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Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis.

The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor.

Ethnopharmacological Relevance In the search for new, safe and efficacious uterine active agents, the plant Ficus exasperata was subjected to phytochemical screening and pharmacological analysis. Materials and methods Ethyl acetate and methanolic leaf extracts of Ficus exasperata were fractionated and purified by a series of chromatographic techniques. The isolation process was guided by in vitro functional uterine assays involving the use of C57Bl/6 female mice. Identification of the active chemical constituents was performed by several spectroscopic techniques which included 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS). The uterine effects of these compounds were investigated on spontaneous, oxytocin-induced and high KCl-induced contractions using isolated uterine segments of non-pregnant female mice. The activity of different compounds on the amplitude (maximum tension above basal force) and frequency of uterine contractions were simultaneously measured and then statistically analysed. The structure–activity relationships were also examined where possible. Results These studies led to the identification of some new phytochemical derivatives. Pharmacological assay revealed the presence of both uterine stimulatory and inhibitory constituents. The new pheophytin/pheophorbide derivatives, flavonoids, fatty acids and glycerol derivatives significantly reduced the frequency and amplitude of uterine contraction, while KCl salt, pyrimidine and pheophorbide-b derivatives significantly augmented both spontaneous and agonist-induced contractions. Conclusion This study has demonstrated that Ficus exasperata generates secondary metabolites which have proven effective in the significant inhibition of uterine contractions and thus a potential source of new tocolytic agents. Additionally, uterine stimulatory constituents were also generated some of which may be potential drugs for contraception and/or labour facilitation. Lead compounds generated from this study are the pheophytin/pheophorbide derivatives, pyrimidine derivatives and flavonoid derivatives.

Purpose: We propose that using remifentanil in ex utero intrapartum treatment (EXIT) procedures reduces the need for maternal exposure to general anesthesia. Using remifentanil along with spinal anesthesia eliminates the fetal and maternal risks associated with inhalational general anesthesia, allows the mother to be awake, and obviates the need for and costs associated with general anesthesia and a second anesthesia team. Materials and Methods: We performed a retrospective review of all sequential patients undergoing ex utero intrapartum treatment procedure at our hospital from 1/1/2009 to 11/1/2010. All procedures were performed under regional neuraxial analgesia, using nitroglycerine as a tocolytic agent and remifentanil for analgesia. Variables included indication, time to secured fetal airway, complications, estimated blood loss, need for additional anesthetics, participating personnel, and survival. Results: All five of our ex utero intrapartum treatment procedures were successfully completed with combined spinal epidural remifentanil anesthetic. No patient was required additional alternative anesthetic. There were no complications with mother or fetus. Indications for procedure were arthyrogryposis (n = 3), fetal goiter, and micrognathia. Average time to secured airway was 10.25 minutes. Average estimated blood loss was 1010 ml. All five mothers were conscious during their procedure. Conclusions: We report the largest series of ex utero intrapartum treatment procedures performed with remifentanil regional anesthesia. We found that the combined use of nitroglycerin and regional remifentanil anesthesia is a safe alternative to the pediatric otolaryngologist for performing ex utero intrapartum treatment procedures without the risks of general anesthesia, allowing the mother to be awake for the delivery, and reducing the cost of providing care.

OBJECTIVE To compare the tocolytic efficacy and tolerability of nifedipine with that of atosiban among pregnant women with preterm labor. METHODS Pregnant women admitted with preterm labor and intact membranes between 24 and 33 weeks 6 days of gestation, between January 2008 and December 2011, were randomly assigned to either atosiban or nifedipine treatment. Assigned treatment was planned for up to 48 hours. If progress was determined after 1 hour or more, a crossover of the study drugs was performed. The primary outcome was to estimate the tocolytic efficacy and tolerability profile that was assessed in terms of the proportion of women who were not delivered and did not require an alternate tocolytic agent within 48 hours. Secondary outcomes were gestational age at delivery and neonatal morbidity. RESULTS Seventy-five women in the nifedipine group and 70 in the atosiban group were included and analyzed. Baseline demographic and obstetric characteristics were comparable. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). At 7 days from enrollment, 55 (78.6%) women allocated to atosiban and 67 (89.3%) to nifedipine remained undelivered with or without a rescue agent (P=.02). Mean gestational age at delivery was 35.2 (±3.0) and 36.4 (±2.8) weeks among the atosiban and nifedipine groups, respectively (P=.01). Mean birth weight and neonatal morbidity were comparable. CONCLUSIONS Atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, www.clinicaltrials.gov, NCT00599898.

Resume Introduction L’utilisation du sulfate de magnesium (MgSO4) est preconisee depuis 2000 en France dans la prise en charge de l’eclampsie. L’objectif de ce travail etait de determiner la frequence du recours a ce traitement lors de la survenue d’une eclampsie a l’echelle d’un departement francais. Patientes et methodes Toutes les patientes obstetricales hospitalisees dans l’ensemble des reanimations de Seine-Maritime pour la prise en charge d’une eclampsie ont ete incluses retrospectivement sur une periode de sept ans (2002–2008). Les donnees obstetricales, les modalites de prise en charge de l’eclampsie et de la preeclampsie ainsi que les complications maternofœtales ont ete recueillies. Le parametre de jugement principal etait le recours au MgSO4 dans le cadre de la prevention secondaire d’une eclampsie. Resultats Trente-neuf patientes ont ete incluses. Dix-neuf patientes (48 %) ont presente une crise convulsive en prepartum, trois (8 %) en per-partum et 17 (44 %) en post-partum. Le recours au MgSO4 dans le cadre de la prevention secondaire d’une eclampsie a ete observe dans 92 % des cas (36/39). Une prevention primaire etait constatee dans 8 % des cas. La duree moyenne de ce traitement etait de deux jours (un a sept jours). La mortalite maternelle et infantile etait respectivement de 2,5 et de 11 %. Conclusion Dans cette etude, le recours du MgSO4 dans le cadre de la prevention secondaire est important. Ce resultat souligne l’importance des recommandations emanant de societes savantes dans l’homogeneisation de la prise en charge de pathologies rares, mais graves comme l’eclampsie.

Preterm labor caused by uterine contractions is a major contributor to neonatal morbidity and mortality. Treatment intended to reduce uterine contractions include tocolytic agents, such as indomethacin. Unfortunately, clinically used tocolytics are frequently inefficient and cross the placenta causing fetal side effects. Here we show for the first time in obstetrics the use of a targeted nanoparticle directed to the pregnant uterus and loaded with a tocolytic for reducing its placental passage and sustaining its efficacy. Nanoliposomes encapsulating indomethacin and decorated with clinically used oxytocin receptor antagonist were designed and evaluated in-vitro, ex-vivo and in-vivo. The proposed approach resulted in targeting uterine cells in-vitro, inhibiting uterine contractions ex-vivo, while doubling uterine drug concentration, decreasing fetal levels, and maintaining the preterm birth rate in vivo in a pregnant mouse model. This promising approach opens new horizons for drug development in obstetrics that could greatly impact preterm birth, which currently has no successful treatments.

