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D espite concerted efforts toward prevention, accurate and p r o m p t diagnosis, and effective t rea tment o f p re t e rm labor, the incidence of p r e t e rm birth has not decreased over the last several decades. In fact, a l though the search for a highly effective, well tolerated tocolytic has been actively pursued, data f rom the United States indicate that the incidence o f p re t e rm birth has actually increased, f rom 9.4% to 10.7% between 1981 and 1989.1 This review will discuss the mechanism o f action o f various tocolytic drugs, some o f the problems inherent to clinical studies o f these agents, and the clinical efficacy and side effects o f commonly used tocolytics such as betaadrenergic agonists, magnesium sulfate, and prostaglandin synthesis inhibitors. Agents that have been less well investigated as tocolytics, including calcium channel blockers, oxytocin recep tor antagonists, and potassium channel stimulators, will also be discussed, but more briefly. P re te rm birth remains the leading cause of perinatal mortali ty and morbidity among nonanomalous infants. In a mult icenter study o f 33,401 neonates, 83% of neonatal deaths occurred in infants born at less than 37 weeks' gestation, and 66% of neonatal deaths occurred in infants born at less than 29 weeks' gestation. 2 However , the neonatal survival rate after 30 weeks' comple ted gestation is more than 90%. Therefore , a t tempts at inhibiting p re t e rm labor between 20 and 29 weeks' gestation are directed at improving the neonatal survival rate and reducing morbidi ty incidence, whereas at tempts at inhibition between 30 and 36 weeks are mainly directed toward reducing neonatal morbidity incidence. 3 In an assessment o f the effect of gestational age on neonatal morbidity, the incidence of respiratory distress was increased until 36 comple ted weeks o f gestation, whereas other

Objective: The purpose of this study was to review the current approaches to preventing preterm delivery. Study Design: The problem of preterm birth was assessed by reviewing the different components that play a role in preterm birth prevention, excluding infection, antibiotic treatment, and tocolytic treatment. Results: Prevention of preterm labor must initially discriminate those at risk. Positive predictive values of various approaches are currently not adequate enough to warrant intervention. Prevention modalities, in part because of poor prediction, are mostly unproved. Accurate diagnoses of preterm labor remains difficult and confuses analyses of tocolytic agents. Cervicovaginal fetal fibronectin, perhaps in combination with cervical evaluation, shows promise. Early detection programs remain controversial, but most reviews indicate that daily patient contact with high-risk patients gives cause for some optimism. Antenatal maternal glucocorticoid treatment at specific gestational ages improves neonatal outcome. Conclusion: The incidence of preterm birth is rising in the country. However, improved definition of the various components of the problem has provided an improved understanding of the problem. There is a new continuing effort and a search for new and innovative ways to address this vexing national problem.

Objectives: This study details the incidence, by gestational age and birth weight, of specific neonatal morbidities in singleton neonates without major congenital anomalies. Study Design: Data were prospectively collected on all deliveries at five tertiary centers in the United States during the years 1983 through 1986. Pregnancies were meticulously dated and the gestational ages of the neonates at delivery were confirmed by Dubowitz score. Results: The incidence of respiratory distress syndrome gradually decreases with increasing gestational age until 36 weeks. A marked decrease in the incidence of necrotizing enterocolitis, patent ductus arteriosus, intraventricular hemorrhage, and sepsis occurs after 32 completed weeks. The number of days of mechanical ventilation for respiratory distress syndrome and newborn stay in the tertiary care facility also were significantly reduced after 32 weeks. Conclusions: The incidence of both respiratory distress syndrome and patent ductus arteriosus is markedly decreased by both increasing gestational age and birth weight. The incidence of grade III and IV intraventricular hemorrhage, necrotizing enterocolitis, and sepsis virtually vanishes after 34 weeks. These data relating neonatal morbidities to gestational age are important to the obstetrician in the critical decision regarding the timing of delivery and to the parents, who can benefit from a realistic prediction of the neonatal course.

