Progesterone and oestradiol levels and cytoplasmic receptor concentrations in the human myometrium at term, before labour and during labour

Progesterone (P) and oestradiol (E2) cytoplasmic receptor levels in the myometrium of 12 women, who underwent cesarean section at term were determined by means of an exchange assay. Six of the women had an elective cesarean section, and the other six were in active labour when the operation was performed. Both the P and the E2 receptor concentrations were significantly higher in the myometrium of those women who were in labour. The plasma P and E2 levels did not change before labour and during labour. The myometrial E2 concentrations were also similar in both groups. The myometrial P concentration was lower in the labour group, but the difference was not statistically significant. This study is the first which compares the steroid receptor levels at term before labour and during labour in human myometrium, although only the unbound and the cytosol receptor levels were determined. The change of levels in receptor concentrations could be a sign of the decrease of the P dominance in the myometrium during labour.     

Delivery after caesarean section: review of 2176 consecutive cases.

A total of 2176 consecutive patients who had had one previous caesarean section were studied retrospectively. A repeat elective caesarean section was performed in 395 (18.2%). Labour started spontaneously in 1363 patients, 301 of whom were given oxytocin to accelerate inert labour, and was induced by amniotomy and infusion of oxytocin in 418 women; 1618 of these 1781 patients (90.8%) delivered vaginally. Patients who had had a previous vaginal delivery were more likely to deliver vaginally again. Those women in whom the initial caesarean section had been performed during labour before the cervix was 4 cm dilated were less likely to deliver vaginally than those who had progressed further in labour or those who had had an elective caesarean section. Similarly, those who received oxytocin to stimulate inert labour were more likely to require a repeat caesarean section than those who did not. The uterine scar ruptured in only eight (0.45%) of the 1781 patients allowed into labour. The risk of rupture of the scar was not increased by the use of oxytocin alone either to induce or to accelerate labour. The combination of oxytocin to accelerate labour and epidural analgesia to provide pain relief, however, was associated with an increased incidence of scar rupture. Labour may be safely allowed in women who have had a previous caesarean section, most of whom will deliver vaginally. Induction of labour does not increase the risk of either a repeat caesarean section or rupture of a uterine scar.     

Paraoxonase 2 Protein Is Spatially Expressed in the Human Placenta and Selectively Reduced in Labour

Humans parturition involves interaction of hormonal, neurological, mechanical stretch and inflammatory pathways and the placenta plays a crucial role. The paraoxonases (PONs 1–3) protect against oxidative damage and lipid peroxidation, modulation of endoplasmic reticulum stress and regulation of apoptosis. Nothing is known about the role of PON2 in the placenta and labour. Since PON2 plays a role in oxidative stress and inflammation, both features of labour, we hypothesised that placental PON2 expression would alter during labour. PON2 was examined in placentas obtained from women who delivered by cesarean section and were not in labour and compared to the equivalent zone of placentas obtained from women who delivered vaginally following an uncomplicated labour. Samples were obtained from 12 sites within each placenta: 4 equally spaced apart pieces were sampled from the inner, middle and outer placental regions. PON2 expression was investigated by Western blotting and real time PCR. Two PON2 forms, one at 62 kDa and one at 43 kDa were found in all samples. No difference in protein expression of either isoform was found between the three sites in either the labour or non-labour group. At the middle site there was a highly significant decrease in PON2 expression in the labour group when compared to the non-labour group for both the 62 kDa form (p = 0.02) and the 43 kDa form (p = 0.006). No spatial differences were found within placentas at the mRNA level in either labour or non-labour. There was, paradoxically, an increase in PON2 mRNA in the labour group at the middle site only. This is the first report to describe changes in PON2 in the placenta in labour. The physiological and pathological significance of these remains to be elucidated but since PON2 is anti-inflammatory further studies are warranted to understand its role.     

Total matrix metalloproteinase-8 serum levels in patients labouring preterm and patients with threatened preterm delivery

Preterm labour and prematurity are still a main cause of perinatal morbidity nowadays. The aim of our study was to assess the role of MMP-8 as a predictive marker of preterm delivery. Four groups of patients were involved to the study: I - pregnant women at 24-34 weeks of gestation with any symptoms of threatened preterm labour; II - threatened preterm labour patients between 24-34 weeks of gestation; III - preterm vaginal delivery patients; IV - healthy term vaginal delivery patients. Serum concentration of total MMP-8 was measured using two enzyme-linked immunosorbent assays. There were no significant differences in the median concentrations of total MMP-8 between physiological pregnancy and threatened preterm labour patients with existing uterine contractility. No significant differences of total MMP-8 were either found between healthy term and preterm labouring patients. The studies on a larger population are needed to reject the hypothesis that preterm labour is connected with increased MMP-8 plasma concentrations of women in preterm labour and threatened preterm delivery.     