Hypertrophic obstructive cardiomyopathy (HOCM) is cardiac hypertrophy of ventricular myocardium with left ventricular outflow tract obstruction. We report a pregnancy with HOCM after defibrillator implantation surgery. The patient was a 33-year-old nulligravida and was categorized as New York Heart Association class II. Her brain natriuretic peptide (BNP) level was 724.6 pg/dL at preconception. She received careful pregnancy management. However, because frequent uterine contractions were observed at 25 weeks and 6 days of pregnancy, she was hospitalized, and magnesium sulfate was started as a tocolytic agent. At 27 weeks and 5 days of pregnancy, she had respiratory discomfort and orthopnea with a sudden decrease in peripheral oxygen saturation. Cardiac ultrasonography showed a worsened condition of HOCM and her BNP level was 1418.0 pg/mL. We performed an emergent cesarean section and she delivered a boy weighing 999 g. The Apgar score was 8 and 9 points at 1 and 5 minutes, respectively. The mother’s heart failure quickly improved after birth and she was discharged at 10 days postoperatively. Fluctuations in circulatory dynamics during pregnancy may sometimes exacerbate heart disease. Therefore, the risks should be fully explained and careful assessment of cardiac function should be performed during pregnancy in patients with severe HOCM.

Progesterone is an essential hormone in the process of reproduction. It is involved in the menstrual cycle, implantation and is essential for pregnancy maintenance. It has been proposed and extensively used in the treatment of different gynecological pathologies as well as in assisted reproductive technologies and in the maintenance of pregnancy. Called “the pregnancy hormone”, natural progesterone is essential before pregnancy and has a crucial role in its maintenance based on different mechanisms such as: modulation of maternal immune response and suppression of inflammatory response (the presence of progesterone and its interaction with progesterone receptors at the decidua level appears to play a major role in the maternal defense strategy), reduction of uterine contractility (adequate progesterone concentrations in myometrium are able to counteract prostaglandin stimulatory activity as well as oxytocin), improvement of utero-placental circulation and luteal phase support (it has been demonstrated that progesterone may promote the invasion of extravillous trophoblasts to the decidua by inhibiting apoptosis of extravillous trophoblasts). Once the therapeutic need of progesterone is established, the key factor is the decision of the best route to administer the hormone and the optimal dosage determination. Progesterone can be administered by many different routes, but the most utilized are oral, the vaginal and intramuscular administration. The main uses of progesterone are represented by: threatened miscarriage, recurrent miscarriage and preterm birth (in the prevention strategy, as a tocolytic agent and also in the maintenance of uterine quiescence).

Objective: To investigate the effects of two tocolytics, nifedipine and magnesium sulfate, on Doppler indices in maternal and fetal vessels. Materials and Methods: We recruited 100 pregnant women with preterm birth between 24-36 gestational weeks who were admitted to our tertiary center over a two-year period. Patients were allocated to nifedipine (n=49) and magnesium sulfate (n=51) groups and Doppler indices of umbilical, middle cerebral, uterine arteries, and ductus venosus were measured before and after tocolysis. Results: There were no differences between the groups in terms of maternal age, gestational week, body mass indexes, cervical dilation, effacement at admission, birth weights and latency periods until birth. Nifedipine decreased resistance indexes in uterine arteries but magnesium sulfate increased resistance especially in the right uterine artery. Nifedipine significantly decreased systole to diastole and resistance index in the umbilical artery, magnesium sulfate increased systole to diastole and resistance index but this was not statistically significant. Nifedipine acted variably on resistance index and pulsatility index in the ductus venosus; however, magnesium sulfate increased resistance. Nifedipine decreased pulsatility index in the middle cerebral artery, contrary to magnesium sulfate with which it increased. Conclusion: Nifedipine had favorable effects on maternal and fetal vessel indexes but magnesium sulfate increased resistance. Despite the proposed neuroprotective benefits of magnesium sulfate, nifedipine seems to be a better and safer tocolytic agent than magnesium sulfate due to its positive beneficial effects on maternal and fetal vessels.

Background Maternal death reviews and obstetric audits identify causes and circumstances related to occurrence of a maternal death or serious complication and inform improvements in quality of care. Given Nigeria’s high maternal mortality, the lessons learned from past experiences can provide a good evidence base for informed decision making. We aimed to synthesise findings from maternal death reviews and other obstetric audits conducted in Nigeria through a systematic review, seeking to identify common barriers and enabling factors related to the provision of emergency obstetric care. Methods We searched for maternal death reviews and obstetric care audits reported in the published literature from 2000–2014. A ‘best-fit’ framework approach was used to extract data using a structured data extraction form. The articles that met the inclusion criteria were assessed using a nine point quality score. Results Of the 1,841 abstracts and titles at initial screening, 329 full text articles were reviewed and 43 papers fulfilled the inclusion criteria. Four types of barriers were reported related to: transport and referral; health workers; availability of services; and organisational factors. Three elements stand out in Nigeria as contributing to maternal mortality: delays in Caesarean section, unavailability of magnesium sulphate and lack of safe blood transfusion services. Conclusions Obstetric care reviews and audits are useful activities to undertake and should be promoted by improving the processes used to conduct them, as well as extending their implementation to rural and basic level health facilities and to the community. Urgent areas for quality improvement in obstetric care, even in tertiary and teaching hospitals should focus on organisational factors to reduce delays in conducting Caesarean section and making blood and magnesium sulphate available for all who need these interventions.

Objective Indomethacin tocolysis is generally limited to 48 hours. Indomethacin has been administered for longer durations to prolong gestation in extreme prematurity. Our aim is to compare perinatal outcomes after a prolonged course, 48 hours versus ≤ 48 hours in preterm labor. Methods A retrospective chart review of women admitted with preterm labor 32 weeks gestation who received indomethacin for tocolysis. The primary maternal outcome was latency from admission until delivery. The primary neonatal outcome was a composite of severe neonatal morbidities. Results A total of 73 women were included: 32 (43.8%) received indomethacin for 48 hours (prolonged) and 41 (56.2%) for ≤ 48 hours (standard). Prolonged group started on indomethacin at an earlier gestational age compared with standard group (23.9 [23.1-27.3] vs. 25.7 [23.8-28.5] weeks, p = 0.03). Latency from admission until delivery was longer in the prolonged group versus the standard group (1.8 [1.1-3] vs. 0.4 [0.1-0.8] weeks, p 0.001). Prolonged use was not associated with increased risk of the composite neonatal outcome; however, there was a trend for more necrotizing enterocolitis. Conclusion A prolonged course of indomethacin may be an option for women with preterm labor at risk of extreme prematurity; it may also be associated with higher risks of some adverse neonatal outcomes.

