MEDLINE Abstracts: Intervention in Preterm Labor

June 07, 2004

What's new concerning preterm labor interventions? This easy-to-navigate collection of recent MEDLINE abstracts highlights research and current thinking about the management of preterm labor and delivery.

McNamara HM
Br J Obstet Gynaecol. 2003;110(Suppl 20):79-85

The main problem with preterm labour is our lack of progress in the successful management of this condition. We need to reassess our approach to this problem because preterm labour is not a disease, but an event, which may result from multiple independent pathways. This problem has also been affected significantly by medical advances such as infertility treatments and changes in neonatal survival at the limit of viability. The specific challenges that we face in managing preterm labour include: problems with definition; aetiology, including genetic and infection components; diagnostic problems, such as true versus false labour and role of cervical length and fetal fibronectin; and specific interventions according to the antepartum, intrapartum and postpartum challenges. In order to address the main issue, and make future progress in the management of preterm labour, we should consider the implementation of a 'Postpartum Preterm Labour Diagnostic Workup Protocol'. These data/workup results could be entered on web-based databases for each preterm labour 'event'. An international research team could analyse data relating to specific aetiological patterns and subgroup analyses, leading to the collaborative development of 'aetiology specific' management modalities. This approach requires a close collaboration between clinicians and researchers, in order to make significant progress in this difficult area, and ultimately improve perinatal outcomes.

Andrews WW, Sibai BM, Thom EA, et al; National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network
Obstet Gynecol. 2003;101(5 Pt 1):847-855

Objective: To estimate whether antibiotic treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the second trimester would reduce the risk of spontaneous preterm delivery.
Methods: Women were screened between 21 weeks 0 days and 25 weeks 6 days of gestation with cervical or vaginal swabs for fetal fibronectin. Women with a positive test (50 ng/mL or more) were randomized to receive metronidazole (250 mg orally three times per day) and erythromycin (250 mg orally four times per day) or identical placebo pills for 10 days. The primary outcome was spontaneous delivery before 37 weeks' gestation after preterm labor or premature membrane rupture.
Results: A total of 16,317 women were screened for fetal fibronectin, and 6.6% had a positive test; 715 fetal fibronectin test-positive women consented to randomization. Outcome data were available for 703 women: 347 in the antibiotic group and 356 in the placebo group. The antibiotic and placebo groups were not significantly different for maternal age (P =.051), ethnicity (P =.849), marital status (P =.127), education (P =.244), and bacterial vaginosis (P =.236). No difference was observed in spontaneous preterm birth before 37 weeks' (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.80, 1.70), less than 35 weeks' (OR 0.92, 95% CI 0.54, 1.56), or less than 32 weeks' (OR 1.94, 95% CI 0.83, 4.52) gestation in antibiotic- compared with placebo-treated women. Among women with a prior spontaneous preterm delivery, the rate of repeat spontaneous preterm delivery at less than 37 weeks' gestation was significantly higher in the active drug compared with the placebo group (46.7% versus 23.9%, P =.039).
Conclusion: Treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the late second trimester does not decrease the incidence of spontaneous preterm delivery.

Meadow WL, Bell A, Sunstein CR
Obstet Gynecol. 2003;102:356-362

We determined the frequency of antenatal corticosteroid use for mothers with threatened premature delivery in 1985, 1990, 1995, and 2000. We next compared published data to the surveyed recollections of 302 obstetricians who were practicing during these years. Two points emerged. First, published reports reveal that the use of antenatal corticosteroids increased steadily, from 8% in 1985 to 20% in 1990, 52% in 1995, and 75% in 2000 (P < .001). Second, "expert" opinions derived from the recollections of practicing obstetricians consistently overestimated the actual use of antenatal corticosteroids during the year in question-31% versus 8% for 1985, 56% versus 20% for 1990, 78% versus 52% for 1995, and 92% versus 72% for 2000 (all Ps < .001). The use of antenatal corticosteroids by obstetricians in the past 15 years reveals a phenomenon that is widely recognized elsewhere-retrospective memories are often wrong, and when they are wrong they are not randomly wrong. Rather, recollections are systematically skewed toward an outcome that, in hindsight, is considered desirable (the "Monday morning quarterback" phenomenon). We offer a simple proposal. In determining the "standard of medical care," the legal system should rely on statistical data about doctors' performance rather than the recollections of experts about doctors' performance. The fallible memories of isolated experts are a crude second-best, far inferior to the data that they approximate. Widespread adoption of this view by professional physician organizations would dramatically increase the rationality of expert testimony in medical malpractice tort law.