The influence of women’s attachment style on the chronobiology of labour pain,analgesic consumption and pharmacological effect

Circadian variation in biological rhythms has been identified as affecting both labour pain and the pharmacological properties of analgesics. In the context of pain, there is also a growing body of evidence suggesting the importance of adult attachment. The purpose of this study was to examine whether labour pain, analgesic consumption and pharmacological effect are significantly affected by the time of day and to analyse whether this circadian variation is influenced by women’s attachment style. This prospective observational study included a sample of 81 pregnant women receiving patient-controlled epidural analgesia (PCEA). Attachment was assessed with the Adult Attachment Scale – Revised. The perceived intensity of labour pain in the early stage of labour (3?cm of cervical dilatation and before the administration of PCEA) was measured using a visual analogue scale (VAS). Pain was also indirectly assessed by measuring the consumption of anaesthetics. The latency period and the duration of effect were recorded for a chronopharmacology characterisation. Pain, as assessed with the VAS, was significantly higher in the night-time group than in the daytime group. An insecure attachment style was significantly associated with greater labour pain at 3?cm of cervical dilatation (p?<?0.001) and before the beginning of analgesia (p?<?0.001) as well as with higher analgesic consumption and lower pharmacological efficacy (p?<?0.05). The time of day was significantly associated with the pharmacological effect: the latency period was longer at night, and the duration of the pharmacological effect was longer during the daytime. The interaction between time of day and attachment style was not significant for any of the study variables. Our results provide evidence of the importance of circadian variation in studying labour pain and the pharmacological effect of labour analgesia involving epidural blockage with a PCEA regimen. Moreover, although there was no evidence that attachment style influenced the circadian variation, these data emphasise that insecure attachment patterns are a risk factor for greater labour pain and analgesic consumption, which should be considered in pain management approaches.     

Effect of progesterone treatment near term on the onset of labour in rats

The effect of systematically delayed progesterone treatment on the onset of labour was examined in 45 pregnant rats. Measurement of progesterone (P) and prostaglandin F (PGF) in uterine vein plasma and uterine tissue before and during spontaneous labour or during prolonged pregnancy showed that the control animals exhibited the expected P-withdrawal (Pw) prior to spontaneous labour, however, properly timed P-treatment predictably prevented Pw and labour. When P was administered 11.7 +/- 2.8 hours before spontaneous labour, the animals delivered normally, despite increased plasma and tissue P-levels. These observations show that P-concentration cannot be equated to P-action.     

Identification of Chemokines Associated with the Recruitment of Decidual Leukocytes in Human Labour: Potential Novel Targets for Preterm Labour

Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.     

Differential expression of proteases in human gestational tissues before, during and after spontaneous-onset labour at term.

A number of tightly regulated proteolytic enzyme systems, including the plasminogen activation cascade and matrix metalloproteases, play integral roles in the remodelling of extracellular matrices during pregnancy and parturition. This study assessed these labour-associated changes in protease activity in human gestational tissues. Amnion, choriodecidua and placenta collected from women before (at caesarean section, not in labour), during (at caesarean section, in labour) and after (spontaneous-onset labour, normal vaginal delivery) labour were examined on gelatin-substrate SDS-PAGE zymography. All tissues displayed major 55 kDa plasminogen-dependent activity that was abolished by the serine protease inhibitors (10 mmol phenylmethyl-sulphonylfluoride l-1, 100 mmol epsilon aminocaproic acid l-1, 1 mmol Glu-Gly-Arg chloromethylketone l-1). The enzymic activity was identified as urokinase plasminogen activator on the basis of its co-migration with reference standard and western blot analysis, and did not vary with labour status. An additional protease with an apparent molecular mass of approximately 90 kDa was detected in all tissues. Densitometric measurement of these tissues showed a significant (P < 0.05) increase in this enzyme activity with labour onset. Heavy metal chelators (1 mmol 1.10 phenanthroline l-1 and 10 mmol EDTA l-1) selectively blocked the 90 kDa activity, consistent with the proposal that it is a metalloprotease. Co-migration with reference standard and western blot analysis confirmed the identity of this protease as the matrix metalloprotease 9 (MMP-9). Immunoreactive MMP-9 protein was also significantly (P < 0.05) increased during and after labour compared with before labour in all tissues examined. It is proposed that the upregulated expression of MMP-9 is involved in fetal membrane rupture and placental separation during and after labour onset, respectively. In conclusion, the regulated repertoire of protease activities expressed by human gestational tissues implies an important role for matrix-degrading enzymes during human parturition.     