Aim: Our aim is to evaluate the effect of nifedipine on fetoplacental hemodynamic parameters. Methods: A retrospective study was conducted at a tertiary center with 30 patients for whom nifedipine treatment was used as a tocolytic therapy for preterm labor. Initiation of this treatment was at 31.6±2.5 weeks of gestation. We combined the pulse Doppler imaging parameters with grayscale imaging via the Bernoulli theorem, which is called the “continuity equation”, to get the fetoplacental perfusion (FPP). Evaluated parameters were the resistance index (RI), the pulsatility index (PI), systole/diastole ratios (S/D), the velocity-time integral of the umbilical artery (VTI), the radius of the umbilical artery, the peak systolic velocity and the mean pressure gradient in the umbilical artery. From these parameters, the FPP was acquired. Results: We found that the RI, the PI and the S/D ratio did not change after treatment with nifedipine. The mean pressure gradient, the VTI and the peak systolic velocity increased after treatment with nifedipine. Nifedipine increases FPP from 166±73.81 beat.cm3/min to 220±83.3 beat.cm3/min. Discussion: Although nifedipine had no effect on the PI, the RI or the S/D, it increased the mean pressure gradient, the VTI and FPP.

Objective To evaluate the efficacy and safety of magnesium sulfate in the resolution of vaginal bleeding and contractions in nonsevere placental abruption. Study Design Thirty women between 24 and 34 weeks of gestation diagnosed with nonsevere placental abruption were randomized to receive magnesium sulfate tocolysis or normal saline infusion. The primary outcome was the proportion of women undelivered at 48 hours with resolution of vaginal bleeding and uterine contractions. Maternal and neonatal outcomes were also compared. Results Fifteen (50%) women received magnesium sulfate tocolysis and 15 (50%) received intravenous saline. There was no difference in the number of women who were undelivered at 48 hours with resolution of vaginal bleeding and contractions in the magnesium sulfate (80.0%) and saline (66.7%; p -value = 0.68) groups. There were no differences between groups in the gestational age at randomization, time to uterine quiescence, time on study drug, length of hospitalization, days from randomization to delivery, incidence of side effects, or admissions to the neonatal intensive care unit. Conclusions Magnesium sulfate tocolysis did not provide a significant difference in pregnancy prolongation in the management of preterm nonsevere placental abruption. Recruitment goals were not met due to the introduction of the use of magnesium sulfate for neuroprotection.

Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed "funneling"). To date, we do not understand why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility.To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility.Using institutional review board-approved protocols, nonpregnant women50 years old undergoing hysterectomy for benign indications were consented. Cervical tissue from the internal and external os were immunostained for smooth muscle cell markers (α-smooth muscle actin, smooth muscle protein 22 calponin) and contraction-associated proteins (connexin 43, cyclooxygenase-2, oxytocin receptor). To evaluate cervical smooth muscle cell morphology throughout the entire cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 μmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate.Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10% cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10(-5) mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10(-4) mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine -4% ± 20%, P = .003), and 10(-3) mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine -15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10(-5) mol/L.Our findings suggest a new paradigm for cervical tissue morphology-one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling.

Objective Previous studies have reported that air medical transfer of women in preterm labor can be safely accomplished, without preterm birth occurring; in fact, many women were later discharged without preterm birth occurring. The purpose of this study was to determine if nifedipine, when used as a tocolytic, is effective at facilitating in utero transfer of women in preterm labor in the Top End of the Northern Territory of Australia. Methods This was a retrospective descriptive study over a 3-year period of all women transported in preterm labor between 23 + 6 to 36 + 6 weeks’ gestation of pregnancy (N = 325). Results The average gestation period was 32 + 2 weeks. The mean retrieval time was 6 hours. The mean time of birth from referral was 33 hours. A number of women gave birth to a preterm newborn in a remote health center (17%). There were 3 in-flight preterm births, and 49% of women were discharged without a preterm birth occurring. All women transported by air medical retrieval were admitted to the tertiary hospital for at least 24 hours. Conclusion In this study, nifedipine was used successfully to facilitate in utero transfer in many cases. Nearly half of the women referred were discharged without preterm birth occurring. Findings compare favorably with other published studies.

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

Objectives: The aim of this study was to determine if the actions of progesterone on preterm labor are accomplished through modulation of the percentage of regulatory T-cells (Treg). Methods: The study was a cohort pilot study made in a single center tertiary obstetrical unit with women in preterm labor arrested with tocolytic treatment. Variation of the number and percentage of Treg cells obtained from peripheral blood samples of women with preterm labor were calculated by flow cytometry, before and after progesterone administration. Results: In the paired samples for each patient, there was a significant difference in the Treg cell pool after progesterone treatment, with an increase in both their percentage (48.9 vs. 53; P = 0.07) and absolute number (14.8 vs. 56.5 cells/μL; P = 0.046). Conclusions: This research demonstrated a considerable increase in the Treg cell pool after progesterone treatment. This indicates a possible mechanism for progesterone treatment benefits in preterm labor, potentially increasing its more rational use.

OBJECTIVE DATA: Fetal fibronectin is an extracellular matrix glycoprotein that is produced by amniocytes and cytotrophoblasts and has been shown to predict spontaneous preterm birth. STUDY: The aim of this systematic review and metaanalysis of randomized clinical trials was to evaluate the effect of the use of fetal fibronectin in the prevention of preterm birth in singleton pregnancies with threatened preterm labor. STUDY APPRAISAL AND SYNTHESIS METHODS: The research was conducted with the use of MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, and Cochrane Library as electronic databases from the inception of each database to February 2016. Selection criteria included randomized clinical trials of singleton gestations with threatened preterm labor that were assigned randomly to management based on fetal fibronectin results (ie, intervention group) or not (ie, comparison group). Types of participants included women with singleton gestations at 23 0/7 to 34 6/7 weeks with threatened preterm labor. Studies that included management that was also based on the use of sonographic cervical length were excluded. The primary outcome was preterm birth at

