Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a reply to a rebuttal

See also Bujold E, Gouin K, Cote S.Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a rebuttal. This issue, pp 1195; de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, on behalf of FRUIT Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT. J Thromb Haemost 2012; 10 : 64–72.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a rebuttal

See also de Vries JIP, Hague WM and van Pampus MG; for the FRUIT‐Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a reply to a rebuttal. This issue, pp 1196; de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, on behalf of FRUIT Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset preeclampsia in women with inheritable thrombophilia: the FRUIT‐RCT. J Thromb Haemost 2012; 10 : 64–72.     

Should Bilateral Uterine Artery Notching Be Used in the Risk Assessment for Preeclampsia,Small‐for‐Gestational‐Age,and Gestational Hypertension?

Objective. The purpose of this study was to determine the value of bilateral uterine artery notching in the second trimester in the risk assessment for preeclampsia, gestational hypertension, and small‐for‐gestational‐age (SGA) without preeclampsia. Methods. This prospective cohort study included 4190 singleton pregnancies that underwent ultrasound examination between 23 and 25 weeks' gestation. The 95th percentiles of the mean pulsatility index (PI) and resistive index (RI) of both uterine arteries were calculated. Multivariable logistic regression analyses were performed to determine if bilateral uterine artery notching is an independent explanatory variable for the occurrence of preeclampsia, early‐onset preeclampsia (≤34 weeks), late‐onset preeclampsia (>34 weeks), gestational hypertension, and delivery of an SGA neonate without preeclampsia, while controlling for confounding factors. Results. (1) The prevalence of preeclampsia, early‐onset preeclampsia, late‐onset preeclampsia, SGA, and gestational hypertension were 3.4%, 0.5%, 2.9%, 10%, and 7.9%, respectively; (2) 7.2% of the study population had bilateral uterine artery notching; and (3) bilateral uterine artery notching was an independent explanatory variable for the development of preeclampsia (odds ratio [OR], 2.1; 95% confidence interval [CI],1.28–3.36), early‐onset preeclampsia (OR, 4.47; 95% CI, 1.50–13.35), and gestational hypertension (OR, 1.50; 95% CI, 1.02–2.26), but not for late‐onset preeclampsia or SGA. Conclusions. Bilateral uterine notching between 23 and 25 weeks' gestation is an independent risk factor for the development of early‐onset preeclampsia and gestational hypertension. Thus, bilateral uterine artery notching should be considered in the assessment of risk for the development of these pregnancy complications.     

A functional variant in the thrombospondin‐1 gene and the risk of small for gestational age infants

Summary. Introduction: Thrombospondin‐1 (TSP‐1) is a prothrombotic and anti‐angiogenic glycoprotein expressed in the placenta. A functional single nucleotide polymorphism in the TSP‐1 gene (TSP‐1 A2210G) is a risk factor for familial premature myocardial infarction. Small for gestational age (SGA) infants are at increased risk of coronary artery disease in adult life and common genetic factors may underlie both conditions. We investigated the association of TSP‐1 A2210G in SGA infants and their parents. Method: The 3234 nulliparous pregnant women, their partners and babies were recruited in Adelaide and Auckland to a prospective multicenter cohort study. Amongst 2123 Caucasian women, 216 (10.2%) delivered an SGA infant, defined as birth weight < 10th customized centile adjusted for maternal height, weight, parity and ethnicity, as well as gestational age at delivery and infant sex. Uncomplicated pregnancies served as controls (n = 1185). DNA extracted from peripheral/cord blood or buccal swabs was genotyped using Sequenom MassARRAY. Multivariable logistic regression was used to compare the odds of SGA between the genotype groups adjusting for potential confounders. Results: Paternal (adjOR, 1.4; 95% CI 1.0–2.0) and neonatal (adjOR, 1.8; 95% CI, 1.1–2.7) TSP‐1 A2210G associates with SGA. The maternal polymorphism approaches significance for an association with SGA (adjOR, 1.3; 95% CI, 0.9–1.9). Maternal TSP‐1 A2210G associates with a reduced maternal birth weight adjusted for gestational age at delivery (P = 0.03). Conclusion: The TSP‐1 A2210G polymorphism, which is a risk factor for myocardial infarction, is associated with SGA pregnancies, suggesting that this polymorphism may associate with the risk of vascular disorders across the life course.     

Prophylaxis with low‐dose low‐molecular‐weight heparin during pregnancy and postpartum: is it effective?

