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Archivos Argentinos de Pediatria Aug 2018Preterm premature rupture of membranes occurs in around 3% of pregnancies, and several aspects related to its management are still controversial. The objective of this... (Review)
Review
Preterm premature rupture of membranes occurs in around 3% of pregnancies, and several aspects related to its management are still controversial. The objective of this update is to provide a detailed review of strategies aimed at reducing morbidity and mortality associated with this maternal condition. We will discuss the available evidence regarding the maternal use of antibiotics, the use of corticosteroids according to gestational age, the use of magnesium sulphate for fetal neuroprotection, the use of tocolytic agents, and the best moment for and route of delivery. This review also covers the effects of prolonged preterm premature rupture of membranes, infant morbidity and mortality in the short and long term, the harmful effects of antibiotics after delivery, including the effects on neurodevelopment and the presence of longterm chronic diseases.
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Female; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Magnesium Sulfate; Pregnancy; Time Factors; Tocolytic Agents
PubMed: 30016035
DOI: 10.5546/aap.2018.eng.e575 -
American Journal of Obstetrics and... Dec 2020This review aimed to examine the existing evidence about interventions proposed for the treatment of clinical chorioamnionitis, with the goal of developing an... (Review)
Review
This review aimed to examine the existing evidence about interventions proposed for the treatment of clinical chorioamnionitis, with the goal of developing an evidence-based contemporary approach for the management of this condition. Most trials that assessed the use of antibiotics in clinical chorioamnionitis included patients with a gestational age of ≥34 weeks and in labor. The first-line antimicrobial regimen for the treatment of clinical chorioamnionitis is ampicillin combined with gentamicin, which should be initiated during the intrapartum period. In the event of a cesarean delivery, patients should receive clindamycin at the time of umbilical cord clamping. The administration of additional antibiotic therapy does not appear to be necessary after vaginal or cesarean delivery. However, if postdelivery antibiotics are prescribed, there is support for the administration of an additional dose. Patients can receive antipyretic agents, mainly acetaminophen, even though there is no clear evidence of their benefits. Current evidence suggests that the administration of antenatal corticosteroids for fetal lung maturation and of magnesium sulfate for fetal neuroprotection to patients with clinical chorioamnionitis between 24 0/7 and 33 6/7 weeks of gestation, and possibly between 23 0/7 and 23 6/7 weeks of gestation, has an overall beneficial effect on the infant. However, delivery should not be delayed to complete the full course of corticosteroids and magnesium sulfate. Once the diagnosis of clinical chorioamnionitis has been established, delivery should be considered, regardless of the gestational age. Vaginal delivery is the safer option and cesarean delivery should be reserved for standard obstetrical indications. The time interval between the diagnosis of clinical chorioamnionitis and delivery is not related to most adverse maternal and neonatal outcomes. Patients may require a higher dose of oxytocin to achieve adequate uterine activity or greater uterine activity to effect a given change in cervical dilation. The benefit of using continuous electronic fetal heart rate monitoring in these patients is unclear. We identified the following promising interventions for the management of clinical chorioamnionitis: (1) an antibiotic regimen including ceftriaxone, clarithromycin, and metronidazole that provides coverage against the most commonly identified microorganisms in patients with clinical chorioamnionitis; (2) vaginal cleansing with antiseptic solutions before cesarean delivery with the aim of decreasing the risk of endometritis and, possibly, postoperative wound infection; and (3) antenatal administration of N-acetylcysteine, an antioxidant and antiinflammatory agent, to reduce neonatal morbidity and mortality. Well-powered randomized controlled trials are needed to assess these interventions in patients with clinical chorioamnionitis.
