Tocolytic Medication Research Articles

Changing Tocolytic Exposures among Neonatal Intensive Care Unit Admitted Preterm Infants.

Since 2010, the American College of Obstetrics and Gynecology have released three committee opinions to recommend and reaffirm the utility of magnesium sulfate for neuroprotection and later for tocolysis to achieve antenatal steroid course completion in preterm labor. We sought to determine changes in antenatal magnesium sulfate exposure and other tocolytic agents for pregnancies resulting in neonatal intensive care unit (NICU)-admitted preterm infants. Using the Pediatrix Clinical Data Warehouse, we evaluated all inborn infants delivered between 22 and 33 weeks' gestation and admitted to the intensive care units from 2009 to 2018. We classified patients based on antenatal exposure to tocolytic medications: calcium channel blockers (nifedipine and amlodipine), betamimetics (terbutaline, theophylline, and ritodrine), prostaglandin inhibitors (indomethacin), and magnesium sulfate. A total of 229,781 patients met inclusion criteria. During the study period, magnesium sulfate exposure increased from 27.6 to 57.7% of births while betamimetic exposure decreased from 10.2 to 5.2%. Increasing magnesium sulfate exposure over time was seen at all gestational ages examined and magnesium exposure was most common between 23 and 31 weeks' gestation. By 2017 to 2018, 70.5% of 24 to 29 weeks' gestation NICU infants received exposure to at least one tocolytic agent while this remained at 53.7% of 32 to 33 weeks' NICU admitted infants. Antenatal steroid exposure increased from 74.8 to 87.4% during the study period. For NICU-admitted preterm infants, prenatal exposure patterns to tocolytic agents has shifted since 2009 with prenatal magnesium sulfate exposure increasing significantly. Antenatal steroid exposure has risen concurrently. Exposure to tocolytic agents is the highest among preterm infants born between 24 and 29 weeks' gestation. · Exposure to magnesium sulfate significantly increased from 2009 to 2018 for NICU admitted infants.. · Concurrently, the use of other tocolytics decreased significantly.. · The use of antenatal steroids has been rising over time..

Incidence and risk factors of neonatal hypoglycemia after ritodrine therapy in premature labor: a retrospective cohort study

BackgroundRitodrine hydrochloride (RD), a β2-adrenergic agonist, is widely used as a tocolytic medication to suppress premature labor, but can cause neonatal hypoglycemia, a potentially severe side effect. We examined the incidence and risk factors of neonatal hypoglycemia following maternal intravenous administration of RD.MethodsThis was a retrospective study of neonates, who had birth weight of ≥2000 g and were delivered at 36 weeks gestation or later in Kanazawa University Hospital from August 2013 to July 2016. We defined neonatal hypoglycemia as blood glucose level < 50 mg/dL. Neonates who were delivered without maternal intravenous RD or who were delivered 8 days or more after stopping maternal RD or who received oral RD were defined as the RD non-administration group, while those delivered within 7 days after stopping maternal RD were defined as the RD intravenous administration group. We examined the incidence and risk factors of RD-induced neonatal hypoglycemia by comparing these two groups.ResultsWe enrolled 603 neonates in this study; 504 (83.6%) showed no neonatal hypoglycemia, while 99 (16.4%) exhibited neonatal hypoglycemia. The incidence of neonatal hypoglycemia was significantly higher (61.7%; 58/94) in the RD intravenous administration group than in the RD non-administration group (8.1%; 41/509) (p < 0.001). Binomial logistic regression analysis in the RD intravenous administration group showed that maternal age over 35 years (AOR: 3.385; 95% CI, 1.082–10.588, p = 0.036) and the interval to delivery from stopping intravenous administration of RD (AOR: 0.974; 95% CI, 0.953–0.996, p = 0.020) were independent factors associated with neonatal hypoglycemia. The cut-off value of the interval to predict the incidence of neonatal hypoglycemia was about 6 h (sensitivity 82.8%, specificity 63.9%).ConclusionsThe incidence of neonatal hypoglycemia was significantly increased by maternal intravenous administration of RD. We newly identified maternal age (over 35 years) and the interval to delivery from stopping intravenous administration of RD (within 6 h) as independent risk factors for neonatal hypoglycemia following maternal intravenous administration of RD. In cases with these risk factors, careful blood glucose monitoring is recommended for early detection and treatment of neonatal hypoglycemia.