Patient and staff education concerning the subtle signs and symptoms that precede a clinical diagnosis of preterm labor have not been well established. Therefore we interviewed 100 patients for the presence or absence of various symptoms and signs during the 7 days preceding diagnosis of preterm labor. An additional 100 patients without preterm labor matched for gestation were chosen at random as control subjects. A history of increased uterine contractions, menstrual cramps, constant backache, constant pelvic pressure, increased amount and consistency and color change of vaginal discharge, and increased frequency of urination were present with a statistically significant higher frequency in patients with preterm labor compared with controls. Twenty-nine percent of patients did not report any uterine contractions and only half described them as painful. Fewer than 50% of the women reported contractions as frequently as every 10 minutes or more.

This analysis was performed to present updated neonatal mortality data by age and birth weight for preterm newborns and to demonstrate the influence of plurality, ethnicity, and infant sex on mortality.Preterm birth weight and gestational age-specific mortality rates were compiled from the five centers that participated in the March of Dimes Multicenter Preterm Birth Prevention Project. In each center gestational age was assessed by standardized methods. A birth weight and gestational age-specific mortality chart for preterm births was created with live-birth data.In each birth weight group mortality decreased as the gestational age advanced; for each gestational age group heavier infants had less mortality. Female infants29 weeks survived better than male infants, and singletons29 weeks survived better than twins. Survival for black preterm newborns was better than that of whites but differences were not significant. Mortality for black term infants was significantly higher. The largest improvement in survival occurred between 25 and 26 weeks. At 30 weeks survival was90% and improved1% per week thereafter.When compared with rates in previous reports, mortality rates appear to have improved, especially at gestational ages29 weeks. These data may be useful in decision-making and in counseling patients at risk for preterm delivery.

We assayed TSH, triiodothyronine, free thyroxine, and prolactin (PRL) in plasma of women and infants participating in a trial of prenatal thyrotropin-releasing hormone (TRH) treatment for prevention of newborn lung disease. Women in labor at 26-34 wk of gestation received 400 micrograms of TRH i.v. every 8 h (one to four doses) plus 12 mg betamethasone (one or two doses); controls received saline plus betamethasone. Mean cord concentrations in control infants were TSH 9.7 mU/L, triiodothyronine 0.6 nmol/L (40.2 ng/dL), free thyroxine 14.4 pmol/L (1.13 ng/dL), and PRL 67.6 micrograms/L. TRH increased maternal plasma TSH by 100% at 2-4 h after treatment and decreased levels by 28-34% at 5-36 h. In cord blood of treated infants delivered at 2-6 h, TSH, triiodothyronine, and PRL were all increased about 2-fold versus control, and free thyroxine was increased 19%; the response was similar after one, two, three, or four doses of TRH. In treated infants delivered at 13-36 h, cord TSH and triiodothyronine levels were decreased 62 and 54%, respectively, and all thyroid hormones were lower after birth at 2 h of age versus control. We conclude that prenatal TRH administration increases thyroid hormones and PRL in preterm fetuses to levels similar to those normally occurring at term. Pituitary-thyroid function is transiently suppressed after treatment to a greater extent in fetus than mother, and infants born during the early phase of suppression do not have the normal postnatal surge in thyroid hormones.

This is a prospective study to determine whether a maternal orally administered azo dye, phenazopyridine hydrochloride, would cross into amniotic fluid, and thus be of potential aid in the diagnosis of rupture of the membranes. Based on anecdotal experience, we hypothesized that this compound would cross the placenta and be excreted in the fetal urine, causing discoloration of the amniotic fluid. Ten patients with uncomplicated pregnancies undergoing elective amniocentesis for obstetric indications received an oral dose of 400 mg of phenazopyridine hydrochloride 4 hours prior to the procedure. Amniotic fluid was also available from five control patients who did not receive phenazopyridine hydrochloride. The typical orange-to-red discoloration of the urine was seen in all study patients, indicating ingestion of the dye. None of the ten patients had evidence of the azo dye in their amniotic fluid by visual inspection or by spectrophotometric absorbance. After the amniotic fluid samples were acidified, the presence of the azo dye was visually demonstrable, and spectrophotometry confirmed measurable concentrations (mean +/- SE: 13.08 +/- 0.72 micrograms/ml). We conclude that although phenazopyridine hydrochloride does cross the placenta into the fetal compartment, its presence causes a visual and spectrophotometric change in the color of amniotic fluid only when the normal basic pH of amniotic fluid is acidified.

