Antenatal risk factors associated with the development of lenticulostriate vasculopathy (LSV) in neonates.

OBJECTIVE: To determine the antenatal risk factors associated with neonatal lenticulostriate vasculopathy (LSV). STUDY DESIGN: Women in preterm labor were randomized to magnesium sulfate (MgSO4), other tocolytic, or saline control. The surviving babies underwent head ultrasounds (HUS) (weeks of life 1, 2, and 4) and periodic developmental examinations (months 4, 8, 12, and 18). RESULTS: Of 140 infants, 17.1% (24) had neonatal intraventricular hemorrhage (IVH), and 10.0% (14) had LSV (half of the latter (7 of 14) had both IVH and LSV). In a regression model in which other risk factors were controlled for, the association between antenatal exposures to tocolytic MgSO4 >or=50 g and LSV were significant (adjusted odds ratio (OR), 8.3; 95% confidence interval (CI), 1.5 to 45.0; p=0.01). CONCLUSION: Based on our data and their analyses, we infer that antenatal exposure to high-dosage, tocolytic MgSO4 may be associated with LSV.     

Association between lenticulostriate vasculopathy (LSV) and neonatal intraventricular hemorrhage (IVH).

OBJECTIVES: To determine whether there is an unconfounded association between neonatal intraventricular hemorrhage (IVH) and lenticulostriate vasculopathy (LSV (also known as thalamostriate or mineralizing vasculopathy)). STUDY DESIGN: During the conduct of the Magnesium and Neurologic Endpoints Trial (MagNET), a randomized controlled trial involving maternal, hence fetal, exposure to antenatal magnesium sulfate in the context of preterm labor, head ultrasounds were obtained for each of the surviving neonates. Because of our previous experience in the diagnosis of LSV, when ascertaining the presence of IVH, as called for by the research protocol of our study, the presence or absence of LSV was also determined. RESULTS: We found LSV to be relatively prevalent (10% (14 of 140) among surviving babies). More importantly, it was significantly associated with the occurrence of neonatal IVH, even when controlled for possible confounding (adjusted OR 9.8, 95% confidence interval 1.3 to 73.1; p=0.03). CONCLUSION: Given the known relationships between IVH and neonatal morbidity and mortality, the finding of a statistically significant association between neonatal IVH and LSV may suggest more substantial implications for the latter than previously believed.     

Celecoxib versus magnesium sulfate to arrest preterm labor: randomized trial

AIM: The effectiveness of the management of preterm birth remains an important health care issue, especially when considering that more than two thirds of singleton neonatal death occurs in preterm labor. The purpose of this study was to compare oral celecoxib with intravenous magnesium sulfate as tocolytic. METHODS: This was a randomized study of patients who were between 24 and 34 weeks of gestation with preterm labor. One hundred and four pregnant women with preterm labor were randomly assigned to receive celecoxib 100 mg b.i.d. for 48 h or intravenous magnesium sulfate (MgSO4) for maximum of 48 h. Outcome variables included delay of delivery for 48 h and the incidence of side-effects. Data was analyzed using the Student t-test and the chi(2) test. RESULTS: There was no difference between the groups over the course of the study in demographic characteristics, cervical examination and amniotic fluid index. Labor was arrested for 48 h was in 42 (81%) and 45 (87%) of the patients in the celecoxib and magnesium sulfate groups, respectively (p-0.298). There were no severe maternal or neonatal complications in either group. CONCLUSION: Celecoxib is as effective as magnesium sulfate for primary tocolysis.     

Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway

Dysfunctional endothelial cell activation and cytokines are implicated in preterm labor, a condition commonly treated with the tocolytic agent, magnesium sulfate (MgSO(4)). Based on recent findings showing the inflammatory effects of magnesium deficiency, we examined the effect of MgSO(4) on human umbilical vein endothelial cell (HuVEC) inflammatory responses in vitro. HuVECs isolated from term umbilical cords were incubated with MgSO(4) prior to stimulation with lipopolysaccharide (LPS) and then assessed for endothelial cell activation. Endothelial cell supernatants were assayed for inflammatory mediator production (interleukin-8; IL-8), and endothelial cell-associated intercellular adhesion molecule (ICAM-1) expression was determined. In the absence of LPS stimulation, MgSO(4) had no effect on HuVEC responses. Treatment of HuVECs with MgSO(4) prior to LPS stimulation inhibited inflammatory mediator production (p<0.05) and cell adhesion molecule expression (p<0.05) in a dose-dependent manner. Mechanistic studies showed that MgSO(4) reduced NFkappaB nuclear translocation and protected cytoplasmic IkappaBalpha from degradation in LPS-treated HuVECs. In conclusion, MgSO(4) inhibits endothelial cell activation, as measured by levels of IL-8 and ICAM-1 expression, via NFkappaB. Our results support the hypothesis that MgSO(4) treatment may function as an anti-inflammatory agent during preterm labor.     