Subtil D, Tiberghien P, Devos P, et al.
Am J Obstet Gynecol. 2003;188:524-531

Objective: The purpose of this study was to evaluate the role of different formulations and different administration kinetics of antenatal corticosteroid therapy on fetal heart rate.
Study Design: One hundred five patients who were at high risk for preterm delivery were assigned randomly to receive two injections of betamethasone acetate + phosphate, four injections of betamethasone phosphate, or four injections of dexamethasone phosphate. Computerized fetal heart rate was recorded daily through day 4.
Results: The three formulations did not differ in their effect on fetal heart rate, which varied significantly as a function of the time of injection. During treatment (day 0-day 1), fetal heart rate variability increased (+9%, P <.05), as did the number of fetal movements felt by the mother (+60% at day 0, P <.001). After treatment (day 2-day 3), variability fell significantly (-14%, P <.01), as did accelerations (-35% at day 2, P <.01). No modifications were still detectable on day 4.
Conclusion: Antenatal corticotherapy is responsible for two different phases of fetal heart rate modifications that do not vary according to the corticosteroid or the dosage regimen.

Belej-Rak T, Okun N, Windrim R, Ross S, Hannah ME
Am J Obstet Gynecol. 2003;189:1679-1687

Objective: The purpose of this study was to determine the effectiveness of cerclage for a shortened cervix on transvaginal ultrasound scanning in terms of the rates of preterm delivery and adverse neonatal and maternal outcomes.
Study Design: Pre-MEDLINE and MEDLINE, EMBASE, and the Cochrane Library were searched for human studies that compared cerclage placement to no cerclage on the basis of transvaginal ultrasound findings of a short cervix (< or =2.5 cm). Two authors independently determined eligibility and abstracted data. Meta-analyses were conducted when possible.
Results: Thirty-five studies were reviewed; 6 studies were eligible and were included in the analysis. There was no statistically significant effect of cerclage on the rates of preterm delivery (< 37, < 34, < 32, and < 28 weeks of gestation), preterm labor, neonatal mortality or morbidity, gestational age at delivery, or time to delivery. Birth weight was significantly higher with than without cerclage (P = .004).
Conclusion: The available evidence does not support cerclage for a sonographically detected short cervix. A randomized controlled trial is needed to determine whether this intervention will reduce adverse neonatal outcomes.

Drakeley AJ, Roberts D, Alfirevic Z
Obstet Gynecol. 2003;102:621-627

Objective: To estimate the effectiveness of prophylactic and therapeutic cerclage by meta-analysis of randomized clinical trials.
Data Sources: We searched the Cochrane Pregnancy and Childbirth Group specialized register of clinical trials (May 2002). Congress proceedings of international society meetings of fetal-maternal and reproductive medicine were searched by hand.
Methods Of Study Selection: Meta-analysis of randomized clinical trials comparing cervical cerclage with expectant management during pregnancy was performed. Further clarification was sought from trial authors when required.
Tabulation, Integration, and Results: Six trials describing a total of 2175 women were analyzed. Prophylactic cerclage was compared with no cerclage in four trials. Pooled results failed to show a statistically significant reduction in pregnancy loss and preterm delivery rates, although a small reduction in births less than 33 weeks' gestation was seen in the largest trial (relative risk [RR] 0.75; 95% confidence interval [CI] 0.58 to 0.98). Cervical cerclage was associated with mild pyrexia, increased use of tocolytic therapy, and hospital admission but no serious morbidity. Two trials examined the role of therapeutic cerclage when ultrasound examination revealed a short cervix. Pooled results failed to show a reduction in total pregnancy loss, early pregnancy loss, or preterm delivery before 28 and 34 weeks in women assigned to cervical cerclage.
Conclusion: The effectiveness of prophylactic cerclage in preventing preterm delivery in women at low or medium risk for second-trimester pregnancy loss has not been proven. The role of cerclage in women whose ultrasound reveals short cervix remains uncertain.