490: Tocolytic options for open fetal repair of myelomeningocele: Systematic review

To describe current evidence on selection, regimen, efficacy and risks of perioperative tocolytic medications at the time of fetal repair of myelomeningocele. A search of MEDLINE, EMBASE, and SCOPUS databases was conducted from inception to March 2017. Studies that described their tocolytic protocol, gestational age at delivery, prenatal and postnatal outcomes were included. Studies that do not specify fetal myelomeningocele or do not adequately report outcomes were excluded. Neither sample size nor language was a basis for exclusion. Selection was done by 2 independent reviewers. Out of 570 studies retrieved on initial search, 462 were excluded for irrelevance. Of the 61 remaining titles, 17 were animal studies, 17 were reviews, 12 were not limited to fetal myelomeningocele, 3 studied the fetoscopic approach, 4 did not report neonatal outcomes, and 1 article was retracted. Eventually, seven articles were included. Four studies were conducted in the US; 1 study used preoperative indomethacin while the 4 studies used loading and maintenance doses of magnesium sulfate intra- and postoperatively along with postoperative indomethacin. Three of these studies used postoperative terbutaline. Three studies were done outside the US; 2 used preoperative indomethacin and one used diclofenac and Nifedipine. Magnesium sulfate was given intraoperatively. Postoperatively, magnesium sulfate was used in 2 studies and nifedipine was reported in 2 studies in different dosages. Among studies conducted in the US, average latency was 7.3 weeks (range 5.8-10.3 weeks). For studies conducted outside the US, the average latency was 13.7 weeks (range was 12 to 15.4 weeks). However, comparing a single to multiple agents, latency was comparable. Complications related to tocolysis are limited; incidence of pulmonary edema was 3.8% (2.2-5.5%) and is not altered by a single versus multiple medications. Preoperative indomethacin, intra- and postoperative course of magnesium sulfate seem to be the most commonly used and effective tocolytic options in women with open fetal myelomeningocele repair. The risk of pulmonary edema is generally small. There is no evidence that the use of multiple drugs would prolong latency compared to magnesium sulfate alone. However, further studies are needed to optimize the duration of postoperative treatment.

Tocolysis for in utero Surgery: Atosiban Performs Distinctly Better than Magnesium Sulfate

Introduction: To compare tocolysis with magnesium sulfate versus atosiban regarding the occurrence of short-term preterm labor and maternal side effects during and after open fetal myelomeningocele (MMC) repair. Material and Methods: A prospective nonrandomized cohort study was performed including 30 fetal MMC cases. The first 15 cases (group 1) received magnesium sulfate according to the MOMS protocol. In the following 15 cases (group 2), magnesium sulfate was substituted by atosiban. Chorioamniotic membrane separation (CMS), premature prelabor rupture of the fetal membranes (PPROM), preterm delivery <3 weeks after fetal MMC repair, and maternal complications due to the tocolytic medication were the major endpoints. Results: In both groups, one CMS but no PPROM was diagnosed <3 weeks after fetal MMC repair. One patient of group 2 delivered <3 weeks after fetal MMC repair because of an intraoperative placental abruption at 25 weeks. All women of group 1 showed an electrolyte imbalance during magnesium sulfate administration. One woman of group 1 developed several episodes of a third-degree atrioventricular block within the first 3 days after fetal surgery. Lethargy was found in all women during magnesium sulfate therapy. No maternal side effects were found under atosiban. Discussion: The use of atosiban resulted in an almost identical short-term uterine outcome without any serious maternal complications as seen when magnesium sulfate was given. Thus, the authors suggest using atosiban instead of magnesium sulfate in the context of open fetal surgery.

