Tocolytic Research Articles

Colonial adventures in tropical agriculture: new estimates of returns to investment in the Netherlands Indies, 1919–1938

How profitable were foreign investments in plantation agriculture in the Netherlands Indies during the late colonial era? We use a new dataset of monthly quoted stock prices and dividends of international companies at the Brussels stock exchange to estimate the returns to investment in tropical agriculture (1919–1938). We adopt the Dimson–March–Staunton method to compute real geometric annual average rates of return and assess our estimates in an international comparative perspective. We find that returns to colonial FDI in the Netherlands Indies during 1919–1928 were impressive (14.3 %), being almost 3 percentage points higher than the world average. In the following decade 1929–1938 fortunes reversed, with a rate of return of −2.8 % compared to a world average of 2.2 %. Over the entire period the returns to colonial FDI (5.4 % in 1919–1938) were about a factor 2.5 higher than returns to investment in the Dutch domestic economy (2.1 % in 1920–1939). We argue that these returns should be interpreted in a colonial context of systematic labour repression, but that they may also partly reflect a higher risk-premium of investments in colonial commodities.

Corticosteroid Use in the Face of Threatened Preterm Labor [165

BACKGROUND: Patients presenting with a shortened cervix and uterine contractility between 24 and 34 weeks of gestation are at risk for preterm delivery and candidates for administration of corticosteroids to abate associated neonatal mortality and morbidity. Our observations indicate that many patients treated with aggressive tocolytic agents deliver well beyond the 7-day steroid effectiveness, giving rise to concerns that such patients are receiving corticosteroids unnecessarily. The goal of this investigation was to determine the number of such cases. METHODS: One hundred six singleton pregnancies, with cervical lengths less than 25 mm, at risk of preterm labor, who subsequently delivered, were reviewed. Patients were stratified by delivery gestational age, ranging from less than 28 weeks of gestation to full term. Variables included maternal demographics, gestational age, and cervical lengths at admission and delivery, time of steroid administration, and neonatal outcomes. RESULTS: No differences were noted between admission cervical length (mean 11.4±9.7) and delivery. Likewise, admission cervical length at less than 34 weeks of gestation compared with deliveries at greater than 34 weeks of gestation were found to be nonsignificant (P=.27). Nor were dynamic changes in cervical length between groups significant (P=.15). Prior steroidal administration (days) to delivery was significant with those greater than 34 weeks of gestation receiving the earliest predelivery doses (mean 71.3±45.2, P<.001). This cohort encompassed 40.8% of the entire steroid group, thus nullifying treatment indications. All other factors were found to be nonsignificant. CONCLUSION: Careful assessment of several factors in women presenting in preterm labor must be taken into consideration before providing a regimen of care that may or may not be beneficial to the fetus or neonate.

Role of Lipocalin-type prostaglandin D2 synthase (L-PGDS) and its metabolite, prostaglandin D2, in preterm birth

The objective of the study was to investigate the role of prostaglandin D2 during pregnancy and its mediator Lipocalin-type prostaglandin D2 synthase (L-PGDS) as a predictor of preterm birth (PTB). Transgenic L-PGDS (+/+), L-PGDS (−/−) and C57BL/6 control pregnant mice models were used to determine the effect of DP1 and DP2 receptor antagonists in lipopolysaccharide (LPS)-induced PTB mice. In addition, L-PGDS levels were measured in the cervicovaginal secretions (CVS) of 370 pregnant women using ELISA and further processed for isoform detection using 2-D gel electrophoresis. Our results found that C57BL/6 control mice (n=26), transgenic L-PGDS (+/+) (n=26), demonstrated an 89% and 100% preterm birth in LPS (intraperitoneal injection, 20mg/kg) induced mice model respectively. Interestingly, the incidence of PTB was significantly reduced to 40% in L-PGDS (−/−) knockout mice (n=26). DP1 and DP2 receptor antagonists (0.264μg/day, dose of 0.1μg/μl with the flow of 0.11μl/h for 28 day using Alzet pumps) were used to investigate the effect in LPS-induced PTB in C57BL/6 mice and found 3.3-fold increase in viable pups after LPS-induction. In addition, L-PGDS levels were measured in CVS samples and found that PTB women (n=296) had two-fold higher levels compared to full term births (n=74) and established a significant inverse correlation between levels of L-PGDS and days to expected delivery by using 370 preterm birth CVS samples. Elevated L-PGDS levels in the CVS of women may be considered as a potential biomarker for PTB in future. Secondly, the use of DP1 and DP2 receptor antagonists may represent novel tocolytic agents for the treatment of PTB.