Terkildsen MF, Parilla BV, Kumar P, Grobman WA
Obstet Gynecol. 2003;101:565-569

Objective: To assess the factors associated with delivery greater than or equal to 28 weeks' gestation after placement of an emergent cerclage in women with singleton gestations.
Methods: All women who underwent emergent cerclage, defined as any cerclage placed between 16 and 24 6/7 weeks' gestation in response to documented cervical change on physical examination, at Northwestern Memorial Hospital from 1980 to 2000 were identified. Univariable and multivariable analyses were used to determine the factors most associated with achieving at least 28 weeks' gestation.
Results: One hundred sixteen women were eligible for analysis. Maternal age, race, and operative variables such as suture type and use of antibiotics were not associated with differences in the frequency of delivery at or after 28 weeks. Cerclage placement at or after 22 weeks' gestation increased the likelihood of reaching 28 weeks, whereas several cervical examination findings (dilatation greater than 3 cm, cervical length less than 0.5 cm, and membranes prolapsing beyond the external cervical os) as well as need for placement in a nullipara significantly reduced the likelihood of reaching 28 weeks. In multivariable analysis, nulliparity (odds ratio 0.31, 95% confidence interval 0.1, 0.8) and membranes prolapsing beyond the external cervical os (odds ratio 0.24, 95% confidence interval 0.1, 0.4) continued to be associated with delivery before 28 weeks, whereas cerclage placement at or after 22 weeks (odds ratio 3.2, 95% confidence interval 1.2, 8.6) increased the chance of achieving at least 28 weeks' gestation.
Conclusion: Nulliparity, the presence of membranes prolapsing beyond the external cervical os, and gestational age less than 22 weeks at cerclage placement are associated with decreased chance of delivery at or after 28 weeks after emergent cerclage; these factors may be used to help counsel patients considering the procedure.

Althuisius SM, Dekker GA, Hummel P, van Geijn HP
Am J Obstet Gynecol. 2003;189:907-910

Objective: The purpose of this study was to compare preterm delivery rates and neonatal morbidity/mortality rates for women with cervical incompetence with membranes at or beyond a dilated external cervical os that was treated with emergency cerclage, bed rest plus indomethacin, versus just bed rest.
Study Design: Women with cervical incompetence with membranes at or beyond a dilated external cervical os, before 27 weeks of gestation, were treated with antibiotics and bed rest and randomly assigned for emergency cerclage and indomethacin or bed rest only.
Results: Twenty-three women were included; 13 women were allocated randomly to the emergency cerclage and indomethacin group, and 10 women were allocated randomly to the bed rest-only group. Gestational age at time of randomization was 22.2 weeks in the emergency cerclage and indomethacin group and 23.0 weeks in the bed rest-only group. Mean interval from randomization until delivery was 54 days in the emergency cerclage and indomethacin group and 20 days in the bed rest-only group (P=.046). Mean gestational age at delivery was 29.9 weeks in the emergency cerclage and indomethacin group and 25.9 weeks in the bed rest-only group. Preterm delivery before 34 weeks of gestation was significantly lower in the emergency cerclage and indomethacin group, with 7 of 13 deliveries versus all 10 deliveries in the bed rest-only group (P=.02).
Conclusions: Emergency cerclage, indomethacin, antibiotics, and bed rest reduce preterm delivery before 34 weeks compared with bed rest and antibiotics alone.

Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group
JAMA. 2003;290:2669-2676

Context: Prenatal magnesium sulfate may reduce the risk of cerebral palsy or death in very preterm infants.
Objective: To determine the effectiveness of magnesium sulfate given for neuroprotection to women at risk of preterm birth before 30 weeks' gestation in preventing pediatric mortality and cerebral palsy.
Design, Setting, and Patients: Randomized controlled trial at 16 tertiary hospitals in Australia and New Zealand with stratification by center and multiple pregnancy. A total of 1062 women with fetuses younger than 30 weeks' gestation for whom birth was planned or expected within 24 hours were enrolled from February 1996 to September 2000 with follow-up of surviving children at a corrected age of 2 years.
Interventions: Women were randomly assigned to receive a loading infusion of 8 mL (4 g [16 mmol] of 0.5 g/mL of magnesium sulfate solution or isotonic sodium chloride solution [0.9%]) for 20 minutes followed by a maintenance infusion of 2 mL/h for up to 24 hours.
Main Outcome Measures: Rates of total pediatric mortality, cerebral palsy, and the combined outcome of death or cerebral palsy at a corrected age of 2 years.
Results: Data were analyzed for 1047 (99%) 2-year survivors. Total pediatric mortality (13.8% vs 17.1%; relative risk [RR], 0.83; 95% confidence interval [CI], 0.64-1.09), cerebral palsy in survivors (6.8% vs 8.2%; RR, 0.83; 95% CI, 0.54-1.27), and combined death or cerebral palsy (19.8% vs 24.0%; RR, 0.83; 95% CI, 0.66-1.03) were less frequent for infants exposed to magnesium sulfate, but none of the differences were statistically significant. Substantial gross motor dysfunction (3.4% vs 6.6%; RR, 0.51; 95% CI, 0.29-0.91) and combined death or substantial gross motor dysfunction (17.0% vs 22.7%; RR, 0.75; 95% CI, 0.59-0.96) were significantly reduced in the magnesium group.
Conclusions: Magnesium sulfate given to women immediately before very preterm birth may improve important pediatric outcomes. No serious harmful effects were seen.

American College of Obstetricians and Gynecologists
Obstet Gynecol. 2003;102(5 Pt 1):1115-1116

Preterm birth affects 12% of all births in the United States. Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women (ie, those with a prior spontaneous birth at <37 weeks of gestation). Despite the apparent benefits of progesterone in this high-risk population, the ideal progesterone formulation is unknown. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation because unresolved issues remain, such as optimal route of drug delivery and long-term safety of the drug.

Meis PJ, Klebanoff M, Thom E, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
N Engl J Med. 2003;348:2379-2385

Background: Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery.
Methods: We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle.
Results: Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen.
Conclusions: Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.

da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M
Am J Obstet Gynecol. 2003;188:419-424

Objective: The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population.
Study Design: A randomized, double-blind, placebo-controlled study included 142 high-risk singleton pregnancies. Progesterone (100 mg) or placebo was administered daily by vaginal suppository and all patients underwent uterine contraction monitoring with an external tocodynamometer once a week for 60 minutes, between 24 and 34 weeks of gestation. Progesterone (n = 72) and placebo (n = 70) groups were compared for epidemiologic characteristics, uterine contraction frequency, and incidence of preterm birth. Data were compared by chi(2) analysis and Fisher exact test.
Results: The preterm birth rate was 21.1% (30/142). Differences in uterine activity were found between the progesterone and placebo groups (23.6% vs 54.3%, respectively; P < .05) and in preterm birth between progesterone and placebo (13.8% vs 28.5%, respectively; P <.05). More women were delivered before 34 weeks in the placebo group (18.5%) than in the progesterone group (2.7%) (P < .05).
Conclusion: Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity.