The role of prostaglandins for the coordination of myometrial forces during labour

Systematic studies using a superfusion technique for recording myometrial contractility in vitro have been conducted in our department to explore whether prostaglandins (PG) have a differential action on the different segments of the pregnant uterus and also whether the qualitative and quantitative response undergoes a change during spontaneous labour. Myometrial specimens were excised from the fundal area and from the lower uterine segment at elective caesarean section in the 39th week of pregnancy before commencement of labour and at acute caesarean section during ongoing labour. Before labour PGF2 alpha was without or had a very weak effect on upper segment preparations but was stimulatory on lower segment specimens. PGE2 and PGI2 generally induced a biphasic dose-dependent response (stimulation followed by inhibition). During spontaneous labour PGF2 alpha and PGE2 always stimulated upper segment preparations while the contractile activity of specimens from the lower segment was inhibited by PGE2, PGF2 alpha was generally without effect. PGI2 had the same biphasic action before as during labour. With all reservations for the validity of in vitro experiments, the results favour the hypothesis that initiation of labour in the human involves a qualitative shift in the myometrial reactivity to prostaglandins. These alterations may involve suppression of expulsive forces and perhaps some tightening of the lower uterine segment during pregnancy. Following initiation of labour there is a marked increase in the excitatory action of both PGE2 and PGF2 alpha in the fundal area while the lower uterine segment reacts in a way that favours dilatation.     

F prostaglandin levels in amniotic fluid in premature labour

The concentration of prostaglandin F (PGF) in amniotic fluid was measured by radioimmunoassay in 27 patients admitted in premature labour. There was a strong correlation between PGF levels in amniotic fluid and both cervical dilatation (r = 0.81; P < 0.001) and duration of labour (r = 0.79; P < 0.001). Cervical dilatation greater than 7 cm was associated with levels exceeding 2000 pg/ml. When contractions were present for less than one hour, levels of PGF were below 50 pg/ml. Low levels of PGF were found in amniotic fluid from a separate group of three patients, of whom two had cervical incompetence. It is concluded that the onset of premature labour is not associated with elevated levels of PGF in amniotic fluid. During premature labour, concentrations rise to an extent comparable to that observed in labour at term.     

Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour.

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E2 induced labour was demonstrated.     

Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E₂ induced labour was demonstrated.     

Development of concepts for human labour accounting in Emergy Assessment and other Environmental Sustainability Assessment methods

Human labour is central to the functioning of any human-influenced process. Nevertheless, Environmental Sustainability Assessments (ESAs) do not systematically include human labour as an input. Systematic omission of labour inputs in ESAs may constitute an unfortunate, significant bias in favour of labour intensive processes and a systematic underestimation of environmental impacts has implications for decision-making. A brief review of the evaluation of human labour in ESAs reveals that only Emergy Assessment (EmA) accounts for labour as standard. Focussing on EmA, we find, however, that there is no agreement on the calculation method for labour. We formalise the calculation of human labour unit emergy values (UEVs) as being the ratio between the emergy resource basis of the labour system and a proxy for labour, with or without allocation to account for different qualities of labour. The formalised calculation approach is demonstrated using examples from the literature (USA, with allocation based on educational level; Ghana, with allocation based on income level; the World, with no allocation). We elaborate on how labour may be considered as endogenous or exogenous to the studied system, and how inputs can be categorised as direct labour taking place in the system under study and indirect labour occurring upstream in the supply chain associated with the studied system. With appropriate modifications, the formalised calculation approach and the distinction between direct and indirect labour may be transferred to other ESA methodologies. Concerning EmA, we recommend that product UEVs should systematically be calculated with and without labour, and that working hours rather than salary should be used when accounting for labour inputs. We recognise that there is a risk of double counting of environmental impacts when including labour. We conclude, however, that it can be ignored for most production systems, since only a negligible fraction of emergy already accounted for is likely to be included in the emergy flow from labour inputs.     

