Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.

BACKGROUND: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy. METHODS: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581. FINDINGS: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51). INTERPRETATION: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy. FUNDING: Chief Scientist Office of the Scottish Government Health Directorate.

Fetal growth in women managed with insulin pump therapy compared to conventional insulin.

OBJECTIVE: Fetal hyperinsulinaemia secondary to maternal hyperglycaemia is considered to be the driving force behind excessive fetal growth. We hypothesised that insulin pump therapy (continuous subcutaneous insulin infusion, CSII) would improve maternal glycaemic control and normalise fetal growth parameters. To this end, this study compares maternal glycaemic control and fetal growth of women receiving insulin pump therapy with those receiving conventional insulin therapy. STUDY DESIGN: Prospective non-randomised study of 42 women with pre-existing diabetes attending a joint obstetric diabetic clinic. Each woman was offered the choice of commencing insulin pump therapy or remaining on a conventional insulin regime. Estimated fetal weight and fetal growth velocity were calculated from routinely collected third trimester ultrasound biometry and expressed as standard deviation (Z) scores. RESULTS: Eighteen women commenced insulin pump therapy. There was no difference in pre-conception glycosylated haemoglobin A1c concentrations (HbA1c) between pump and conventional therapy groups (mean HbA1c 7.62 versus 8.01; p=0.49) or third trimester glycaemic control (mean HbA1c 6.63 versus 6.44; p=0.51). Women using pump therapy had similar mean growth velocity Z scores (1.5 versus 1.36; p=0.83), similar mean estimated fetal weight Z scores prior to delivery (2.80 versus 2.16; p=0.16) and similar mean birthweight Z scores (2.09 versus 2.00; p=0.86) compared to women using conventional insulin therapy. CONCLUSION: This small, non-randomised study suggests that the use of insulin pump therapy offers no benefit in terms of normalising fetal growth velocity, fetal size, birthweight or improving maternal glycaemic control compared to conventional insulin therapy.

First and third trimester ultrasound in the prediction of birthweight discordance in dichorionic twins.

OBJECTIVE: Birthweight discordance amongst twins is associated with an increase in perinatal morbidity and mortality. Clinical decisions regarding the management of twins are often made on the basis of estimated fetal weight in the third trimester. This study assesses the efficacy of routine third trimester ultrasound fetal biometry, third trimester fetal growth velocity and first trimester differences in size in the prediction of subsequent birthweight discordance. STUDY DESIGN: Structurally and chromosomally normal dichorionic twin gestations resulting in two live births after 24 weeks gestation were identified. Ultrasound examinations of dichorionic twin pregnancies between 10 and 14 weeks of gestation were evaluated for inter-twin biometric disparity in crown-rump length (CRL). Estimated fetal weight (EFW) was calculated from the last scan before delivery. Fetal growth velocity (FGV) was calculated from two estimates of fetal weight between 21 and 35 days apart and incorporating the last EFW before delivery. EFW and FGV were expressed as standard deviation scores (Z scores). Disparity between these ultrasound parameters was correlated to inter-twin birthweight difference. Birthweight discordance was defined as > or =20% difference in birthweight relative to the heavier twin. Fishers exact and Spearman rho tests were used for statistical analysis. Test performance is expressed as area under the ROC curve and likelihood ratios (LR). RESULTS: One hundred and thirty-five dichorionic gestations were identified over a consecutive 3-year-period. One hundred and eight twin gestations had both crown-rump length (CRL) and sufficient ultrasound measurements in the third trimester to calculate FGV. Twenty-six pregnancies (24%) had discordant birthweight. Only EFW Z score difference was correlated with birthweight disparity (r=0.36, p = <0.001). An EFW Z score difference of 0.6 had an area under the ROC curve of 0.70 (95% C.I. 0.59-0.79) but this did not differ significantly from first trimester prediction of growth discordance which had an area of 0.55 (95% C.I. 0.44-0.66). The LR for first and third trimester prediction of discordance were low. CONCLUSION: Ultrasound measurement of fetal growth velocity and size both in the first and third trimesters is a poor predictor of birthweight discordance. Disparate fetal growth is exhibited as early as 10-14 weeks gestation and differences at this early stage in fetal development are no less accurate than EFW within 1 month of delivery. First trimester ultrasound, third trimester growth velocity and third trimester EFW do not accurately predict the delivery of twins with discordant birthweight.

Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs.