The pathophysiology leading to preterm labor is not well understood and often multifactorial; initiating factors include intrauterine infection, inflammation, ischemia, overdistension, and hemorrhage. Given these different potential causes, directing therapy for preterm labor has been difficult and suboptimal. To date, no single drug has been identified as successful in treating all of the underlying mechanisms leading to preterm labor. In addition, the methodology of many of the tocolytic studies is limited by lack of sufficient patient numbers, lack of comparison with a placebo, and inconsistent use of glucocorticoids. The limitations in these individual studies make it difficult to evaluate the efficacy of a single tocolytic by meta-analysis. Despite these limitations, the goals for tocolysis for preterm labor are clear: To complete a course of glucocorticoids and secure the appropriate level of neonatal care for the fetus in the event of preterm delivery. The literature demonstrates that many tocolytic agents inhibit uterine contractility. The decision as to which tocolytic agent should be used as first-line therapy for a patient is based on multiple factors, including gestational age, the patient’s medical history, common and severe side effects, and a patient’s response to therapy. In a patient at less than 32 weeks gestation, indomethacin may be a reasonable first choice based on its efficacy, ease of administration, and minimal side effects. Concurrent administration of magnesium for neuroprotection may be given. At 32 to 34 weeks, nifedipine may be a reasonable first choice because it does not carry the fetal risks of indomethacin at these later gestational ages, is easy to administer, and has limited side effects relative to beta-mimetics. In an effort to review a commonly faced obstetrical complication, this article has provided a summary of the most commonly used tocolytics, their mechanisms of action, side effects, and clinical data regarding their efficacy.

Background The gold standard for diagnosis of proteinuria in pre-eclampsia is traditionally a 24-h urine collection. Current Australian guidelines advocate use of the spot urine protein-to-creatinine ratio (PCR); however, there is controversy in the international literature about its accuracy and little recent Australian data exists. Aim To clarify the accuracy of the spot urine PCR in a cohort of Australian women with pre-eclampsia. Methods Women with pre-eclampsia over a 52-month period from a single obstetric unit were included in the study. Spot urine PCR, 24-h urine collection, gestation at delivery, severe hypertension in labour and magnesium sulphate requirement were recorded. Primary analysis of predictive values was performed on women who had had both a spot urine PCR and a 24-h collection. Continuous data were assessed using least squares analysis with Pearson correlation coefficient, Bland–Altman plot and receiver operator characteristics curve. Results Two hundred and seventeen women had pre-eclampsia, and 121 of these underwent both tests. The two tests were highly correlated (r = 0.98, P

The oxytocin receptor (OTR) and the β(2)-adrenergic receptor (β(2)AR) are key regulators of uterine contraction. These two receptors are targets of tocolytic agents used to inhibit pre-term labor. Our recent study on the nature of OTR- and β(2)AR-mediated ERK1/2 activation in human hTERT-C3 myometrial cells suggested the presence of an OTR/β(2)AR hetero-oligomeric complex (see companion article). The goal of this study was to investigate potential allosteric interactions between OTR and β(2)AR and establish the nature of the interactions between these receptors in myometrial cells. We found that OTR-mediated ERK1/2 activation was attenuated significantly when cells were pretreated with the β(2)AR agonist isoproterenol or two antagonists, propranolol or timolol. In contrast, pretreatment of cells with a third β(2)AR antagonist, atenolol resulted in an increase in OTR-mediated ERK1/2 activation. Similarly, β(2)AR-mediated ERK1/2 activation was strongly attenuated by pretreatment with the OTR antagonists, atosiban and OTA. Physical interactions between OTR and β(2)AR were demonstrated using co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and protein-fragment complementation (PCA) assays in HEK 293 cells, the latter experiments indicating the interactions between the two receptors were direct. Our analyses suggest physical interactions between OTR and β(2)AR in the context of a new heterodimer pair lie at the heart of the allosteric effects.

Background:: One of the most serious complications of pregnancy is preterm labor (PTL) and delivery. Further, there are different tocolytic agents available to enhance the time of delivery. Objectives:: The aim of this study was to compare the effectiveness of transdermal nitroglycerin (glyceryl trinitrate, GTN) and oral nifedipine for managing preterm labor. Patients and Methods:: This was a randomized clinical trial involving women who were admitted to our hospital with a diagnosis of PTL. Group one received transdermal GTN, whereas group two received oral nifedipine. All vital signs, fetal heart rate (FHR), contractions, dilation, and effacement, as well as gestation age at the time of delivery, have been monitored and evaluated in both groups of patients. Our main goal was the postponement of delivery so as to secure the most beneficial effect of primary corticosteroid administration for the fetus. Results:: Both groups were matched regarding age, gestational age at the time of tocolytic therapy, height of fundus, history of pregnancy, abortion, delivery, and stillbirth, primary body temperature, and systolic and diastolic blood pressure. Those who received GTN had a more prolonged delay of delivery. Also, the GTN group had infants with better one- and five-minute Apgar scores. Although both groups reported minimal side effects, tachycardia and nausea were reported more frequently in GTN patients. Conclusions:: Transdermal GTN was shown to be more effective in controlling PTL compared to oral nifedipine in terms of both maternal and neonatal effects.

Background Magnesium sulphate has been used to inhibit preterm labour to prevent preterm birth. There is no consensus as to the safety profile of different treatment regimens with respect to dose, duration, route and timing of administration. Objectives To assess the efficacy and safety of alternative magnesium sulphate regimens when used as single agent tocolytic therapy during pregnancy. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. Selection criteria Randomised trials comparing different magnesium sulphate treatment regimens when used as single agent tocolytic therapy during pregnancy in women in preterm labour. Quasi-randomised trials were eligible for inclusion but none were identified. Cross-over and cluster trials were not eligible for inclusion. Health outcomes were considered at the level of the mother, the infant/child and the health service. Intervention: intravenous or oral magnesium sulphate given alone for tocolysis. Comparison: alternative dosing regimens of magnesium sulphate given alone for tocolysis. Data collection and analysis Two review authors independently assessed trial eligibility and quality and extracted data. Main results Three trials including 360 women and their infants were identified as eligible for inclusion in this review. Two trials were rated as low risk of bias for random sequence generation and concealment of allocation. A third trial was assessed as unclear risk of bias for these domains but did not report data for any of the outcomes examined in this review. No trials were rated to be of high quality overall. Intravenous magnesium sulphate was administered according to low-dose regimens (4 g loading dose followed by 2 g/hour continuous infusion and/or increased by 1 g/hour hourly until successful tocolysis or failure of treatment), or high-dose regimens (4 g loading dose followed by 5 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment, or 6 g loading dose followed by 2 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment). There were no differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the primary outcome of fetal, neonatal and infant death (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.12 to 1.56; one trial, 100 infants). Using the GRADE approach, the evidence for fetal, neonatal and infant death was considered to be VERY LOW quality. No data were reported for any of the other primary maternal and infant health outcomes (birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome). There were no clear differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the secondary infant health outcomes of fetal death; neonatal death; and rate of hypocalcaemia, osteopenia or fracture; and secondary maternal health outcomes of rate of caesarean birth; pulmonary oedema; and maternal self-reported adverse effects. Pulmonary oedema was reported in two women given high-dose magnesium sulphate, but not in any of the women given low-dose magnesium sulphate. In a single trial of high and low doses of magnesium sulphate for tocolysis including 100 infants, the risk of respiratory distress syndrome was lower with use of a high-dose regimen compared with a low-dose regimen (RR 0.31, 95% CI 0.11 to 0.88; one trial, 100 infants). Using the GRADE approach, the evidence for respiratory distress syndrome was judged to be LOW quality. No difference was seen in the rate of admission to the neonatal intensive care unit. However, for those babies admitted, a high-dose regimen was associated with a reduction in the length of stay in the neonatal intensive care unit compared with a low-dose regimen (mean difference -3.10 days, 95% confidence interval -5.48 to -0.72). We found no data for the majority of our secondary outcomes. Authors' conclusions There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy and the role for repeat dosing. Downgrading decisions for our primary outcome of fetal, neonatal and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre-specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long-term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect) and lack of blinding. There is some evidence from a single study suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome where a high-dose regimen of magnesium sulphate has been used compared with a low-dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution. Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy and role for repeat dosing in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required.