Vaginal Progesterone as Maintenance Treatment After an Episode of Preterm Labour (PROMISE) Study: A Multicentre, Double-blind, Randomised, Placebo-Controlled Trial

(Abstracted from BJOG 2016;123:1990–1999) A large proportion of both short-term neonatal morbidity and mortality and long-term disability is associated with preterm birth. Women with previous preterm delivery, a short cervical length at midgestation, a twin pregnancy, and an episode of preterm labor arrested with tocolytic medication all have an increased risk of preterm delivery.

Techniques for assisting difficult delivery at caesarean section.

Caesarean section involves making an incision in the woman's abdomen and cutting through the uterine muscle. The baby is then delivered through that incision. Difficult caesarean birth may result in injury for the infant or complications for the mother. Methods to assist with delivery include vacuum or forceps extraction or manual delivery utilising fundal pressure. Medication that relaxes the uterus (tocolytic medication) may facilitate the birth of the baby at caesarean section. Delivery of the impacted head after prolonged obstructed labour can be associated with significant maternal and neonatal complication; to facilitate delivery of the head the surgeon may utilise either reverse breech extraction or head pushing. To compare the use of tocolysis (routine or selective use) with no use of tocolysis or placebo and to compare different extraction methods at the time of caesarean section for outcomes of infant birth trauma, maternal complications (particularly postpartum haemorrhage requiring blood transfusion), and long-term measures of infant and childhood morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. All published, unpublished, and ongoing randomised controlled trials comparing the use of tocolytic agents (routine or selective) at caesarean section versus no use of tocolytic or placebo at caesarean section to facilitate the birth of the baby. Use of instrument versus manual delivery to facilitate birth of the baby. Reverse breech extraction versus head pushing to facilitate delivery of the deeply impacted fetal head. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Seven randomised controlled trials, involving 582 women undergoing caesarean section were included in this review. The risk of bias of included trials was variable, with some trials not adequately describing allocation or randomisation.Three comparisons were included. 1. Tocolysis versus no tocolysisA single randomised trial involving 97 women was identified and included in the review. Birth trauma was not reported. There were no cases of any maternal side-effect reported in either the nitroglycerin or the placebo group. No other maternal and infant health outcomes were reported. 2. Reverse breech extraction versus head push for the deeply impacted head at full dilation at caesarean section Four randomised trials involving 357 women were identified and included in the review. The primary outcome of birth trauma was reported by three trials and there was no difference between reverse breech extraction and head push for this rare outcome (three studies, 239 women, risk ratio (RR) 1.55, 95% confidence interval (CI) 0.42 to 5.73). Secondary outcomes including endometritis rate (three studies, 285 women, average RR 0.52, 95% CI 0.26 to 1.05, Tau I² = 0.22, I² = 56%), extension of uterine incision (four studies, 357 women, average RR 0.23, 95% CI 0.13 to 0.40), mean blood loss (three studies, 298 women, mean difference (MD) -294.92, 95% CI -493.25 to -96.59; I² = 98%) and neonatal intensive care unit (NICU)/special care nursery (SCN) admission (two studies, 226 babies, average RR 0.53, 95% CI 0.23 to 1.22, Tau I² = 0.27, I² = 74%) were decreased with reverse breech extraction. No differences were observed between groups for many of the other secondary outcomes reported (blood loss > 500 mL; blood transfusion; wound infection; mean hospital stay; average Apgar score).There was significant heterogeneity between the trials for the outcomes mean blood loss, operative time and mean hospital stay, making comparison difficult. However the operation duration was significantly shorter for reverse breech extraction, which may correspond with ease of delivery and therefore, the amount of tissue trauma and therefore, significantly less blood loss. Given the heterogeneity, we cannot define the amount of difference in blood loss, operative time or hospital stay however. 3. Instrument (vacuum or forceps) versus manual extraction at elective caesarean section Two randomised trials involving 128 women were identified and included in the review. Only one trial reported maternal and infant health outcomes as prespecified in this review. This trial reported birth trauma as an outcome but there were no instances of birth trauma in either comparison group. There were no differences found in mean fall in haemoglobin (Hb) between groups (one study, 44 women, MD 0.03, 95% CI -0.53 to 0.59), or in uterine incision extension (one study, 44 women, RR 0.70, 95% CI 0.13 to 3.73). There is currently insufficient information available from randomised trials to support or refute the routine or selective use of tocolytic agents or instrument to facilitate infant birth at the time of difficult caesarean section. There is limited evidence that reverse breech extraction may improve maternal and fetal outcomes, though there was no difference in primary outcome of infant birth trauma. Further randomised controlled trials are needed to answer these questions.