The biophysical profile has proved to be a valuable tool for the assessment of fetal well-being, independent of gestational age. Magnesium sulfate is commonly used as a tocolytic agent, yet relatively little is known about its effects on the biophysical activities of the fetus. To investigate the effects of magnesium sulfate on the biophysical profile, we performed serial studies on patients who received tocolytic therapy with this agent because of preterm labor. A total of 16 women with 22 fetuses at 26 to 34 weeks' gestation in spontaneous preterm labor were studied. An initial biophysical profile was performed at the time of admission, and a second examination was performed when maternal serum magnesium levels reached 6 to 8 mg/dl. On admission all fetuses had reactive nonstress test results and 21 of 22 (95%) demonstrated sustained fetal breathing movements. With magnesium sulfate tocolysis, 50% of fetuses had nonreactive nonstress test results, and only 4 of 22 (18%) demonstrated sustained fetal breathing movements. Fetal tone, gross body movements, and amniotic fluid volume were found to be unaffected by magnesium sulfate tocoysis. (Ann J OBSTET GYNECOL 1989;161:771-4.)

A scoring system was used prospectively to screen 7329 patients for risk of preterm labor over a 6-year period. When 15.8% of patients (1156 of 7329) were scored as high risk, sensitivity was 42.4% (multiparas, 55.2%, nulliparas, 29.8%) and positive predictive value was 22.8%. The incidence of preterm labor increased with increasing risk score; gestational age at delivery was negatively correlated with risk score. Analysis of individual factors revealed that more than half were not of predictive value in the population under investigation. A simplification of the system, defining 12 of the factors as major (high risk) and six as minor (2 or more indicates high risk) yielded a high risk group of 14.1%, sensitivity of 41.0%, and positive predictive value of 24.6%. Thus, although risk scoring does predict a substantial proportion of patients with preterm labor, its sensitivity is less than ideal. No advantage was gained with a larger and more complex system. Planning for preterm birth prevention programs should include recognition of the limitations of risk scoring, consideration of simplified systems, and investigation of additional biochemical or biophysical screening methods.

Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.

Recent literature has suggested that total intrauterine volume (TIUV) estimation is useful fir distinguishing normal from growth-retarded fetuses. One hundred seventy-nine measurements of TIUV were obtained from the ultrasonograms taken between 21 and 40 weeks of gestation in 140 patients who delivered average birthweight babies. We constructed a mean curve for TIUV with upper and lower 2.5 and 10% tolerance limits and later evaluated the TIUV's of 16 patients with growth-retarded fetuses. Nine of these fetuses had birthweights below the fifth percentile for gestational age, and in each of these pregnancies the TIUV ultimately fell below the lower 2.5% tolerance limit.

Fifty pregnant women at term, with a cervix unfavorable for induction, were electively induced with intravenous oxytocin after priming with either oral prostaglandin E2 or a placebo. Oral PGE2 was effective in increasing the Bishop score and in inducing labor prior to the induction, but did not increase the incidence of successful inductions.50 pregnant women were included in a double-blind study aimed at determining whether oral prostaglandin E2 (PGE2) can effectively prime an unripe cervix prior to oxytocin induction of labor. Study participants ranged in age from 20-37 years and were 36-41 weeks pregnant. Patients were randomly assigned to receive either PGE2 or a placebo. 2 tablets were administered at 3 hour intervals for 3 doses. Oxytocin infusion began 9-11 hours after the 3rd dose of oral medication and was increased until adequate uterine contractions were induced. No difference in the frequency of contractions was seen in the 2 groups during priming; however, PGE2 patients showed a 2 point advance in Bishop score, which was significantly greater than the 0.7 change in the control group. The most striking finding was that 6 women in the PGE2 group, compared with 1 in the placebo group, went into active labor during the priming phase and delivered without induction. Oxytocin failed to induce effective labor in 9 patients in each group. There was no difference between the 15 control and 10 PGE2 patients successfully induced in terms of duration or dosage of oxytocin. However, the more inducible patients in the PGE2 group may have begun labor before oxytocin induction, rendering the groups less equivalent for the induction part of the study. These results suggest that oral PGE2 priming results in an easier course to delivery, although not in a higher incidence of successful induction. It is recommended that the PGE2-oxytocin induction regimen be studied in patients at various stages of induction, perhaps with an increased dosage of PGE2 or a shorter interval between dosages.

