Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials

BackgroundThe risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject.Methods and findingsWe searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available.From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] −57/10,000 [95% CI −106/10,000 to −8/10,000], I² 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267).Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD −31/10,000, [95% CI −56/10,000 to −5/10,000], I² 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD −97/10,000 [95% CI −169/10,000 to −26/10,000], I² 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results.Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD −127/10,000, [95% CI −204/10,000 to −50/10,000], I² 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI −29/10,000 to 84/10,000], I² 55%).A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited.ConclusionsIn this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks.Study Registration: PROSPERO CRD42020163174

Mårten Alkmark and co-workers report on a meta-analysis of randomized trials of labour induction at 41 weeks'' gestation as compared with expectant management until 42 weeks.     

United Nations involvement in ocean mining

Abstract

Developing country governments seek implementation of the New International Economic Order (NIEO) through the medium of United Nations involvement in ocean mining. To understand the debate over the Draft Treaty it is important to identify the various functions that a UN authority could perform. There is, for example, no full precedent for a joint venture in which one of the parties, the Enterprise, is an international organization. Moreover, a central question regarding the proposed Seabed Authority is whether both promotion and control of commercial activity can be performed appropriately by the same agency. The essay considers a mining regime as envisaged under the Draft Treaty and alternatively as it may be under an interim reciprocal regime in the event of nonratification. Whatever the outcome of LOS III, another alternative, incremental implementation, should be rereviewed carefully.     

Antinociceptive effects in mice after intrathecal injection of a substance P receptor antagonist, Spantide: lack of 'neurotoxic' action

The present investigation was undertaken to determine the antinociceptive potency and possible neurotoxic effects of a substance P (SP) receptor antagonist, [D-Arg,D-Trp,Leu]SP (Spantide), after intrathecal injection in mice. After the nociceptive tests had been carried out, the animals were sacrificed and the spinal cords were investigated for histopathological changes, since such have been reported previously to occur in rats. It was found that the reaction latency in the tail-flick test increased in the dose range 0-10 micrograms. The effect was maximal at 10 and 45 min after 10 micrograms Spantide, and somewhat lower when 5 micrograms was used. None of the animals showed the complete motor impairment reported previously to occur after intrathecal administration in rats. In some of the mice we observed a slight rigidity in the hind-legs. At histopathological examination, it was found that Spantide produced no histological changes indicative of 'neurotoxic' effects. In agreement with this, the immunohistochemical evaluation, using calcitonin gene-related peptide (CGRP) as a marker for motoneurons and central branches of primary sensory neurons, did not provide evidence that the intrathecal injection of 10 micrograms Spantide produced any effects when compared to vehicle-injected animals. In conclusion, the present results demonstrate an antinociceptive effect of Spantide when injected intrathecally in mice, and that this occurred without any signs of toxic reactions in spinal cord as previously has been reported for the rat.     

Light-scattering study of DNA condensation: Competition between collapse and aggregation

Light-scattering studies were done to investigate the DNA collapse transition, a large and discontinuous reduction in the radius of gyration. Of particular concern was differentiating the compaction of a single DNA molecule from aggregation. Solutions of RK2 plasmid DNA (M_r = 37 × 10⁶) or bacteriophage T7 DNA (M_r = 25 × 10⁶) were titrated with the condensing reagents spermidine in aqueous solvent or magnesium ion in ethanol–water solvent. The transition was followed by the change in scattering at a single angle or by the change in the angular dependence of scattering. At concentrations below 1 μg/mL, only aggregation could be detected by observation at a single angle; therefore, to study the collapse transition, it was necessary to measure the angular dependence of scattering. The intensities measured between the angles 30° and 60° were fit to known scattering functions. At low concentrations of the condensing reagent, the data were consistent with the scattering function of a random coil. On the other hand, during the transition at higher reagent concentrations, the curve that fit the data required two components—the scattering function for a random coil with a large radius of gyration, plus that for a sphere with a radius about one-fifth of that of the coil. The fractional concentration of the sphere increased with increasing condensing-reagent concentration. This two-component behavior is in apparent contrast to the situation with a more flexible polymer such as polystyrene, in accord with theoretical predictions. At still higher reagent concentrations, aggregation was apparent. Condensation to a collapsed state was reversible without hysteresis, while dissolution of the aggregated state nearly always occurred with hysteresis. Qualitative agreement between the observed DNA collapse transition and the theoretical phase diagram presented in the preceding paper was found, although the light-scattering results did not show quantitative agreement with the simple theoretical model.     

Composition and organization of sarcolemmal fatty acids in cultured neonatal rat cardiomyocytes

This paper describes studies on the fatty acid composition of individual phospholipids of the neonatal rat cardiomyocyte as well as in the gas-dissected sarcolemma derived from those cells. There is a sarcolemmal fatty acid asymmetry between the two leaflets of the membrane, which results from an asymmetric phospholipid distribution and particular fatty acid composition of each phospholipid class. The cytoplasmic leaflet is shown to be more unsaturated than the outer one. The phospholipids preferring the inner sarcolemmal leaflet (PE, PS, and PI) are particularly rich in two fatty acids, stearic acid and arachidonic acid. The implications of the data in current models for Ca2+ binding and for disruption of sarcolemma following ischemia and reperfusion damage are discussed.     