Topics: Acetylcysteine; Adrenal Cortex Hormones; Ampicillin; Anti-Bacterial Agents; Anti-Infective Agents, Local; Antioxidants; Antipyretics; Ceftriaxone; Cesarean Section; Chorioamnionitis; Clarithromycin; Clindamycin; Delivery, Obstetric; Endometritis; Evidence-Based Medicine; Female; Gentamicins; Gestational Age; Humans; Magnesium Sulfate; Metronidazole; Practice Guidelines as Topic; Pregnancy; Puerperal Infection; Tocolytic Agents
PubMed: 33007269
DOI: 10.1016/j.ajog.2020.09.044 -
The Cochrane Database of Systematic... Aug 2022Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.
OBJECTIVES
To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.
SELECTION CRITERIA
We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.
DATA COLLECTION AND ANALYSIS
At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.
MAIN RESULTS
This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.
Topics: Adrenergic beta-Agonists; Birth Weight; Calcium Channel Blockers; Child; Female; Headache; Humans; Infant, Newborn; Magnesium Sulfate; Network Meta-Analysis; Nitric Oxide Donors; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Receptors, Oxytocin; Tocolytic Agents; Vomiting
PubMed: 35947046
DOI: 10.1002/14651858.CD014978.pub2 -
American Family Physician Feb 2010Preventing preterm delivery remains one of the great challenges in modern medicine. Preterm birth rates continue to increase and accounted for 12.7 percent of all U.S.... (Review)
Review
Preventing preterm delivery remains one of the great challenges in modern medicine. Preterm birth rates continue to increase and accounted for 12.7 percent of all U.S. births in 2005. The etiology of preterm delivery is unclear, but is likely to be complex and influenced by genetics and environmental factors. Women with previous preterm birth are at increased risk of subsequent preterm delivery and may be candidates for treatment with antenatal progesterone. Fetal fibronectin testing and endovaginal ultrasonography for cervical length are useful for triage. For the patient in preterm labor, only antenatal corticosteroids and delivery in a facility with a level III neonatal intensive care unit have been shown to improve outcomes consistently. Tocolytic agents may delay delivery for up to 48 hours, enabling the administration of antenatal corticosteroids or maternal transfer. Routine use of antibiotics in preterm labor is not indicated except for group B streptococcus prophylaxis or treatment of chorioamnionitis.
Topics: Adrenal Cortex Hormones; Antihypertensive Agents; Calcium Channel Blockers; Female; Humans; Obstetric Labor, Premature; Pregnancy; Risk Factors; Tocolytic Agents; Ultrasonography, Prenatal; United States
PubMed: 20148502
DOI: No ID Found -
Seminars in Perinatology Dec 2017In the United States, the generally accepted indication for tocolytic therapy centers on suppression of preterm labor. This may be in the form of preventative therapy... (Review)
Review
In the United States, the generally accepted indication for tocolytic therapy centers on suppression of preterm labor. This may be in the form of preventative therapy with progesterone in women with prior spontaneous preterm birth or as an acute intervention to suppress established uterine contractions associated with cervical change occurring at less than 37 weeks gestation. This article seeks to apply this perspective to tocolytic therapy. Here, we provide a review of current tocolytic options and what the last decade of discovery has revealed about the regulation of myometrial excitability and quiescence. Moving forward, we must incorporate the emerging molecular data that is amassing in order to develop novel and effective tocolytic therapeutic options to prevent preterm labor and spontaneous preterm birth (sPTB).
Topics: Adult; Female; Humans; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Tocolysis; Tocolytic Agents; Treatment Outcome
PubMed: 29191291
DOI: 10.1053/j.semperi.2017.08.008 -
EClinicalMedicine Jul 2022Preterm birth is a leading cause of neonatal mortality and morbidity, and imposes high health and societal costs. Antenatal corticosteroids (ACS) to accelerate fetal...
BACKGROUND
Preterm birth is a leading cause of neonatal mortality and morbidity, and imposes high health and societal costs. Antenatal corticosteroids (ACS) to accelerate fetal lung maturation are commonly used in conjunction with tocolytics for arresting preterm labour in women at risk of imminent preterm birth.