Methods of prolonging a pregnancy threatened with preterm labour

Both prolonged and shortened pregnancies carry the risk of increased mortality of the offspring. The main causes of early delivery are genetic factors, bacterial and viral infections, corpus luteum insufficiency and pathologies of the placenta. Antepartum luteolysis is due to the activity of prostaglandin F2α. A decrease in the progesterone concentration activates the sensitivity of the uterine muscles to oxytocin. Calcium ions move into the myocytes and bind to calmodulin, starting enzymatic reactions necessary for muscle contraction. Oxytocin promotes prostaglandin F2α release. Cholesterol and magnesium stimulate the binding of oxytocin to its receptors. A premature delivery is caused by a disorder of the balance between contractility and relaxation of the myometrium, which is regulated by many signalling pathways. Birth in humans can be postponed by the use of many different tocolytic medications, β-adrenergic drugs (ritodrine, hexoprenaline, fenoterol, terbutaline), magnesium salts, prostaglandin synthesis inhibitors (indomethacin, naproxen), pentoxifylline, metoprolol, calcium antagonists – calcium channel blockers (nifedipine), oxytocine antagonists (atosiban), nitric oxide donors (nitroglycerin) as well as progesterone and its synthetic analogs. In dogs and cats, in the presence of endogenous hormone deficiency, progesterone and its derivatives (gestagens) are recommended. In small animals with the risk of premature delivery, terbutaline has successfully been used. Premature delivery is a serious problem in both human and veterinary medicine, and experience from human medicine is being gradually introduced into veterinary practice.

Tocolytics used as adjunctive therapy at the time of cerclage placement: a systematic review.

To review the published literature on whether the use of empiric perioperative tocolytic medications could provide additional benefit when used in combination with cerclage. Systematic review of published medical literature reporting the efficacy of empiric tocolytics used as a perioperative adjunct to vaginal cerclage in high-risk patients. A PubMed search without date criteria of various tocolytics and cerclage yielded 42 studies. Review articles were excluded, as were reports of abdominal cerclage, emergent cerclage, or cerclage for the purpose of delayed interval delivery in twin gestations. Only five publications on the topic of perioperative tocolytic use at the time of history or ultrasound-indicated vaginal cerclage placement were identified. These included zero clinical trials, three retrospective cohort studies, one case series and one case report. Only one cohort study compared cerclage with indomethacin and cerclage without indomethacin and suggested no difference between the groups. The other two published cohort studies had no referent group who received cerclage without tocolysis. One case series and one case report were also published reporting cerclage with empiric beta-mimetic and progesterone adjunctive therapy. There is a paucity of published data on the topic of adjunctive perioperative tocolytics with cerclage. Adequately powered clinical trials on perioperative use of tocolysis with cerclage compared with a standard cerclage placement alone are needed to establish efficacy. Until adequately studied, this practice should be considered investigational.

425: Obesity does not impair indomethacin treatment of short cervix and preterm labor

Obesity is a state of increased inflammation. Our protocol of long-term indomethacin therapy to prevent preterm delivery prolongs pregnancy in the overall cohort. We sought to identify if obesity impacted the efficacy of this anti-inflammatory tocolytic medication.