Keirse MJ
Br J Obstet Gynaecol. 2003;110(Suppl 20):94-97

In 1950, the World Health Organisation (WHO) defined prematurity as a birthweight of 2500 g or less and in 1961 as a gestational age of less than 37 weeks. The time in between marks an era in which there was growing recognition of the importance of gestational age at birth and how to influence it. The latter was facilitated too by the development of tocography, which permitted some semi-objective measurement of uterine contractility. Along with it, came a growing interest in agents that could control uterine contractility beyond the earlier classical approaches of hormones and gastrointestinal spasmolytics. Hence, the early 1960s saw much research interest in agents, such as nylidrine, isoxsuprine, and orciprenaline that could suppress uterine contractility as one of their many beta-agonist properties. Subsequently, two approaches would be used to shift the balance towards uterine function over and above the influence on other bodily functions. One consisted of supplementing these drugs with agents, such as calcium antagonists and beta-receptor blockers that were hoped to suppress non-uterine actions. The other was a search for drugs in the same class with greater uterospecificity and more selective binding to uterine as opposed to other receptors. Neither of these approaches has ever fully fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility. The advent of prostaglandins as regulators of uterine contractility and the ability to suppress their biosynthesis saw another range of attempts to suppress uterine activity. They included aspirin, sodium salicylate, flufenamic acid, sulindac and indomethacin, but some were clearly based on a defective understanding of how uterine prostaglandin synthesis can be influenced. In the meantime, a flurry of other agents came and went, often more than once, testifying to the ingenuity of clinicians in trying to solve a problem that is poorly understood. Some, such as relaxin and ethanol, came and disappeared. Others, such as calcium antagonists, entered the scene as protectors against the non-uterine effects of other agents, went, and re-entered the scene in their own right. Still others, such as magnesium sulphate, came, lingered around, and became credited with effects in preterm labour that do not depend on affecting uterine contractility. Amidst this all arose the term tocolysis, coined in 1964 by Mosler from the Greek stems 'tauomicronkappaomicronzeta' and 'lambdaupsilonepsiloniotanu', to epitomise all of this ingenuity.

Smith GN
Br J Obstet Gynaecol. 2003;110(Suppl 20):103-106

Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, is a major public health problem in terms of loss of life, long-term disability (e.g. cerebral palsy, chronic lung disease), and health-care costs. The outcome of preterm infants is directly related to the gestational age at delivery. The goal of tocolytic therapy is to reduce neonatal morbidity and mortality by delaying delivery, to allow for the administration of corticosteroids and/or the safe transfer to a tertiary-care centre. However, currently available tocolytics in Canada (ritodrine, indomethacin, calcium antagonists, magnesium sulphate) have poor efficacy, have not been shown to increase the completion of a course of corticosteroids, are potentially associated with significant maternal/fetal side effects, and most importantly, have not been shown to improve neonatal outcomes. At the Canadian Tocolysis Consensus Conference, there was general agreement that recommendations should be based on good quality research evidence, particularly that of randomised clinical trials when available. It was concluded that there is little evidence to support the use of any of the currently available tocolytics; tocolytic use has not been associated with improved perinatal outcomes and often have detrimental effects on the mother. Therefore, questionable efficacy and potentially serious side effects may outweigh their use. Any new tocolytic demonstrated to improve neonatal outcome will have an immediate impact on societal and long term public health-care costs.

Fisk NM, Chan J
Br J Obstet Gynaecol. 2003;110(Suppl 20):98-102

The failure of tocolytics to improve neonatal outcomes in placebo-controlled trials has wrongly been interpreted as evidence that they do not work. While delivery is unequivocally prolonged by 24 hours, 48 hours and 7 days, the time gained was not exploited to optimise neonatal outcome. These trials typically studied women at relatively advanced gestational ages with predictably good outcomes, enrolled them in tertiary centres where they could not benefit from in-utero transfer, and had low levels of corticosteroid administration. No study has been powered to detect clinically meaningful differences that might be expected to accrue from 1-7 days prolongation of gestation. Despite this, Bayesian interpretation suggests that tocolytics do improve neonatal outcome. The largest placebo-controlled study showed clear trends towards better survival in fetuses <28 weeks, lower rates of cerebral palsy and higher Bayley mental scores. Meta-analysis of neonatal morbidity in the beta-agonist trials suggests a near-significant reduction in respiratory distress syndrome (RDS), together with trends towards reduced intraventricular haemorrhage, necrotising enterocolitis, and patent ductus arteriosus. Finally, there is the Orwellian analogy that tocolytics don't work, but some work better than others. Although calcium antagonists have not been evaluated against placebo, meta-analysis of comparative trials with beta-agonists demonstrate a significantly lower incidence of RDS and neonatal jaundice, presumably mediated through the reduced chance of delivery within 48 hours and 7 days. Development of tocolytics that are safe for mother and baby should facilitate adequately-powered placebo-controlled studies, which both focus on women most likely to benefit and capitalise on the 1-7 days gained.