Wybrane metaloproteinazy i ich inhibitory w przewidywaniu skuteczności tokolizy nifedypiną

Wybrane metaloproteinazy i ich inhibitory w przewidywaniu skuteczności tokolizy nifedypiną

The effect of Indomethacin and Betamethasone on the cytokine response of human neonatal mononuclear cells to gram-positive bacteria

Intrauterine infections with gram-positive bacteria pose a serious threat to neonates since they can result in neonatal sepsis, induce a fetal inflammatory response and also cause preterm birth. Despite intensive care, prematurity remains a leading cause of neonatal death, and is often accompanied by a number of morbidities. In order to prevent premature birth, tocolytic agents like Indomethacin are administered. Betamethasone is used to promote lung maturation and prevent respiratory distress syndrome. A combination of both drugs is assumed to prevent premature delivery while simultaneously facilitating lung maturation. This study investigates the effect of Betamethasone, Indomethacin and a combination of both on the cytokine production of neonatal cord blood mononuclear cells (CBMC) after stimulation with lysates of the gram-positive pathogens Streptococcus agalactiae and Enterococcus faecalis. The aim of the study is to determine the impact of these drugs on the function of the neonatal immune system which should aid clinicians in choosing the optimal therapy in case of preterm birth associated with intrauterine infection. Betamethasone reduced the production of the pro-inflammatory cytokines IL-6, IL-12p40, MIP-1α and TNF and increased the expression of the anti-inflammatory cytokine IL-10, depending on the pathogen used for stimulation. In contrast to Betamethasone, Indomethacin almost exclusively increased IL-10 production. The combination of both drugs decreased the expression of IL-6, IL-12p40, MIP-1α and TNF while increasing IL-10 production, depending on the concentration of Indomethacin and the pathogen used for stimulation. Based on our results, the combination therapy with Indomethacin and Betamethasone has a similar effect on cytokine production as Betamethasone alone, which is generally administered in case of impending preterm birth. However, the combination therapy has the advantage of promoting lung maturation while simultaneously blocking preterm labor effectively.

Recent trend of acute appendicitis during pregnancy.

We report the clinical presentation, management and outcomes of 33 patients who underwent surgery for acute appendicitis during pregnancy between April 1997 and March 2011. Several variables were compared between these 33 patients (pregnant group, n = 33) and non-pregnant females aged 20-40 years who underwent an acute appendectomy during the same period (control group, n = 124). No significant differences were found between the two groups in terms of the type of anesthesia, operative method, duration of surgery, pathology, duration of antibiotic use, and incidence of surgical site infection, except for a higher frequency of pararectal incision performed and higher leukocyte counts in the pregnant group (P < 0.01). Tocolytic agents were administered to 17 patients (52%). Preterm labor occurred in 10 patients (30%), one of whom experienced preterm delivery. These results suggest that acute appendicitis during pregnancy can be managed successfully without fetal loss.

Study on role of magnesium Sulphate as a Tocolytic agent in preventing preterm labour

A prospective study was done to assess the effectiveness of magnesium sulphate therapy given to women in preterm labour with the aim preventing preterm birth and its sequel. The place of study was the Department of Obstetrics &amp; Gynecology, Sir Salimullah Medical College &amp; Mitford Hospital, Dhaka. The study population were all primi and multigravida with preterm labour admitted in the above mentioned hospital, from January to December, 2009. Gestational age, maternal pulse, blood pressure, temperature, urine output, respiratory rate, uterine contractions, cervical effacement, dilatation and amniotic membrane status were elicited. Data were collected by questionnaire and analyzed with SPSS version 12.0. The results showed that magnesium sulphate injection is an effective method for tocolysis and appears to be safe for the mother and fetus and is a promising option for the treatment of preterm labour in a low resourced setting. DOI: http://dx.doi.org/10.3329/jdmc.v22i2.21538 J Dhaka Medical College, Vol. 22, No.2, October, 2013, Page 179-184

“Dermal Nitroglycerin Patch” in Treatment of Preterm Labour

Although preterm birth is the delivery before 37 + 0 weeks of gestation, the majority of prema-turity-related complications occur before 33 + 0 weeks of gestation. The need of today is to select the best agent out of the broad spectrum of available tocolytic agents, for providing maximum benefit to unfortunate sufferers of prematurity. The study aims to assess the role of “Dermal Nitroglycerin Patch” in treatment of preterm labour. Method: Study conducted in Department of Obstetrics & Gynecology, NIMS Medical College & Hospital, Jaipur from July 2014-December 2014. A prospective randomized study of 50 women of preterm labor was enrolled after informed consent. Patients were given dermal nitroglycerin patch as tocolytic agent according to study protocol. Result: 1) Results of NTG PATCH are comparable with other tocolytic drugs in terms of successful tocolysis; 2) Maternal and fetal outcome is favourable in cases of NTG PATCH USE in preterm labour; 3) Side effect profile was also better with NTG Patch. Conclusion: This randomized prospective study lends support to the proportion that Transdermal Nitroglycerine (NTG Patch) may be promising safe, effective, well tolerated, cost effective and non invasive method of tocolysis.

