Maternal plasma corticotrophin-releasing hormone—elevated in preterm labour but unaffected by indomethacin or nylidrin

Summary. The role of corticotrophin-releasing hormone (CRH) in preterm labour was studied in 23 women in preterm labour at between 26 and 33 weeks gestation who were randomly allocated to receive treatment with indomethacin (  n=11  ) or with nylidrin a beta-sympathomi-metic agent (  n=12  ). Maternal plasma CRH in the preterm group (median 70, range 9–597 pmol/1) before therapy was higher (   P < 0.05  ) than that in 23 control pregnancies, without uterine contractions, matched for gestational age (median 51, range 4–127 pmol/1). CHR levels determined after 3 and 24 h of treatment showed a 10% decrease in the indomethacin group and 10–20% decrease in the nylidrin group, but these changes were not statistically significant. After cessation of uterine contractions during tocolysis, 12 women proceeded to give birth preterm (<37 weeks) and their pretreatment CRH levels (median 195, range 9–597 pmol/1) were higher (   P < 0.05  ) than those in women whose pregnancy proceeded to term (median 52, range 16–207 pmol/1). In another group of women, full-term labour was not accompanied by any changes in maternal CRH levels. Umbilical plasma CRH levels were 1.1–9.8% of the paired maternal levels and did not rise with advancing gestational age. Nor had the type of delivery (elective caesarean section before labour, or preterm or term vaginal delivery) any effect on fetal CRH levels. Neither maternal nor fetal CRH was related to maternal or fetal cortisol levels. We conclude that: (i) maternal CRH is elevated in preterm labour, (ii) maternal CRH is not affected by treatment with indomethacin or nylidrin and (iii) fetal CRH is of no significance in the initiation of preterm or term labour.     

A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor

We compared the tocolytic effect of indomethacin and nylidrin in a prospective double-blind trial in which the appearance of the tocolytic treatment (always intravenous infusion and rectal suppositories/oral capsules) was identical to the subjects. Sixty healthy women in imminent preterm labor between 25-34 weeks of singleton gestation were included. Thirty of these women received indomethacin (concomitantly with placebo infusion), with doses as follows: day 1, 100-mg rectal suppository followed by two oral capsules (50 mg) at 8-hour intervals; days 2 and 3, three 50-mg oral capsules each day. Thirty women received intravenous nylidrin (concomitantly with rectal/oral placebo), initiated with the dose of 50 micrograms/minute and continued at the dose of 100-150 micrograms/minute for a maximum of 3 days. Preterm labor was arrested for 24, 48, and 72 hours in 100, 96, and 90%, respectively, of subjects in the indomethacin group, compared with 100, 76, and 73% of women in the nylidrin group; the difference was significant (P less than .05) at 48 hours. Women progressed beyond 37 gestational weeks more commonly (P less than .05) with indomethacin (21 of 30, 70%) than with nylidrin (13 of 30, 43%). Indomethacin treatment was accompanied by maternal side effects 20% of the time, significantly less commonly (P less than .001) than with nylidrin (83%). The neonatal outcome was similar in the two study groups. We conclude from this double-dummy technique trial that indomethacin is more effective and better tolerated than nylidrin in arresting imminent preterm labor.     

Catechol-O-methyltransferase activity in red blood cells in threatened preterm labor; effect of indomethacin and nylidrin

Catecholamines that are released in excess during human labor are inactivated mainly by catechol-O-methyltransferase (COMT). To ascertain whether uterine contractions are associated with changes in COMT activity in red blood cells (RBCs), we studied 25 women with established threat of preterm labor between 25 and 33 weeks of gestation, 25 gestational age-matched control women not experiencing uterine contractions, 25 women who were in term labor, and 25 non-pregnant healthy women. COMT activity in pregnant women without uterine contractions (median 0.3, range 0.1-0.8 pmol/mg/min) was lower (p less than 0.05) than that in non-pregnant control series (median 0.5, range 0.3-0.7 pmol/mg/min). RBCs' COMT activity in women with preterm labor (median 0.6, range 0.2-1.1 pmol/mg/min) was greater (p less than 0.05) than that in pregnant and non-pregnant control women, but similar to that during term labor (median 0.5, range 0.2-1.7 pmol/mg/min). Women with preterm labor were treated with indomethacin (12 women) or nylidrin (13 women). Nylidrin treatment was accompanied by a 35% rise in COMT activity 3 h later, whereas indomethacin caused no significant change. Apart from cessation of uterine contractions during tocolysis, 13 women went into labor before the 37th gestational week, but their pretreatment COMT activity (median 0.7, range 0.2-1.1 pmol/mg/min) did not differ from COMT activity in women whose pregnancy proceeded to term (median 0.5, range 0.3-1.0 pmol/mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Maternal plasma visfatin in preterm labor

Objective.?Visfatin, a novel adipokine with diabetogenic and immunoregulatory properties, has been implicated in the pathophysiology of insulin resistance, as well as in various acute and chronic inflammatory disorders. We have previously reported that amniotic fluid concentrations of visfatin are higher in patients with preterm labor (PTL) and intra-amniotic infection than in patients with PTL without infection. The aim of this study was to determine whether spontaneous PTL with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal plasma circulating visfatin concentrations.