A review of the role for magnesium sulphate in preterm labour

During the last decade, the body of medical knowledge concerning the use of pharmacological doses of magnesium sulphate (MgSO₄) for preterm labour has increased substantially. Several randomised controlled trials (RCTs) have provided compelling evidence that MgSO₄ is the drug of choice for maternal seizure prophylaxis in pre-eclampsia, whether preterm or term. In contrast, a recent Cochrane systematic review of the relevant contemporary literature has found no evidence basis to support the use of MgSO₄ for tocolysis in preterm labour. Furthermore, associated with high-dosage tocolytic MgSO₄, recent data indicate a possible increased risk for neonatal intraventricular haemorrhage (IVH), as well as increased total paediatric mortality. It is possible, on the other hand, that the prophylactic administration of much lower dosages of MgSO₄, in selected cases of preterm labour, may have a neuroprotective effect for a small number of infants.     

Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor

OBJECTIVE: The aim of this study was to compare the efficacy and safety of oral nicardipine in acute therapy for preterm labor with those of parenteral magnesium sulfate. STUDY DESIGN: Patients between 24 and 34 weeks' gestation with documented preterm labor were randomly assigned to receive oral nicardipine (n = 57) or intravenous magnesium sulfate (n = 65) as initial tocolytic therapy. Patients in the nicardipine group received a 40-mg loading dose and then 20 mg every 2 hours as needed to stop contractions (total 80 mg). Patients in the magnesium sulfate group received a 6-g bolus followed by 2 to 4 g/h to provide uterine quiescence. Patients could be switched to another tocolytic regimen if they continued to have contractions after 6 hours of therapy. The main outcome variables examined were time to uterine quiescence, time gained in utero, recurrence of preterm labor, failure of tocolysis, and pertinent maternal and neonatal outcomes. RESULTS: There were no significant differences in maternal demographic characteristics between the groups. Among patients who responded with uterine quiescence within 6 hours, there was a significant decrease in the time to uterine quiescence in the nicardipine group (P <.01). Patients in the magnesium sulfate group were more likely to have recurrence of preterm labor necessitating further tocolytic attempts (P =.048). The patients in the magnesium sulfate group had more adverse side effects, mainly nausea and vomiting (P =.004). There were no differences in birth weight, estimated gestational age at delivery, or neonatal complications between the 2 groups. CONCLUSIONS: Oral nicardipine is an effective, safe, and well-tolerated tocolytic agent. In this prospective clinical trial patients randomly assigned to receive oral nicardipine had arrest of preterm labor more rapidly than did those randomly assigned to receive parenteral magnesium sulfate. Patients who received magnesium sulfate were more likely to have adverse medication effects and recurrent preterm labor.     

Increasing amniotic fluid magnesium concentrations with stable maternal serum levels: a prospective clinical trial

OBJECTIVE: To compare the effect of prolonged maternal intravenous MgSO4 administration on amniotic fluid and serum concentrations of magnesium over time in preterm labor patients. STUDY DESIGN: Patients at 24-34 weeks of singleton gestation who presented with contractions (> 8 in 60 minutes) underwent amniocentesis to rule out intrauterine infection after signing an informed consent form. Some of these women who were clinically judged to have preterm labor received intravenous MgSO4: a 4-g loading dose followed by a 2 g/h maintenance dose. For technical reasons some patients had amniocentesis performed before initiation of MgSO4 (controls), while others had the procedure during tocolytic therapy (study subjects). Duration of treatment until amniocentesis was recorded, and blood samples were drawn at the time of amniocentesis. Maternal serum and amniotic fluid magnesium levels were measured using a colorimetric end point method. Data were evaluated using the Student t test and linear regression analysis. RESULTS: Mean magnesium levels in maternal serum rose from 1.74 +/- 0.2 mg/dL in controls to 4.01 +/- 0.4 mg/dL in the study group. Mean magnesium levels in Mean magnesium levels in amniotic fluid were 1.41 +/- 0.18 mg/dL in the controls versus 2.28 +/- 0.53 mg/dL in the treatment group. Duration of MgSO4 treatment ranged from 3 to 22 hours. Amniotic fluid magnesium concentrations increased significantly during therapy (correlation coefficient = 0.89; p < 0.001), while maternal serum levels remained stable over time (correlation coefficient between maternal serum levels and time = -0.39; p=0.34). CONCLUSION: Although maternal serum magnesium levels remained stable with intravenous MgSO4 therapy, concentrations continued to rise in amniotic fluid over time. However, amniotic fluid magnesium levels never exceeded maternal serum concentrations during the study period.     