Magnesium Sulphate as a Tocolytic Agent in Preterm Labour

Background: Prematurity and its prevention continue to be a major challenge for both the obstetrician and neonatologist. Preterm labour is the most common obstetrical complication associated with perinatal deaths. Despite all advances in neonatology, the delivery of a preterm neonate is a clinical crisis that threatens the life and health of an infant. The obstetrician thus faces the challenge of affecting the delivery in such a way as to optimize the status of fetus-infant at birth. It is far more preferable to prevent the intiation of preterm labour than once the cascade of events has already been established. Objective: To assess the efficacy of magnesium sulphate as a tocolytic agent in preterm labour. Material and Methods: 50 pregnant patients with gestational age 28- 37 weeks with cervical dilatation not more than 3cm and cervical effacement not more than 50 % with intact membranes with regular uterine contractions with a frequency of 2 or more per 10 minutes lasting for at least 30 seconds were put on magnesium sulphate. Results: Magnesium sulphate was successful in attaining tocolysis in majority of patients and had no adverse effects on immediate neonatal out come. Conclusion: Magnesium sulphate is effective, safe and well tolerated tocolytic agent with no adverse effects on the fetus-infant.

Preclinical appraisal of terbutaline analogues in precipitation of autism spectrum disorder

Terbutaline is a β2 agonist used in the clinical management of asthma and as a tocolytic agent during pregnancy.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Preterm placental abruption: Tocolytic therapy regarded as a poor neonatal prognostic factor

Aim: To elucidate factors associated with a poor neonatal prognosis in preterm placental abruption. Methods: A multicenter retrospective study was conducted. A total of 247 cases with preterm placental abruption during 2009, derived from an electronic database constructed by the Japan Society of Obstetrics and Gynecology, were investigated as the subjects of this study, and were divided into three groups: very preterm (VPT, n=66) was delivered at 28 to 31 gestational weeks, preterm (n=56) was at 32 and 33 weeks, and late preterm (LPT, n=125) was at 34 to 36 weeks. Risk factors, clinical course, and neonatal/infantile outcomes were compared. Poor neonatal outcome was defined as stillbirth, or neonatal and infantile death, or cases with neurological disability at 2 years of age. Results: The number of subjects who received tocolytic therapy was significantly higher in the VPT group as compared with the LPT group. It was higher in the VPT group even after excluding the 57 stillbirths. Multiple logistic regression analysis revealed that poor prognostic factors were umbilical arterial pH (Δ=0.1) (0.17 [0.069-0.417], p<0.0001) and tocolytic therapy (28.5 [2.014-403.9], p<0.0132). Conclusion: Administration of tocolytic agents is a possible factor in a poor neonatal prognosis in preterm placental abruption. This finding may suggest that differential diagnosis could improve the prognosis.

The Tortuous Path to a New Economic Agenda in Egypt and Tunisia

Three overarching features characterize the recent economic evolution of Egypt and Tunisia. First, they were the celebrated macroeconomic “success stories” of neoliberalism in the Arab Mediterranean and participated fully in the worldwide economic boom of the 2000-2008 period. Second, the accompanying spread of negative features ultimately underpinned the uprisings of 2010-2011, including unemployment, especially among educated youth, poverty, especially in the neglected hinterlands, expanding informal sectors, corruption and cronyism, electoral fraud, and repression of labor, civil society organizations and political opposition. Third, as of March 2014, none of the governments that followed the ousting of the Mubarak and Ben Ali regimes had presented a coherent program for more equitable and sustainable economic transformation, while political turmoil, violence – two political assassinations in Tunisia and the overthrow of the elected president in Egypt -- and instability prevailed. Aside from the perpetuation of stagnation in an atmosphere of mistrust and uncertainty, there was a spectrum of possible approaches for economic transformation. From “right to left” these included (1) neoliberalism with an inclusive mask, as promoted by the IFIs and Deauville Partnership, (2) a developmental state and industrial policy in the East Asian mode, (3) a more egalitarian developmental state as proposed by the United Nations Development Program (UNDP) and International Labor Organization (ILO), and (4) a citizen-led developmental state as encoded in the work of NGOs and the independent trade union movement.