Study design.?This cross-sectional study included patients in the following groups: (1) normal pregnant women (n = 123); (2) patients with an episode of PTL and intact membranes without IAI who delivered at term (n = 57); (3) PTL without IAI who delivered preterm (n = 47); and (4) PTL with IAI who delivered preterm (n = 57). Plasma visfatin concentrations were determined by ELISA. Non-parametric statistics were used for analysis.

Results.?(1) PTL with IAI leading to preterm delivery was associated with a higher median maternal plasma concentration of visfatin than normal pregnancy; (2) among patients with PTL, those with IAI had the highest median maternal concentration of visfatin; (3) the changes in maternal plasma visfatin remained significant after adjusting for maternal age, body mass index, gestational age at sampling, and birth weight.

Conclusion.?(1) PTL with IAI is characterized by high maternal circulating visfatin concentrations; (2) these findings suggest that visfatin plays a role in the regulation of the metabolic adaptations to insults resulting in PTL in the context of IAI.     

Maternal serum cytokine levels in pregnancies complicated with threatened preterm labour

Objective: To investigate serum inflammatory markers in singleton gestations complicated with threatened preterm labour (TPL).

Methods: Pregnant women complicated with TPL (n?=?61) were recruited to measure maternal serum levels of a panel of cytokines and C-reactive protein and then compared to controls without TPL, matched for gestational age (n?=?64) and term pregnancies in the prodromal phase of labour (PPL) (n?=?31). In addition, baseline cytokine levels were compared among cases and controls according to the outcome.

Results: Women with TPL displayed higher CRP and white blood counts levels together with lower granulocyte macrophage colony-stimulating factor (GMC-SF) compared to both controls without TPL and to term gestations in the PPL. Also, interleukin 10 (IL-10), IL-6, IL-7, IL-8 and tumour necrosis alpha (TNF-α) levels were found significantly higher in TPL cases as compared to controls without TPL and term women in the PLL. Baseline cytokine levels (except IL-10) were higher among TPL cases who later delivered preterm. TPL cases delivering preterm displayed lower GMC-SF levels as compared to those delivering at term. Multivariate analysis found that gestational age at birth positively correlated with cervical length and inversely with CRP, IL-6 and TNF-α levels (p?<?0.0001).

Conclusions: TPL and preterm birth were related to inflammatory changes in the maternal side that correlate with cervical shortening and the initiation of uterine contractions.     

The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial

Objective To determine whether indomethacin tocolysis in preterm labour is associated with a better perinatal outcome than placebo.
Design A randomised placebo-controlled trial.
Setting Two university teaching hospitals with level three neonatal intensive care units.
Population Women in preterm labour with intact membranes between 23 and 30 weeks of gestation.
Methods Random allocation to tocolysis with indomethacin (50 mg followed by 25 mg 6 hourly for 48 hours) or placebo in a double-blind fashion.
Main outcome measures The primary outcome, perinatal mortality or severe neonatal morbidity, was defined as perinatal death, necrotising enterocolitis, bronchopulmonary dysplasia, intraventricular haemorrhage or pen-ventricular leucomalacia. Data were analysed using odds ratios (OR) and 95% confidence intervals (95% CI).
Results Between March 1995 and February 1996, 34 women (39 babies) were recruited. The baseline characteristics of the two groups were similar. No patient was lost to follow up. In the indomethacin group, gestation was prolonged by > 48 hours in 13/16 (81%) of women vs 10/18 (56%) in the placebo group. The incidence of perinatal mortality or severe neonatal morbidity was not significantly different between the groups, but occurred in twice as many babies in the indomethacin group as in the placebo group d/l9 (32%) vs 3/20 (15%) OR (95% CI) 2.62 (0.44–18.8). There was one perinatal death, of a baby delivered at 24 weeks of gestation. This occurred in the indomethacin group.
Conclusion There is no evidence that indomethacin tocolysis is beneficial, and further trials are needed to assess the impact of indomethacin tocolysis in preterm labour.     

Maternal posture in labour

The position adopted naturally by women during birth has been described as early as 1882 by Engelmann. He observed that primitive woman, not influenced by Western conventions would try to avoid the dorsal position and was allowed to change position as and when she wished. Different upright positions could be achieved using posts, slung hammock, furniture, holding on to a rope, knotted piece of cloth, or the woman could kneel, crouch, or squat using bricks, stones, a pile of sand, or a birth stool. Today the majority of women in Western societies deliver in a dorsal, semi-recumbent or lithotomy position. It is claimed that the dorsal position enables the midwife/obstetrician to monitor the fetus better and thus to ensure a safe birth.This paper examines the historical background of the different positions used and its evolution throughout the decades. We have reviewed the available evidence about the effectiveness, benefits and possible disadvantages for the use of different positions during the first and second stage of labour.     