Seventy patients with preterm labor and intact membranes were initially treated with ritodrine hydrochloride to delay preterm delivery. Tocolysis beyond 24 hours was achieved in 59 patients. Fifty-five of the 59 patients were then placed on either oral ritodrine or placebo as maintenance therapy in a randomized double-blind manner. If preterm labor recurred, the sequence of intramuscular and then oral treatment was repeated. The number of days gained after initiation of intramuscular treatment was similar in both groups (oral ritodrine = 34 days, oral placebo = 36 days). In those 55 patients receiving oral treatment, there was a smaller number of relapses requiring repeat intramuscular treatment in the oral ritodrine group (1.11 in the ritodrine patient vs. 2.71 in the placebo patient, p less than 0.05), and the mean interval between beginning oral treatment and the first relapse/delivery was 5.8 days in the oral placebo group and 25.9 in those receiving oral ritodrine (p less than 0.05). Cardiovascular side effects, notably maternal tachycardia and palpitations were frequent but well tolerated. The results suggest that oral ritodrine maintenance will decrease the incidence of recurrent preterm labor in patients who have had initial successful tocolysis.

With recent advances in neonatal medicine, the risk of mortality for premature newborns has been markedly reduced. Attention has shifted to the morbidity associated with preterm delivery. Consideration of anticipated neonatal morbidity at a particular gestational age plays an important part in the decision of whether or not to treat preterm labor. We have assessed eight indices of short-term morbidity in 170 liveborn infants delivered between 26 and 35 completed weeks of gestation and calculated the gestational age-specific rates of each measure of morbidity. Five measures of short-term morbidity were significantly reduced by extending the gestation from 34 to 35 weeks. To illustrate the effect of prolonged pregnancy on the incidence of short-term neonatal morbidity, the actual incidence of morbidity from a group of preterm labor patients who were part of a preterm birth prevention program was compared to the anticipated incidence of these same morbidity factors has birth occurred when preterm labor was first diagnosed. There was a significant decrease in the number of observed, as opposed to anticipated, neonatal deaths and in morbidity occurrences in four of the six factors tested. Implications for considering short-term neonatal morbidity in the decision to initiate treatment for preterm labor after 33 weeks gestation are discussed.

Preterm labor and delivery remain a significant problem in contemporary obstetric practice. Although the exact cause remains unclear, it is most likely to be multifactorial in nature. No satisfactory screening tool or marker currently exists to firmly establish the diagnosis of impending labor. However, epidemiologic and historical variables associated with preterm delivery show some promise in this regard and are currently being evaluated in preterm prevention programs. Appropriate management of preterm labor mandates early recognition of subtle signs and symptoms; successful therapy is dependent on this issue. The approach to the clinical management of the patient in preterm labor used at our institution is described. Therapy with beta-adrenergic receptor agonists is currently the recommended pharmacologic treatment of this disorder. A review of other tocolytic agents and their usefulness in the management of preterm labor are presented.

Perinatal deaths can be decreased most effectively by reducing the incidence of preterm delivery. Therapy with a tocolytic agent, such as ritodrine ( Yutopar ), can be of significant benefit if applied to patients in whom preterm labor is correctly diagnosed and has not advanced beyond the early stages. Identification of the patient at risk, intensive education and surveillance of such patients, and education of hospital and clinic staff can extend the application and success of labor-inhibiting therapy.