Summary. Background: The optimal approach for venous thrombosis (VTE) prophylaxis during pregnancy and postpartum in women with an increased risk of VTE is not established. Objectives: To evaluate the effectiveness, represented as the incidence of pregnancy‐related VTE, and safety, represented as incidence of postpartum hemorrhage (PPH), of a protocol recommending prophylaxis with low‐dose low‐molecular‐weight heparin (LMWH) in women at intermediate to high risk of VTE. Patients/methods: In this retrospective cohort study, we analyzed 34 women (44 pregnancies) with intermediate risk of VTE who received low‐dose LMWH for 6 weeks postpartum and 57 women (82 pregnancies) with high risk of VTE who received low‐dose LMWH during pregnancy and for 6 weeks postpartum. Pregnancy‐related VTE was defined as VTE during pregnancy or ≤ 3 months postpartum. PPH was defined as blood loss > 500 mL and severe PPH as blood loss > 1000 mL. Results: The incidence of pregnancy‐related VTE was 5.5% (95% CI, 2.4–12.3) despite prophylaxis with low‐dose LMWH. All events occurred in women at high risk, with a postpartum incidence of 7.0% (95% CI, 2.9–16.7) and antepartum incidence of 1.8% (95% CI, 0.4–9.2). The risk of PPH was 21.6% (95% CI, 14.3–31.3) and severe PPH 9.1% (95% CI, 4.7–16.9), which was not different in women who started LMWH postpartum and those who used LMWH during pregnancy. Conclusions: Although prophylaxis with low‐dose LMWH during pregnancy and postpartum proved to be safe, the risk of pregnancy‐related VTE is considerable in women with a high risk of VTE. VTE prophylaxis with low‐dose LMWH may not be sufficiently effective in these women.     

Low-molecular-weight heparin improves the performance of uterine artery Doppler velocimetry to predict preeclampsia and small-for-gestational age infant in women with gestational hypertension

This study investigated whether a short course of subcutaneous low-molecular-weight heparin (LMWH) might modify the performance of uterine artery Doppler to predict preeclampsia and small-for-gestational age (SGA) newborns in a high-risk population. A controlled, open-labeled study included 94 women with gestational hypertension and 30 healthy women enrolled at 24 to 26 weeks gestation. Doppler evaluation of uterine arteries resistance index (RI) was performed before and after a two-week course of LMWH (enoxaparin, 4000 IU/d, n = 56 hypertensive patients) or no treatment (n = 38 hypertensive women and 30 healthy controls). There was a significant decrease of uterine artery RI after LMWH (p < 0.001, paired Student's t-test), whereas the untreated hypertensive patients and the healthy control group showed no change between the two Doppler evaluations. The change induced by LMWH was restricted to women with normal outcome, whose RI decreased from (mean +/- standard error) 0.62 +/- 0.01 to 0.56 +/- 0.01 (p < 0.0001). By consequence, the second RI measurement, performed after LMWH administration, had fewer false positive results and higher positive likelihood ratios (LR+) to predict both preeclampsia (LR + 5.91) and SGA (LR + 4.69) compared with the first Doppler examination (LR + 1.97 and 2.22, respectively). Thus, LMWH improved the performance of uterine artery RI to predict preeclampsia and SGA in women with gestational hypertension.     

Increased anticoagulant response to low‐molecular‐weight heparin in plasma from patients with advanced cirrhosis

Summary. Introduction: Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low‐molecular‐weight heparin (LMWH) in this clinical setting is still unclear. Aims/methods: To evaluate the in vitro effect of LMWH on thrombin generation (TG) in cirrhotic patients at different stages of liver disease. Thirty cirrhotics (10 Child Pugh A, 10 Child Pugh B and 10 Child Pugh C), 10 subjects with inherited type 1 antithrombin (AT) defect and 10 healthy controls were studied. TG was determined at baseline and with anti‐Xa levels after the addition of enoxaparin at 0.35 and 0.7 U anti‐Xa mL. The endogenous thrombin potential (ETP) ratio at 0.35 and 0.7 U anti‐Xa mL was obtained by dividing ETP with LMWH by ETP at baseline. Results: Mean AT levels in all cirrhotic subgroups and in patients with AT deficiency were significantly lower than in controls. The 0.35 ETP ratio was significantly lower in cirrhotic patients than in controls (0.26 ± 0.1 vs. 0.48 ± 0.1, P < 0.001) and the reduction paralleled the severity of liver disease, in spite of the concomitant decrease in AT and anti‐Xa activity. AT‐deficient subjects showed a significantly increased 0.35 ETP ratio compared with both cirrhotic patients and controls (0.69 ± 1 vs. 0.26 ± 0.1, P < 0.001, and vs. 0.48 ± 0.1, P = 0.04 respectively). LMWH at 0.7 U anti‐Xa mL completely inhibited TG in 9/30 cirrhosis patients with more advanced liver disease (Child Pugh B and C), whereas complete TG abolition was seen in only 1/10 controls. Conclusions: Cirrhotic patients show an increased response to LMWH, which correlates with the severity of liver disease, in spite of reduced AT and anti‐Xa activity levels. Thrombin generation may be a useful tool to monitor the response to LMWH in cirrhotic patients.     

Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review

Summary. Background: The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non‐recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. Objective and methods: We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non‐recurrent pregnancy loss in the absence of antiphospholipid antibodies. Results: For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q‐value was 41.7, P = 0.000, and I² = 90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. Conclusion: There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.     

Women’s views on and adherence to low‐molecular‐weight heparin therapy during pregnancy and the puerperium

Summary. Background: Non‐adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low‐molecular‐weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women’s views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. Objectives: To monitor women’s adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. Patients/Methods: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self‐completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. Results: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t‐test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity‐concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. Conclusions: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women’s antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period.     

Association of Crown‐Rump Length at 11 to 14 Weeks' Gestation and Risk of a Large‐for‐Gestational‐Age Neonate

Objective. The purpose of this study was to evaluate the association between crown‐rump length (CRL) and the risk of a large‐for‐gestational‐age (LGA) neonate. Methods. Data were retrospectively collected on consecutive women with a healthy singleton pregnancy followed to delivery at our center from 2003 to 2006 who underwent nuchal translucency, pregnancy‐associated plasma protein‐A, and free β‐human chorionic gonadotropin screening at 11 to 14 weeks' gestation. Pregnancies were dated by the last menstrual period (LMP) confirmed by CRL at 6 to 10 weeks or the known time of fertilization. The fetal CRL at 11 to 14 weeks was obtained from frozen sonographic images. The measured CRL was converted to gestational weeks using the method of Hadlock et al (Radiology 1992; 182:501–505). The expected gestational age (GA) by the LMP was subtracted from the measured GA to yield the ΔCRL. The association between the ΔCRL and birth weight was statistically analyzed. Results. The sample included 521 women. Fifty neonates (9.6%) were LGA (≥90th percentile), 38 (7.3%) small for gestational age, and 433 (83.1%) appropriate for gestational age. The LGA group was characterized by significantly larger‐than‐expected CRL measurements (P = .033). The birth weight percentile and rate of LGA neonates were significantly higher in pregnancies in which the ΔCRL was ½ week or greater (P = .007 and .033, respectively). There was a significant linear correlation between the ΔCRL and birth weight percentile (P = .001). On multivariate logistic regression analysis, the ΔCRL was the only significant predictor of an LGA neonate (odds ratio, 1.6; 95% confidence interval, 1.07–2.4; P = .023). Conclusions. Pregnancies with LGA neonates are characterized by larger‐than‐expected CRL measurements at 11 to 14 weeks' gestation.     

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.     

Discordance of First‐Trimester Crown‐Rump Length Is a Predictor of Adverse Outcomes in Structurally Normal Euploid Dichorionic Twins

Objective. The purpose of this study was to determine the association between discordant crown‐rump length (CRL) measurements in structurally normal euploid dichorionic twins and adverse pregnancy outcomes. Methods. This retrospective cohort study included women with dichorionic twins who underwent chorionic villus sampling and delivered in our facility from January 2000 to September 2007. Only pregnancies with viable twin fetuses and normal karyotypes were included. The association between CRL discordance, defined as a CRL discrepancy of 9% or greater, and adverse pregnancy outcomes was evaluated. Results. Seventy‐eight women met inclusion criteria and included 24 discordant twins (group 1) and 54 concordant twins (group 2). Maternal ages were similar: mean ± SD, 38.2 ± 3.1 years in group 1 versus 39.2 ± 3.9 years in group 2 (P = not significant). The median gestational ages at delivery were 35.6 ± 3.1 weeks in group 1 and 37.3 ± 2.0 weeks in group 2 (P < .01). At least 1 major complication occurred in 19 women (79%) in group 1 and 25 (46%) in group 2 (P = .01). Group 1 had significantly more major complications overall (P = .0008). Preterm premature rupture of membranes occurred in 10 women (42%) in group 1 and 6 (11%) in group 2 (P = .005). Delivery before 37 weeks' gestation occurred in 19 of 24 women (79%) in group 1 and 24 of 54 (44%) in group 2 (P = .006). There was a significant difference for younger gestational age at delivery in the discordant group (P < .01). Conclusions. Our data suggest that there is an increased risk of adverse pregnancy outcomes in chromosomally normal dichorionic twins with first‐trimester discordant CRL measurements. These results may be clinically useful for counseling, management, and antenatal surveillance.     