Current practices in the prediction and prevention of preterm birth in patients with higher-order multiple gestations

We sought to determine the interventions utilized by maternal-fetal medicine specialists in the prediction and prevention of preterm labor in higher-order multiple (HOM) gestations. Online questionnaires and email surveys were sent to all the maternal-fetal medicine specialists in Canada (n=122). Questionnaire items included interventions physicians routinely recommended for HOM gestations including: (1) bed rest; (2) cervical length measurement on transvaginal ultrasound; (3) corticosteroids use; (4) cerclage; and (5) tocolytic therapy. Response rate was 66% (81/122), with 68% of respondents in practice for >10 years. Of physicians, 91% did not routinely recommend bed rest (95% confidence interval [CI], 84.7-97.2). In all, 82% (95% CI, 73.63-90.4%) recommended routine cervical length assessment with 32.3% (95% CI, 20.7-43.2) and 37.1% (95% CI, 25.3-48.6) of this group suggesting assessment at 16-18 and 19-21 weeks, respectively. Frequency of assessment varied from biweekly (53.3%; 95% CI, 40.9-65.0), to monthly (23.3%; 95% CI, 12.8-33.1), to a single measurement repeated only if abnormal (12.5%; 95% CI, 4.5-20.8). In all, 28% (95% CI, 18.2-37.8) recommended routine administration of corticosteroids for lung maturation. Timing of administration varied, with 24% initiating steroids between 24-26 weeks, 59% between 27-28 weeks, and 17% after 28 weeks. None reported routine cerclage placement. However, 71% (95% CI, 61.1-80.8) would perform cerclage based on history or ultrasound. Of respondents, 81% (95% CI, 72.4-89.5) would consider using tocolytic agents for threatened preterm labor including calcium channel blockers (94%), nonsteroidal antiinflammatory drugs (5%), and nitroglycerin transdermal patch (24%). The variable practice guidelines and paucity of data for management of HOM pregnancy places the onus on individual practitioners to develop their own management schemes. This results in heterogeneous management, which is based on conflicting international guidelines, studies, expert opinion, or past experience.

Synthesis and alkylation of Aza-Gly-Pro building blocks of peptidomimetic libraries for developing prostaglandin F2α receptor modulators as therapeutics to inhibit preterm labor.

Premature birth is a steadily increasing unmet medical need, for which new "tocolytic" agents are required to arrest contractions and delay labor. A peptide-based approach was developed to produce modulators of the prostaglandin F2α receptor as a novel target for tocolytic development. In this strategy, the solution-phase synthesis and alkylation of aza-glycyl-proline building blocks were key for the preparation of a series of modulators exhibiting biased signaling. An optimized method is now provided for making the aza-Gly-Pro unit with minimum side product, and alkylation of the unit is described to illustrate the library diversification step. Conditions have been reported for selectively unmasking the protecting groups at the N- and C-terminal of the aza-dipeptide unit and for its introduction into analogs that modulate the signaling of the PGF2α receptor. The merits of this protocol for azapeptide synthesis have thus been demonstrated by the synthesis of inhibitors of myometrial contraction exhibiting potential as prototypes for developing tocolytics to treat preterm labor.

84: Effect of tocolytic medications on synthesis and secretion of surfactant in an in-vitro human lung cell model

84 Effect of tocolytic medications on synthesis and secretion of surfactant in an in-vitro human lung cell model Ziad Haidar, Shamili Sammohi, David Cool, David Mckenna UT HealthUniversity of Texas Medical School at Houston, OB/GYN, Houston, TX, Wright State University, OB/GYN, Dayton, OH OBJECTIVE: To compare the effects of magnesium sulfate, nifedipine, and indomethacin on surfactant synthesis and secretion in adult human lung cells STUDY DESIGN: Human adult lung cells (NCI-H441) were grown to confluence in Waymouth’s MB571/5 medium containing 2% Hyclone and 1.5% Cellgro, containing 10,000 unit/ml penicillin G sodium, 10,000 ug/ml streptomycin sulfate, and 25 ug/ml amphotericin B. The plates were then divided into 4 groups, consisting of three tocolytics and a control. Tissue-equivalent doses of the tocolytics were used to mimic the steady state in-vivo levels of the following doses and routes of administration: indomethacin: 25mg po q6h, nifedipine 10mg po q6h, and magnesium sulfate 2 g/h IV. Betamethasone (BMZ) was added to each group to achieve a comparable tissue concentration to what is achieved clinically when 12 mg IM is given, and then repeated twenty four hours later. Lipids were extracted from the supernatant and separated on anHP-TLC plate in an organic solvent system. The lipids were primuline stained and examined for relative density under a DyLight 488 nmwith a ChemDocMP imaging camera (Bio-Rad, Hercules, CA) from 1 to 10 seconds, and the best image was saved for evaluation. RESULTS: The primuline stained cells showed an increased amount of surfactant B synthesis in each of the combinations: BMZ+nifedipine, BMZ+magnesium, BMZ+indomethacin. Compared to cells containing BMZ alone, the lipid extraction, which is indicative of the cells’ secretion phase, showed a significant increase with BMZ+magnesium and BMZ+indomethacin and decrease with BMZ+nifedipine CONCLUSION: This in-vitro human adult lung cell model demonstrated significant effects on surfactant synthesis and secretion when different tocolytic agents were given along with betamethasone. It is speculated this may be due to intracellular calcium-dependent interactions with the specific tocolytic agents in the type II pneumocytes. Further work is required to illicit the exactmechanism responsible for thesefindings.

