Maternal paralytic ileus as a complication of magnesium sulfate tocolysis

Beta-adrenergic agonists tocolysis is currently the most popular treatment modality in the United States. However, magnesium sulfate is receiving increasing attention as an alternating tocolytic agent in the presence of various clinical situations, such as the treatment of insulin-dependent diabetes. While there is an abundance of information about the maternal and fetal side effects associated with beta-adrenergic tocolysis, little information is available about maternal adverse side effects of magnesium sulfate treatment for preterm labor. Side effects such as pulmonary edema, respiratory depression, hypocalcemia, and hypermagnesemia have been reported in patients receiving this agent for either tocolysis or pre-eclampsia, though their occurrence is quite rare. One of the infrequent complications of beta-adrenergic agonist tocolysis is the occurrence of a paralytic ileus, which to our knowledge has not yet been reported in association with magnesium sulfate tocolysis. This article therefore concerns the development of a paralytic ileus in a patient receiving parenteral magnesium sulfate for tocolysis. The clinical features are described and the possible mechanisms involved discussed.     

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.     

Magnesium sulfate tocolysis and pulmonary edema: the drug or the vehicle?

OBJECTIVES: This study was undertaken to determine the: (1) risk factors for developing pulmonary edema associated with magnesium sulfate (MgSO4) tocolysis; (2) mean latency period to diagnosis; (3) role of maternal transport; and (4) safety of continued therapy. STUDY DESIGN: A total of 150 antenatal patients treated for preterm labor with MgSO4 were identified for this retrospective, case-control study. Cases were compared 1:2 with controls in regard to maternal demographics, MgSO4 concentration and infusion rates, maternal transport status, and maternal net fluid balance. RESULTS: Risk factors for developing pulmonary edema include: greater MgSO4 and intravenous fluid infusion rates, less concentrated MgSO4, infection, multiple gestations, concomitant tocolytics, large positive net fluid balances, and maternal transport. The mean latency period to diagnosis was 1.96 days. Six percent of patients had recurrence if MgSO4 tocolysis was continued. CONCLUSIONS: MgSO4 and intravenous fluid rates are both associated with the development of pulmonary edema. Once appropriately treated, MgSO4 tocolysis can be continued with little risk of recurrence.     

Risk factors for acute pulmonary edema in preterm delivery

OBJECTIVE: To determine the risk factors for pulmonary edema in women with preterm delivery. STUDY DESIGN: This was a case-controlled study of 52 (6.7%) cases with and 722 (93.3%) cases without pulmonary edema in a cohort of women who delivered between 24 and 33 weeks. Univariate and logistic regression analysis were used as indicated. RESULTS: Of subjects with pulmonary edema 98% received tocolytics while 94% had antenatal corticosteroid therapy versus 50% and 40% in controls. Significant positive associations of pulmonary edema only on univariate analysis were multiple pregnancy, earlier presenting gestational age, positive maternal cultures, small for gestational age while significant negative associations were indicated by preterm delivery and premature rupture of membranes. Independent predictors of pulmonary edema on logistic regression analysis were spontaneous preterm labor (odds ratio {OR}=10.9, p=0.026; 95% CI 1.3, 90), tocolytic therapy (OR=4.3, p=0.000; 95% CI 2.3, 8.4) especially magnesium sulfate and nifedipine, antenatal corticosteroid therapy (OR=2.3, p=0.002; 95% CI 1.3, 4), chorioamnionitis (OR=2.7, p=0.028; 95% CI 1.1, 6.5), blood product transfusion (OR=2.3, p=0.038; 95% CI 2.2, 8.4) and tobacco use (OR=2.5, p=0.016; 95% CI 1.2, 5.4). CONCLUSIONS: In mothers delivering prematurely, pulmonary edema is more likely with spontaneous preterm labor, smokers, infections or those receiving blood transfusions. It occurs almost exclusively in patients treated with antenatal corticosteroids and tocolytic medication.     

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.     

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.     

Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study

It is hypothesized that ampicillin may treat subclinical deciduitis and prolong the "effective" latent period in patients with preterm premature rupture of the membranes. We studied 82 patients with preterm rupture of membranes who were managed expectantly and were randomly assigned either to receive ampicillin prophylaxis (n = 43) or not to receive ampicillin prophylaxis (n = 39). Patients were excluded from study entry on admission if they had suspected or frank chorioamnionitis, active preterm labor, a history of penicillin allergy, multiple gestation, or cervical cerclage. There were no significant differences between the groups in duration of membrane rupture prior to admission, gestational age at membrane rupture, use of steroids and tocolysis, and demographic factors. Life-table analysis showed that the risk of delivery was significantly lower for the group of patients receiving prophylactic ampicillin. The incidence of neonatal infection was significantly lower in the ampicillin group, 1 (2%) versus 6 (17%), p less than 0.04.     