Three‐Dimensional Ultrasonography of the Fetal Vermis at 18 to 26 Weeks' Gestation

Objective. The purpose of this study was to establish the normality of the fetal vermis, ie, the time of appearance of the primary fissure, as well as its measurements between 18 and 26 weeks' gestation, using 3‐dimensional (3D) ultrasonography. Methods. A prospective cross‐sectional study of normal singleton pregnancies was conducted. Examinations were performed with high‐resolution transabdominal ultrasonography using the axial plane in 173 fetuses between 18 and 26 weeks' gestation. Postprocessing measurements of the fetal vermis were done with 4‐dimensional software using static volume contrast imaging and tomographic ultrasound imaging in the C‐plane. Detection of the primary fissure was evaluated in all cases, and the time of appearance was documented. Results. Adequate vermis measurements were obtained in 173 fetuses. Vermian length as a function of gestational age was expressed by regression equations, and the correlation coefficients were found to be highly statistically significant (P < .001). The normal mean ± 2 SD for each gestational week was defined. The primary fissure was observed at 24 weeks' gestation in all cases, at 22 weeks in 94% of cases, and as early as 18 weeks in 40%. Conclusions. This 3D study documents the appearance of the primary fissure and presents the normal range of vermian measurements, confirming normal development of the fetal vermis starting as early as 18 weeks' gestation. It also shows an easy method for visualizing the vermis with 3D ultrasonography at every gestational week regardless of fetal presentation.     

Ultrasound diagnosis of severe thrombotic placental damage in the second trimester: an observational study.

OBJECTIVES: To screen women with uteroplacental insufficiency between 18 and 26 weeks' gestation for sonographic evidence of destructive placental lesions, to observe the effect of low molecular-weight heparin (LMWH) in these cases, and to compare the outcome with similar but untreated controls. METHODS: We screened 180 women at high risk for placental damage using 16-week maternal serum screening (alpha-fetoprotein and human chorionic gonadotropin), placental shape and texture, and uterine artery Doppler waveforms at the 18-20-week level II examination. Serial gray-scale examinations of placental texture were performed at 22, 24 and 26 weeks. LMWH was offered to women with ultrasound evidence of destructive placental lesions in the absence of intrauterine growth restriction and/or pre-eclampsia. RESULTS: We prospectively identified six women (3.3%) with abnormal maternal serum screening and uterine artery Doppler in whom abnormal placental texture (echogenic cystic lesions) suggestive of destructive lesions in the placental parenchyma was found either at the 18-20-week ultrasound examination (n = 4), or by 26 weeks of gestation (n = 2). All six received LMWH and had live births (gestational age at delivery, 33-37 weeks; birth weight, 1000-3200 g). A further 14 women were referred with similar multiparameter evidence of placental damage at or after 26 weeks, outside the screening study. All had significant fetal growth restriction and were therefore not offered heparin. In 9/14 cases there was a perinatal death. Ischemic and/or thrombotic placental pathology was confirmed in each case, but no maternal thrombophilia disorders were identified in the 20 women. CONCLUSIONS: Integrated biochemical and ultrasound testing of placental function at 16-20 weeks of gestation, followed by serial placental gray-scale ultrasound, may be an effective method of identifying a subset of pregnancies at high risk of adverse pregnancy outcome due to destructive lesions in the placental parenchyma. This strategy of identifying thrombo-occlusive placental lesions before the development of pregnancy complications may prove useful in the design of trials to study the effectiveness of LMWH in the prevention of clinical complications resulting from thrombo-occlusive placental disease.     

Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy

Summary. Background: Although women with antiphospholipid antibodies (APLAs) are at increased risk of recurrent miscarriage, the outcome of a subsequent pregnancy is not clearly elucidated. Objectives: To assess the pregnancy outcome of a subsequent pregnancy in women with APLAs and compare this outcome with women with unexplained recurrent miscarriage. Methods: We performed a cohort study among all women who attended the Miscarriage Clinic at Liverpool Women’s Hospital between 1987 and 2006 after being referred due to recurrent miscarriage (≥ 2 consecutive pregnancy losses). All women underwent a standardized investigation sequence. Women with other reasons for recurrent miscarriage were excluded. Results: A total of 693 women fulfilled the selection criteria, of whom 176 (25%) had APLAs. One hundred and twenty‐two (69%) women with APLAs had a subsequent live birth compared with 324 (63%) women with unexplained recurrent miscarriage (OR 1.3, 95% CI 0.9–1.9). No differences were found for birth weight, gestational age, and intra‐uterine growth restriction. When treatment was analyzed, 53/67 (79%) of women with APLAs who had received aspirin and heparin during their pregnancy had a live birth, compared with 64/104 (62%) of women with APLAs who received aspirin only (adjusted OR 2.7, 95% CI 1.3–5.8). In unexplained recurrent miscarriage, stratification for treatment showed no differences in outcome. Conclusion: The prognosis of a subsequent pregnancy in women with APLAs is good. Although this was not a randomized clinical trial, combined treatment of aspirin and heparin seemed associated with a better outcome in women with APLAs, but not in women with unexplained recurrent miscarriage.     

Plasminogen activator inhibitor type‐1 is an independent marker of metabolic disorders in young adults born small for gestational age

Summary. Background: Metabolic syndrome (MS) has been associated with being born small for gestational age (SGA). In epidemiological studies plasminogen activator inhibitor type‐1 (PAI‐1) levels have been associated with MS. Few studies have examined this association in subjects born SGA. Patients and methods: Five hundred and fifty‐seven SGA adults (birth weight < 10th percentile) were compared with 671 subjects with a birth weight between the 25th and 75th percentiles (control group). MS was defined using the World Health Organization (WHO) definition. Active PAI‐1 was measured on citrated plasma with bio‐immunoassay. Results: MS was more prevalent in the SGA group (8.7%) than in the control group (5.5%; P = 0.03). In both groups, PAI‐1 concentrations were significantly correlated with waist circumference, plasma triglycerides, homeostatic model assessment‐insulin resistance (HOMA‐IR) and associated with male sex and MS. PAI‐1 concentrations were significantly increased in the SGA group (12.2 ± 21.2 vs. 10.0 ± 13.5 IU mL^?1, P = 0.03) and this remained after adjustment of metabolic variables (P = 0.009). PAI‐1 concentrations above 4.9 IU mL^?1 (= median of PAI‐1 concentration in the control group) were present in 94% of the subjects with MS. Moreover, the adjusted odds ratio (OR) for having elevated PAI‐1 was 1.48 (1.08; 1.95) in the SGA group in comparison with the control group (P = 0.005). Conclusions: PAI‐1 plasma concentrations were significantly increased in SGA subjects independently of MS. These data suggest that elevation of PAI‐1 concentrations might be an indication of an abnormal secretion at the level of the adipose tissue, endothelial cells or liver and implicated in metabolic disorders reported in SGA subjects.     

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

A prospective management study of slow-release aspirin in the palliation of uteroplacental insufficiency predicted by uterine artery Doppler at 20 weeks.