The effect of nifedipine tocolysis on Doppler indices of the uterine and umbilical arteries.

The aim of this study was to evaluate the effect of oral nifedipine on Doppler indices of the uterine artery (UtA) and umbilical artery (UA) before and 24 hours, 48 hours, and 1 week after tocolytic treatment. This was a prospective, self-controlled, cohort study of 65 pregnant women undergoing nifedipine tocolysis. Doppler assessment of the UtA and UA was performed before treatment and 24 hours, 48 hours, and 1 week after the initial 4 doses of 10 mg of oral nifedipine, administered at 20-minute intervals. The maintenance dosage was 20 mg of oral nifedipine administered every 6 hours for 48 hours, for a total dose of 80 mg/day. There was a decrease in the 24-hour values of the UA pulsatility index, resistance index (RI), systolic-diastolic (S:D) ratio, right UtA pulsatility index, RI, S:D ratio, and left UtA RI and S:D ratio with nifedipine therapy in comparison with the values recorded prior to nifedipine therapy. However, these differences were not statistically significant. There were no statistically significant differences between the data recorded prior to nifedipine administration and those obtained at 48 hours and 1 week after treatment. Oral nifedipine is a safe tocolytic agent with no long-term effect on fetomaternal circulation in pregnant women at risk of preterm delivery.

Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis

The purpose of this study was to provide an updated summary of the literature regarding the effects of tocolysis with indomethacin on neonatal outcome by systematically reviewing previously and recently reported data. All previously reported studies pertaining to indomethacin tocolysis and neonatal outcomes along with recently reported data were identified with the use of electronic databases that had been supplemented with references that were cited in original studies and review articles. Observational studies that compared neonatal outcomes among preterm infants who were exposed and not exposed to indomethacin were included in this systematic review. Data were extracted and quantitative analyses were performed on those studies that assessed the neonatal outcomes of patients that received antenatal tocolysis with indomethacin. Twenty-seven observational studies that met criteria for systematic review and metaanalysis were identified. These studies included 8454 infants, of whom 1731 were exposed to antenatal indomethacin and 6723 were not exposed. Relative risks with 95% confidence intervals were calculated for dichotomous outcomes with the use of random and fixed-effects models. Metaanalysis revealed no statistically significant differences in the rates of respiratory distress syndrome, patent ductus arteriosus, neonatal mortality rate, neonatal sepsis, bronchopulmonary dysplasia, or intraventricular hemorrhage (all grades). However, antenatal exposure to indomethacin was associated with an increased risk of severe intraventricular hemorrhage (grade III-IV based on Papile's criteria; relative risk, 1.29; 95% confidence interval, 1.06-1.56), necrotizing enterocolitis (relative risk, 1.36; 95% confidence interval, 1.08-1.71), and periventricular leukomalacia (relative risk, 1.59; 95% confidence interval, 1.17-2.17). The use of indomethacin as a tocolytic agent for preterm labor is associated with an increased risk for severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia.

Dual tocolysis with fenoterol and atosiban in human myometrium demonstrates additive effect in vitro

Introduction: A combination of tocolytic agents may be reasonable in order to expand therapeutic options. In vitro studies in rats have demonstrated that the combination of ritodrine with atosiban led to a synergistic inhibition of myometrial contractility. Currently there are no studies in human myometrium.

Histological features of placenta diagnosed with twin anemia-polycythemia sequence

Histological features of placenta diagnosed with twin anemia-polycythemia sequence