The impact of acute tocolysis on neonatal outcome in women hospitalized with preterm labor at 32 to 34 weeks' gestation

We compared neonatal outcomes from singleton pregnancies in women hospitalized with preterm labor (PTL) at 32 0/7 to 34 6/7 weeks managed with and without acute tocolysis. Women enrolled for outpatient surveillance who were hospitalized and diagnosed with PTL between 32 0/7; to 34 6/7 weeks' gestation without conditions necessitating interventional delivery during hospitalization were identified ( N = 2921). Patients with contraindications to pregnancy prolongation were excluded ( N = 168). Data were compared between patients whose clinical management included tocolysis ( N = 2342) and patients in whom tocolysis was not utilized ( N = 411). The incidence of preterm birth (77.9% versus 48.1%), low birth weight (48.9% versus 16.7%), neonatal intensive care unit admission (41.4% versus 16.2%), and nursery length of stay > 7 days (28.0% versus 9.7%) were all higher in women not receiving acute tocolysis compared with the acute tocolysis group (all P < 0.001). Using acute tocolysis to prolong pregnancy in patients hospitalized with PTL at 32 0/7 to 34 6/7 weeks' gestation is associated with improved neonatal outcomes.     

The occurrence of adverse events in women receiving continuous subcutaneous terbutaline therapy

OBJECTIVE: The purpose of this study was to determine the frequency of serious adverse events in patients receiving continuous subcutaneous terbutaline after arrested preterm labor. STUDY DESIGN: Women with singleton, twin, and triplet pregnancies prescribed continuous subcutaneous terbutaline were studied. Electronic patient records were reviewed for patient tolerance of medication and serious adverse events. The primary study outcome was the frequency of serious adverse events. RESULTS: Available for analysis were 9359 patient records. Transient medication side effects were reported by 1447 (15.5%) patients. Severe adverse events were identified on 12 patients either during treatment with continuous subcutaneous terbutaline (n=4), or after discontinuation of outpatient treatment (n=8). The most frequent serious adverse event was pulmonary edema (n=9). There was no maternal mortality. CONCLUSION: Continuous subcutaneous terbutaline infusion was associated with an extremely low incidence of serious adverse events. Patients with comorbidities and/or concomitant tocolysis with intravenous magnesium sulfate should be closely assessed for development of serious adverse events.     

Preterm birth is associated with increased risk of maternal and neonatal infection.

Much information suggests that maternal reproductive tract infections, both recognized and unrecognized, account for an important and possibly preventable portion of preterm births. If such infections do mediate instances of preterm labor and premature rupture of the membranes (PROM), then associated risks of subsequent maternal and neonatal infections would be increased, even after controlling for confounding variables. To evaluate possible associations between preterm birth and maternal and neonatal infections, we conducted a retrospective study of 9642 births at the University of Colorado Health Sciences Center between July 1980 and June 1985. Clinical chorioamnionitis occurred more frequently among women delivering before term with intact membranes at the onset of labor (5.8% preterm versus 1.7% term) and among women with PROM (26.5% preterm versus 6.7% term). Among the women delivered by cesarean, the incidence of postpartum endometritis was higher in those with preterm PROM than in those with term rupture of membranes. The incidence of neonatal infection increased significantly as the gestational age of the neonates decreased (P less than .01). The rate of culture-proven neonatal infection was significantly higher following PROM (P less than .01) than after birth without PROM. Both neonatal infection and perinatal mortality were increased in association with chorioamnionitis in both preterm and term pregnancies. These consistent observations complement and support suggestions that reproductive tract infection plays a possibly preventable role in the pathogenesis of preterm birth.     

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.     

The association of Chlamydia trachomatis, Neisseria gonorrhoeae, and group B streptococci with preterm rupture of the membranes and pregnancy outcome

There is conflicting evidence regarding a possible causal role for Chlamydia trachomatis in the development of preterm premature rupture of the membranes. We investigated the relative prevalence of endocervical infection with C. trachomatis and group B streptococci in patients with preterm premature rupture of membranes compared with a control group taken from the same obstetric population. C. trachomatis was isolated from 23/52 (44%) patients with preterm premature rupture of membranes versus 13/84 (15%) women in the control group (p less than 0.001). This association was independent of infection with group B streptococci or Neisseria gonorrhoeae. Group B streptococci were isolated from 16% of the patients with preterm premature rupture of membranes versus 4% of the control population (p less than 0.05). The risk of preterm premature rupture of membranes associated with group B streptococcal infection was independent of infection with C. trachomatis and N. gonorrhoeae. Endocervical infection with C. trachomatis did not significantly affect early maternal complication rates after delivery.     

Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes

The purpose of this study was to examine the relationship between intraamniotic infection and the onset of labor in patients with preterm premature rupture of the membranes. Two hundred and thirty consecutive patients were admitted with premature rupture of the membranes to Yale-New Haven Hospital from January 1985 to July 1987. Amniotic fluid was retrieved by amniocentesis from 96% (221/230). Sixty-one patients were in labor on admission (27.6%, 61/221) and 39% of them (24/61) had a positive amniotic fluid culture. Patients in labor on admission were more likely to have a positive amniotic fluid culture than those who were not in labor on admission (24/61 versus 41/160, p = 0.049). Of the 160-patients who were not in labor on admission, 81 subsequently went into spontaneous labor; microbiologic information at the time of labor was known in 48 of these patients (59.2%). Seventy-five percent (36/48) of these patients had a positive amniotic fluid culture. The incidence of intraamniotic infection in quiescent women who subsequently went into labor was higher than that of patients admitted in active labor (75% versus 39%, p = 0.0004). These results provide a basis for the clinical impression that the onset of labor in women with preterm premature rupture of the membranes is associated with a subclinical intraamniotic infection. The mechanisms responsible for the onset of labor in women without an intraamniotic infection may be associated with an extraamniotic infection (e.g., deciduitis) or a noninfectious process.     

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.     

Correlation of maternal serum C-reactive protein with outcome of tocolysis

Subclinical intrauterine infection is an important cause of preterm labor, specifically where tocolysis has failed. Fifty patients in preterm labor with singleton pregnancies were studied prospectively to determine whether the presence or absence of C-reactive protein, a nonspecific marker for infection, would correlate with success or failure of tocolysis. Of the 50 patients, tocolysis failed in 11 of 15 women with a positive C-reactive protein determination. Tocolysis succeeded in 33 of 35 cases where C-reactive protein was negative (P less than .0005). Urinary tract infection occurred in 40% of the study patients, but was not a confounding factor in the interpretation of C-reactive protein.     

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.     

The therapeutic efficacy and cost-effectiveness of aggressive tocolysis for premature labor associated with premature rupture of the membranes

We conducted a randomized trial comparing bed rest with tocolysis to determine the therapeutic efficacy, safety, and cost-effectiveness of tocolysis for the treatment of preterm labor after membrane rupture. One hundred nine women participated over a 26-month interval. Treatment groups did not differ significantly in terms of gestational age at membrane rupture, gestational age at delivery, birth weight, maternal or fetal infectious morbidity, respiratory distress syndrome, necrotizing enterocolitis, or perinatal mortality. Prolongation of intrauterine time after the onset of uterine contractions was seen in women receiving tocolysis (105.2 +/- 157 hours versus 62.1 +/- 77 hours, p = 0.06). This prolongation was not associated with a significant reduction in the total cost per surviving infant (tocolysis, $38,593 +/- $40,887 versus bed rest, $43,158 +/- $37,116; p = 0.445). The cost difference was artifactual. The number of very premature infants born (less than 28 weeks' gestation) was unequal in the two groups (12 in the bed rest group and 5 in the tocolysis group) and skewed the results. Before 28 weeks' gestation tocolysis was associated with a significant increase in intrauterine time after the onset of regular contractions (p = 0.05). However, there was no identifiable perinatal benefit garnered from the additional 5 days. After 28 weeks there were no significant differences between treatment groups in terms of intrauterine time after the onset of regular contractions and total cost per surviving infant. Because tocolysis does not improve perinatal outcome and can itself be associated with major maternal morbidity, it should be avoided after 28 weeks' gestation. Before 28 weeks' gestation tocolysis may greatly increase intrauterine time, but the benefit of this prolongation is not clear.     

Bolus tocolysis: treatment of preterm labor with pulsatile administration of a beta-adrenergic agonist

The treatment of premature labor with beta-adrenergic substances is complicated by side effects. Although most human control mechanisms are pulsatile, therapy is usually administered continuously. We designed a microprocessor-controlled pump to allow pulsatile tocolytic infusion, hoping to reduce the total dose and thus the side effects. In 33 patients pulsatile bolus tocolysis was compared with continuous tocolysis in a control group of 38 patients. Bolus tocolysis required considerably less beta-sympathomimetic agent for comparable therapeutic success (median dosage 3.0 versus 15.9 mg, p less than 0.001). Duration of therapy under bolus tocolysis was also significantly shorter (p less than 0.05). Birth weight was higher after bolus tocolysis (median 3070 versus 2580 gm, p = 0.05). Additional indicators favored bolus tocolysis but were not statistically significant: a longer gestational period, fewer infants weighing less than 2500 gm, and a lower incidence of respiratory distress syndrome. Pulmonary edema occurred in one patient during continuous tocolysis.     

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.     

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.