Background Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. Objectives To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. Search methods We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 September 2015), MEDLINE (January 1966 to 31 July 2015), EMBASE (January 1985 to 31 July 2015) and reference lists of retrieved studies. Selection criteria Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not eligible for inclusion. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two authors assessed the quality of the evidence using the GRADE approach. Main results Overall, the quality of evidence is low for the primary outcomes. All of the included trials had small numbers of participants and few events. Preterm birth, the most important primary outcome, had wide confidence intervals crossing the line of no effect. Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo. Betamimetics reduced the incidence of preterm labour (two trials, 194 twin pregnancies, risk ratio (RR) 0.37; 95% confidence interval (CI) 0.17 to 0.78; low quality evidence). However, betamimetics did not reduce prelabour rupture of membranes (one trial, 144 twin pregnancies, RR 1.42; 95% CI 0.42 to 4.82; low quality evidence), preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10; low quality evidence), or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50; low quality evidence). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.21 to 200.24). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects), or small-for-gestational age neonates (two trials, 178 neonates, average RR 0.90; 95% CI 0.41 to 1.99, random-effects). Two trials showed that betamimetics significantly reduced the incidence of respiratory distress syndrome (388 neonates, RR 0.30; 95% CI 0.12 to 0.77), but the difference was not significant when the analysis was adjusted to account for the non-independence of twins (194 twins, RR 0.35; 95% CI 0.11 to 1.16). Three trials showed no evidence of an effect of betamimetics in reducing neonatal mortality, either with the unadjusted analysis, assuming twins are completely independent of each other (452 neonates, average RR 0.90; 95% CI 0.15 to 5.37, random-effects), or in the adjusted analysis, assuming non-independence of twins (226 twins, average RR 0.74; 95% CI 0.23 to 2.38, random-effects). A maternal death was reported in one trial without a significant difference between the groups (144 women, RR 2.84; 95% CI 0.12 to 68.57). Authors' conclusions There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy.

Background Preterm birth is the leading cause of death and disability in newborns worldwide. A wide variety of tocolytic agents have been utilized to delay birth for women in preterm labor. One of the earliest tocolytics utilized for this purpose was ethanol infusion, although this is not generally used in current practice due to safety concerns for both the mother and her baby. Objectives To determine the efficacy of ethanol in stopping preterm labor, preventing preterm birth, and the impact of ethanol on neonatal outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. Selection criteria We included randomized and quasi-randomized studies. Cluster-randomized trials and cross-over design trials were not eligible for inclusion. We only included studies published in abstract form if there was enough information on methods and relevant outcomes. Trials were included if they compared ethanol infusion to stop preterm labor versus placebo/control or versus other tocolytic drugs. Data collection and analysis At least two review authors independently assessed studies for inclusion and risk of bias. At least two review authors independently extracted data. Data were checked for accuracy. Main results Twelve trials involving 1586 women met inclusion criteria for this review. One trial did not report on the outcomes of interest in this review. Risk of bias of included studies: The included studies generally were of low quality based on inadequate reporting of methodology. Only three trials had low risk of bias for random sequence generation and one had low risk of bias for allocation concealment and participant blinding. Most studies were either high risk of bias or uncertain in these key areas. Comparison 1: Ethanol versus placebo/control (two trials, 77 women) Compared to controls receiving pain medications and dextrose solution, ethanol did not improve any of the primary outcomes: birth < 48 hours after trial entry (one trial, 35 women; risk ratio (RR) 0.93, 95% confidence interval (CI) 0.43 to 2.00), or neonatal mortality (one trial, 35 women; RR 1.06, 95% CI 0.31 to 3.58). Serious maternal adverse events and perinatal mortality were not reported by either of the two trials in this comparison. Maternal adverse events (overall) were not reported but one trial (42 women) reported that there were no maternal adverse events that required stopping or changing drug) in either group. One trial did report delay until delivery but this outcome was reported as a median with no mention of the standard deviation (median 19 days in ethanol group versus "less than 1" day in the glucose/water group). There were no differences in any secondary outcomes reported: preterm birth < 34 weeks or < 37 weeks; serious infant outcome; fetal alcohol syndrome/fetal alcohol spectrum disorder; or small-for-gestational age. Comparison 2: Ethanol versus other tocolytic (betamimetics) (nine trials, 1438 women) Compared to betamimetics (the only tocolytic used as a comparator in these studies), ethanol was associated with no clear difference in the rate of birth < 48 hours after trial entry (two trials, 130 women; average RR 1.12, 95% CI 0.53 to 2.37, Tau² = 0.19, I² = 59%), similar rates of perinatal mortality (six trials, 698 women; RR1.20, 95% CI 0.78 to 1.84), higher rates of neonatal mortality (eight trials, 1238 women; RR 1.43, 95% CI 1.02 to 2.02), higher rates of preterm birth < 34 weeks (two trials, 599 women; RR 1.56, 95% CI 1.11 to 2.19), higher rates of neonatal respiratory distress syndrome (three trials, 823 women; RR 1.76, 95% CI 1.33 to 2.33), and higher rates of low birthweight babies < 2500 g (five trials, 834 women; RR 1.30, 95% CI 1.09 to 1.54). These outcomes are likely all related to the lower incidence of preterm birth seen with other tocolytics, which for all these comparisons were betamimetics. Serious maternal adverse events were not reported in any of the nine trial reports. However, ethanol had a trend towards a lower rate of maternal adverse events requiring stopping or changing the drug (three trials, 214 women; RR 0.25, 95% CI 0.06 to 0.97). There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Planned sensitivity analysis, excluding quasi-randomized trials did not substantially change the results of the primary outcome analyses with the exception of neonatal mortality which no longer showed a clear difference between the ethanol and other tocolytic groups (3 trials, 330 women; RR 1.49, 95% CI 0.82 to 2.72). Authors' conclusions This review is based on evidence from twelve studies which were mostly low quality. There is no evidence that to suggest that ethanol is an effective tocolytic compared to placebo. There is some evidence that ethanol may be better tolerated than other tocolytics (in this case betamimetics), but this result is based on few studies and small sample size and therefore should be interpreted with caution. Ethanol appears to be inferior to betamimetics for preventing preterm birth in threatened preterm labor. Ethanol is generally no longer used in current practice due to safety concerns for the mother and her baby. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth in threatened preterm labour. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.

