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Pharmacologic inhibition of preterm labor.

Preterm labor is responsible for a majority of cases of perinatal morbidity and deaths. Prevention of preterm labor is not usually possible; thus pharmacologic treatment is the only recourse available. Numerous agents have been used to treat preterm labor, but none has proved to be superior. This report reviews the current information available about the pharmacology of labor-inhibiting drugs and discusses the clinical approach to the management of preterm labor.

Adrenergic beta-Agonists

Induction of preterm labor in the rat by antiprogesterone.

The validity of a new concept, predicting that preterm labor can be induced without oxytocic stimulation by a regulatory imbalance, generated by antiprogesterone (A-P)-provoked P withdrawal (Pw), has been examined in the rat model. At day 19 of pregnancy a single oral dose of the steroidal A-O isoxazol, which inhibits P synthesis, significantly reduced uterine P levels, increased uterine estradiol and prostaglandin F levels, and induced preterm labor. This precocious regulatory imbalance and preterm labor were prevented, by blocking the A-P-induced Pw with P treatment. The regulatory imbalance which triggered the onset of spontaneous labor in the control animals was similar, but it occurred at term rather than before term. The potential of this method in improving the management of medically indicated induction of preterm labor is discussed.

Administration, Oral

Contemporary management and conduct of preterm labor and delivery: a review.

Current concepts in the conduct of preterm labor and management of delivery of the premature infant are reviewed. Pharmacologic modalities available for inhibiting preterm labor are discussed as well as the efficacy, indications and contraindications for these agents. An analysis of the role of corticosteroids in achieving fetal pulmonary maturity in the preterm infant is reviewed, and based on the existent literature the intrapartum management of the small fetus is outlined. The mode of delivery, vaginal or via cesarean section, for these infants is likewise discussed.

Adrenal Cortex Hormones

Plasma concentrations of prostaglandins during late human pregnancy: influence of normal and preterm labor.

Highly sensitive and specific RIA procedures have been used to measure prostaglandin concentrations in the peripheral circulation of late pregnant and parturient women. The concentrations of prostaglandin E (PGE) and prostaglandin F (PGF) in plasma samples assayed within 4 weeks of collection were not significantly different among the groups studied, the levels (mean +/- SEM, picograms per ml) were: late pregnancy (n = 13): PGE, 4.8 +/- 1.0; PGF, 6.2 +/- 0.5; early term labor (n = 5): PGE, 6.8 +/- 1.5; PGF, 7.9 +/- 0.7; late term labor (n = 5): PGE, 5.4 +/- 2.2; PGF, 12.4 +/- 3.5; and preterm labor (n = 7): PGE, 4.4 +/- 0.4; PGF, 6.9 +/- 1.4. The concentration of 13,14-dihydro-15-keto-prostaglandin F (PGFM) in late pregnancy was 59.0 +/- 7.8 pg/ml. During spontaneous term labor, the concentration of PGFM was significantly elevated (P less than 0.01) to 142.8 +/- 32.3 pg/ml in early labor and 282.7 +/- 55.3 pg/ml in late labor. The concentration of PGFM in plasma from patients in preterm labor (62.7 +/- 17.4 pg/ml) was not significantly different from that found during late pregnancy, but was significantly lower than levels found at term during early labor (P less than 0.05). The concentration of PGE increased significantly in frozen plasma samples stored for more than 4 weeks in all groups studied; the concentration of PGF was significantly elevated after storage only in the late pregnancy group (P less than 0.01). The plasma concentration of PGFM in all groups studied was unaffected by storage. It is concluded that measurement of PGFM concentrations is the most reliable method available of monitoring prostaglandins in the peripheral circulation and that great care must be exercised in the assay and interpretation of prostaglandin levels in human plasma.

Female

Alcohol, indomethacin, and salbutamol. A comparative trial of their use in preterm labor.