84: Effect of tocolytic medications on synthesis and secretion of surfactant in an in-vitro human lung cell model

84 Effect of tocolytic medications on synthesis and secretion of surfactant in an in-vitro human lung cell model Ziad Haidar, Shamili Sammohi, David Cool, David Mckenna UT HealthUniversity of Texas Medical School at Houston, OB/GYN, Houston, TX, Wright State University, OB/GYN, Dayton, OH OBJECTIVE: To compare the effects of magnesium sulfate, nifedipine, and indomethacin on surfactant synthesis and secretion in adult human lung cells STUDY DESIGN: Human adult lung cells (NCI-H441) were grown to confluence in Waymouth’s MB571/5 medium containing 2% Hyclone and 1.5% Cellgro, containing 10,000 unit/ml penicillin G sodium, 10,000 ug/ml streptomycin sulfate, and 25 ug/ml amphotericin B. The plates were then divided into 4 groups, consisting of three tocolytics and a control. Tissue-equivalent doses of the tocolytics were used to mimic the steady state in-vivo levels of the following doses and routes of administration: indomethacin: 25mg po q6h, nifedipine 10mg po q6h, and magnesium sulfate 2 g/h IV. Betamethasone (BMZ) was added to each group to achieve a comparable tissue concentration to what is achieved clinically when 12 mg IM is given, and then repeated twenty four hours later. Lipids were extracted from the supernatant and separated on anHP-TLC plate in an organic solvent system. The lipids were primuline stained and examined for relative density under a DyLight 488 nmwith a ChemDocMP imaging camera (Bio-Rad, Hercules, CA) from 1 to 10 seconds, and the best image was saved for evaluation. RESULTS: The primuline stained cells showed an increased amount of surfactant B synthesis in each of the combinations: BMZ+nifedipine, BMZ+magnesium, BMZ+indomethacin. Compared to cells containing BMZ alone, the lipid extraction, which is indicative of the cells’ secretion phase, showed a significant increase with BMZ+magnesium and BMZ+indomethacin and decrease with BMZ+nifedipine CONCLUSION: This in-vitro human adult lung cell model demonstrated significant effects on surfactant synthesis and secretion when different tocolytic agents were given along with betamethasone. It is speculated this may be due to intracellular calcium-dependent interactions with the specific tocolytic agents in the type II pneumocytes. Further work is required to illicit the exactmechanism responsible for thesefindings.

Different effects of tocolytic medication on blood pressure and blood pressure amplification

The importance of tocolysis has been discussed extensively. Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs in most countries. Cardiovascular side-effects are frequent. Atosiban, a newer tocolytic drug, is a competitive antagonist of oxytocin and has fewer cardiovascular side effects. Although large studies exist, there is mainly subjective reporting of adverse reactions with a focus on blood pressure data. Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban in comparison to placebo on central and peripheral blood pressures, central-to-peripheral blood pressure amplification and the augmentation index (AIx) in healthy non-pregnant female volunteers. A double-blind, randomized, crossover trial was carried out in 20 healthy non-pregnant female volunteers. Hemodynamic measurements were performed under standardized conditions. At steady state, central and peripheral pressures did not differ from placebo in the atosiban group. During ritodrine -infusion, central SBP increased by 11% versus placebo (p = 0.012) and peripheral SBP by 10% (p = 0.004). In contrast to atosiban and placebo, blood pressure amplification was absent in the ritodrine group. While the AIx did not change in the atosiban group, with ritodrine, the AIx tended to decrease. The present study shows the significant effects of ritodrine on the cardiovascular system. Atosiban has no significant effects and may be an appropriate alternative to tocolyticum, particularly in cardiovascularly complicated pregnancies.