To characterize tocolytic use and examine perinatal outcomes among women presenting very preterm with spontaneous labor and cervical dilation 4 cm or greater.This was a retrospective cohort study. Data from January 2000 to June 2011 in a single health care system were reviewed. Women with singleton, nonanomalous fetuses and preterm labor with intact membranes between 23 and 32 weeks of gestation who had cervical dilation 4 cm or greater and less than 8 cm at admission were included. Women receiving one or more tocolytics (magnesium sulfate, indomethacin, or nifedipine) were compared with those who did not receive tocolysis. The primary outcome was composite major neonatal morbidity.Two hundred ninety-seven women were included; 233 (78.5%) received at least one tocolytic. Women receiving tocolysis were slightly less dilated (median 5 compared with 6 cm, P.001) at presentation and were more likely to receive at least a partial course of corticosteroids (88.4% compared with 56.3%, P.001). Initial composite severe neonatal morbidity rates were similar (41.6% compared with 43.8%, P=.761) regardless of tocolytic administration. Those receiving tocolysis were significantly more likely to be pregnant at least 48 hours after admission (23.6% compared with 7.8%, P=.005), but a similar proportion delivered within 7 days of admission (94.8% compared with 95.3%, P.99), and delivery gestational ages were similar (28.9 compared with 29.2 weeks, P=.408). The incidence of chorioamnionitis and postpartum endometritis was similar between groups.The majority of women presenting very preterm with advanced cervical dilation received tocolysis. Although tocolysis administration increased the likelihood of achieving at least 48 hours of latency, initial neonatal outcomes were similar.II.

In pregnant women, magnesium sulfate infusions are a treatment commonly used for preeclampsia and as a tocolytic agent. In this case report, a 33-year-old woman at 26 weeks of gestation received intravenous magnesium sulfate in Ringer's lactate solution and corticosteroids for preterm uterine contractions without preeclampsia. She developed polyuria of more than 18L in 48 hours, with urine chemistries documenting that magnesium sulfate contributed 30% of the solute in this massive isosthenuric diuresis. Therefore, magnesium sulfate should be added to the common solutes, glucose, sodium chloride, urea, and mannitol, as a cause of solute diureses.

The prostaglandin-F2α (PGF2α) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both Gαq- and Gα12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model ( Goupil ; et al. J. Biol. Chem. 2010 , 285 , 25624 - 25636 ). Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2α-induced myometrial contractions, potentiated the effect of PGF2α on Gαq-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the Gα12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.

Preterm labor (PTL) is a major cause of neonatal morbidity and mortality worldwide. Among the available tocolytics, indomethacin, a prostaglandin synthetase inhibitor, has been in use since the 1970s. Recent studies have suggested that prostaglandin synthetase inhibitors are superior to other tocolytics in delaying delivery for 48 hours and 7 days. However, increased neonatal complications including oligohydramnios, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the patent ductus arteriosus have been reported with the use of indomethacin. Indomethacin has been also used in women with short cervices as well as in those with idiopathic polyhydramnios. This article describes the mechanism of action of indomethacin and its clinical applications as a tocolytic agent in women with PTL and cerclage and its use in the context of polyhydramnios. The fetal and neonatal side effects of this drug are also summarized and guidelines for its use are proposed.

ATP-sensitive potassium channels (KATPchannels) are composed of sulfonylurea receptors (SURs) and potassium inward rectifiers (Kir6.x) that assemble to form a large octameric channel. This study was designed to examine the expression and role of sulfonylurea-binding regulatory subunits 1 (SUR1 (ABCC8)) and 2 (SUR2 (ABCC9)) of the KATPchannels in the pregnant rat myometrium with particular regard to the contractility. RT-PCR and western blot analyses were performed to detect the presence of SUR1 and SUR2. The SUR1 levels were markedly increased in the early stages of pregnancy. The highest level was detected on day 6 of pregnancy, whereas in the late stages, the levels of SUR1 were significantly decreased. The SUR2 level remained unchanged throughout pregnancy. The SUR non-selective diazoxide and the SUR2-selective pinacidil inhibited oxytocin-induced contractions. Glibenclamide, a KATPchannel blocker, antagonized both pinacidil- and diazoxide-induced relaxations. It was established that SURs are responsible for pharmacological reactivity of KATPchannel openers. We conclude that both SURs are involved in the KATPchannel in the pregnant rat myometrium. It may further be concluded that ‘pinacidil-like’ KATPchannel openers may be of therapeutic relevance as tocolytic agents in the future.

To characterize the pharmacokinetics of nifedipine when used for tocolysis in preterm labor and to determine the impact of genetics on these parameters.Pharmacokinetic study performed on women given tocolytic nifedipine. Over one dosing interval, drug concentrations, clinical data, and genotype for Cytochrome P450 (CYP)3A5 polymorphisms were obtained. Non-compartmental pharmacokinetic analysis was used to estimate nifedipine exposure at steady state.The mean nifedipine area under the curve in 20 pregnant women was 86.1±61.1 ng/ml/h. The mean nifedipine exposure differed by expression of CYP3A5 (expressers [exp]: 139.5±97.3 ng/ml/h vs. nonexpressers[non]: 68.3 ± 31.8 ng/ml/h, p = 0.02). Four women consumed CYP3A inhibitors and this affected the nifedipine concentrations (p 0.001). CYP3A5 expressers had less improvement in contraction frequency after the loading dose (p = 0.04), at steady state (p = 0.006), and at 0-1 h after the study dose (p 0.001).CYP3A5 genotype plays a role in nifedipine concentration when used as a tocolytic.

Purpose Animal models have confirmed high efficiency of combined tocolytic treatment in preterm labour. In humans, the recommended doses of tocolytic drugs prolong pregnancy in threatened preterm labour. The aim of the study was to evaluate the inhibitory effect of dual combinations of atosiban, nifedipine and celecoxib on human myometrial strips contractility on the in vitro model of preterm labour. Material/methods Two groups of patients who delivered by cesarean section were involved in the study: 36 patients who delivered preterm between the 24 th and 34 th week of pregnancy and 40 patients who delivered at term. Myometrial samples were obtained from the lower uterine segment during cesarean sections. Contractile activity was recorded with digital software for each drug combination: atosiban/nifedipine; atosiban/celecoxib, nifedipine/celecoxib. Tocolytic efficiency of the drug combinations was assessed using IC 50 parameter – a molar drug concentration inhibiting 50% of contractility. Results The atosiban/nifedipine combination has shown additive tocolytic effect on myometrial strips contractility in preterm and term patients. The other combinations: atosiban/celecoxib and nifedipine/celecoxib presented only antagonistic effects in both studied groups. Conclusions The effect of the combined therapy on human myometrial contractility presented in the study could be a base for further in vivo clinical trials.