OBJECTIVE: To investigate the effect of low-dose, slow-release aspirin in reducing the incidence and/or severity of pregnancy complications in women identified as high risk of developing problems associated with uteroplacental insufficiency, namely pre-eclampsia or delivering a small-for-gestational age (SGA) baby. DESIGN: A prospective, randomized management study. One thousand and twenty-two women of mixed parity underwent color flow/pulsed Doppler (CFPD) imaging of the uterine arteries at the time of the 17-23 week (mean 19.9) anomaly scan. Women who were screen positive were randomized to a control or treatment group. The treatment group was given 100-mg slow-release aspirin (Disprin CV) daily and followed up at regular intervals. Women in the routine group received routine antenatal care. Main outcome measures were pre-eclampsia and SGA < 3rd centile. Secondary outcome measures were: SGA < 10th centile, pre-eclampsia requiring delivery before 34 weeks, placental abruption, an Apgar score < 7 at 5 min, admission to neonatal intensive care unit or a pregnancy that resulted in a stillbirth or neonatal death. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for severe and any complications. RESULTS: Two hundred and sixteen women were screen positive according to the defined criteria. One hundred and three women were assigned to the treatment group and 113 to the control group. The difference in the incidence of pre-eclampsia and SGA < 3rd centile between the control and treatment groups did not reach statistical significance. There was a statistically significant reduction in any (OR 0.41 (CI 0.35-0.45), P < 0.01) and severe pregnancy complications (OR 0.43 (CI 0.21-0.84), P < 0.05) in the treatment group compared with the controls. CONCLUSIONS: The administration of slow-release aspirin to women identified as high risk, using color Doppler imaging of the uterine arteries at 20 weeks' gestation, did not significantly alter the incidence of pre-eclampsia or delivery of a SGA baby. It did, however, improve the outcome by reducing the overall incidence of complications associated with uteroplacental insufficiency.     

Recurrent venous thromboembolism after surgery‐provoked versus unprovoked thromboembolism

Summary. Background: The incidence of recurrent venous thromboembolism (VTE) varies depending on the nature of the initial provoking risk factor(s). Objectives: To compare the incidence and time course of recurrent VTE after unprovoked VTE vs. VTE provoked by nine different types of surgery. Methods: Retrospective analysis of linked California hospital and emergency department discharge records. Between 1997 and 2007, all surgery‐provoked VTE cases had a first‐time VTE event diagnosed within 60 days after undergoing a major operation. The incidence of recurrent VTE was compared during specified follow‐up periods by matching each surgery‐provoked case with three unprovoked cases based on age, race, gender, VTE event, calendar year and co‐morbidity. Results: The 4‐year Kaplan–Meier cumulative incidence of recurrent VTE was 14.7% (95%CI: 14.2–15.1) in the matched unprovoked VTE group vs. 7.6% (CI: 7.0–8.2) in 11 797 patients with surgery‐provoked VTE (P < 0.001). The overall risk reduction was 48%, which ranged from 64% lower risk (P < 0.001) after coronary bypass surgery to 25% lower risk (P = 0.06) after disc surgery. The risk of recurrent VTE 1–5 years after the index event was significantly lower in the surgery group (HR = 0.47, CI: 0.41–0.53). Within the surgery‐provoked group, the risk of recurrent VTE was similar in men and women (HR = 1.0, CI: 0.8–1.3). Conclusions: The risk of recurrent VTE after surgery‐provoked VTE was approximately 50% lower than after unprovoked VTE, confirming the view that provoked VTE is associated with a lower risk of recurrent VTE. However, there was appreciable heterogeneity in the relative risk of recurrent VTE associated with different operations.     

Association Between Second‐Trimester Cervical Length and Spontaneous Preterm Birth in Twin Pregnancies

Objective. The purpose of this study was to define normal second‐trimester cervical length (CL) measurements and to estimate the association between second‐trimester CL and spontaneous preterm birth (SPTB) in twin pregnancies. Methods. A retrospective cohort of 309 asymptomatic patients with twin pregnancies who had routine outpatient CL assessment in the second trimester was studied. We looked at the gestational age periods of 16 to 17 6/7, 18 to 19 6/7, 20 to 21 6/7, and 22 to 23 6/7 weeks. We estimated the association between the CL measurement during each period and SPTB. A short CL was defined both as a CL at or below the 10th percentile for gestational age and 25 mm or less. We also performed regression analyses controlling for a number of clinically important factors: maternal age, chorionicity, in vitro fertilization, multifetal reduction, prior term births, prior preterm births, prepregnancy body mass index, and cerclage. Results. The CL measurement at 16 to 17 6/7 weeks was not associated with gestational age at delivery or SPTB. At 18 to 19 6/7 and 20 to 21 6/7 weeks, the CL measurement was not significantly associated with gestational age at delivery or SPTB before 28 and 32 weeks. There was an association with SPTB before 35 weeks. At 22 to 23 6/7 weeks, the CL measurement had a significant association with gestational age at delivery and SPTB before 28, 32, and 35 weeks (P < .05). A short CL at 22 to 23 6/7 weeks was significantly associated with SPTB before 32 and 35 weeks (P < .05). Conclusions. In second‐trimester twin pregnancies, the strongest association between CL and SPTB is at 22 to 23 6/7 weeks.