Lamont RF
Br J Obstet Gynaecol. 2003;110(Suppl 20):108-112

The perfect tocolytic agent, which is completely safe for both the mother and fetus and, which will inhibit uterine contractions and stop preterm labour in every case does not exist and the search continues. Recently, research into a new group of tocolytic agents (the oxytocic antagonists) has led to the introduction of a new licensed drug, atosiban. Since the early 1950s, modifications of the oxytocin molecule have resulted in many analogues and antagonists, though initially none emerged as potentially useful drugs. Further modifications resulted in full uterotonic antagonism in animal models before an analogue was found that inhibited vasopressin-stimulated uterine contractions in non-pregnant healthy women. In vitro and animal models suggested the molecule was fully antagonistic, although it was found to be only partially agonistic in women. Further developments led to two modified oxytocin molecules with higher receptor affinity for human myometrium, both of which lacked agonism in humans. The analogue, atosiban, was found to be more potent and so was chosen for clinical evaluation in dysmenorrhoea and preterm labour. The first clinical reports were open label, observational pilot studies. Randomised, double-blind, phase II placebo-controlled studies followed showing that atosiban was significantly more effective than placebo with very few side effects. Dose-response studies and phase III studies in which study or placebo groups could use alternative tocolytic agents also suggested that atosiban was an effective tocolytic agent with very few adverse events. The recent worldwide comparative study of atosiban versus different beta-agonists represents the largest and most strictly controlled study of tocolytics ever published. Atosiban was found to be at least as effective as the beta-agonists as a tocolytic agent, but significantly less likely to result in maternal cardiovascular side effects or the need to discontinue therapy as a result of unacceptable side effects.

Berkman ND, Thorp JM Jr, Lohr KN, et al.
Am J Obstet Gynecol. 2003;188:1648-1659

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.

Coomarasamy A, Knox EM, Gee H, Song F, Khan KS
Br J Obstet Gynaecol. 2003;110:1045-1049

Objective: To explore the effectiveness of nifedipine compared with atosiban for tocolysis in preterm labour.
Design: A systematic review of randomised controlled trials with meta-analysis using adjusted indirect comparison.
Population: Six hundred and seventy-nine women recruited in nine randomised trials evaluating the effectiveness of nifedipine versus beta-agonists, and 852 women recruited in four trials of atosiban versus beta-agonists. There were no trials comparing nifedipine directly with atosiban.
Methods: We performed meta-analysis with a technique involving an adjusted indirect comparison between nifedipine and atosiban using beta-agonists as the common comparator. This approach preserves the benefit accrued by randomisation in the original comparisons.
Main Outcome Measures: Reduction in neonatal respiratory distress syndrome and delay in delivery by 48 hours.
Results: Nifedipine tocolysis was associated with a significant reduction in respiratory distress syndrome compared with atosiban (OR 0.55, 95% CI 0.32-0.97). It also increased the number of women whose delivery was delayed by 48 hours (OR 1.20, 95% CI 0.73-1.95), although this result was not statistically significant.
Conclusions: When indirectly compared with atosiban, nifedipine tocolysis is more effective. In the absence of a direct comparison, our analysis provides a way to explore the potential benefits of nifedipine versus atosiban.

Morrison JC, Chauhan SP, Carroll CS Sr, Bofill JA, Magann EF
Am J Obstet Gynecol. 2003;188:1460-1465; discussion 1465-1467

Objective: This study was undertaken to study the effectiveness of continuous subcutaneous terbutaline (SQT) in the home after recurrent preterm labor (RPTL).
Study Design: Women with RPTL at less than 32 weeks' gestation were treated with continuous SQT administered in the home compared with matched control patients.
Results: Fifteen SQT patients were compared with 45 women (3:1) treated with no tocolytic therapy after hospitalization. Gestational age at delivery more than 37 weeks (53% vs 4%), percentage delivered at less than 32 weeks (0% vs 47%), overall and pregnancy prolongation (49.8 ± 19.2 days vs 24.5 ± 12.8 days) were all significantly better in the study group (P <.001). The total number of maternal hospital days (9.8 ± 2.1 vs 15.9 ± 7.4, P <.0001), duration of NICU stay (1.9 ± 4.9 vs 19.8 ± 29.3 days, P <.001), and total cost for newborn care (6,995 ± 14,822 US dollars vs 62,033 ± 89,978 US dollars, P <.002) favored the study patients. For every dollar spent on SQT, there was a savings of 4.67 US dollars in newborn hospital costs for control patients.
Conclusion: In this small study, the use of SQT significantly prolongs pregnancy, decreases serious neonatal complications, and reduces the duration of hospitalization for both mother and infant, as well as neonatal costs.

