The association of subclinical infection with preterm labor: the role of C-reactive protein

The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tocolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful.     

Silent chorioamnionitis as a cause of preterm labor refractory to tocolytic therapy

Thirty-seven consecutive patients with singleton pregnancies in "uncomplicated" preterm labor with intact membranes suitable for tocolysis were evaluated for evidence of silent chorioamnionitis by means of maternal serum C-reactive protein and amniotic fluid white blood cell count, Gram stain, and cultures. Abnormalities in these markers of infection were found to be significantly more common in cases that were refractory to tocolysis. These cases also showed both pathologic evidence of chorioamnionitis and a significantly greater neonatal early infectious morbidity. We conclude that silent chorioamnionitis is a significant cause of "uncomplicated" preterm labor refractory to conventional methods of tocolysis.     

Systemic tocolysis for premature labor is associated with an increased incidence of pulmonary edema in the presence of maternal infection

Our hypothesis is that systemic tocolysis of patients in premature labor is associated with a higher incidence of pulmonary edema in the presence of maternal infection. Over a 64-month period, medical records of all patients with a diagnosis at discharge of pulmonary edema or congestive heart failure were reviewed. There were 27 cases of pulmonary edema, 16 of which (59.3%) were associated with treatment of preterm labor. The incidence of pulmonary edema in patients receiving systemic tocolysis for treatment of preterm labor was significantly higher than that in our general obstetric population (3.04% versus 0.05%). Of the 527 patients receiving tocolysis, there was evidence of maternal infection in 52. The incidence of pulmonary edema was higher in the presence of maternal infection than in its absence (11/52 or 21% versus 5/475 or 1%, p = 0.0000). We conclude that there is a very strong association between the development of pulmonary edema and the presence of maternal infection in patients being treated for premature labor with systemic tocolysis.     

Magnesium sulfate and beta-mimetic dual-agent tocolysis in preterm labor after single-agent failure

Twenty-three patients in preterm labor failed to respond to single-agent tocolytic therapy or could not tolerate the dosage necessary to inhibit contractions. A combination of magnesium sulfate and ritodrine or terbutaline was used to inhibit labor in these patients. Fourteen patients (60.9%) responded to dual-agent tocolysis by delaying delivery for 48 hours or more. Six patients had delivery delayed for more than one week. Five patients had multiple gestations; three of them had delivery delayed more than 48 hours. Five patients developed pulmonary edema under treatment with dual-agent tocolysis; all responded to diuretic and/or oxygen therapy after the termination of tocolysis. Dual-agent tocolysis may significantly prolong some pregnancies complicated by preterm labor, but only at some risk to maternal well-being.     

Maternal C-reactive protein and preterm labor

Maternal C-reactive protein (CRP) was measured in 109 pregnant women: 34 who were in labor before 35 weeks, 25 who were in labor at term and 50 who were not in labor. CRP values were correlated with outcome of tocolysis and with gestational age. Among 34 women in preterm labor, a CRP of greater than of equal to 0.8 mg/dL had a sensitivity of 85% (17/20) and a value of 81% (17/21) in predicting delivery within one week. Ten of the 14 who delivered more than one week following tocolysis had a CRP less than 0.8 mg/dL (71% specificity). Maternal CRP of greater than or equal to 0.8 mg/dL identifies a subgroup of women in preterm labor at highest risk of preterm delivery.     

A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor

Because subclinical genital tract infection may play a major role in preterm birth, the efficacy of adjunctive antibiotic therapy in combination with standard parenteral tocolysis was examined in a randomized, blinded study of patients with idiopathic preterm labor. Labor was documented by three contractions in 20 minutes, cervical dilation of 1 cm or more, and the need for parenteral tocolysis. Enrollment was restricted to patients with intact membranes and without known causes for preterm labor. One hundred three patients at 24-34 weeks' gestation were randomized to intravenous ampicillin plus oral erythromycin or corresponding placebos. Compared with the placebo group, the adjunctive antibiotic group had a similar frequency of preterm birth (38 versus 44%), time to delivery (34 versus 34 days), birth weight (2847 versus 2855 g), and episodes of recurrent labor requiring parenteral tocolysis (0.43 versus 0.49). In our population, we found no benefit to the adjunctive use of ampicillin plus erythromycin. Significant differences in genital microflora between our patients and those of other studies may explain our results.     

