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Biomolecules Jun 2023Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The... (Review)
Review
Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the β2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that β2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by β2 receptors is unable to provide meaningful tocolysis. The failure of β2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The β3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of β2 agonists as tocolytics and suggests a non-canonical signaling role for β3AR in myometrium. The addition of the β3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to β3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Myometrium; Tocolytic Agents; Premature Birth; Nitric Oxide; Endothelial Cells; Obstetric Labor, Premature; Cyclic AMP-Dependent Protein Kinases; Receptors, Adrenergic
PubMed: 37371585
DOI: 10.3390/biom13061005 -
The Cochrane Database of Systematic... Feb 2014Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. Betamimetics are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. Betamimetics are tocolytic agents that have been widely used, especially in resource-poor countries.
OBJECTIVES
To assess the effects of betamimetics given to women with preterm labour.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2013) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised controlled trials of betamimetics, administered by any route or any dose, in the treatment of women in preterm labour where betamimetics were compared with other betamimetics, placebo or no treatment.
DATA COLLECTION AND ANALYSIS
Two review authors assessed risk of bias and extracted the data independently.
MAIN RESULTS
Twenty-eight trials were assessed as eligible for inclusion in the review, but eight did not report any outcome data relevant to the review. Results are based on the 20 trials that contributed data.Twelve trials, involving 1367 women, compared betamimetics with placebo. Betamimetics decreased the number of women in preterm labour giving birth within 48 hours (average risk ratio (RR) 0.68, 95% confidence interval (CI) 0.53 to 0.88, 10 trials, 1209 women). There was a decrease in the number of births within seven days (average RR 0.80; 95% CI 0.65 to 0.98, five trials, 911 women) but there was no evidence of a reduction in preterm birth (before 37 weeks' gestation) (RR 0.95; 95% CI 0.88 to 1.03, 10 trials, 1212 women). No benefit was demonstrated for betamimetics for perinatal death (RR 0.84; 95% CI 0.46 to 1.55, 11 trials, 1332 infants), or neonatal death (RR 0.90; 95% CI 0.27 to 3.00, six trials, 1174 infants). No significant effect was demonstrated for respiratory distress syndrome (RR 0.87; 95% CI 0.71 to 1.08, eight trials, 1239 infants). A few trials reported on cerebral palsy, infant death and necrotising enterocolitis; no significant differences between groups were identified for any of these outcomes. Betamimetics were significantly associated with the following outcomes: withdrawal from treatment due to adverse effects; maternal chest pain; dyspnoea; palpitation; tremor; headaches; hypokalaemia; hyperglycaemia; nausea or vomiting; nasal stuffiness; and fetal tachycardia.Nine trials compared different types of betamimetics. Other betamimetics were compared with ritodrine in five trials (n = 948). Other comparisons were examined in single trials: hexoprenaline compared with salbutamol (n = 140), slow versus moderate release salbutamol (n = 52) and salbutamol compared with terbutaline (n = 200). Trials were small, varied, and of insufficient quality to delineate any consistent patterns of effect.
AUTHORS' CONCLUSIONS
Betamimetics help to delay birth, which may give time to allow women to be transferred to tertiary care or to complete a course of antenatal corticosteroids. However, multiple adverse effects must be considered. The data are too few to support the use of any particular betamimetic.
Topics: Adrenergic beta-Agonists; Female; Fenoterol; Hexoprenaline; Humans; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Ritodrine; Terbutaline; Tocolytic Agents
PubMed: 24500892
DOI: 10.1002/14651858.CD004352.pub3 -
Scientific Reports May 2020Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm...
Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32-36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09-2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21-3.01]) and with concomitant usage of ritodrine and MgSO (aOR 2.59 [CI 2.13-3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia.
Topics: Adult; Drug Synergism; Female; Humans; Hyperkalemia; Hypoglycemia; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Japan; Magnesium Sulfate; Obstetric Labor, Premature; Pregnancy; Risk Factors; Ritodrine
PubMed: 32385354
DOI: 10.1038/s41598-020-64687-w -
Case Reports in Obstetrics and... 2020Ritodrine hydrochloride is used for preterm labor, although serious side effects, including agranulocytosis, are reported. We report a case of ritodrine...