Objective To compare the effectiveness and adverse effects of nifedipine versus indomethacin in the treatment of preterm labor. Methods In a randomized clinical trial, 79 women with labor pain at 26–33 weeks of gestation were treated with either oral nifedipine (n = 40) or rectal indomethacin (n = 39). Results Twenty-three (59%) women in the indomethacin group, and 10 (25%) in the nifedipine group did not respond to treatment (P = 0.002). None of the 16 and 30 women remaining in the indomethacin and nifedipine groups, respectively, delivered during the subsequent 48 hours. Of these remaining women, 1 (6.25%) in the indomethacin group and 4 (13.3%) in the nifedipine group delivered between 48 hours and 7 days (P = 0.162). For the women who responded to treatment, the mean gestational age at time of delivery was 238.5 ± 19.4 days and 246.4 ± 15.4 days in the nifedipine and indomethacin groups, respectively (P = 0.182). Seventeen (42.5%) women in the nifedipine group, and 11 (28.2%) in the indomethacin group showed adverse effects (P = 0.184). Conclusion Indomethacin was less effective than nifedipine for the fast treatment of preterm labor. For women who responded to treatment within 2 hours, however, the delaying of delivery by indomethacin was similar to that by nifedipine.

Aim: To compare the success rates and gestational ages at delivery of nifedipine, proluton depot administration as a tocolytic agent and bed rest groups to pregnant women with threatened preterm labor. Material and Methods: A total of 150 pregnant women with threatened preterm labor between 28 and 35 weeks of gestation were enrolled in the study. All women underwent contraction inhibition randomly sorted into three groups. The first and second groups were inhibited with nifedipine and proluton depot, respectively. The third group was admitted for bed rest. Results: Nifedipine, proluton depot and bed rest can be used to inhibit contraction in threatened preterm labor. However, when time-to-event test was used, nifedipine took the shortest time for contraction inhibition with statistical significance. Conclusion: Nifedipine, proluton depot and bed rest can be used successfully to inhibit contraction in threatened preterm labor. However, nifedipine took the shortest time to inhibit uterine contraction in threatened preterm labor.

The aim of this paper is to review available data about drugs for preventing preterm labour. Tocolytic therapy includesβadrenergic receptor agonists, NO donors, magnesium sulphate, prostaglandin-synthase inhibitors, oxytocin receptor antagonists, calcium-channel blockers, progesterone, 17-α-hydroxyprogesterone caproate, and antibiotics. Their specific effects on myometrial contractility, their safety, their efficiency, and side effects profile for the mother and the fetus are presented. The main question of why and for what reasons tocolysis should be administrated is discussed.

SUMMARY The common availability of assisted reproductive techniques (ART) has brought the increase of multiple pregnancies. Usually, soon after the preterm delivery of the first fetus in multiple pregnancies, the delivery of the remaining fetus also happens. Delayed interval delivery of the remaining fetus after preterm delivery of the first one allows to gain time for fetal lung maturity and to cope with prematurity. We present here live healthy neonatal outcomes in two sequential cases, one twin and one triplet pregnancies, after emergency cerclage followed by second emergency cerclage due to cervical tear with a delayed delivery of 72 and 74 days respectively. The success of pregnancy prolongation in cervical cerclage cases depends on how effectively uterine contractions are prevented and how possible subclinical infections are controlled. We suggest that use of antibiotics, anti-inflammatory and tocolytic agents should be the main target to safely postpone delivery of the remaining twin.

In the present study, we examined the uterine relaxant activity of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative opener of the large conductance Ca2+-activated K+ (BKCa) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC50 = 4.63 µmol/l; Emax = 94.85 ± 1.85%; 100 µmol/l, n = 6). It also reduced contractions induced by oxytocin (EC50 = 4.10 µmol/l; Emax = 84.3 ± 3.83%; 100 µmol/l, n = 6), prostaglandin F2α (EC50 = 2.14 µmol/l; Emax = 73.70 ± 5.21%; 100 µmol/l, n = 6) and acetylcholine (EC50 = 4.37 µmol/l; Emax = 83.67 ± 4.82; 100 µmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC50 = 3.04 µmol/l; Emax = 94.0 ± 3.12%; 100 µmol/l, n = 6) indicating its K+ channel opening activity. BKCa channel blockers penitrem A (100 nmol/l) and tetraethylammonium chloride (1 mmol/l) attenuated the inhibitory activities of TBIC (p < 0.001) but not other K+ channel blockers such as barium chloride and glibenclamide (KIR and KATP channel blockers, respectively). These results demonstrate the uterine relaxant effects of TBIC in a mechanism of action largely referable to the potentiation of the BKCa channels. We have provided evidence for the potential use of TBIC as a tocolytic agent and support for the utility of BKCa channel openers in pathophysiologic conditions involving smooth muscle hyperactivity.

Background: Antenatal MgSO4 administration is used extensively as a tocolytic agent and to treat preeclampsia. Various effects on the fetus and newborn have been reported, and MgSO4 has well-documented vasoactive effects. Objective: To determine if antenatal MgSO4 administration affects intestinal blood flow velocity in newborn preterm infants. Methods: Peak, mean and end-diastolic velocities in the superior mesenteric artery were measured on day 1 of life. Maternal medical records were reviewed to identify infants whose mothers had been administered MgSO4 for preterm labor or preeclampsia within 24 h of delivery. Result: Fifty-six infants were studied: 27 were exposed and 29 were not exposed to antenatal MgSO4. Mean birth weight (1,371 ± 349 and 1,401 ± 469 g, respectively), gestational age (29.7 ± 2.0 and 30.0 ± 2.9 weeks, respectively) and infant hemodynamic and clinical variables (other than clinical indication for antenatal MgSO4 administration) were similar between groups. There were no significant differences between the exposed and unexposed groups in intestinal blood flow velocities. For the exposed group, however, there was a significant negative correlation between mean velocity and the number of hours from birth to the time superior mesenteric artery blood flow velocity measurements were made (p = 0.002); there was no correlation for the unexposed group (p = 0.852). Conclusion: Group mean values indicate that antenatal exposure to MgSO4 does not significantly affect intestinal blood flow velocity in newborn preterm infants. However, the significant negative relationship between mean blood flow velocity and time from birth to blood flow velocity measurement in exposed infants suggests that there may be measurable effects of MgSO4 exposure within the hours immediately after birth. Trials that prospectively evaluate the development of intestinal blood flow velocities are needed to further clarify potential effects of antenatal MgSO4 on the gastrointestinal tract of preterm infants.