Detection of preterm labor by ambulatory monitoring of uterine activity for the management of oral tocolysis

A study to evaluate whether ambulatory tocodynamometry at home could enhance the management of oral tocolysis was performed. On discharge from the hospital, after completing parenteral tocolysis, 60 patients received a lightweight tocodynamometer, designed for storage and transmission of uterine activity data. Sixty additional contemporary patients, who were matched for maternal age, parity, and risk factors, served as a control group. In addition to instructions regarding self-detection of recurrent preterm labor, monitored patients recorded uterine activity for greater than or equal to 200 min/day and then transmitted the data to the study center. Tocolytic dosage was adjusted to maintain mean uterine contraction frequency of less than 4/hr. Persistent uterine contractions of greater than or equal to 4/hr lead to in-hospital evaluation for recurrent preterm labor. The results indicate that the monitored group had a lower incidence of preterm births mostly because of a decrease in the proportion of patients with failed tocolysis. It is suggested that surveillance of uterine activity at home during oral treatment for preterm labor may be instrumental in improving perinatal outcome in high-risk patients.     

Contemporary practice patterns and beliefs regarding tocolysis among u.s. Maternal-fetal medicine specialists

OBJECTIVE: To estimate maternal-fetal medicine specialists' practice patterns and perceived risks and benefits to tocolysis. METHODS: We performed a mail-based survey of all Society for Maternal-Fetal Medicine (SMFM) members in the United States. Subjects were asked whether they would recommend tocolysis and what would be their first-line tocolytic in five scenarios: 1) acute preterm labor; 2) maintenance tocolysis after arrested preterm labor; 3) repeat acute preterm labor; 4) preterm premature rupture of membranes (PROM) without contractions; and 5) preterm PROM with contractions. RESULTS: A total of 827 (46%) SMFM members responded. Ninety-six percent, 56%, 56%, 32%, and 29% would recommend tocolysis for acute preterm labor, repeat acute preterm labor, preterm PROM with contractions, preterm PROM without contractions, and maintenance tocolysis, respectively. The most common first-line tocolytic was magnesium for acute preterm labor (45%) and repeat acute preterm labor (41%); nifedipine was the most common maintenance tocolysis (79%). Eighty percent believed tocolysis was associated with moderate or significant benefit in the setting of acute preterm labor; however, fewer than 50% responded similarly for the other four scenarios. In all five scenarios, more than 50% of respondents indicated there was minimal or no risk associated with tocolysis. Having a nonacademic practice was independently associated with the recommendation for tocolysis. CONCLUSION: Almost all maternal-fetal medicine specialists recommend tocolysis in the setting of acute preterm labor, and many recommend tocolysis for other indications. Magnesium and nifedipine are the most commonly prescribed first-line tocolytics. LEVEL OF EVIDENCE: III.     

C-reactive protein in preterm labour: association with outcome of tocolysis and placental histology

Tocolytics were administered in 66 consecutive women in uncomplicated preterm labour with intact fetal membranes (53 singleton and 13 twin pregnancies). C-reactive protein (CRP), a marker of infection, was determined daily and used retrospectively to investigate the role of subclinical infection in preterm labour and to predict the efficacy of tocolysis and the development of a clinical perinatal infection. CRP was also determined in 66 women in uncomplicated labour at term (53 singleton and 13 twin pregnancies). The placenta was examined for histological evidence of infection in all patients who were delivered before 36 weeks (n = 21) and in all women in the control group (n = 66). Elevated CRP levels were more often found in patients who were refractory to tocolysis, suggesting an underlying infectious morbidity. Placental infection was found in 62% of the preterm delivery group and in 12% of the control group. There was an association between elevated CRP levels and histological evidence of placental infection. However, confounding factors such as urinary tract infections limit the usefulness of the CRP test. Because CRP cannot predict clinical perinatal infection accurately, its clinical relevance is very limited.     

The presence of amniotic fluid leukoattractants accurately identifies histologic chorioamnionitis and predicts tocolytic efficacy in patients with idiopathic preterm labor.