Marked hypocalcemia after tocolytic magnesium sulphate therapy

Symptomatic hypocalcemia has been reported infrequently in association with magnesium sulfate (MgSO (4)) tocolytic therapy. We report a 38-year-old woman who presented in preterm labor at 24 3/7 weeks. Twenty hours after starting MgSO (4), she developed chest pain. Studies revealed therapeutic serum Mg level, total serum calcium (Ca) = 5.5 mg/dL, 24-hour urine Ca = 763.9 mg, and low serum uric acid and phosphate levels. All studies corrected day 1 postpartum; urine Ca level corrected on day 2. Even short courses of MgSO (4) can result in severe hypocalcemia, raising the question of whether Ca levels should be routinely monitored.     

Randomized investigation of magnesium sulfate for prevention of preterm birth

One hundred fifty-six women with preterm labor between 24 and 34 weeks' gestation were randomized to receive either intravenous magnesium sulfate or no tocolytic therapy. Magnesuim sulfate infusions of up to 3 gm/hr were used in 76 pregnancies and resulted in a mean serum magnesium concentration of 5.5 +/- 1.4 mEq/L (mean +/- SEM). Compared with 80 control pregnancies, magnesium sulfate tocolysis had no significant effect on duration of gestation, birth weight, neonatal morbidity, and perinatal mortality. We conclude that clinically safe infusions of magnesium sulfate are ineffective when used to prevent preterm birth.     

Maternal magnesium level effect on preterm labor treatment

Abstract

Objective: To compare the initial serum magnesium levels between preterm labor (PL) and control groups and to evaluate MgSO4 treatment response in preterm labor group according to their initial serum magnesium levels.

Methods: Hundred women diagnosed as preterm labor between 28 and 33 weeks of gestation and 100 non-complicated pregnant women were enrolled in this prospective study. Total basal serum magnesium levels were measured in both the groups. After a 6?g intravenous bolus of MgSO4, a dose of 2?g/h was given as an infusion in the preterm labor group.

Results: Serum magnesium levels were significantly lower in preterm labor group (p?<?0.001). The active contractions stopped in 69 (73,4%) preterm patients. The basal Mg level was significantly lower in this preterm group (1.6 versus 1.9, respectively, p?<?0.001). Predictive value of basal magnesium level measurement for magnesium tocolysis response was calculated by receiver operating characteristic analyses with 95% confidence interval. Positive predictive and negative predictive values were found as 64.5% and 92.5%, respectively, with 83% accuracy, when cut-off magnesium value was taken as a <1.75?mg/dl (sensitivity?=?80%, specificity?=?84,1%).

Conclusions: Basal magnesium levels in preterm labor had a predictive value in evaluating MgSO4 tocolysis response. It may help to select patients who are appropriate for MgSO4 tocolysis.     

Preterm labour. The present and future of tocolysis

This chapter discusses the tocolytic agents currently in use for the treatment of preterm labour and considers them in light of the evidence base. These agents are the beta2 sympathomimetic agonists, magnesium sulphate (MgSO(4)), indomethacin, nifedipine and atosiban. The available evidence for these agents shows that the beta2 agents are effective but have significant maternal side effects and no effect on perinatal outcome. MgSO(4) and glyceryl trinitrate are clearly ineffective. Nifedipine is effective with a low maternal side effect profile and is associated with improved perinatal outcomes. Meta-analyses of the several randomized controlled trials of atosiban show that it is no more effective than other tocolytic therapies. Possible directions for the future will be discussed.     

Magnesium sulfate as a tocolytic agent

Magnesium sulfate (MgSO4) has been successfully used to inhibit premature labor. A retrospective review was performed on the use of MgSO4 as a tocolytic agent at Memorial Hospital, Long Beach, California, during a 4-year period (1978-1982). Three hundred fifty-five patients with diagnoses of premature labor were treated with MgSO4 after transport from another hospital. Two hundred seventy-four patients (77%) had a singleton pregnancy with intact membranes, 38 (11%) had a singleton pregnancy with ruptured membranes, 35 (10%) had a multiple gestation with intact membranes, and eight (2%) had a multiple gestation with ruptured membranes. Delivery was successfully delayed in the majority of patients, and the incidence of unexplained failure of tocolysis was only 2%. Side effects occurred in 24 patients (7%) and necessitated stopping the drug in only seven (2%). Serum magnesium levels are reported and the use of MgSO4 in patients with significant vaginal bleeding is discussed. MgSO4 was found to be a successful, inexpensive, and relatively nontoxic tocolytic agent that had few side effects.     