In a comparative trial, ethanol effectively arrested preterm labor for 48 hours for more in 32% of cases, a beta-adrenergic agent (salbutamol) in 60% of cases (not statistically significant), and a combination of ethanol and indomethacin in 70% of cases (statistically significant, P less than 0.5). Labor was delayed for 14 days or more in 36, 60, and 50%, respectively (not statistically significant). The numbers studied were small, and tests of statistical significance were of doubtful value. Salbutamol was more acceptable to patients and the staff than ethanol. The trial was suspended and eventually abandoned due to reports of prostaglandin synthetase inhibitors causing premature closure of the ductus arteriosus. In this series no problems were encountered with the use of indomethacin.

Albuterol

Effect of flufenamic acid on uterine contractions and plasma levels of 15-keto-13,14-dihydroprostaglandin F2alpha in preterm labor.

Flufenamic acid (FA), an inhibitor of the synthesis and action of prostaglandins, was administered to 18 women with preterm labor during the 28th to 36th week of gestation. In 15 patients delivery postponed, the mean admission/delivery interval being 21.5 days. 2 patients with cervical dilatation of 4 cm delivered within 48 h despite medication. The peripheral plasma levels of 15-keto-13,14-dihydroprostaglandin F2alpha (KH2 PG2alpha) was high on admission (216 +/- i4 pg/ml, mean +/- SEM), declined by 50% within 2 h of instituting treatment and remained near the normal level seen in 13 controlled women after the 24th hour.

Adult

Plasma estradiol as a predictor of preterm labor.

Studies have shown a rapid rise of plasma estradiol-17beta in the maternal circulation before the occurrence of preterm labor. We have attempted to perform a linear regression analysis of the data from normal pregnancies and to set up a 95% upper prediction limit for the normal range of the estradiol level for each week of gestation. The prediction limits were reasonably good, with only five (13%) false negatives. False negatives tend to occur only in late pregnancy.

Estradiol

A study of indomethacin combined with ritodrine in threatened preterm labor.

A prospective and double-blind study was undertaken to compare the effectiveness of two different treatments on two randomized groups of patients with threatened preterm labor. The first treatment consisted of the administration of ritodrine and a placebo; in the second, ritodrine was combined with indomethacin. 22 patients were evaluated in each group. The results obtained for gain in days, number of patients delivered at term, weight of newborns and number of recurrences in each group suggest that treatment with ritodrine and indomethacin is slightly but significantly more effective than treatment with ritodrine and placebo in prolonging pregnancy. No evidence has been found of possible unfavorable vascular effects of indomethacin in the fetus or the newborn.

Adult

Whole-genome sequencing-based phylogeny, antibiotic resistance, and invasive phenotype of Escherichia coli strains colonizing the cervix of women in preterm labor.

BACKGROUND: Escherichia coli is a major neonatal pathogen and the leading cause of early-onset sepsis in preterm newborns. Maternal E. coli strains are transmitted to the newborn causing invasive neonatal disease. However, there is a lack of data regarding the phenotypic and genotypic characterization of E. coli strains colonizing pregnant women during labor. METHODS: This prospective study performed at the University of Oklahoma Medical Center (OUHSC) from March 2014 to December 2015, aimed to investigate the colonization rate, and the phylogeny, antibiotic resistance traits, and invasive properties of E. coli strains colonizing the cervix of fifty pregnant women diagnosed with preterm labor (PTL). Molecular analyses including bacterial whole-genome sequencing (WGS), were performed to examine phylogenetic relationships among the colonizing strains and compare them with WGS data of representative invasive neonatal E. coli isolates. Phenotypic and genotypic antibiotic resistance traits were investigated. The bacteria's ability to invade epithelial cells in vitro was determined. RESULTS: We recruited fifty women in PTL. Cervical samples yielded E. coli in 12 % (n=6). The mean gestational age was 32.5 (SD±3.19) weeks. None delivered an infant with E. coli disease. Phenotypic and genotypic antibiotic resistance testing did not overall demonstrate extensive drug resistance traits among the cervical E. coli isolates, however, one isolate was multi-drug resistant. The isolates belonged to five different phylogroups, and WGS analyses assigned each to individual multi-locus sequence types. Single nucleotide polymorphism-based comparisons of cervical E. coli strains with six representative neonatal E. coli bacteremia isolates demonstrated that only half of the cervical E. coli isolates were phylogenetically related to these neonatal invasive strains. Moreover, WGS comparisons showed that each cervical E. coli isolate had distinct genomic regions that were not shared with neonatal E. coli isolates. Cervical and neonatal E. coli isolates that were most closely related at the phylogenetic level had similar invasion capacity into intestinal epithelial cells. In contrast, phylogenetically dissimilar cervical E. coli strains were the least invasive among all isolates. CONCLUSIONS: This pilot study showed that a minority of women in PTL were colonized in the cervix with E. coli, and colonizing strains were not phylogenetically uniformly representative of E. coli strains that commonly cause invasive disease in newborns. Larger studies are needed to determine the molecular characteristics of E. coli strains colonizing pregnant women associated with an increased risk of neonatal septicemia.