OBJECTIVES: We tested these hypotheses: (1) that amniotic fluid from patients with idiopathic preterm labor and histologic chorioamnionitis contains leukoattractants and (2) that the detection of amniotic fluid leukoattractants is an accurate predictor of tocolytic efficacy. STUDY DESIGN: Amniotic fluid from 86 patients in idiopathic preterm labor was evaluated by microbiologic tests and leukotaxis assay. The tests' ability to predict histologic chorioamnionitis and response to tocolysis (51 tocolytic candidates) is established. Statistical analysis was performed with Fisher's exact test and unpaired Student t test. RESULTS: The detection of amniotic fluid leukoattractants was a better predictor of histologic chorioamnionitis (97%) than were amniotic fluid microbiologic tests (62%) (p less than 0.01). Also, in patients with detectable amniotic fluid leukoattractants tocolysis failed significantly more often than in patients without detectable leukoattractants (93% vs 7%, p less than 0.01). CONCLUSION: The presence of leukoattractants in amniotic fluid detected by the leukotaxis assay accurately identifies histologic chorioamnionitis and can additionally predict tocolytic efficacy in patients with idiopathic preterm labor.     

Maternal plasma interleukin-6, interleukin-1beta and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery.

OBJECTIVE: To investigate whether maternal serum interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and high sensitive C-reactive protein (CRP) could be used as markers of tocolysis failure and adverse neonatal outcome in pregnancies with preterm labor (PL). METHODS: Forty-seven maternal blood samples taken because of PL at admission and delivery were analyzed. Control samples were taken from 20 gravidas with normal pregnancies. Differences in interleukins and CRP levels with or without chorioamnionitis, connatal infection or periventricular leukomalacia (PVL) were analyzed. Cut-off values were estimated for prediction of tocolysis failure and adverse neonatal outcome. RESULTS: All three parameters were significantly higher in patients delivering prematurely than in patients delivering at term. All three parameters were significantly higher with than without histologic chorioamnionitis (p < 0.001), with than without connatal infection (p < 0.01), with than without PVL (p < 0.01 for IL-6 and IL-1beta, p < 0.05 for CRP), and in pregnancies with preterm premature rupture of membranes (PPROM) delivered within 48 hours compared to those more prolonged (p < 0.01). Choosing 50.9 pg/mL of IL-6 and a CRP of 19.7 as cut-offs in maternal blood admission concentrations for neonatal PVL, resulted in sensitivity of 81% and specificity of 91% and sensitivity of 91% and specificity of 81%, respectively. At respective maternal blood admission cut-off levels of 27.8 pg/mL of IL-6 and 8.9 of CRP, both parameters were effective predictors of connatal infection. CONCLUSIONS: Maternal blood IL-6 and CRP could become useful in predicting tocolysis failure and intrauterine treat for the fetus.     

Randomized trial of antibiotics in addition to tocolytic therapy to treat preterm labor

Objective: The objective of this study was to assess whether antibiotic therapy plus tocolysis given to women in preterm labor would prolong pregnancy compared with tocolysis alone.Methods: A randomized, double-blind trial of intravenous mezlocillin and oral erythromycin therapy vs. placebo was used in addition to tocolysis among women in preterm labor 相似文献   

Sulindac to prevent recurrent preterm labor: a randomized controlled trial

OBJECTIVE: To assess the efficacy of oral sulindac in low doses for prolonged duration to decrease the risk of recurrent preterm labor and extend gestation. METHODS: This was a randomized, double-blind, placebo-controlled study of patients between 24 and 34 weeks' gestation with preterm labor treated with intravenous magnesium sulfate. After successful tocolysis, patients were randomized by the pharmacy to receive either oral sulindac (100 mg) or placebo orally every 12 hours until 34 weeks' gestation. A power analysis required 43 patients in each group. RESULTS: Ninety-five patients were enrolled (46 in the sulindac group, 49 controls). No significant differences were found with respect to time gained in utero (39 +/- 25 versus 45 +/- 26 days, P = .29), delivery at more than 35 weeks' gestation (61% versus 74%, P = .29), recurrent preterm labor (20% versus 18%, P = .86), birth weight (2562 +/- 623 versus 2624 +/- 543 g, P = .62), or time spent in the neonatal intensive care unit (2.8 +/- 9.2 versus 2.4 +/- 8.6 days, P = .83) for the sulindac and control groups, respectively. CONCLUSION: The use of oral sulindac until 34 weeks' gestation after successful parenteral tocolysis failed to reduce the incidence of readmission for preterm labor.     

Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor

Objective: To compare the safety and efficacy of high-dose intravenous (IV) nitroglycerin with those of IV magnesium sulfate for acute tocolysis of preterm labor.Methods: Thirty-one women with preterm labor before 35 weeks’ gestation were assigned randomly to IV magnesium sulfate or IV nitroglycerin for tocolysis. Preterm labor was defined as the occurrence of at least two contractions in 10 minutes, with cervical change or ruptured membranes. Acute tocolysis was defined as tocolysis for up to 48 hours. Magnesium sulfate was administered as a 4-g bolus, then at a rate of 2–4 g/h. Nitroglycerin was administered as a 100-μg bolus, then at a rate of 1- to 10-μg/kg/min. The primary outcome measure was achievement of at least 12 hours of successful tocolysis.Results: Thirty patients were available for analysis. There were no significant differences in gestational age, cervical dilation, or incidence of ruptured membranes between groups at the initiation of tocolysis. Successful tocolysis was achieved in six of 16 patients receiving nitroglycerin, compared with 11 of 14 receiving magnesium sulfate (37.5 versus 78.6%, P = .033). Tocolytic failures (nitroglycerin versus magnesium sulfate) were due to persistent contractions with cervical change or rupture of previously intact membranes (five of 16 versus two of 14), persistent hypotension (four of 16 versus none of 14), and other severe side effects (one of 16 versus one of 14). Maternal hemodynamic alterations were more pronounced in patients who received nitroglycerin, and 25% of patients assigned to nitroglycerin treatment had hypotension requiring discontinuation of therapy.Conclusion: Tocolytic failures were more common with nitroglycerin than with magnesium sulfate. The hemodynamic alterations noted in patients receiving nitroglycerin, including a 25% incidence of persistent hypotension, might limit the usefulness of IV nitroglycerin for the acute tocolysis of preterm labor.     

C-reactive protein: a limited test for managing patients with preterm labor or preterm rupture of membranes?

C-reactive protein has been used to identify patients at high risk for infectious morbidity with preterm labor or preterm rupture of membranes. In this article we report on 104 patients with preterm labor symptoms (n = 45) or preterm rupture of the membranes (n = 59) and serial evaluations of C-reactive protein measured by latex agglutination and laser nephelometry. The simple, inexpensive latex method appears comparable to the laser method in predicting infectious morbidity and can be used clinically. Elevated C-reactive protein values before delivery predict infectious morbidity in only 8% to 29% of patients, and up to 18% of patients with serious infections may be misdiagnosed as having normal C-reactive protein values before delivery.     

The Treatment of Preterm Labor Using a Portable Subcutaneous Terbutaline Pump

The perinatal mortality rate related to preterm delivery has led researchers to investigate new methods of tocolysis. A new concept in managing preterm labor uses continuous administration of terbutaline sulfate via a portable subcutaneous infusion pump. Use of the terbutaline pump to treat 13 preterm labor patients at the Baylor College of Medicine demonstrated an efficacy rate of 9 for a population failing all other methods of tocolysis. This unique treatment modality offers new hope for patients experiencing recalcitrant preterm labor.     

A review of premature birth and subclinical infection.