Prostaglandin E production by the fetal membranes in unexplained preterm labour and preterm labour associated with chorioamnionitis

The production of prostaglandin E (PGE) by amnion, choriodecidua and placenta was measured in 45 women delivered after spontaneous preterm labour, in 10 women delivered electively preterm, in 30 women at elective caesarean section at term, and in 28 women after spontaneous labour at term. In the preterm labour group 24 women had normal placental histology, and gestational age was 34 (31-36) weeks (median and range); 18 women had evidence of chorioamnionitis and gestational age was significantly shorter, 30 (24-36) weeks; three other patients had placental abruption. In the absence of inflammatory infiltration of these tissues the highest PGE output (fmol/mg dry weight/2 h) was found after labour at term and the lowest after uncomplicated preterm labour: 2640 (360-15,580) (median and range) compared with 1414 (164-11,045) in amnion, 677 (100-3245) compared with 308 (39-1086) in choriodecidua, and 1200 (520-3022) compared with 578 (150-1859) in placenta, respectively. Tissues showing chorioamnionitis produced much higher outputs of PGE from amnion (12,278, 1799-82,617) and from choriodecidua (1018, 216-11,768), but not from placenta (616, 89-4131). Chorioamnionitis seems to cause very early preterm labour by increasing PG production in the amnion and choriodecidua.     

Clinical predictive factors for preterm birth in women with threatened preterm labour or preterm premature ruptured membranes?

Background: Independent predictive factors of preterm delivery were evaluated using clinical data at hospitalisation by multivariate analysis.
Aim: The aim of this study was to clarify independent predictive factors related to preterm delivery by multivariate analysis of clinical data at hospitalisation of patients with threatened preterm delivery or premature rupture of membranes (PROM), and to realise the early and highly reliable prediction of preterm delivery in pregnant women at risk.
Methods: The subjects were 200 patients, which diagnosed with threatened preterm delivery or PROM and admitted at gestational ages of 22–35 weeks. Univariate and multivariate analyses were performed; 20 factors were evaluated concerning clinical data, and we extracted prognostic factors using logistic regression analysis.
Results: The mean age of the patients was 30.5 years, and the mean gestational age at admission was 30.0 weeks. Preterm delivery was observed in 55 (27.5%), and term delivery in 145 (72.5%). On multivariate analysis, haemorrhage, prepregnancy body mass index, fetal fibronectin and cervical length were extracted as independent predictive factors related to preterm delivery.
Conclusions: If the reliable and reproducible prediction of preterm delivery becomes possible using the four factors extracted in this study, further evaluation of these factors may lead to clarification of the mechanism of preterm delivery.     

Changes in plasma steroid hormones during treatment of preterm labour with ritodrine-HCl

Peripheral plasma concentrations of unconjugated oestradiol 17-beta, progesterone and total oestriol were measured in 21 patients presenting with 'uncomplicated' preterm labour. Serial measurements were made during intravenous treatment with ritodrine over a period of 24 h. Mean levels of unconjugated oestradiol 17-beta fell significantly during infusion with ritodrine. Changes in progesterone levels remained within the range of diurnal fluctuations normally found in uncomplicated late pregnancy. Mean total oestriol levels fell significantly, but the changes did not exceed normal variations. No correlation was found between the magnitude, the rate or the timing of changes in any of the hormones measured and the short or long term effects of ritodrine on uterine activity. Although alterations in the peripheral oestrogen concentrations may be a direct effect of beta-mimetics, it is unlikely that this mechanism is important in the inhibition of uterine activity.     

The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial.

OBJECTIVE: To determine whether indomethacin tocolysis in preterm labour is associated with a better perinatal outcome than placebo. DESIGN: A randomised placebo-controlled trial. SETTING: Two university teaching hospitals with level three neonatal intensive care units. POPULATION: Women in preterm labour with intact membranes between 23 and 30 weeks of gestation. METHODS: Random allocation to tocolysis with indomethacin (50 mg followed by 25 mg 6 hourly for 48 hours) or placebo in a double-blind fashion. MAIN OUTCOME MEASURES: The primary outcome, perinatal mortality or severe neonatal morbidity, was defined as perinatal death, necrotising enterocolitis, bronchopulmonary dysplasia, intraventricular haemorrhage or peri-ventricular leucomalacia. Data were analysed using odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Between March 1995 and February 1996, 34 women (39 babies) were recruited. The baseline characteristics of the two groups were similar. No patient was lost to follow up. In the indomethacin group, gestation was prolonged by > 48 hours in 13/16 (81%) of women vs 10/18 (56%) in the placebo group. The incidence of perinatal mortality or severe neonatal morbidity was not significantly different between the groups, but occurred in twice as many babies in the indomethacin group as in the placebo group--6/19 (32%) vs 3/20 (15%) OR (95% CI) 2.62 (0.44-18.8). There was one perinatal death, of a baby delivered at 24 weeks of gestation. This occurred in the indomethacin group. CONCLUSION: There is no evidence that indomethacin tocolysis is beneficial, and further trials are needed to assess the impact of indomethacin tocolysis in preterm labour.     

