Alteration of circulating Placental Leucine Aminopeptidase (P-LAP) activity in preeclampsia.

OBJECTIVE: Placental Leucine Aminopeptiadse (P-LAP) also known as oxytocinase, is secreted by syncytiotrophoblast and increases gradually during pregnancy until delivery. It is a regulator of uterine contractions, of vascular resistance and of volume of the retroplacental blood pool. Recently, it was shown that it could also regulate metalloproteinase 9 activity and thus, invasiveness of trophoblastic cells. Since development of preeclampsia could be initiated by decreased cytotrophoblastic invasion of spiral arterioles and a reduced uteroplacental perfusion, we speculate that circulating P-LAP activity could be decreased during preeclampsia. MATERIALS AND METHODS: Case-control study was evaluated in 84 women. P-LAP activity was measured in n=51 healthy pregnant women at term, and compared with n=16 normotensive women delivering preterm and n=17 women diagnosed with pre-eclampsia. P-LAP activity was determined by colorimetry in plasma samples using L-Leucine-p-nitroanilide as substrate. RESULTS: P-LAP activity was significantly lower in sera of preeclamptic women (0.91+/-0.122 mDO/min) as compared to normotensive controls (1.41+/-0.103 mDO/min; p=0.003) irrespective of time of delivery. CONCLUSIONS: These findings confirm the probable involvement of P-LAP in trophoblast invasion and development of preeclampsia.

Arg16 homozygosity of the beta2-adrenergic receptor improves the outcome after beta2-agonist tocolysis for preterm labor.

BACKGROUND: Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor. METHODS: Sixty white women with preterm labor between 24 and 34 weeks' gestation were treated for 48 hours with intravenous hexoprenaline. The effect of tocolysis and outcome of pregnancy were recorded. The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined. A control group of 116 women delivered at term was also genotyped. RESULTS: Preterm labor was not associated with beta(2)AR genotype at codon 16 (17% of patients with preterm labor were Arg16 homozygotes versus 19% of control subjects) or codon 27. Gestation was significantly prolonged in Arg16 homozygotes (median, 69 days; interquartile range, 63-79 days) compared with the other 2 genotypes (median, 58 days; interquartile range, 2-72 days) (P = .04). Tocolysis was 100% successful in delaying delivery for 48 hours in Arg16 homozygotes (n = 10), just failing to achieve statistical significance (P = .069). In contrast, only 37 of 50 women carrying 1 or 2 glycine alleles (74%) had delivery delayed by more than 48 hours with tocolysis. Neonatal outcomes were significantly better in babies born to mothers homozygous for arginine than in women with 1 or 2 Gly16 alleles. CONCLUSIONS: This is the first study examining the pharmacogenetics of beta(2)AR agonist therapy for preterm labor. It appears that Arg16 homozygosity improves pregnancy outcome after beta(2)-agonist tocolysis. The relatively low frequency of Arg16 homozygotes in our population limited the power of this investigation. Future assessments of tocolytic therapy may need to assess beta(2)AR genotype.

Accuracy of single measurements of pregnancy-associated plasma protein-A, human chorionic gonadotropin and progesterone in the diagnosis of early pregnancy failure.

BACKGROUND: Circulating human chorionic gonadotropin (hCG) and progesterone are commonly used as markers of abnormal pregnancies. Previous studies have shown that pregnancy-associated plasma protein-A (PAPP-A) was also depressed in extrauterine pregnancies (EUP). Previously, PAPP-A was measured with polyclonal antibodies which were later shown to recognise also the pro-form of major basic protein (pro-MBP). OBJECTIVE: To evaluate the clinical usefulness of PAPP-A measurements in early pregnancy. STUDY DESIGN: Circulating PAPP-A, hCG and progesterone were measured in patients with EUP (n=68), abnormal intrauterine pregnancies (abIUP, n=31) and normal intrauterine pregnancies (nIUP, n=72). Gestational age was 30-70 days from the last menstruation. RESULTS: For PAPP-A and hCG, a steep increase was observed from day 30 after last menstrual period onwards, this increase being much less important for abIUP and EUP. The values of PAPP-A and hCG were significantly decreased in abIUP and EUP, from 42 days after LMP onwards. There were no significant differences between abIUP and EUP. Progesterone concentration does not vary with amenorrhoea and was significantly lower in abIUP and EUP. Values in abIUP were significantly (P=0.02) lower compared with EUP for amenorrhoea above 42 days. ROC curves were constructed for amenorrhoea above 42 days. For a specificity of 99%, the sensitivity of PAPP-A, hCG and progesterone were 64.5, 93.3 and 76%, respectively. The threshold values were 14.3mIU/l, 10,400IU/l and 10.1ng/ml for PAPP-A, hCG and progesterone. CONCLUSION: We confirm the decrease of PAPP-A concentrations in pregnancy failure, but hCG and progesterone remain the best clinical tools.

Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.

BACKGROUND: Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. METHODOLOGY/PRINCIPAL FINDINGS: We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. CONCLUSION/SIGNIFICANCE: Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.