Ritodrine hydrochloride is used for preterm labor, although serious side effects, including agranulocytosis, are reported. We report a case of ritodrine hydrochloride-induced agranulocytosis accompanied by bacteremia due to catheter infection. At 24 weeks of gestation, a female patient presented due to threatened premature labor and was administered continuous intravenous infusion of ritodrine hydrochloride. On day 36 after starting intravenous ritodrine hydrochloride, she was diagnosed with agranulocytosis. The white blood cell and granulocyte count nadirs were 1,660/l and 438/l. The cumulative dose of ritodrine hydrochloride was 2,610 mg. Ritodrine therapy was immediately stopped, and she was given an intravenous injection of antibiotics and granulocyte colony-stimulating factor. From her blood culture, methicillin-sensitive was detected. However, she started vaginal delivery two days after we stopped the ritodrine infusion. When using ritodrine hydrochloride, it is necessary to frequently check the white blood cell count, regardless of the total dose and treatment period.
PubMed: 32832175
DOI: 10.1155/2020/5846161 -
Taiwanese Journal of Obstetrics &... Sep 2023To evaluate the safety and efficacy of atosiban and ritodrine in pregnant women who were hospitalized for threatened preterm labor (TPL).
A multicenter, retrospective comparison of pregnancy outcomes between groups of preterm labor nulliparous mothers treated with atosiban vs. ritodrine in singleton and multiple pregnancies.
OBJECTIVE
To evaluate the safety and efficacy of atosiban and ritodrine in pregnant women who were hospitalized for threatened preterm labor (TPL).
MATERIALS AND METHODS
Diagnosis records of preterm labor and subsequent pregnancy-related records and medical records of newborns were extracted from the Clinical Data Warehouse of the Catholic Medical Center's affiliated hospital. Since 2009, cases of preterm labor diagnosed before 34 weeks of pregnancy for first-time mothers who delivered at any one of three hospitals and who received drug treatment for more than 2 days to delay delivery were included in the dataset. Based on characteristics of Korea's national health insurance system, the drug treatment after diagnosis of preterm labor could be classified into cases using only ritodrine (571 women), cases using only atosiban (244 women), and cases where ritodrine treatment was started and then changed to atosiban (275 women). Demographic factors, obstetric outcomes, neonatal outcomes of the two groups were analyzed.
RESULTS
The duration and maintenance of pregnancy were found to be similar between the two groups, although the initial cervical length was significantly shorter in the atosiban cohort (AC). Only in multifetal pregnancies, the maintenance of pregnancy was significantly longer in the AC. The total duration of pregnancy did not show any significant difference between the two groups regardless of singleton or multiple pregnancy. However, the distribution graph showed non-responders in the ritodrine cohort (RC). Our study showed a difference in neonatal birth weight of singleton between the two groups. The length of hospitalization and the NICU admission rate were also significantly higher in the RC for singleton. Although not significant, the proportion of numbers with an Apgar score less than 7 was higher in the RC. Neonatal death was more common in the RG (8 cases in AC and 18 cases in RC).
CONCLUSIONS
Using atosiban for TPL is more effective than using ritodrine for maintaining pregnancy in the case of a multifetal pregnancy. In singleton pregnancies, neonatal outcomes of the atosiban group were superior to those of the ritodrine group. There seems to be a non-responder group when using ritodrine for TPL. Further studies are needed to determine causes of non-responders of ritodrine and effects of ritodrine on the fetus.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Ritodrine; Mothers; Pregnancy Outcome; Retrospective Studies; Pregnancy, Multiple; Obstetric Labor, Premature
PubMed: 37678995
DOI: 10.1016/j.tjog.2023.07.009 -
Journal of the Turkish German... 2015The aim of this study was to investigate and compare the effects of nifedipine and ritodrine treatment on fetomaternal blood flow parameters in women with preterm labor.
OBJECTIVE
The aim of this study was to investigate and compare the effects of nifedipine and ritodrine treatment on fetomaternal blood flow parameters in women with preterm labor.