METHODS
We conducted a systematic review on the cost-effectiveness of ACS and/or tocolytics as part of preterm birth management. We systematically searched MEDLINE and Embase (December 2021), as well as a maternal health economic evidence repository collated from NHS Economic Evaluation Database, EconLit, PubMed, Embase, CINAHL and PsycInfo, with no date cutoff. Eligible studies were economic evaluations of ACS and/or tocolytics for preterm birth. Two reviewers independently screened citations, extracted data on cost-effectiveness and assessed study quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
FINDINGS
35 studies were included: 11 studies on ACS, eight on tocolytics to facilitate ACS administration, 12 on acute and maintenance tocolysis, and four studies on a combination of ACS and tocolytics. ACS was cost-effective prior to 34 weeks' gestation, but economic evidence on ACS use at 34-<37 weeks was conflicting. No single tocolytic was identified as the most cost-effective. Studies disagreed on whether ACS and tocolytic in combination were cost-saving when compared to no intervention.
INTERPRETATION
ACS use prior to 34 weeks' gestation appears cost-effective. Further studies are required to identify what (if any) tocolytic option is most cost-effective for facilitating ACS administration, and the economic consequences of ACS use in the late preterm period.
FUNDING
UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by WHO.
PubMed: 35747187
DOI: 10.1016/j.eclinm.2022.101496 -
Journal of Clinical Medicine Jun 2021Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear... (Review)
Review
Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.
PubMed: 34209869
DOI: 10.3390/jcm10132912 -
American Family Physician Feb 1999Preterm labor is the leading cause of perinatal morbidity and mortality in the United States. It is characterized by cervical effacement and/or dilatation and increased... (Review)
Review
Preterm labor is the leading cause of perinatal morbidity and mortality in the United States. It is characterized by cervical effacement and/or dilatation and increased uterine irritability before 37 weeks of gestation. Women with a history of preterm labor are at greatest risk. Strategies for reducing the incidence of preterm labor and delivery have focused on educating both physicians and patients about the risks for preterm labor and methods of detecting preterm cervical dilatation. Methods used to predict preterm labor include weekly cervical assessment, transvaginal ultrasonography, detection of fetal fibronectin and home uterine activity monitoring. As yet, it is unclear if any of these strategies should be routinely employed. At present, management of preterm labor may include the use of tocolytic agents, corticosteroids and antibiotics.
Topics: Female; Humans; Obstetric Labor, Premature; Pregnancy; Risk; Risk Factors; Tocolytic Agents; Ultrasonography, Prenatal
PubMed: 10029786
DOI: No ID Found -
Fertility and Sterility Aug 1989In the early 1950s, when treatment of cervical incompetence was first described, diagnosis seemed relatively simple and management favorable, but after more than 35... (Review)
Review
In the early 1950s, when treatment of cervical incompetence was first described, diagnosis seemed relatively simple and management favorable, but after more than 35 years of trying multiple variations of procedures and treatment regimens, no advances have been made. In 1959, Neser questioned the very existence of cervical incompetence as an entity, and concluded that, in the final analysis, the problem is a diagnostic one. Liberal use of cerclage in situations of moderate risk of preterm delivery or as a prophylactic measure for multiple gestation does not appear to improve outcome, as judged by prematurity or survival. Because of advances in neonatal care in the last decade, fetal survival has improved tremendously. It is hoped that, in the future, more objective and accurate criteria for the diagnosis of cervical incompetence will emerge, and that outcome of treatment will be measured not by fetal survival, but by prolongation of pregnancy and by birth weight. At present, making an unequivocal diagnosis of cervical incompetence remains an elusive, challenging, and unsolved problem.
Topics: Anti-Bacterial Agents; Cervix Uteri; Female; Humans; Pregnancy; Progesterone; Progestins; Surgical Wound Infection; Tocolytic Agents; Uterine Cervical Incompetence
PubMed: 2666173
DOI: 10.1016/s0015-0282(16)60839-7 -
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