Premature birth causes high rates of neonatal morbidity and mortality. There are multiple causes of preterm birth. This article reviews the evidence linking subclinical infection and premature birth. Although maternal genital tract colonization with specific organisms has been inconsistently associated with preterm birth and/or premature rupture of membranes, some infections have been consistently associated with preterm delivery. The association of histologic chorioamnionitis with prematurity is a consistent finding, but the mechanisms require further study. The relationship between histologic chorioamnionitis infection and the chorioamnionitis of prematurity requires additional research. A varying number of patients in "idiopathic" preterm labor have positive amniotic fluid cultures (0% to 30%), but it is not clear whether infection preceded labor or occurred as a result of labor. Evidence of subclinical infection as a cause of preterm labor is raised by finding elevated maternal serum C-reactive protein and abnormal amniotic fluid organic acid levels in some patients in preterm labor. Biochemical mechanisms for preterm labor in the setting of infection are suggested by both in vitro and in vivo studies of prostaglandins and their metabolites, endotoxin and cytokines. Some, but by no means all, antibiotic trials conducted to date have reported decreases in prematurity. These results support the hypothesis that premature birth results in part from infection caused by genital tract bacteria. In the next few years, research efforts must be prioritized to determine the role of infection and the appropriate prevention of this cause of prematurity.     

Management of recurrent preterm labor in twin gestations with nifedipine tocolysis

We examined outcomes of twin pregnancies complicated by recurrent preterm labor receiving nifedipine tocolysis. In a retrospective study design, twin pregnancies receiving outpatient preterm labor surveillance services and oral nifedipine tocolysis following a diagnosis of preterm labor were identified from a database ( N = 1421). Eligible for inclusion were patients subsequently rehospitalized with recurrent preterm labor symptoms ( N = 862). Included were patients at < 35 weeks' gestation, having intact membranes, and remaining undelivered for > 48 hours after recurrent preterm labor ( N = 656). Pregnancy outcomes of women resuming nifedipine tocolysis ( N = 418) following hospitalization were compared with those having an alteration in treatment ( N = 238) to continuous subcutaneous terbutaline. Alteration of tocolytic treatment versus resuming nifedipine resulted in increased pregnancy prolongation (34.7 +/- 18.8 days versus 27.5 +/- 19.9 days, P < 0.001), with delivery of fewer low birth weight (67.2% versus 78.3%, P < 0.001) and very low birth weight infants (6.5% versus 15.0%, P < 0.001) and a decreased incidence of neonatal intensive care unit admission (44.7% versus 52.9%, P = 0.005). In twin pregnancies receiving nifedipine tocolysis, alteration of tocolytic treatment to subcutaneous terbutaline following hospitalization for recurrent preterm labor symptoms had a positive impact on pregnancy prolongation and neonatal outcomes.     

Amniotic fluid concentrations of adrenomedullin in preterm labor.

OBJECTIVE: To determine whether adrenomedullin levels in amniotic fluid were associated with preterm labor. METHODS: We measured immunoreactive adrenomedullin in amniotic fluid collected by amniocentesis from 36 women with clinical diagnosis of preterm labor or preterm premature rupture of membranes (PROM) and from 18 normal pregnant women. RESULTS: Amniotic fluid from cases of PROM and failure to respond to tocolysis were associated significantly with higher amniotic fluid adrenomedullin concentrations (177.0 +/- 22.5 pg/mL and 182.7 +/- 22.0 pg/mL, respectively, P < .01) than that from uncomplicated pregnancies (101.2 +/- 28.1 pg/mL) or preterm labor responsive to tocolysis (102.3 +/- 26.8 pg/mL). CONCLUSION: Amniotic fluid adrenomedullin is higher than normal in cases of PROM and preterm labor unresponsive to tocolysis, perhaps indicating enhanced synthesis from placenta or fetal membranes being stimulated by bacterial products.     

Magnesium tocolysis: serum levels versus success

The relationship between maternal serum magnesium levels and tocolytic success is poorly established. We performed a retrospective analysis of 101 episodes of preterm labor treated with magnesium sulfate and compared the initial, average, and maximum serum magnesium levels with tocolytic success at 48 hours and 7 days. There was no difference in the proportions of tocolytic success when serum levels were less than 6 mg/dl compared with levels of greater than or equal to 6 mg/dl. Similar analyses on either side of 5 mg/dl also revealed no significant relationship. Mean serum magnesium levels in patients with successful tocolysis were statistically similar to those of patients in whom tocolysis failed. Multiple logistic regression analysis also failed to establish a positive relationship between serum magnesium levels and tocolytic success. We conclude that serum magnesium levels alone should not serve as an end point of therapy.