P-selectin glycoprotein ligand 1 (PSGL-1) is central to the trafficking of immune effector cells to areas of inflammation through direct interactions with P-selectin, E-selectin and L-selectin. Here we show that PSGL-1 was also required for efficient homing of resting T cells to secondary lymphoid organs but functioned independently of selectin binding. PSGL-1 mediated an enhanced chemotactic T cell response to the secondary lymphoid organ chemokines CCL21 and CCL19 but not to CXCL12 or to inflammatory chemokines. Our data show involvement of PSGL-1 in facilitating the entry of T cells into secondary lymphoid organs, thereby demonstrating the bifunctional nature of this molecule.

Can ultrasound fetal biometry predict fetal hyperinsulinaemia at delivery in pregnancy complicated by maternal diabetes?

OBJECTIVE: The aim of this study was to determine whether there is an association between ultrasound fetal biometry and amniotic fluid insulin levels at delivery in women with pre-existing diabetes or impaired glucose tolerance in pregnancy. STUDY DESIGN: This retrospective cohort study identified 93 women who had amniotic fluid insulin levels measured at time of delivery. Standardised estimated fetal weight and fetal growth velocity were calculated from serial third trimester fetal ultrasound measurements. RESULTS: Women with pre-existing diabetes had significantly greater mean growth velocity [1.39 (95% CI: 0.43-2.23) versus 0.39 (95% CI: -01.7-0.95); p=0.04], significantly greater mean estimated fetal weight (EFW) Z score prior to delivery [2.36 (95% CI: 1.82-2.9) versus 1.38 (95% CI: 1.02-1.74); p=0.002] and greater mean birthweight centile [82 (95% CI: 0.74-0.89) versus 67 (95% CI: 58-76); p=0.02] than those with GDM/IGT. Amniotic fluid insulin levels demonstrated a similar significant difference between the pre-existing and GDM/IGT groups [20.5 (95% CI: 12.9-28.1) versus 8.5 (95% CI: 5.4-11.7); p=0.001]. An association between fetal growth and size and amniotic fluid insulin was observed in women with pre-existing diabetes. Positive likelihood ratios were 1.67 and 2.08, respectively, for the prediction of liquor insulin greater than the 95th centile in women with pre-existing diabetes. CONCLUSION: Ultrasound measures of fetal size and growth used in this study are not sufficiently accurate to predict those infants likely to be at risk from the adverse effects of fetal hyperinsulinaemia.

The levonorgestrel-releasing intrauterine system in modern gynaecology.

The levonorgestrel-releasing intrauterine system was initially developed for contraception but is now widely used for a variety of gynaecological conditions. Compliance can sometimes be hampered by troublesome side effects (principally breakthrough bleeding) but appropriate counselling can reduce unnecessary discontinuation.

Self-malonylation is an intrinsic property of a chemically synthesized type II polyketide synthase acyl carrier protein.

During polyketide biosynthesis, malonyl groups are transferred to the acyl carrier protein (ACP) component of the polyketide synthase (PKS), and it has been shown that a number of type II polyketide ACPs undergo rapid self-acylation from malonyl-CoA in the absence of a malonyl-CoA:holo-acyl carrier protein transacylase (MCAT). More recently, however, the observation of self-malonylation has been ascribed to contamination with Escherichia coli MCAT (FabD) rather than an intrinsic property of the ACP. The wild-type apo-ACP from the actinorhodin (act) PKS of Streptomyces coelicolor (synthetic apo-ACP) has therefore been synthesized using solid-state peptide methods and refolded using the GroEL/ES chaperone system from E. coli. Correct folding of the act ACP has been confirmed by circular dichroism (CD) and 1H NMR. Synthetic apo-ACP was phosphopantetheinylated to 100% by S. coelicolor holo-acyl carrier protein synthase (ACPS), and the resultant holo-ACP underwent self-malonylation in the presence of malonyl-CoA. No malonylation of negative controls was observed, confirming that the use of ACPS and GroEL/ES did not introduce contamination with E. coli MCAT. This result proves unequivocally that self-malonylation is an inherent activity of this PKS ACP in vitro.

Documentation of preoperative counselling for female sterilisation: a complete audit cycle.