Between 1986 and 1988, 1924 term nulliparous patients with spontaneous onset of labor were studied to assess the importance of obtaining umbilical cord blood gas levels on all deliveries. The umbilical cord arterial and venous pH values (expressed as mean +/- 2 SD) were 7.24 +/- 0.14 (n = 1694) and 7.32 +/- 0.12 (n = 1820), respectively. The incidence of newborn depression (1- or 5-minute Apgar score less than 7) was 14.1%; of these depressed newborns, the incidence of normal umbilical cord arterial pH values (greater than or equal to -2 SD) was 77.8%. Of the vigorous newborns, there was a 2.1% incidence of umbilical cord arterial blood acidemia. Umbilical cord arterial blood acidemia in vigorous newborns was not highly predictive of specific morbidity in the immediate newborn period. Regression analysis demonstrated the umbilical cord arterial pH to correlate best with the Apgar scores when compared with all other arterial or venous blood gas measurements. We reached the following conclusions: (1) that obtaining cord arterial pH values in vigorous newborns should be considered since the values will provide objective documentation or normal fetal acid base balance in 98% of infants. (2) Only a cord arterial pH determination is recommended since it reflects fetal or newborn status more accurately than all other measurements. Additional measurements increase the likelihood of abnormal results and do not contribute to neonatal management. (3) An umbilical cord blood pH value is extremely useful in ruling out the diagnosis of birth asphyxia in the depressed newborn.

Chromosome analysis of amniotic fluid cells and amniotic fluid alpha-fetoprotein determinations were used to investigate a fetus with severe intrauterine growth retardation in the third trimester. The karyotype was 47,XY,18+ and increased alpha-fetoprotein levels indicated the presence of congenital malformations. We suggest that when severe fetal growth retardation is detected early in the antepartum course, amniotic fluid alpha-fetoprotein and amniotic fluid cell chromosome studies be done to determine if congenital anomalies may be an etiological factor.

To assess the relative diagnostic efficacy of the "1 cm sign" for qualitative amniotic fluid volume determination in the prenatal evaluation of intrauterine growth retardation, 125 pregnancies resulting in small-for-gestational age infants were studied in a retrospective fashion. Qualitative amniotic fluid volume was designated as normal if at least one pocket of amniotic fluid measuring 1 cm in broadest diameter was identified. Of the 125 pregnancies with delivery of small-for-gestational age infants, only five would have been correctly predicted prenatally with qualitative amniotic fluid volume used as the sole criterion for intrauterine growth retardation. When this criterion was applied to a defined subset of 52 of these patients with last scans 0 to 15 days prior to delivery, only four cases would have been accurately predicted as having intrauterine growth retardation.

CONCENITALATRIOVENTRICULARBLOCK (CAVB) is a rare cause of fetal bradycardia. If mistaken for fetal distress, it may lead to inappropriate obstetric intervention and delivery of a premature infant. In this report we present two infants with CAVB. The diagnosis in one was made only following emergency delivery for suspected fetal distress. The second was diagnosed antepartum and the fetus was monitored in utero for some weeks prior to delivery. Both cases occurred in mothers with systemic lupus erythematosus (SLE).

The efficacy of regular cervical examinations in detecting preterm labor, as well as possible risks, was studied for 133 preterm labor patients who had received regular cervical examinations as part of a preterm birth prevention program. When compared to all other patients experiencing preterm labor during the study period, the rates of preterm premature rupture of the membranes, chorioamnionitis, and postpartum endomyometritis were not increased. For 95 patients with preterm labor within 7 days of a routine cervical examination, labor onset was not temporally associated with the preceding examination. Preterm labor was diagnosed in 18 asymptomatic patients (18.2%) when the weekly examination revealed cervical change. Routine cervical exams, therefore, did not increase morbidity, and for some patients identified preterm labor before symptoms appeared.

Previous studies suggest that plasma estradiol-17 beta and progesterone concentration values differ between patients who deliver before term and those who deliver at term. To determine if these values would aid in preterm delivery risk prediction, we measured plasma estradiol-17 beta and progesterone concentrations serially in 90 patients at high risk for preterm delivery. Measurements from 17 patients who developed documented preterm labor and/or were delivered before term were compared to the tenth and ninetieth percentiles of 42 patients who were delivered at term. The sensitivity of these measurements to predict preterm delivery was very low. Also, the mean plasma estradiol-17 beta and progesterone concentrations in patients with preterm labor who had term deliveries and in patients with preterm labor that progressed to preterm delivery were not different from each other or from patients delivering at term. No change in plasma estradiol-17 beta or progesterone concentration was noted preceding labor. We conclude that serial measurements of plasma estradiol-17 beta and progesterone concentrations do not improve preterm delivery risk prediction.