Local and systemic control of myometrial contractile activity during labour in the sheep

The relative contribution of systemic versus local (intrauterine) factors in the activation and stimulation of the sheep myometrium during labour was examined using an in-vivo myometrial explant preparation. Myometrial tissue alone (MYO) or with attached endometrium (ENDO/MYO) was removed from the pregnant uterine horn, sutured to a stainless-steel frame and placed into the omental fat. After 7-10 days the explants developed a pattern of electromyographic activity qualitatively similar to that of the uterine myometrium. Induction of preterm labour by infusion of ACTH (66.6 ng/min for 15 min every 2 h) to the fetus resulted in a reduction in plasma progesterone concentrations and increases in values of oestradiol-17 beta and 13,14-dihydro 15-keto PGF-2 alpha in maternal plasma. The onset of labour, which followed these endocrine changes, was characterized by an increase in EMG burst frequency and reduction in burst duration occurring simultaneously in both the uterine myometrium and in the explants. The response of the uterine and explant myometrium to oxytocin also exhibited a parallel significant increase over the 24-h period leading to delivery. No differences were apparent between the explants containing myometrial tissue alone or those comprising endometrial and myometrial tissue. There was no significant change in uterine or explant EMG activity, or oxytocin responsiveness, after saline administration to the fetus. The pattern of EMG activity changes during spontaneous labour were not distinguishable from those during ACTH-induced labour. As with oxytocin, the responsiveness of the explants to electrical stimulation increased significantly at labour compared to pre-labour. These data suggest that factors within the systemic circulation play a major role in both the onset of labour contractions and the increased response to electrical or hormonal (oxytocin) stimulation during parturition in sheep.     

Prolonged pregnancy: the management debate.

A prospective trial was conducted to compare the effects of conservative management of prolonged pregnancy (conservative group) with routine induction of labour at 42 weeks'' gestation (active group) in otherwise uncomplicated pregnancies. Of the 402 pregnancies studied, 207 (51%) were allocated to conservative management and 195 (49%) were allocated to have labour induced. The groups were well matched for age, parity, and smoking habits. One hundred and sixty six (80%) of the patients in the conservative group went into spontaneous labour. Of the remainder, two underwent elective caesarean section, 19 had labour induced because of clinical concern, and the remaining 20 had labour induced at the patient''s own request. One hundred and twenty five (64%) of the patients in the planned active group underwent induction of labour. Of the remaining 70, 49 went into spontaneous labour and 21 (11%) asked that they should not have labour induced. Comparison of the two groups showed no difference in the length of the first stage of labour but a trend towards an increased need for intervention for fetal distress (p less than 0.06) in the active group. There were no differences in the length of the second stage, the need for intervention, or the mode of delivery. In terms of Apgar scores the neonatal outcome was not significantly different between the two groups, but a greater proportion of the babies (15% v 8%) in the active group required intubation. Umbilical cord venous pH estimated in the last 183 consecutive deliveries in the study showed a significantly lower mean value in the active group (p less than 0.05). There was no difference in birth weight between the two groups. Two deaths occurred in the study. There was a stillbirth in the conservative group at 292 days after massive abruption, and one neonatal death in the active group owing to multiple congenital abnormalities. The outcome for mother and baby in patients from both groups who went into spontaneous labour was generally good. The outcome for patients for whom conservative management was planned but induction became necessary was no different from that of patients who underwent planned induction at term. Thus from our results we can find no evidence to support the view that women with normal prolonged pregnancy should undergo routine induction of labour at 42 weeks'' gestation.     

Endocrine Changes in Premature Labour

Plasma oestradiol and progesterone levels in peripheral blood have been studied before and during premature labour of unknown aetiology. Hormones were measured by radio-immunoassay using specific antisera. Levels in patients who delivered prematurely were compared with levels measured serially in 33 primigravidae during normal pregnancy and labour.In 19 out of 25 patients admitted in progressive premature labour the plasma oestradiol level was two standard deviations or more above the mean for the control patients of similar gestational age. The mean (± S.E. of mean) plasma oestradiol in premature labour was 19·1 ± 1·1 ng/ml, similar to levels found in labour at term (18·5 ± 1·4 ng/ml). In contrast, in over 50% of cases levels of plasma progesterone during premature labour lay below the mean for gestation though within the normal range. In six patients studied serially oestradiol levels rose dramatically, high values being detected one to 10 days before the onset of premature labour. Serial progesterone levels gave no consistent trend though one patient showed steadily decreasing values.These studies suggest that the onset of premature labour is preceded by a marked increase in peripheral plasma oestradiol levels, which may be of value not only in the prediction of premature labour but also in its prevention by suppression of the premature oestradiol surge.     