Adult

Intra-amniotic infection: diagnosis, nomenclature, clinical significance, management, and microbiologic tools used for the diagnosis.

SUMMARYIntra-amniotic infection is the main cause of spontaneous preterm birth and adverse maternal-fetal outcomes; therefore, rapid, robust, and accurate diagnosis remains a clinical priority. Conventional microbiological techniques, especially culture-based methods, are limited by long turnaround times and the inability to detect fastidious or unculturable organisms. This review summarizes the diagnosis, nomenclature, clinical significance, management, and laboratory approaches for diagnosing intra-amniotic infection. Targeted nucleic acid amplification methods, including species-specific polymerase chain reaction and broad-range 16S rRNA gene sequencing, have improved the detection of bacterial DNA and enabled the identification of organisms that evade routine culture in intra-amniotic infection. More recently, whole-genome sequencing and metagenomic next-generation sequencing have provided culture-independent strategies for comprehensive pathogen profiling, allowing simultaneous detection of bacteria, viruses, and fungi, as well as characterization of antimicrobial resistance determinants and virulence-associated genes. However, challenges remain, particularly in low-biomass samples such as amniotic fluid, where contamination, host DNA background, and data interpretation can compromise specificity. This review critically evaluates the advantages and limitations of each molecular modality and discusses pre-analytical, analytical, and bioinformatic considerations essential for reliable implementation. Integration of molecular diagnostics into clinical workflows holds promise for improving etiological diagnosis and guiding targeted therapy in intra-amniotic infection, thereby improving maternal and fetal outcomes.

Humans

Effect of prophylactic outpatient administration of fenoterol on the time of onset of spontaneous labor and fetal growth rate in twin pregnancy.

A double-blind trial was conducted on outpatients with twin gestations to assess the effect of prophylactic administration of fenoterol on the fetal growth rate and the timing of the spontaneous onset of labor. No significant differences could be shown between the fenoterol-treated group of patients and the control group given a placebo. It is concluded that prophylactic administration of fenoterol does not have a significant effect upon the incidence of preterm labor or growth retardation in twin pregnancy.

Clinical Trials as Topic

High-risk prematurity--progestin treatment and steroid studies.

Studies have been undertaken regarding the efficacy and modus operandi of 17 alpha-hydroxyprogesterone caproate (17 alpha-OHP-C) in preventing premature labor in high-risk patients. In a total of 70 patients, the treated patient population had a prematurity rate (12.8%) and a perinatal mortality rate (5%) which were significantly lower than those of the total placebo or untreated patient group (40.9 and 25%, respectively). In addition, sequential plasma steroid values were determined in 21 patients, 10 of whom delivered prematurely. The results indicate that low plasma progesterone (P) and 17 alpha-hydroxyprogesterone (17 alpha-OHP) levels precede the onset of preterm labor by weeks. Successful treatment with 17 alpha-OHP-C was characterized by elevated P levels. Plasma estradiol (E2) and cortisol (C) values did not vary with time of delivery or treatment. These findings support the progesterone block theory as an important mechanism affecting preterm delivery in this high-risk population.

