born within 48 hours (RR 0.71; 95% CI 0.58-0.87) and 7 days (RR 0.80; 95% CI 0.71-0.90). Neonatal infection was significantly reduced in the babies whose mothers received antibiotics (RR 0.68; 95% CI 0.53-0.87). There was also a significant reduction in the number of babies with an abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.82; 95% CI 0.68-0.98).26

4. Use of tocolytics: Prophylactic tocolysis in women with PPROM without uterine activity is not recommended. Women with PPROM and uterine activity who require intrauterine transfer or antenatal corticosteroids should be considered for tocolysis. Three randomized studies of a total of 235 women with PPROM reported that the proportion of women remaining undelivered 10 days after membrane rupture was not significantly higher in those receiving tocolysis compared with those receiving none.27-29 A recent retrospective case–control study showed that tocolysis after PPROM did not increase the interval between membrane rupture and delivery or reduce neonatal morbidity.30

• PPROM under 23 weeks:

There are insufficient data to make recommendations in the setting of PPROM under 23 to 24 weeks including the possibility of home, daycare, and outpatient monitoring. It would be considered reasonable to maintain the woman in hospital for at least 48 hours before a decision is made to allow her to go home.24 The management of these cases should be individualized and outpatient monitoring restricted to certain groups of women after careful consideration of other risk factors and the access to the hospital.

Delivery

1. Timing: If the diagnosis of chorioamnionitis is made, regardless of the gestational age of the fetus it is in the best interest for the mother and the fetus to be separated and to begin the process of delivery, if it has not started on its own by then. Parents need to be counseled at that point of the fetal chances for survival and the associated morbidities. Arrangements need to be made to provide the fetus with the best possible facilities if time allows it. 

Other indications for delivery include spontaneous labor, death of the fetus, cord prolapse, abruption of the placenta, or demonstration of fetal lung maturity. 

2. Interventions during delivery: If the patient is a candidate for a vaginal delivery and the fetal tracing exhibits recurrent variable decelerations (associated with oligohydramnios) the placement of an intrauterine pressure catheter and amnioinfusion might improve the tracing and increase the likelihood for a vaginal delivery. If a GBS culture is not available prior to delivery antibiotic prophylaxis is recommended. Neuroprophylaxis with magnesium sulfate can also be considered for fetuses under 34 weeks.

3. Route: The route of delivery in the setting of PPROM will depend on the urgency of the indication (eg, cord prolapse is more common in PPROM), the previous surgical history of the mother (cesarean sections in particular), presentation of the fetus, number of fetuses, and presence or absence of labor. The rates of cesarean section are increased among women with PPROM.

4. After delivery: Women who deliver as a result of PPROM need to be counseled to seek early prenatal care in future pregnancies and on the use of 17α-hydroxyprogesterone for the prevention of recurrent episodes of PPROM.31 Cervical length monitoring may be beneficial in a subset of patients and needs to be considered in the evaluation of these patients in subsequent pregnancies.

Comprehension Questions

41.1 What is the contribution of PPROM to the rate of preterm labor?

A. 15%

B. 30%

C. 66%

D. 80%

41.2 A 33-year-old woman G1P0 at 360/7 weeks’ gestation complains of leakage of clear fluid per vagina. Speculum examination is consistent with spontaneous preterm premature rupture of membranes. The patient would prefer nonintervention and for a natural labor course. Which of the following statements is the most accurate in counseling of this patient of expectant management versus induction of labor?

A. Expectant management has been shown to lead to equal perinatal and maternal outcomes.

B. Expectant management has an equal perinatal and maternal outcome in GBS-negative individuals.

C. Intramuscular corticosteroids would be recommended if expectant management is entertained.

D. Maternal infection and length of stay are increased with expectant management.

41.3 A 22-year-old G1P0 woman at 25 weeks’ gestation is admitted to the hospital with a diagnosis of PPROM. Which of the following is the most accurate statement regarding the use of corticosteroids?

A. Has been shown to reduce the risk of NEC.

B. Has been shown to increase the risk of maternal infection.

C. Has been shown to increase the risk of neonatal sepsis.

D. Should not be administered until the patient reaches 28 weeks’ gestation.

ANSWERS

41.1 B. PPROM contributes to approximately a third of the cases of preterm labor.

41.2 D. PPROM between 34 and 36 weeks’ gestation is generally best treated by delivery. Expectant management in this gestational age window is associated with a higher likelihood of maternal infection, greater length of stay, and lower cord pH values.

41.3 A. Corticosteroid use has been associated with a reduction of NEC, intraventricular hemorrhage (IVH), and RDS, without increasing the risk of maternal or neonatal infection, provided that there is no overt infection evident.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ The diagnosis of spontaneous rupture of the membranes is best achieved by maternal history followed by a sterile speculum examination of the vagina and cervix (Level II).

➤ Ultrasound examination is useful in some cases to help confirm the diagnosis (Level III).

➤ Digital examination should be avoided when PPROM is suspected (Level III).

➤ Routine amniocentesis is not recommended for women with PPROM (Level II).

➤ Antenatal corticosteroids should be administered in women with PPROM (Level I).

➤ Prophylactic tocolysis in women with PPROM without uterine activity is not recommended (Level I).

➤ The use of antibiotics for up to 1 week after diagnosis prolongs the latency period and outcomes of PPROM (Level I).

➤ Delivery should be considered for all cases at 34 weeks of gestation (Level I).