Prostaglandin inhibitors in preterm labour

Prematurity accounts for the majority of neonatal morbidity and mortality in the developed world. The process of labour resembles inflammation, with prostaglandin and cytokine production both before and during labour. Anti-inflammatory drugs therefore have the potential to prevent preterm delivery. Indomethacin is the only tocolytic drug proven to delay delivery beyond 37 weeks and to reduce the incidence of low birth weight (<2500 g). There are, however, fetal side-effects such as ductal constriction and impaired renal function associated with its use. It is the type 2 isoform of cyclo-oxygenase (COX-2), which is important for the production of prostaglandins within intrauterine tissues and that up-regulation of COX-2 is associated with labour. Although indomethacin is currently the most common non-steroidal anti-inflammatory drug (NSAID) used in the treatment of preterm labour, it was hoped that COX-2-selective drugs, used as tocolytics, would target COX-2 activity and potentially spare COX-1-specific fetal side-effects. Experience with sulindac and nimesulide has been linked with both constriction of the ductus arteriosus and oligohydramnios. It is unclear whether this is due to COX-2-dependent side-effects, or due to accumulation of drug in the fetal circulation leading to levels that would cause COX-1 inhibition. Currently, the use of COX-2-selective drugs should therefore be confined to randomized controlled trials.     

Changes in plasma steroid hormones during treatment of preterm labour with ritodrine-HC1

Summary. Peripheral plasma concentrations of unconjugated oestradiol 17-β, progesterone and total oestriol were measured in 21 patients presenting with 'uncomplicated' preterm labour. Serial measurements were made during intravenous treatment with ritodrine over a period of 24 h. Mean levels of unconjugated oestradiol 17-β fell significantly during infusion with ritodrine. Changes in progesterone levels remained within the range of diurnal fluctuations normally found in uncomplicated late pregnancy. Mean total oestriol levels fell significantly, but the changes did not exceed normal variations. No correlation was found between the magnitude, the rate or the timing of changes in any of the hormones measured and the short or long term effects of ritodrine on uterine activity. Although alterations in the peripheral oestrogen concentrations may be a direct effect of β-mimetics, it is unlikely that this mechanism is important in the inhibition of uterine activity.     

Maternal serum 25-hydroxyvitamin D and C-reactive protein levels in pregnancies complicated with threatened preterm labour

Objective and methods: To measure 25-hydroxyvitamin D [25(OH)D] and C-reactive protein (CRP) serum levels in singleton gestations complicated with threatened preterm labour (TPL, n?=?59) and compare to normal controls matched for gestational age (n?=?64). Cases were treated after blood sample according to institutional protocol. Also, analyte levels were compared among cases according to the outcome.

Results: Mean serum 25(OH)D levels were similar between cases and controls, with median white blood cell count and CRP levels found significantly higher in TPL cases. Women with TPL delivering preterm displayed shorter mean cervical lengths along with higher CRP and lower 25(OH)D serum levels when compared to those delivering at term. Two multiple linear regression models were constructed to analyse factors related to gestational age at delivery (pooled analysis and only those with TPL). In both models, gestational age positively correlated to cervical length and inversely to CRP levels; whereas, in the TPL model, only 25(OH)D levels correlated positively.

Conclusion: Women complicated with TPL showed similar serum 25(OH)D yet higher CRP levels as compared to controls. TPL cases delivering preterm displayed lower 25(OH)D and higher CRP correlated levels.     

Maternal plasma and amniotic fluid interleukin-6 levels in imminent preterm labor

Our purpose was to investigate the maternal plasma and amniotic fluid interleukin-6 levels in women with preterm labour. The present study was designed to evaluate IL-6 levels in 93 pregnant women with threatened preterm labour and 40 normal pregnant. Maternal blood samples were collected by routine forearm venipuncture at admission during routine laboratory tests. Amniotic fluid was collected during hysteretomy during caesarean delivery from women at term but not in labour and by amniotomy or hysteretomy from women with preterm labour. Maternal plasma and amniotic fluid IL-6 concentrations were significantly elevated in women in preterm labour (premature rupture of membranes and uterine contractions) compared to gestationally matched, non-laboring controls.