Second overview of relationships between antenatal pharmacologic magnesium sulfate and neurologic outcomes in children

In the last ten years, the body of scientific knowledge concerning the use of antenatal pharmacologic magnesium sulfate (MgSO4) has become substantially larger. Several randomized controlled trials have provided compelling evidence that MgSO4 is the drug of choice for maternal seizure prophylaxis in toxemia. In contrast, the recent Cochrane Systematic Review, as well as other studies, have shown there is no evidence basis for the use of MgSO4 for tocolysis. Furthermore, when tocolytic-strength doses of MgSO4 are employed, there is an excess risk for total pediatric mortality (Cochrane Systematic Review and our own previous work). It is conceivable, nonetheless, that low doses of MgSO4, when used as prophylaxis in some selected cases of preterm labor, may ultimately be shown to be neuroprotective for a relatively small number of children. Unfortunately, the indiscriminate use of high-dosage MgSO4 for attempted tocolysis in preterm labor is much more likely to cause harm than do good.     

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.     

Umbilical cord serum ionized magnesium level and total pediatric mortality.

OBJECTIVE: To estimate whether higher magnesium levels in umbilical cord blood at delivery are associated with increased total pediatric (fetal + neonatal + postneonatal) mortality. METHODS: During the Magnesium and Neurologic Endpoints Trial, in addition to randomizing mothers having preterm labor into arms containing magnesium sulfate, other tocolytic agents, or saline controls, we obtained biologic specimens at delivery, including umbilical cord venous blood on which was determined the serum ionized magnesium level using the AVL 988-4 analyzer (Graz, Austria). Laboratory results were then matched with the pediatric mortalities. The study power was based on the anticipated reductions in neonatal intraventricular hemorrhage related to magnesium usage from 18.9% to 4.4%. For alpha =.05, 1-beta (power)=80%, two tailed, the total number of infants needed would be 140. RESULTS: Of 149 mothers who gave permission for randomization, ionized magnesium levels were available for 82 children. Seven deaths occurred (one immediately before delivery, three as neonates, and three in the postneonatal period). The median level of ionized magnesium among the seven dead children was 0.76 mmol/L; among the 75 survivors, the median level of ionized magnesium was 0.55 mmol/L (Mann-Whitney U test, P =.03). Using multivariable logistic regression analysis, the association remained statistically significant when controlling for possible confounding factors (adjusted odds ratio 7.7, 95% confidence interval 1.2, 47.6, P =.03). CONCLUSION: These findings of a dose response between serum ionized magnesium and deaths in children increase our concern about the improper use of tocolytic magnesium.     

Maintenance oral nifedipine for preterm labor: a randomized clinical trial.

OBJECTIVE: This study was undertaken to evaluate the efficacy of maintenance oral nifedipine in patients initially treated with intravenous magnesium sulfate for preterm labor. STUDY DESIGN: Patients with a diagnosis of preterm labor between 24 and 33.9 weeks' gestation were randomly assigned to receive either maintenance tocolytic therapy with oral nifedipine (20 mg every 4-6 hours) or no treatment (control) after discontinuation of magnesium tocolysis. Pregnancy and neonatal outcomes were evaluated. A sample size of 50 patients was required to detect a 10-day difference in mean time gained (beta =.2, alpha =.05). Statistical analyses were based on intent to treat. The t, chi(2), and Fisher exact tests were performed. RESULTS: Seventy-four patients were randomly assigned to receive either oral nifedipine (n = 37) or no treatment (n = 37). There were no statistically significant differences in age, race, parity, preterm delivery risk factors, enrollment gestational age, results of cervical examination, delivery gestational age, time gained, or neonatal complications between the groups. Delivery gestational age (mean +/- SD) was 35.4 +/- 3.2 weeks for patients randomly assigned to receive nifedipine and 35.3 +/- 3.2 weeks for patients who received no treatment (P =.9). Time gained during pregnancy was 37 +/- 23.9 days in the nifedipine group and 32.8 +/- 20.4 days in the control group (P =.4). CONCLUSION: Maintenance therapy with oral nifedipine does not significantly prolong pregnancy in patients initially treated with intravenous magnesium sulfate for preterm labor.     