BACKGROUND: Female sterilisation is a commonly performed gynaecological procedure that attracts a disproportionate number of complaints and litigation. Documentation of the key counselling issues provides an important record of the information given to the woman prior to undergoing sterilisation. METHODS: Auditable standards were obtained from published guidelines. After the initial audit of 100 cases a proforma was introduced in an effort to improve documentation. A re-audit of 50 cases was undertaken to ascertain compliance of documentation following the introduction of the proforma. RESULTS: The proforma was used in 62% of cases and in all such cases documentation was 100% compliant with the auditable standards. Overall, documentation of standards pre- and post-proforma, respectively, was as follows (all the figures quoted are percentage values, with the range given in parentheses): 33 (24-43) vs 68 (53-80) for long-term alternatives, 94 (87-98) vs 78 (62-87) for irreversibility, 96 (90-99) vs 78 (64-88) for failure rate, 48 (38-58) vs 66 (51-79) for ectopic pregnancy risk if sterilisation fails, 39 (29-49) vs 66 (51-79) for the intended method, 67 (57-76) vs 66 (51-79) for operative risks and 37 (28-47) vs 64 (49-77) for continuing current contraception until sterilisation performed. CONCLUSIONS: Documentation of preoperative counselling for female sterilisation is often incomplete and does not comply with published recommendations. The introduction of a proforma resulted in a mixture of both improvement and deterioration of documentation. When the proforma was used, compliance with recommendations was 100%.

Management of late intrauterine death using a combination of mifepristone and misoprostol--experience of two regimens.

OBJECTIVE: To determine the safety and effectiveness of managing intrauterine death after 24 weeks gestation using a combination of mifepristone and misoprostol. STUDY DESIGN: Two regimens are compared. Twenty-nine women (group one) were managed using a combination of oral mifepristone and vaginal/oral misoprostol. After a change in dosage and route of administration, a further 20 women were managed with oral mifepristone and vaginal misoprostol (group two). RESULTS: All women delivered vaginally. The mean induction to delivery interval in group one was 7 h compared with 10.2 h in group two. Group two experienced fewer gastrointestinal side-effects than group one. CONCLUSION: This study confirms that the combined use of mifepristone and misoprostol is a safe and effective way of managing IUD after 24 weeks gestation. Regimen one results in a shorter induction to delivery interval but is associated with a higher incidence of gastrointestinal side-effects.

Unadjusted and customised weight centiles in the identification of growth restriction among stillborn infants.

The study aims to compare the utility of unadjusted with customised weight standards in the identification of intrauterine growth restriction (IUGR) among unexplained stillborn infants undergoing postmortem examination. Unadjusted and customised birthweight centiles were determined for 51 unexplained stillborn infants undergoing perinatal autopsy. Unadjusted centiles were calculated from an ultrasonically derived fetal weight standard. Customised centiles were calculated from an online calculator which adjusts the standard to account for important physiological variables. IUGR was defined as moderate or severe according to brain/liver ratios of > 3 and > 5, respectively. The relationship between the weight centiles and abnormal brain/liver weight ratios was explored. Neither unadjusted nor customised standards identify stillborn infants with brain/liver ratios > 3:1. Both unadjusted and customised weight standards identify stillborn infants with brain/liver ratios > 5 equally well with high sensitivity (95%) but low specificities (63% and 66%, respectively). Customising weight standards to account for physiological variables does not identify growth restricted stillborn infants more usefully than an unadjusted fetal weight standard.

Management of premenstrual dysphoric disorder.

Premenstrual dysphoric disorder is a complex disorder characterized by severe physical and psychological symptoms. The pathophysiology and effective treatment of premenstrual dysphoric disorder are presented. Evidence for the effective treatment of premenstrual dysphoric disorder by correction of neuroendocrine abnormalities or suppression of cyclical ovarian activity is reviewed.

The second stage of labour.

Obstetric intervention in the second stage of labour is frequently indicated. An appreciation of the physiology of the second stage and an awareness of the range of interventions with their appropriate selection and application will contribute towards ensuring a safe delivery.

Prediction of intrauterine growth restriction with customised estimated fetal weight centiles.