Prematurity prevention: the role of acute tocolysis

The preterm birth rate in the United States remains at an all-time high and continues to rise. Acute tocolysis has potential to delay preterm birth for 48 h, the critical period of antenatal steroid administration, or to arrest an episode of preterm labor, thus delaying birth and improving neonatal outcomes. It is therefore paramount that medical providers remain up-to-date regarding the usefulness, indications and contraindications, and side-effects and adverse effects of all tocolytics. Magnesium sulfate remains the most common tocolyic agent in the United States. Recent evidence comparing oral nifedipine with magnesium sulfate suggests equal efficacy with fewer maternal side-effects, thus supporting this oral medication as first-line treatment. This review will summarize the most common acute tocolytic drugs, their methods of action, and clinical data regarding their utility. All tocolytic medications have side-effects, some of them potentially life-threatening. Decisions regarding whether to use a tocolytic and which tocolytic to use require the diagnosis of preterm labor, knowledge of the patient's gestational age, medical conditions, and cost. Once tocolysis is initiated, attention must be paid to the patient's response, side-effects, and adverse events. Larger studies are needed which incorporate, in addition to efficacy, data on safety and side-effect profiles and cost.

Laparoscopic Appendectomy During Pregnancy: Between Personal Experiences and Scientific Evidence

Although laparoscopic appendectomy is a safe and effective procedure for management of acute appendicitis, data about the feasibility and safety during pregnancy are limited. We aimed to study our experience in this field and to review the scientific evidence available. All patients undergoing laparoscopic appendectomy during pregnancy, from January 2003 to December 2005, were included. Medical files were reviewed retrospectively. In addition, 133 cases from the literature were reviewed. General features of the cases, surgical technique details, and outcomes were analyzed. All laparoscopic procedures were completed without conversion to open operation. No substantial hemodynamic or gasometric changes were detected during the procedures. Tocolytic medication was not administered in any patient. All patients were discharged from hospital within the first 48 postoperative hours, and no complications were recorded during this period or in the followup. All newborns had an adequate weight for gestational age, satisfactory parameters of well-being at birth, and an uneventful development after 1-year followup. Laparoscopic appendectomy during pregnancy is as effective and safe as the conventional approach and has all the benefits of minimally invasive operation, provided that specific recommendations for these types of patients are strictly followed. It must be mentioned that there is only limited scientific evidence to support this statement.

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.

Regulatory and methodologic challenges to tocolytic development

The development of tocolytic medications faces challenges common to all drug development programmes, principally related to evolving understanding of the pathophysiology. There are unique impediments to drug development for pregnancy-related conditions in general and for tocolysis in particular. The purpose of this brief overview is to familiarize the obstetrician with the current challenges to drug development, focusing in particular on the problems of tocolytic development. A strategy for encouraging drug development for preterm labour and for pregnancy-related problems in general is presented.

Racial differences in prenatal care of mothers delivering very low birth weight infants

To determine whether there are any racial differences in the prenatal care of mothers delivering very low birth weight infants (VLBW). Retrospective cohort study of infants cared for at a single regional level III neonatal intensive care unit over a 9-year period, July 1993-June 2002, N = 1234. The main outcome variables investigated included antenatal administration of steroids, delivery by cesarean section, and use of tocolytic medications. Both univariate and multivariate analyses were performed. After controlling for potential confounding variables, white mothers delivering VLBWs had an increased odds of cesarean delivery (odds ratio 1.5, 95% confidence intervals (CI) 1.1-2.0), receiving antenatal steroids (1.3, CI 1.01-1.8), and tocolysis (1.4, CI 1.1-2.0) compared to black mothers. The models controlled for gestational age, multiple gestation, premature labor, clinical chorioamnionitis, maternal age, income, year of birth, and presentation. In our population of VLBWs, white mothers are more likely to receive antenatal steroids, tocolytic medications, and deliver by cesarean section when compared to black mothers. From our data we cannot determine the reasons behind these racial differences in care of mothers delivering VLBWs.

Tocolytic therapy for preterm labour: assessing its potential for reducing preterm delivery.