Sawdy RJ, Lye S, Fisk NM, Bennett PR
Am J Obstet Gynecol. 2003;188:1046-1051

Objective: The purpose of this study was to establish whether nimesulide causes fewer fetal side effects than indomethacin or sulindac after short-term maternal exposure for tocolysis.
Study Design: This was a double-blind, double-dummy prospective randomized study with three drug treatment groups (n = 10 per group) that were comprised of subjects who were at 28 to 32 weeks of gestation with preterm contractions. The subjects were treated in the delivery suites of two busy inner-city teaching hospitals; the intervention consisted of 48 hours of treatment and with 72 hours of follow-up observation with indomethacin 100 mg (twice daily), sulindac 200 mg (twice daily), or nimesulide 200 mg (twice daily). The amniotic fluid index, hourly fetal urine production, and ductal Doppler pulsatility index observations were monitored before the treatment and at 4, 24, 48, 72, and 120 hours after the treatment was started. The statistical analysis used repeated measures analysis of variance, Bonferroni test, and Bland-Altman agreement. Significance assumed when the probability value was <.05.
Results: Each drug caused a significant reduction in all three observations over the 48-hour treatment period, which recovered to pretreatment levels by 72 hours after treatment. There were no significant differences among drugs for any of these effects.
Conclusion: Nimesulide causes similar short-term fetal side effects to indomethacin and sulindac.

Helmer H, Brunbauer M, Rohrmeister K
Br J Obstet Gynaecol. 2003;110(Suppl 20):113-115

The purpose of this retrospective study is to evaluate the effects of atosiban (Tractocile available in Austria since February 2000) for routine treatment of women with threatened preterm delivery. The advantage of this drug compared to other tocolytic agents is its specific action on reproductive tissues without the accompanying severe side effects. Women (n = 208) were retrospectively evaluated. Diagnoses at admission were preterm labour (n = 117), preterm rupture of membranes (n = 65), incompetent cervix (n = 19) and vaginal bleeding (n = 7). Gestational age was between weeks 21 and 33 of pregnancy. Preterm labour was defined as ≥4 uterine contractions/30 min and cervical length <30 mm examined by vaginal ultrasound and/or detection of vaginal fetal fibronectin. Tocolytic effectiveness was determined as the number of women having a diagnosis of preterm labour who were still pregnant after 48 hours and after 7 days. The influence on the frequency of contractions before and 3-12 hours after the start of treatment was assessed. Maternal side effects, perinatal and neonatal morbidity and transfers to the NICU were also evaluated. The proportion of women who remained undelivered was 78.7% after 48 hours, and 64.3% after 7 days. Atosiban decreased the frequency of contractions from 5.4/30 min before treatment to 1.6 contractions/30 min after the start of treatment. At the initial bolus application, 20.2% of women presented drug-related side effects, such as nausea, vertigo and flush over a short period of 1-2 minutes. During infusion, side effects possibly related to atosiban could be detected in 6% of women. Mean length of stay was 11.8 days in the NICU and 30.9 days in intermediate care. Twenty-three children developed intraventricular haemorrhage (I-IV). In conclusion, atosiban is an effective tocolytic drug in the treatment of preterm labour and preterm rupture of the membranes. It has significantly less side effects due to its lack of cardiovascular activity.

Lawson Y, Dombrowski MP, Carter S, Hagglund KH
Am J Obstet Gynecol. 2003;189:1396-1397

A prospective study was performed on 63 women at risk for preterm delivery who recorded maternally perceived contractions for 1 hour before and after placement of an external tocodynamometer. Fifteen women had an increase, 11 had a decrease, and 37 had no change (P not significant) in the number of perceived contractions after placement of the tocodynamometer.