Comparative study of a two dose schedule of PGE2 3 mg pessary and 1700 micrograms film for induction of labour in nulliparae with poor cervical score

Efficacy of a two dose schedule of 3 mg pessary or 1700 micrograms film of PGE2 for induction of labour was compared in nulliparae with poor cervical score. Patient characteristics in the two groups (43 in 3 mg and 40 in 1700 micrograms group) were comparable in age, period of gestation, indications for induction of labour and in their initial cervical score. The number of patients who started labour with a two dose schedule 4 hours apart were similar in each group. The improvement of cervical score, length of labour, mode of delivery and the neonatal outcome were not different in the two groups. There was no advantage of using a film preparation over that in the form of a pessary and the use of 3 mg dose did not give significantly better results compared with the 1700 micrograms dose, in terms of obstetric or neonatal outcome.     

Pathogenesis of neonatal hyperbilirubinaemia after induction of labour with oxytocin.

To determine the pathogenesis of neonatal hyperbilirubinaemia after oxytocin-induced labour venous cord blood from 95 healthy newborn infants was examined. Of these, 15 were delivered by elective caesarean section, 40 after spontaneous labour, and 40 after oxytocin-induced labour. There was no significant difference in any haematological or biochemical variable between the first two groups. Infants born after oxytocin-induced labour, however, showed clear evidence of increased haemolysis associated with significantly decreased erythrocyte deformability (P less than 0.001). In-vitro studies showed a time- and dose-related reduction in erythrocyte deformability in response to oxytocin. The findings suggest that the vasopressin-like action of oxytocin causes osmotic swelling of erythrocytes leading to decreased deformability and hence more rapid destruction with resultant hyperbilirubinaemia in the neonate.     

The effects of gestational age and intrafetal ACTH administration on the concentration of progesterone in the fetal membranes, endometrium, and myometrium of pregnant sheep

To examine the hypothesis that progesterone withdrawal from intrauterine tissues is a prerequisite to spontaneous labour or labour induced by administering ACTH to the ovine fetus, we measured the concentration of progesterone in amnion, chorion, endometrium, and myometrium of sheep at different stages of pregnancy and during ACTH-induced labour. There was no significant change in the concentration of progesterone nor in the progesterone:estradiol ratio in amnion or chorion in association with either spontaneous or ACTH-induced labour. The concentration of progesterone in endometrium rose significantly between days 50-60 and days 130-135 of gestation and decreased at term. There was also a fall in the progesterone:estradiol ratio in endometrium between days 130-135 and term. Neither the progesterone concentration not the progesterone:estradiol ratio changed in endometrium during ACTH-induced labour. In the myometrium the concentration of progesterone rose significantly between days 50-60 and day 100 of pregnancy and decreased between day 100 and days 130-135, with a further decline towards term. After intrafetal ACTH there was no change in the concentration of progesterone in the myometrium, although there was a fall in the progesterone:estradiol ratio. We conclude that labour occurring spontaneously at term is associated with a decrease in the progesterone concentration of maternal intrauterine tissues, the myometrium and endometrium. In contrast, there is no decline in the progesterone concentrations of the fetal membranes, the amnion and chorion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postpartum haemorrhage after induced and spontaneous labour.

The labour records of 1000 consecutive deliveries were studied to compare the incidence of postpartum haemorrhage after induced labour with that after spontaneous labour. The discovery of an increased incidence of postpartum haemorrhage in the induced group prompted further analysis of the incidence of haemorrhage among 3674 normal deliveries. This analysis confirmed that the incidence of postpartum haemorrhage was increased after induction of labour; among primiparous patients the increased incidence after induced labours was nearly twice that after spontaneous labours, even when only normal deliveries were considered. These findings indicate that postpartum haemorrhage is another complication of induction that needs to be taken into account when induction is being considered.