The response of small vessel endothelial cells from fetal rat lung to growth factors

Small vessel pulmonary endothelial cells were obtained from rat fetal lung at day 20 of gestation, and were maintained in culture to passage three for study. Endothelial cells grown on a collagen matrix with Dulbecco's minimal essential medium: Ham's F12 medium (1:1, v/v) supplemented with 20 ml/l fetal bovine serum, bovine pituitary extract (50 mg/l), endothelial cell growth supplement (100 mg/l), hydrocortisone (1 mg/l) and an increased (10 mmol/l) magnesium concentration retained the characteristic endothelial cell marker factor VIII antigen during the third passage in culture. The factors responsible for small vessel growth in the developing fetal lung are unknown. To test the hypothesis that small vessel pulmonary endothelial cells would respond to autocrine or paracrine growth factors the effects of conditioned media from fetal lung endothelial cells, fibroblasts and pneumocytes from lungs of the same gestational age were studied in vitro. None of the tested conditioned media had any effect on endothelial cell DNA synthesis in the presence of 20 ml/l fetal bovine serum. Since no paracrine or autocrine effects of conditioned media were observed, the effect of other growth factors that could be derived from the circulation, or from storage sites in subcellular matrix, were studied for effect. When endothelial cells were studied in the presence of 20 ml/l fetal bovine serum and 100 mg/l endothelial cell growth supplement they had enhanced DNA synthesis in response to the progression-type growth factors insulin (5 mg/l), insulin-like growth factor-I and insulin-like growth factor-II (20 micrograms/l) and epidermal growth factor (10 micrograms/l). In the absence of serum or endothelial growth supplement endothelial cell DNA synthesis was enhanced by the competence-type growth factors acidic and basic fibroblastic growth factors at 100 micrograms/l and platelet derived growth factor at 10 micrograms/l. In the absence of exogenous competence-type growth factors neutralizing antibodies to basic fibroblast growth factor reduce DNA synthesis. Of various cytokines tested only interleukin-1 (1 x 10(3) U/l) and tumor necrosis factor (25 x 10(4) U/l) had an effect on endothelial cell DNA synthesis. Endothelial cell division during fetal lung development may be controlled by progression growth factors present in serum, and by either autocrine release of the competence factor basic fibroblast growth factor or paracrine release of platelet-derived growth factor by other cell types.     

Concentrations of testosterone and androsterone in peripheral and umbilical venous plasma of fetal rats

Mean +/- s.d. testosterone concentrations in the peripheral plasma of 21- and 22-day-old male fetuses (1.32 +/- 0.43 ng/ml) were significantly (P less than 0.05) higher than those in the umbilical venous plasma (0.37 +/- 0.08 ng/ml). Testosterone concentrations in umbilical venous plasma of male and female (0.29 +/- 0.06 ng/ml) fetuses and in peripheral plasma of female fetuses (0.36 +/- 0.10 ng/ml) were not significantly different. Androsterone levels measured in umbilical venous plasma of male (11.5 +/- 2.5 ng/ml) and female (12.3 +/- 2.1 ng/ml) fetuses were nearly as high as those in peripheral plasma (males, 12.9 +/- 3.1; females, 13.3 +/- 3.5 ng/ml). There were high concentrations of androsterone in the placentas of male (33 +/- 4 ng/g) and female (33 +/- 5 ng/ml) fetuses, suggesting that this organ is the major source of fetal androsterone. We also conclude that a major part of the testosterone present in female fetuses is secreted by the placentas.     

Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice.

Hypodactyly (Hoxa13Hd) mice have a small deletion within the coding sequence of Hoxa13 and a limb phenotype that is more severe than that of mice with an engineered null allele of Hoxa13. We used whole-mount in situ hybridization, Nile blue sulfate staining and genetic crosses to determine the basis for the phenotypic differences between these two mutants. Expression of Hoxd13 was unaffected in Hoxa13-/- mice, but its domain was reduced at the anterior and posterior margins of the autopod in Hoxa13Hd/Hd limb buds. The maturation of Hoxd11 expression was delayed and expression of Hoxa11 failed to become restricted to the autopod/zeugopod junction in both Hoxa13Hd/Hd and Hoxa13-/- limb buds compared to wild-type mice. Fgf8 expression was normal in both Hoxa13Hd/Hd and Hoxa13-/- mice throughout limb development. A dramatic increase in cell death was observed in limb bud mesenchyme of Hoxa13Hd/Hd mice as early as E11.5 but not in mice homozygous for the null allele. Genetic background was excluded as the basisforthe phenotypic differences. Compound heterozygotes (Hoxa13-/Hd) displayed an intermediate phenotype relative to both homozygotes suggesting that Hoxa13Hd has an effect on the development of the autopod beyond that which may result from a loss of HOXA13 protein. These results showthat Hoxa13Hd has a negative effect on the survival of the mesenchyme in the autopod, unlike the Hoxa13 null mutation, that cannot be explained by a failure of the AER to express Fgfs. In addition, at least one target of HOXA13 may be Hoxa11.