MATERIAL AND METHODS
Sixty women with gestational age between 24 and 36 weeks admitted to the obstetrics clinic for preterm labor were enrolled in this study. Patients were randomly assigned to receive either nifedipine (n=30) or ritodrine (n=30) treatment. Demographic features, clinic and laboratory parameters, fetal and maternal side effects, and Doppler ultrasound indices of the umbilical artery (UA), uterine arteries (UtA), and middle cerebral artery (MCA) before, 2 hours after, and 48 hours after the initiation of tocolytic treatments were compared between the two groups.
RESULTS
In both the groups, early- and late-onset changes in the pulsatility index (PI) and other Doppler indices for UA, UtA, and MCA were similar. In addition, time elapsed till delivery, fetal mortality, and maternal morbidity in both the groups were not statistically significant (p>0.05). However, maternal side effects such as tachycardia was more frequent (p<0.05) in the ritodrine group. Besides, in the ritodrine group, anxiety was only minimally observed.
CONCLUSION
Nifedipine and ritodrine used as tocolytic agents did not significantly alter early- and late-onset changes in Doppler ultrasonography parameters in fetal and fetomaternal circulation.
PubMed: 26097389
DOI: 10.5152/jtgga.2015.15156 -
Kidney International Jun 1997The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed blood and urine samples were obtained for two hours before and during six hours of intravenous ritodrine (N = 5) and terbutaline (N = 5) administered in pharmacologically equivalent doses. No differences were found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9 mEq/liter occurred after 30 minutes of drug infusion (4.2 +/- 0.1 to 3.3 +/- 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose (75.0 +/- 4.7 to 93.7 +/- 6.1 mg/dl, P = NS) or plasma insulin (12.4 +/- 6.0 to 28.4 +/- 5.1 mU/ml, P = NS). The mean plasma potassium after four hours of drug infusion was 2.5 +/- 0.1 mEq/liter. Plasma insulin rose to a level known to induce cellular potassium uptake (39.2 +/- 7.7 mU/ml) after 60 minutes of drug therapy and remained at this level for four hours. Hyperlactatemia occurred at four hours (4.7 +/- 0.8 mmol/liter) and the plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugs significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinary flow rate. Changes in acid-base homeostasis, plasma aldosterone, or renal potassium excretion did not contribute to ritodrine-or terbutaline-induced hypokalemia. In 83 women with preterm labor randomly assigned to ritodrine (N = 42) or terbutaline (N = 41), the maximum decrease in plasma potassium occurred after six hours of drug infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest plasma potassium while no women treated with saline and morphine (N = 12) developed cardiac arrhythmias (P = 0.14). We conclude that ritodrine and terbutaline induce profound hypokalemia by stimulating cellular potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, fluid balance, and cardiac rhythm should occur during tocolytic therapy with ritodrine or terbutaline.
Topics: Adolescent; Adult; Aldosterone; Blood Glucose; Female; Heart Rate; Humans; Hypokalemia; Injections, Intravenous; Insulin; Kidney; Obstetric Labor, Premature; Potassium; Pregnancy; Pregnancy Complications; Renin; Ritodrine; Terbutaline
PubMed: 9186877
DOI: 10.1038/ki.1997.255 -
Pharmaceutics Jun 2022Ritodrine, a β2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide...
Ritodrine, a β2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide polymorphisms in , and with the risk of ritodrine-induced adverse events (AEs) and develop a risk scoring system to identify high-risk patients. This is the prospective cohort study conducted at the Ewha Woman's University Mokdong Hospital between January 2010 and October 2016. Pregnant women were included if they were treated with ritodrine for preterm labor with regular uterine contractions (at least 3 every 10 min) and cervical dilation. A total of 6, 3, and 5 single nucleotide polymorphisms (SNPs) of , , and genes were genotyped and compared in patients with and without ritodrine-induced AEs. A total of 163 patients were included in this study. After adjusting confounders, rs3730168 (per-allele odds ratio (OR): 2.1; 95% confidence interval (95% CI): 1.0-4.3) and rs1152746 (per-allele OR: 2.6, 95% CI: 1.1-6.5) were significantly associated with ritodrine-induced AEs. According to the constructed risk scoring models, patients with 0, 1, 2, 3, 4, and 5 points showed 0%, 13%, 19%, 31%, 46%, and 100% risks of AEs. This study suggested that and polymorphisms could affect the risk of AEs in patients treated with ritodrine.