OBJECTIVES: 1. To determine the value of third trimester customized estimated fetal weight centile ranking in the prediction of infants born with anthropometric features of intrauterine growth restriction (IUGR). 2. To compare the performance of customized centiles with fetal growth velocity in the prediction of IUGR. DESIGN: Prospective, observational study. SETTING: Department of Obstetric Ultrasound. POPULATION: Two hundred and seventy-four women with low risk pregnancies who were participants in a previously published longitudinal study of fetal biometry. METHODS: Third trimester estimated fetal weight customized centiles were obtained after adjustment for gestational age at the time of ultrasound, birth order and gender, maternal weight, height and ethnic origin. Fetal growth velocity was calculated using the increment in the fetal abdominal area over a mean 28-day interval. Fetal abdominal area growth velocity was expressed as a standard deviation (Z score). Three neonatal anthropometric measures were used to define IUGR: subscapular or triceps skinfold thickness <10th centile, ponderal index <25th centile, mid-arm circumference to occipito-frontal circumference <-1 SD. The ability of estimated fetal weight customized centiles <5th centile and <10th centile to identify growth restriction was determined by calculating likelihood ratios. MAIN OUTCOME MEASURE: Likelihood ratios for the prediction of neonatal anthropometric features of IUGR. RESULTS: Two hundred and fifty-eight infants had an estimated fetal weight customized centile calculated and one or more anthropometric measurements. The mean customized estimated fetal weight centile for cases with and without a low skinfold thickness were 16.4 vs 41.7 (P < 0.01); the mean values of customized estimated fetal weight centile for cases with and without ponderal index <25th centile were 22.8 vs 42.7 (P < 0.01); mean estimated fetal weight customized centiles for cases with and without mid-arm circumference to occipito-frontal circumference <-1 SD were 26.3 vs 40.5 (P > 0.05). A customized estimated fetal weight centile of 5 or less had likelihood ratios (95% CI) of 4.9 (2.7-6.3), 6.8 (4.5-10.6) and 6.3 (3.7-14) for skinfold thickness <10th centile, ponderal index <25th centile and mid-arm circumference to occipito-frontal circumference <-1 SD, respectively. An estimated fetal weight customized centile of 10 or less had likelihood ratios of 4.5 (2.6-8.6), 4.1 (2.5-7.2) and 7.1 (3.5-24) for skinfold thickness <10th centile, ponderal index <25th centile and mid-arm circumference to occipito-frontal circumference <-1 SD, respectively. In the prediction of a ponderal index <25th centile, the fetal abdominal area velocity likelihood ratio for a positive test is higher than the likelihood ratio for the 10th estimated fetal weight customized centile (P = 0.04) but is not significantly higher for the other outcomes. The fetal abdominal area velocity likelihood ratio is not significantly higher than the likelihood ratios for the fifth estimated fetal weight customized centile for any of the three outcomes. CONCLUSION: Customized estimated fetal weight centiles in the late third trimester are moderately useful in the identification of infants with IUGR but are less accurate than calculated growth velocity in the prediction of an infant with a low ponderal index.

Relationship between customised birthweight centiles and neonatal anthropometric features of growth restriction.

OBJECTIVE: To determine the relationship between customised birthweight centiles (adjusted for maternal and fetal physiological variables) and neonatal anthropometric features of intrauterine growth restriction (IUGR). DESIGN: Observational study. POPULATION: Two-hundred and seventy women with low risk pregnancies participating in a cohort study of serial ultrasound biometry. METHODS: Customised birthweight centiles were calculated following adjustment for maternal weight, height and ethnic origin, gestational age at delivery, birth order, and sex of the infant. Three separate neonatal anthropometric measures were used to define IUGR: subscapular or triceps skinfold thickness <10th centile; ponderal index <25th centile; and mid-arm circumference to occipito-frontal circumference ratio (MAC/OFC) <- 1 standard deviation (SD). Relationship of the centiles to these outcomes was evaluated using likelihood ratios (LR) and kappa statistic. These approaches allowed us to examine the strength of the association: an LR of 5-10 would be expected to generate moderate changes in the pre-test probability of IUGR, whereas a kappa value of 0.2-0.4 would reflect fair agreement between customised birthweight centiles and neonatal anthropometric measures. RESULTS: Customised birthweight centile of 10 or less had the following LR values for the various anthropometric criteria for IUGR: 5.1 (95% CI 3-8.5) for low skinfold thickness; 4.3 (95% CI 2.5-7.1) for low ponderal index; and 3.9 (95% CI 2-6.6) for low MAC/OFC ratio. The kappa values were: 0.4 (95% CI 0.26-0.51) for low skinfold thickness; 0.33 (95% CI 0.21-0.46) for low ponderal index; and 0.13 (95% CI 0-0.26) for low MAC/OFC ratio. CONCLUSION: In a low risk population, customised birthweight centiles can only be moderately useful in the identification of neonates with low skinfold thickness and low ponderal index.