Tocolytic treatment for the management of preterm labor: a review of the evidence

OBJECTIVE: Preterm labor is often a prelude to early births and the significant attendant burden of infant morbidity and mortality. Treatment consists of bedrest, hydration, pharmacologic interventions, and combinations of these. We systematically reviewed the effectiveness of tocolytics to stop uterine contractions (first-line therapy) or maintain quiescence (maintenance therapy). Our objective was to evaluate the evidence on the benefits and harms of five classes of tocolytic therapy for treating uterine contractions related to preterm labor--beta-mimetics, calcium channel blockers, magnesium, nonsteroidal anti-inflammatory agents, and ethanol. STUDY DESIGN: Reports of randomized controlled trials and other study designs in English, French, and German identified from searches of MEDLINE, EMBASE, specialized databases, bibliographies of review articles, unpublished literature, and discussions with investigators in the field were identified. Studies on women with preterm labor between 1966 and February 1999 that met our inclusion criteria were included. Through dual review, we abstracted the following information: study design and masking; definitions of preterm labor and successful tocolysis; patient inclusion/exclusion characteristics; patient demographic characteristics; drug and cointerventions; and numerous birth, maternal, and neonatal outcome measures. RESULTS: Of the 256 articles evaluated, we abstracted data from 60 first-line and 15 maintenance studies. Of these, 16 first-line and 8 maintenance studies met more stringent requirements for meta-analyses. Studies of first-line tocolysis (grade Fair) reveal a mixed outcome pattern with small improvement in pregnancy prolongation and birth at term relative to placebo. Data were insufficient to show directly a beneficial effect on neonatal morbidity or mortality. Ethanol was less beneficial than, and beta-mimetics were not superior to, other tocolytic options. Maintenance tocolytics (grade Poor) showed no improvements in birth or infant outcomes relative to placebo; these results were confirmed through meta-analysis. In contrast to other tocolytic treatments, maternal harms from beta-mimetics were rated High; all tocolytics were rated as Low risk for short-term neonatal harms. CONCLUSIONS: Management of uterine contractions with first-line tocolytic therapy can prolong gestation. Among the tocolytics, however, beta-mimetics appear not to be better than other drugs and pose significant potential harms for mothers; ethanol remains an inappropriate therapy. Continued maintenance tocolytic therapy has little or no value.     

Umbilical artery pH may be a possible confounder for neonatal adverse outcomes in preterm infants exposed to antenatal magnesium

Objectives: To determine the normal range of ionized magnesium (IMg) levels in cord blood during preterm gestation and to investigate whether antenatal Mg administration affects neonatal intraventricular hemorrhage (IVH) or patent ductus arteriosus (PDA). Methods: In this retrospective case–control study, we reviewed 118 pregnant women with antenatal Mg administration and their infants after they gave birth at one tertiary care center between January 2006 and December 2010. Thirty-seven cases with IVH and/or PDA were compared to 81 controls by multiple logistic regression analysis. The normal range of IMg levels was determined by another 79 subjects without any tocolytic agents and possible confounders. Perinatal and neonatal characteristics were then compared between three groups divided by the IMg levels in cord serum. Results: The normal range of IMg levels in cord blood was determined to be 0.47?±?0.07 mmol/L, regardless of gestational weeks. IMg level in cord serum could not be a risk factor for IVH or PDA. Elevation of IMg level in cord blood resulted in an increased incidence of IVH and a decreased incidence of PDA, but not significantly. IMg level in cord blood was inversely correlated with umbilical artery pH (p = 0.067). Conclusions: There was no significant relationship between the IMg levels in cord serum and neonatal IVH and PDA. Umbilical artery pH may be a possible confounder.     

Home uterine activity monitoring.

Despite tremendous improvements in maternal and neonatal care, preterm delivery remains the leading cause of infant mortality. Widespread use of tocolytics and aggressive preterm labor management have had little effect on reducing the overall neonatal mortality. To improve the success of tocolysis and preterm labor management, it is critical that preterm labor be diagnosed prior to significant cervical change. At present, a combination of several components is indicated for successful preterm birth prevention programs. These should include periodic risk assessment, patient education, cervical assessment, daily contact by highly skilled perinatal nurses, daily home uterine activity monitoring, and aggressive patient management. Studies support that this approach results in early detection of preterm labor, subsequently more effective tocolytic therapy and prevention of preterm birth.