PubMed: 35745791
DOI: 10.3390/pharmaceutics14061220 -
American Journal of Translational... 2022To investigate the efficacy of atosiban combined with ritodrine in threatened preterm labor (TPL) treatment and analysis of related risk factors of different pregnancy...
OBJECTIVE
To investigate the efficacy of atosiban combined with ritodrine in threatened preterm labor (TPL) treatment and analysis of related risk factors of different pregnancy outcomes.
METHODS
A retrospective study was conducted on the clinical data of 127 patients with TPL who were hospitalized in the Children's Hospital of Shanxi and Women's Health Center of Shanxi from January 2020 to November 2021. There from, 58 patients treated with ritodrine were seen as the control group (CG), and 69 treated with atosiban and ritodrine were regarded as the joint group (JG). The inhibition rate after treatment was compared, and the changes of tissue inhibitor of metalloproteinase-1 (TIMP-1), nitric oxide (NO), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in the amniotic fluid before and after treatment were assessed. The pregnancy outcomes of patients were recorded, and the risk factors of adverse pregnancy outcomes were analyzed. The full-term delivery rate, cesarean section rate and neonatal Apgar score >7 were compared, and their adverse reactions were evaluated.
RESULTS
Compared with the JG, the improvement of uterine contraction in the CG was obviously lower, and so was the inhibition rate (P<0.05). The rates of full-term delivery and neonatal Apgar score >7 in the CG were lower than those in the JG, while that of cesarean section was higher (P<0.01). After treatment, the TIMP-1 level in the amniotic fluid in the CG was markedly lower (P<0.001), while the NO, IL-6 and PGE2 levels were higher (P<0.001) as compared with the joint group. The total incidence of adverse reactions in the JG was lower than that in the CG (P<0.05). Logistics regression analysis revealed that age<26 and use of Atosiban combined with Ritodrine are protective factors for pregnancy outcomes, while BMI≥20 before pregnancy is a risk factor for adverse pregnancy.
CONCLUSION
Atosiban combined with ritodrine can improve the condition of TPL patients, enhance the treatment efficacy, and reduce the occurrence of adverse pregnancy outcomes.
PubMed: 36105038
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2014Prematurity is not only the leading cause of perinatal morbidity and mortality but is associated with long-term impairment. Studies of various tocolytic agents have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Prematurity is not only the leading cause of perinatal morbidity and mortality but is associated with long-term impairment. Studies of various tocolytic agents have shown mixed results with little effect in improving pregnancy duration and insufficient data to confirm a definite beneficial effect on neonatal morbidity or mortality. Progesterone is known to have an inhibitory effect on uterine contractility and is thought to play a key role in the maintenance of pregnancy until term.
OBJECTIVES
To determine if the use of progestational agents is effective as a form of treatment or co-treatment for women with threatened or established preterm labour with intact membranes.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013), CENTRAL (The Cochrane Library 2013, Issue 10), MEDLINE (1966 to August 31 2013) and Embase (1974 to 31 August 2013). We checked the reference lists of all included studies to identify any additional studies and communicated with authors and the pharmaceutical industry.
SELECTION CRITERIA
Randomised controlled trials that compared progestational agents, given either alone or in combination with other tocolytics, with a control group receiving another tocolytic, placebo or no treatment, for the treatment of preterm labour.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed trial quality.
MAIN RESULTS
Eight studies were included in this review, involving 563 women, but only seven studies, involving 538 women, contributed data for analyses. There are some data suggesting that the use of progestational agents results in a reduction of preterm deliveries at less than 37 weeks of gestation and an increase in birthweight. The use of a progestational agent may also reduce the frequency of uterine contractions, prolong pregnancy and attenuate the shortening of cervical length. However, the analysis was limited by the relatively small number of available studies. The power of the meta-analysis was also limited by the varying types, dosages and routes of administration of progesterone.
AUTHORS' CONCLUSIONS
There is insufficient evidence to advocate progestational agents as a tocolytic for women presenting with preterm labour.
Topics: Female; Humans; Obstetric Labor, Premature; Pregnancy; Progesterone; Progestins; Randomized Controlled Trials as Topic; Ritodrine; Tocolytic Agents
PubMed: 24482121
DOI: 10.1002/14651858.CD006770.pub3