Lumley J
Br J Obstet Gynaecol. 2003;110(Suppl 20):88-92

The principal issue concerning the mode of delivery is that while elective caesarean births may reduce the chances of fetal or neonatal death, this method of delivery might also increase maternal morbidity. Six trials with a total of 122 women investigated the effects of a policy of elective caesarean delivery (ECD) versus expectant management for small babies. A meta-analysis of these six trials also included additional unpublished data from several of the authors. Babies in the 'elective' group were less likely to develop respiratory distress syndrome and were more likely to have a low pH after birth. They were also less likely to have neonatal seizures and there were fewer perinatal deaths, although the studies were too small to detect even very large differences. However, there was significantly more serious maternal morbidity. There is insufficient evidence to evaluate a policy of ECD. All trials described major problems in recruitment and no subsequent trials have been identified. Changes in population-based data suggest that ECD of very preterm infants has increased markedly in the last 20 years. Given these changes, it seems unlikely that recruitment for future trials will be any easier than it was in the recent past.

GRIT Study Group
Br J Obstet Gynaecol. 2003;110:27-32

Objectives: To compare the effect of delivering early to pre-empt terminal hypoxaemia with delaying for as long as possible to increase maturity.
Design: A randomized controlled trial.
Setting: 69 hospitals in 13 European countries.
Participants: Pregnant women with fetal compromise between 24 and 36 weeks, an umbilical artery Doppler waveform recorded and clinical uncertainty whether immediate delivery was indicated.
Methods: The interventions were 'immediate delivery' or 'delay until the obstetrician is no longer uncertain'. The data monitoring and analysis were Bayesian.
Main Outcome Measures: 'Survival to hospital discharge' and 'developmental quotient at two years of age', this latter to be reported later.
Results: Of 548 women (588 babies) recruited, outcomes were available on 547 mothers (587 babies). The median time-to-delivery intervals were 0.9 days in the immediate group and 4.9 days in the delay group. Total deaths prior to discharge were 29 (10%) in the immediate group versus 27 (9%) in the delay group (odds ratio 1.1, 95% CI 0.61-1.8). Total caesarean sections were 249 (91%) in the immediate group versus 217 (79%) in the delay group: (OR 2.7; 95% CI 1.6-4.5). These odds ratios were similar for those randomized at gestational ages above or below 30 weeks.
Interpretation: The lack of difference in overall mortality suggests that clinicians participating in this trial were on average prepared to randomize at about the correct equivocal threshold between delivery and delay. However, there was insufficient evidence to convince enthusiasts for either immediate or delayed delivery that they were wrong.

Pierrehumbert B, Nicole A, Muller-Nix C, Forcada-Guex M, Ansermet F
Arch Dis Child Fetal Neonatal Ed. 2003;88:F400-F404

Background: Progress in perinatal medicine has made it possible to increase the survival of very or extremely low birthweight infants. Developmental outcomes of surviving preterm infants have been analysed at the paediatric, neurological, cognitive, and behavioural levels, and a series of perinatal and environmental risk factors have been identified. The threat to the child's survival and invasive medical procedures can be very traumatic for the parents. Few empirical reports have considered post-traumatic stress reactions of the parents as a possible variable affecting a child's outcome. Some studies have described sleeping and eating problems as related to prematurity; these problems are especially critical for the parents.
Objective: To examine the effects of post-traumatic reactions of the parents on sleeping and eating problems of the children.
Design: Fifty families with a premature infant (25-33 gestation weeks) and a control group of 25 families with a full term infant participated in the study. Perinatal risks were evaluated during the hospital stay. Mothers and fathers were interviewed when their children were 18 months old about the child's problems and filled in a perinatal post-traumatic stress disorder questionnaire (PPQ).
Results: The severity of the perinatal risks only partly predicts a child's problems. Independently of the perinatal risks, the intensity of the post-traumatic reactions of the parents is an important predictor of these problems.
Conclusions: These findings suggest that the parental response to premature birth mediates the risks of later adverse outcomes. Preventive intervention should be promoted.


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