A retrospective study of 343 women treated with isoxsuprine and/or terbutaline for preterm labor (PTL) was performed to determine the incidence and nature of maternal morbidity which is associated with this treatment. The incidence of mild cardiovascular (CV), neurological and gastrointestinal side effects was similar with both medications. The incidence, however, of severe CV complications such as pulmonary edema and myocardial ischemia was higher among women treated with i.v. terbutaline (5.3%) than among those treated with isoxsuprine (0.8%, P less than 0.05). Patients with multiple gestations on i.v. terbutaline therapy had an exceptionally high incidence of severe CV complications (43%), while none of the twin pregnancies on i.v. isoxsuprine had such complications. Corticosteroid treatment was not associated with a significant increase of complications with either tocolytic medication. Both medications had similar success in inhibiting PTL.

To determine the association between levels of major basic protein and onset of preterm labor, plasma levels of major basic protein were measured in 13 women from weeks 22 to 41 of gestation. Twelve of the 13 women studied experienced spontaneous onset of labor. All of these women demonstrated a late rise in serum levels of major basic protein characterized by an increase in concentration of 156% ± 14%. A temporal association between a rise in concentrations of major basic protein and the onset of preterm labor, which was successfully treated with tocolytic agents, was observed in three patients. Increases in major basic protein began 3 to 4 weeks before delivery. The rise in levels of major basic protein was absent in one patient who was delivered of her infant at 30 weeks' gestation after induction of labor with oxytocin. Analysis of these data indicate that a protein marker is associated with the onset of human labor not only at term but also preterm.

It is now well recognized that a priming agent without untoward effects on mother or fetus is highly desirable when an indicated induction is required in the face of an unripe cervix. There appears to be a potential role for Laminaria, estrogens, relaxin, and various forms and routes of administration of prostaglandins because efficacy has been reported with all of these methods. With careful selection of patients and judicious fetal monitoring, there are multiple reasonable modes available, although an ideal priming agent has not yet emerged.

A rapid, simple inexpensive test has been devised to determine whether pulmonary surface-active material (surfactant) is present in amniotic fluid. The test depends on the ability of the pulmonary surfactant to generate stable foam in the presence of ethanol. Analysis of 138 samples of amniotic fluid showed that an appreciable titer of the surfactant appears on the average at 33 weeks' estimated gestation but that the time of appearance is variable from 25 weeks to term. When test results were sorted into three zones (clearly negative, intermediate, and clearly positive) infants of 12 of 12 patients with clearly negative tests had severe respiratory-distress syndrome or transitional respiratory distress, whereas those of 68 of 68 patients with clearly positive tests were free of respiratory distress. In 13 cases with intermediate tests eight of the infants showed mild to severe respiratory difficulty. The test has high predictive value for respiratory-distress syndrome when applied to uncontamina...

A prospective, interinstitutional comparative trial was undertaken to examine the efficacy, safety, and pharmacodynamics of different administration routes of ritodrine hydrochloride for the management of preterm labor. Forty-five subjects between 20 and 36 weeks' gestation received either intravenous (n = 24) or intramuscular (n = 21) therapy. Successful tocolysis occurred in 14 of 21 (67%) patients in the group treated intramuscularly and in 16 of 24 (67%) patients in the group treated intravenously. A greater mean dose (8.6 versus 3.3 mg/hour) and a higher mean serum concentration (38.9 versus 24.7 micrograms/ml) were needed to achieve successful tocolysis in the intravenous group as compared with the intramuscular group. Patients who did not respond to tocolytic therapy in both groups had levels of ritodrine in the blood either equivalent to or greater than those of subjects who were successfully treated. Analysis of ritodrine levels in the successfully treated intramuscular group demonstrated significant differences in blood levels depending on muscle group used. These differences can be at least partially attributed to higher mean doses administered to patients receiving vastus lateralis injections as compared with those receiving gluteal muscle injections. The results suggest that intramuscular administration of ritodrine is an efficacious and safe route of drug delivery. Additional studies are needed to better define dose-response curves for the intramuscular administration of ritodrine hydrochloride.