Effect of crew resource management training in a multidisciplinary obstetrical setting.

OBJECTIVE: To assess the effect of a Crew Resource Management (CRM) intervention specifically designed to improve teamwork and communication skills in a multidisciplinary obstetrical setting. METHOD: Design--A before-and-after cross-sectional study designed to assess participants' satisfaction, learning and change in behaviour, according to Kirkpatrick's evaluation framework for training programmes. Setting--Labour and delivery units of a large university-affiliated hospital. Participants--Two hundred and thirty nine midwives, nurses, physicians and technicians from the department of anaesthesia, obstetrics and paediatrics. Intervention--All participants took part in a CRM-based training programme specifically designed to improve teamwork and communication skills. Principal measures of outcome-We assessed participants' satisfaction by means of a 10-item standardized questionnaire. A 36-item survey was administered before and after the course to assess participants' learning. Behavioural change was assessed by a 57-item safety attitude questionnaire measuring staff's change in attitude to safety over 1 year of programme implementation. RESULTS: Most participants valued the experience highly and 63-90% rated their level of satisfaction as being very high. Except for seven items, the 36-item survey testing participants' learning demonstrated a significant change (P<0.05) towards better knowledge of teamwork and shared decision making after the training programme. Over the year of observation, there was a positive change in the team and safety climate in the hospital [odds ratio (OR) 2.9, 95% confidence interval (CI) (1.3-6.3) to OR 4.7, 95% CI (1.2-17.2)]. **There was also improved stress recognition [OR 2.4, 95% CI (1.2-4.8) to OR 3.0, 95% CI (1.0-8.8)]. CONCLUSION: The implementation of a training programme based on CRM in a multidisciplinary obstetrical setting is well accepted and contributes to a significant improvement in interprofessional teamwork.

The dose-sparing effect of clonidine added to ropivacaine for labor epidural analgesia.

UNLABELLED: To determine the effects of clonidine with ropivacaine during epidural labor analgesia, we studied 66 nulliparous women in early active labor. Women were randomized to receive ropivacaine 0.1% 8 mL plus 75 microg of clonidine (Group 1), ropivacaine 0.2% 8 mL plus 0.5 mL of NaCl 0.9% (Group 2), or ropivacaine 0.2% 8 mL plus 75 microg of clonidine (Group 3) 5 min after a bupivacaine 7.5 mg with epinephrine 15 microg test dose. Upon request, additional analgesia with ropivacaine 0.1% 8 mL followed by ropivacaine 0.2% 8 mL/h was administered. With clonidine, duration of analgesia was increased (132 +/- 48 min [Group 1] and 154 +/- 42 min [Group 3] versus 91 +/- 44 min [Group 2]; P < 0.05), and total ropivacaine dose over the first 4 h was significantly reduced (40.5 +/- 15 mg [Group 1] and 47.0 +/- 16 mg [Group 3] versus 72.5 +/- 18 mg [Group 2]; P < 0.01). The incidence of more profound motor block was more frequent in Group 2 (P < 0.05). Although there was a trend for more women receiving clonidine to require ephedrine for treatment of hypotension, this did not seem to have an impact on fetal outcome or incidence of cesarean deliveries for nonreassuring fetal heart rate tracings. This study demonstrates the dose-sparing effect of clonidine when added to ropivacaine. IMPLICATIONS: The effect of adding 75 microg of clonidine to ropivacaine for epidural labor analgesia was studied. Clonidine increased analgesia duration and produced dose sparing compared with ropivacaine alone. Despite a tendency for hypotension in women receiving clonidine, there was no apparent effect on delivery mode or neonatal outcome.

Spontaneous delivery or manual removal of the placenta during caesarean section: a randomised controlled trial.

OBJECTIVE: To compare blood loss with spontaneous delivery and manual removal of the placenta during caesarean section. DESIGN: A randomised controlled trial. SETTING: Four university hospitals between September 1999 and June 2002. POPULATION: A total of 472 women delivering by caesarean section at term were randomised to spontaneous placental delivery (n= 235) or manual removal (n= 237). METHODS: The allocation was made by opening the next available of a series of sealed opaque envelopes and derived from a computer-generated list of numbers. MAIN OUTCOME MEASURES: Significant blood loss, defined as either a drop in haemoglobin of greater than 2.5 g/dL, or the need for blood transfusion. RESULTS: The mean interval between delivery of the newborn and the placenta was longer in the spontaneous delivery group (3.4 vs 1.9 minutes), but the mean duration of the operation was similar. Significant blood loss occurred in 30 women (13%) in the spontaneous delivery group and 49 women (21%) in the manual removal one (RR 0.62; 95% CI 0.41-0.94). Post-operative fever affected 6 and 5 cases, respectively, and antibiotics were used in 14 and 12 cases, respectively. CONCLUSIONS: Allowing spontaneous delivery of the placenta reduces significant blood loss without increasing operating time.