➤ The recurrence of PPROM can be reduced in future pregnancies with the prophylactic administration of 17α-hydroxyprogesterone caproate (Level I).

REFERENCES

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2. Creasy RK, Resnik R. Chapter 38: Premature rupture of the membranes. Maternal- Fetal Medicine Principles and Practice. 5th ed. Philadelphia, PA: WB Saunders; 2004; 723-739. 

3. Carroll SG, Sebire NJ, Nicolaides KH. Pre-term pre-labour amniorrhexis. Curr Opin Obstet Gynecol. 1996;8:441-448. 

4. Broekhuizen FF, Gilman M, Hamilton PR. Amniocentesis for Gram stain and culture in preterm premature rupture of the membranes. Obstet Gynecol. 1985;66:316-321. 

5. Galask RP, Varner MW, Petzold CR, Wilbur SL. Bacterial attachment to the chorioamniotic membranes. Am J Obstet Gynecol. 1984;148:915-928. 

6. Gyr TN, Malek A, Mathez–Loic, et al. Permeation of human chorioamniotic membranes by Escherichia coli in vitro. Am J Obstet Gynecol. 1994;170:223-227. 

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8. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol. 2003; 101:178-193. 

9. Cotton DB, Hill LM, Strassner HT, Platt LD, Ledger WJ. Use of amniocentesis in preterm gestation with ruptured membranes. Obstet Gynecol. 1984;63:38-48. 

10. Friedman ML, McElin TW. Diagnosis of ruptured fetal membranes. Clinical study and review of the literature. Am J Obstet Gynecol. 1969;104:544-550. 

11. Gaucherand P, Guibaud S, Awada A, et al. Comparative study of three amniotic fluid markers in premature rupture of membranes: fetal fibronectin, alpha-fetoprotein, diaminooxidase. Acta Obstet Gynecol Scand. 1995;74:118-121. 

12. Rutanen EM, Pekonen F, Karkkainen T. Measurement of insulin-like growth factor binding protein-1 in cervical/vaginal secretions: comparison with the ROM-check membrane immunoassay in the diagnosis of ruptured fetal membranes. Clin Chim Acta. 1993;214:73-81. 

13. Brown CL, Ludwiczak, MH, Blanco J, Hirsch CE. Cervical dilation: accuracy of visual and digital examinations. Obstet Gynecol. 1993;81:215-216. 

14. Lewis DF, Major CA, Towers, CV, Asrat T, Harding JA, Garite TJ. Effects of digital vaginal examinations on latency period in preterm premature rupture of membranes. Obstet Gynecol. 1992;80:630-634. 

15. Mercer BM, Rabello YA, Thurnau GR, et al. The NICHD-MFMU antibiotic treatment of preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome. Am J Obstet Gynecol. 2006;194:438-445. 

16. Naef RW 3rd, Albert JR, Ross EL, Weber BM, Martin RW, Morrison JC. Premature rupture of membranes at 34 to 37 weeks’ gestation: aggressive versus conservative management. Am J Obstet Gynecol. 1998;178:126-130. 

17. 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. 1999;180:349-352. 

18. Ismail A, Zinaman MJ, Lowensohn RI, Moawad AH. The significance of C-reactive protein levels in women with premature rupture of membranes. Am J Obstet Gynecol. 1985;151:541-544. 

19. Carlan SJ, O’Brien WF, Parsons MT, Lense JJ. Preterm premature rupture of membranes: a randomised study of home versus hospital management. Obstet Gynecol. 1993;81:61-64. 

20. Romem Y, Artal R. C-reactive protein as a predictor for chorioamnionitis in cases of premature rupture of the membranes. Am J Obstet Gynecol. 1984;150:546-550. 

21. Kurki T, Teramo K, Ylikorkala O, Paavonen J. C-reactive protein in preterm premature rupture of the membranes. Arch Gynecol Obstet. 1990;247:31-37. 

22. Carroll SG, Papiaoannou S, Nicolaides KH. Assessment of fetal activity and amniotic fluid volume in the prediction of intrauterine infection in preterm prelabour amniorrhexis. Am J Obstet Gynecol. 1995;172:1427-1435. 

23. Ferguson MG, Rhodes PG, Morrison JC, Puckett CM. Clinical amniotic fluid infection and its effect on the neonate. Am J Obstet Gynecol. 1985;151:1058-1061. 

24. Royal College of Obstetricians and Gynaecologists. Preterm prelabour rupture of membranes. RCOG Guideline No. 44. London: RCOG, November 2006. 

25. Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes. Am J Obstet Gynecol. 2001;184:131-139. 

26. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2003;2:CD001058. 

27. How HY, Cook CR, Cook VD, Miles DE, Spinnato JA. Preterm premature rupture of membranes: aggressive tocolysis versus expectant management. J Matern Fetal Med. 1998;7:8-12. 

28. Levy D, Warsof SL. Oral ritodrine and preterm premature rupture of membranes. Obstet Gynecol. 1985;66:621-633. 

29. Dunlop PDM, Crowley PA, Lamont RF, Hawkins DF. Preterm ruptured membranes, no contractions. J Obstet Gynecol.1986;7:92-96. 

30. Combs CA, McCune M, Clark R, Fishman A. Aggressive tocolysis does not prolong pregnancy or reduce neonatal morbidity after preterm premature rupture of the membranes. Am J Obstet Gynecol. 2004;190:28-31. 

31. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24): 2379-2385. 

32. ACOG Committee Opinion 455. Magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol. 2010;115:669-671.

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