Preterm labour (PTL) is a major contributor to preterm delivery (PTD) but delivery is often not preventable by current therapies. We conducted this study to determine the proportion of women with PTL who were and who were not candidates for tocolytic therapy. The cohort comprised residents of Olmsted County, Minnesota who delivered at >20 weeks' gestation in 1985--94 and who experienced PTL. Medical records were abstracted to identify episodes of PTL, its treatment and outcome. We developed an algorithm that accounted for gestation at delivery and pregnancy complications to determine the proportion of pregnancies complicated by PTL that were candidates for tocolytic therapy. Of 651 pregnancies complicated by PTL, a 50% probability sample, stratified by delivery year, were selected and abstracted. The cumulative incidence of PTL ranged from 3.6 to 6.4 per 100 deliveries of live or stillborn infants. Tocolysis was not contraindicated for 49.4% of all women with PTL and for a third of women with only one PTL episode. Delivery was delayed to >35 weeks in 53.8% of candidates for tocolysis. Only an additional 11.7% of women with one or more PTL episodes could have had their PTD delayed beyond 35 weeks if a perfect tocolytic therapy had been available. Many pregnancies complicated by PTL occurred at > or =35 weeks or involved maternal or obstetric factors that contraindicated tocolytic medications. The maximum incremental benefit that could be expected of a new safe and efficacious tocolytic therapy would be to reduce current PTD rates resulting from PTL by about 12%.

External Cephalic Version (ECV) and the Early ECV Trial

The Caesarean section rate among women with breech pregnancies at term is approximately 70 percent. External cephalic version (ECV) has a recognized role in decreasing the likelihood of Caesarean section in women with breech pregnancies. External cephalic version prior to 37 weeks gestation has been abandoned in favour of initiating ECV at or after 37 weeks, with or without the use of tocolytic medication to facilitate the procedure. In North America and Europe, when the manoeuvre is undertaken at or after 37 weeks gestation, the rate of successful version resulting in a cephalic presentation at the time of delivery has remained low, particularly amongst nulliparous women. There is increasing interest in beginning ECV as early as 34 weeks gestation for selected women, as an approach to decreasing the overall rate of non-cephalic presentations at term. The Early ECV Trial is a multicentred, randomized controlled trial comparing the selective use of ECV beginning at 34 weeks gestation to ECV after 37 weeks. The primary outcome is the rate of non-cephalic presentation at the time of birth. Collaborators in the Early ECV Trial include midwives and obstetricians from Toronto, Scarborough, Mississauga, Calgary, Ottawa, Thunder Bay and Hamilton.

EMERGENT MANAGEMENT OF THE PATIENT IN PRETERM LABOR

Clinicians who treat PTL should realize that side effects rarely occur when tocolytic medications are properly used. The beneficial effects of tocolytic therapy vastly outweigh the risks associated with their use for the prolongation of gestation. Even a short extension of in utero life for a few days or weeks can significantly and positively affect neonatal survival and long-term outcome. Although the opponents of tocolytic therapy argue that no reduction in the PTB rate has occurred since their introduction, this argument does not consider that the large majority of PTBs are not eligible for tocolytic intervention. If patients with clear indications for tocolysis could be compared with those that were not treated (which most studies have not done), a substantial beneficial effect of tocolytic administration probably would be demonstrated. Based on available data, we consider MgSO4 and terbutaline to be first-line tocolytics. Magnesium is used more often because of its lower side-effect profile. Indomethacin and nifedipine should be reserved for difficult or refractory preterm labor, and should only be used for intervals of < or = 48 hours. We have attempted to present a method of decision analysis which should be followed for every patient who is admitted to the obstetric care unit for a presumptive diagnosis of premature labor. We realize that many of the issues included here are controversial, however, we hope that by developing a decision tree (see Fig. 1), a more complete management scheme will be created and lead to improved care of the patient undergoing premature labor.

Hepatotoxicity with the administration of nifedipine for treatment of preterm labor

Nifedipine, a calcium channel blocker, is becoming increasingly popular as a tocolytic medication. Previous reports of hepatitis associated with nifedipine in the medical literature have been published. We present the first case reported of a patient with preterm labor treated with nifedipine who had development of a concurrent elevation in serum liver enzyme levels.