OBJECTIVES Cervical length assessment is helpful to predict and prevent preterm birth. However, transvaginal sonography is not easy to perform. The aim of this study was to investigate the relationship and discrepancies between cervical lengths measured by transabdominal and transvaginal sonography in midpregnancy. METHODS Transabdominal and transvaginal cervical lengths were measured in 255 pregnant women between 20 and 29 gestational weeks. The discrepancies in cervical lengths between the two methods were analyzed for the following maternal and fetal conditions: (1) vertex versus breech fetal presentation, (2) whether the fetal presenting part overlay the cervical internal os, (3) whether both the internal os and external os were visible or only the internal os was clearly visible, (4) maternal bladder filling status, (5) maternal age, (6) parity, and (7) gestational age. RESULTS The mean cervical lengths were not significantly different (mean ± SD, 3.88 ± 0.73 cm on transabdominal sonography and 3.93 ± 0.72 cm on transvaginal sonography; P = .129; Pearson r = 0.75). The 5th-percentile transabdominal cervical length was 26.0 mm, and the transvaginal length was 27.8 mm. There were significant discrepancies between the two methods in the cases in which a fetal presenting part overlay the internal os, in the cases in which the external os was not clearly visible, and in primiparous women. Transabdominal cervical measurements were consistently shorter than transvaginal measurements in the cases with discrepancies. CONCLUSIONS Transabdominal cervical length measurements are correlated with transvaginal measurements overall, and the transabdominal length is consistently shorter than the transvaginal length in cases with discrepancies. Transabdominal sonography could be used as a cervical length screening tool.

Please cite this paper as: Wilcox C, Nassar N, Roberts C. Effectiveness of nifedipine tocolysis to facilitate external cephalic version: a systematic review. BJOG 2011;118:423–428. Background The success rates of external cephalic version (ECV) are improved with the use of betamimetic tocolytics, but these drugs are associated with maternal side effects. Objectives To critically evaluate the effectiveness and advantages, if any, of nifedipine as a tocolytic for ECV. Search strategy We searched PubMed, OVID [Medline, all evidence-based medicine (EBM) reviews], Embase, the Cochrane clinical trials register and references therein. Selection criteria Randomised trials comparing nifedipine with placebo or another tocolytic agent among women with a singleton, term breech or transverse presentation. Data collection and analysis Two reviewers evaluated search results and extracted data from eligible studies using a standard data extraction form. Primary outcomes were success rates of ECV and cephalic presentation at delivery. Pooled relative risks and 95% confidence intervals were calculated for comparable studies, and where similar outcomes were assessed. Main results Three trials met the inclusion criteria. Two trials (n = 176) compared nifedipine with terbutaline and found lower rates of successful ECV among women receiving nifedipine, pooled risk ratio = 0.67 (95% CI 0.48–0.93, P = 0.016). One trial (n = 320) comparing nifedipine with placebo did not find any significant difference in ECV success rates (41.6% nifedipine versus 37.2% placebo, P = 0.43). Although minor side effects were slightly higher with nifedipine compared with placebo, there was no significant difference in the rate of adverse maternal or neonatal outcomes or maternal satisfaction between the nifedipine and terbutaline groups, and women in both groups showed a similar preference for oral administration (62% nifedipine and 71% terbutaline). Authors’ conclusions This review found no evidence to support the use of nifedipine for tocolysis to facilitate external cephalic version.

Summary Objective Pregnancies with extremely preterm premature rupture of membranes (EPPROM), especially before 20 weeks of gestation, are usually considered to be a termination of pregnancy. By improvement of obstetric and neonatal care, we can prolong the pregnancy across the threshold of survival by aggressive tocolysis. Case Report Using intrauterine insemination, a 32-year-old woman became pregnant with twins (first pregnancy). Threatened abortion occured since 9 weeks of gestation and EPPROM of the upper twin was noted at 18 weeks. Massive vaginal bleeding and vigorous uterine contractions occurred at 22 weeks. Poor control of preterm labor occurred using ritodrine and MgSO 4 . Atosiban was applied to calm uterine activities. After discontinuation of atosiban at 30 weeks, the uterine contractions became severe again and an emergency cesarean section was performed to deliver two live, premature babies weighing 1,518 g and 830 g, respectively. Twin A was healthy, weighing 2,030 g at 35 days after birth and subsequently discharged. The smaller twin B was dependent on continuous positive airway pressure and died of pulmonary infection 120 days after birth. Conclusion Comparing to other tocolytic agents, Atosiban has few side effects and assisted in prolonging a pregnancy involving twins that experienced EPPROM.

To investigate the outcomes of singleton and twin pregnancies that were complicated by spontaneous preterm labor and received nifedipine tocolysis.We identified the following subjects from a computerized, hospital database: 58 singleton and 32 twin pregnancies that were between 24 and 34 weeks of gestation, admitted for spontaneous preterm labor without rupture of the membranes, and receiving tocolysis with nifedipine. Data were analyzed using the Chi-square test, the Mann-Whitney test, and the Kaplan-Meier survival analysis.Spontaneous, preterm delivery occurred in 31.1% cases of singleton and 81.3% of twin pregnancies. Although the 22% of the mothers of twins did not have cervical changes upon admission, 37% of twins were delivered within 48 h. Mean for delivery weeks from admission to 36 weeks was significantly less for twin than it was for singleton gestations (32.3 ± 1.0 vs. 35.0 ± 0.5 weeks, respectively; Mantel-Cox X (2) = 41.118; p0.001). The maternal side effects were not significantly different between the groups. No serious cardiovascular complication had been found in either group.Tocolysis with nifedipine is effective and safe for use in both singleton and twin gestations.

The following review includes a number of studies on the effect of fetal fibronectin (fFN) testing and non-testing, as well as the positive and negative test results, some combining with transvaginal ultrasonographic measurement of cervical length primarily to reduce hospital admissions and length of hospital stay (with associated reduction in health service costs), in women presenting to hospital with symptoms of pre-term labour. English language medical literature was analysed using the search parameters: fetal fibronectin, cervical length, preterm labour, hospital admissions and length of stay. A total of 19 studies were included. Ten of these discussed the role of fFN in decreasing hospital admissions, transfers, length of stay and interventions like corticosteroids and tocolytics. Seven studies demonstrated a correlation of fFN testing with an actual estimate of cost savings of health resources. Five studies explored the combined predictability of fetal fibronectin and cervical length with regards to pre-term labour.