Estradiol

Perinatal hazards of chronic antenatal tocolysis with indomethacin.

Indomethacin was administered from the 20th to the 34th week of gestation to 51 women (59 fetuses) in whom bed rest and a beta-mimetic compound (ritodrine) had failed to stop preterm labor. No serious maternal side effects were observed. Of the 8 perinatal deaths, 5 were not and 3 were possibly related to the prostaglandin synthesis inhibitor. The sole case of serious neonatal morbidity is not considered to have had a causal relationship with the indomethacin treatment.

Adult

Effects of ritodrine and isoxsuprine with and without dexamethasone during late pregnancy.

beta-Adrenergic agents are used to inhibit preterm labor and glucocorticoids to accelerate fetal pulmonary maturation. A study was designed to investigate the metabolic effects of intravenous infusion of ritodrine (150 to 100 microgram/min) or isoxsuprine (200 to 150 microgram/min) in a series of 28 patients with gestations of 28 to 40 weeks, with and without concomitant dexamethasone therapy. Ritodrine was more potent than isoxsuprine in increasing the circulating levels of cyclic AMP, glucose, insulin, and triglycerides. The diabetogenic effect of both ritodrine and isoxsuprine was so slight that it did not have any clinical significance in women with normal glucose tolerance. The results were similar when these beta-adrenergic tocolytics were given to women concomitantly with intramuscular dexamethasone therapy, although dexamethasone appeared to minimally impair carbohydrate metabolism. Both ritodrine and isoxsuprine caused a significant fall in serum iron and potassium, and this effect was unaltered by dexamethasone. Serial serum potassium levels should be obtained during long-term infusion of beta-mimetics.

Adolescent

Tracheal fluid in fetal lambs: spontaneous decrease prior to birth.

We studied tracheal fluid (TF) production in 14 fetal lambs: 6 controls, 6 receiving atropine on 1 or more of the last 7 days before birth, and 2 with bilateral section of the cervical vagosympathetic trunk. A cannula diverted all TF into an intrauterine bag; we collected TF intermittently and measured its volume. All ewes delivered spontaneously at 128-150 days' gestation. TF production decreased before birth in all fetuses except one control. TF production decreased before birth in all fetuses except one control. TF production did not correlate with fetal arterial blood gas tensions, hematocrit, or plasma proteins. In controls only, TF production correlated with fetal arterial pH (P less than 0.02); however, the pH range was small and the correlation has questionable physiological significance. For all fetuses, TF production during the 7 days before birth correlated inversely with the plasma cortisol concentration of 48 h previously (n = 36; r = -0.603; P less than 0.001). We conclude a) TF production in fetal lambs decreases before spontaneous term or preterm labor; b) this decrease is not affected by atropine or by section of the cervical vagosympathetic trunk; and c) the decrease in TF production may be related to increased secretion of cortisol.

Animals

Effects of intravenous isoxsuprine and ritodrine, with and without concomitant dexamethasone, on fetoplacental and pituitary hormones and cyclic adenosine monophosphate during late pregnancy.

Beta sympathomimetic drugs are used to inhibit preterm labor and glucocorticoids to accelerate fetal pulmonary maturation. A study was designed to investigate the hormonal effects of intravenous infusion of isoxsuprine 150 to 200 mcg. per minute or ritodrine 100 to 150 mcg. per minute in a series of 28 women at 28 to 40 weeks' gestation, with and without concomitant dexamethasone therapy. Serial serum samples taken before and during the six hours of infusion were assayed for cyclic adenosine-3,5-monophosphate (AMP), estradiol, estriol, progesterone, human placental lactogen (hPL), thyrotropin (TSH), follicle-stimulating hormone (FSH), and human growth hormone (gGH). Ritodrine was more potent than isoxsuprine in increasing the circulating levels of cyclic AMP. The levels of placental steroid hormones decreased slightly, as did the ratio of progesterone to estradiol. Human placental lactogen and pituitary hormones showed no consistent changes. Simultaneous administration of dexamethasone did not modify these results.

Adult