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Lesley Regan

Publications and source records attributed to Lesley Regan.

17 recordsLinked to original sources
PubMed2006

Recurrent miscarriage.

Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, affects 1% of couples trying to conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and clinician. A third of women attending specialist clinics are clinically depressed, and one in five have levels of anxiety that are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and treatment of women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research has emphasised the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and late pregnancy complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-based management.

Abortion, Habitual↗
PubMed2006

Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome.

Antiphospholipid syndrome (APS), characterized by circulating antiphospholipid (aPL) antibodies, is a major cause of early pregnancy failure and placental insufficiency. In this study, we examined whether impaired endometrial differentiation before conception contributes to the high incidence of pregnancy complications in APS. Timed secretory endometrial biopsies were obtained from a cohort of women with recurrent pregnancy loss (RPL). Real-time quantitative (RTQ)-PCR was used to determine the expression levels of transcripts that encode for decidual markers, proinflammatory cytokines and complement regulatory proteins. Expression of decidual markers such as prolactin (PRL), tissue factor (TF) and signal transducer and activator of transcription 5 (Stat5), but not insulin-like growth factor-binding protein 1 (IGFBP-1), was significantly lower in samples obtained from aPL(+) patients (n = 24) when compared with aPL(-) group (n = 58) (P < 0.05). The abundance of transcripts encoding for interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha) or Stat1 did not differ significantly between both groups (P >/= 0.05). However, analysis of transcripts that encode for complement regulatory proteins showed a marked decrease in decay-accelerating factor (DAF/CD55) levels in aPL(+) patients (P = 0.005), which was mimicked at protein level as demonstrated by immunohistochemistry. In summary, patients with RPL have distinct endometrial gene expression profiles depending on the presence or absence of circulating aPL antibodies. In APS, impaired endometrial differentiation and lower DAF/CD55 expression before conception may compromise implantation and predispose to complement-mediated pregnancy failure.

Abortion, Habitual↗
PubMed2006

Heparin prevents programmed cell death in human trophoblast.

Heparin is used clinically for the prevention of pregnancy complications associated with prothrombotic disorders, especially antiphospholipid antibody syndrome. Recent studies have suggested that heparin may exert direct effects on placental trophoblast, independently of its anticoagulant activity. We now demonstrate that heparin abrogates apoptosis of primary first trimester villous trophoblast in response to treatment with the pro-inflammatory cytokines interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. This multifunctional glycosaminoglycan also inhibited apoptosis induced by other agents, including staurosporin, broad-spectrum kinase inhibitor and thrombin. Furthermore, heparin attenuated caspase-3 activity, a hallmark of apoptosis, in human first trimester villous and extravillous trophoblast cell lines treated with peptidoglycan, a Toll-like receptor-2 agonist isolated from Staphylococcus aureus. The ability of heparin to antagonize cell death induced by such diverse apoptotic signals suggested that it acts as a survival factor for human trophoblast. We demonstrate that heparin, like epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), elicits phosphorylation of the EGF receptor and activation of the phosphatidyl inositol 3-kinase (PI3K)-, the extracellular signal-related kinase 1/2 (ERK1/2)- and the c-Jun NH2 terminal kinase (JNK)-signal transduction pathways in primary villous trophoblast. In summary, we have demonstrated that heparin activates multiple anti-apoptotic pathways in human trophoblast. Our results suggest that heparin may be useful in the management of at-risk patients, even in the absence of an identifiable thrombophilic disorder.

Apoptosis↗
PubMed2005

Effects of vasoactive agents on intracellular calcium and force in myometrial and subcutaneous resistance arteries isolated from preeclamptic, pregnant, and nonpregnant woman.

OBJECTIVE: Preeclampsia is a common and serious complication of pregnancy, characterized by maternal hypertension and proteinuria, placental insufficiency, and fetal growth restriction. The purpose of this study was to investigate whether intracellular Ca 2+ ([Ca 2+ ] i ) and contractile responses of vascular smooth muscle to vasoactive agents are altered in preeclampsia compared with normal pregnancy and the nonpregnant state. STUDY DESIGN: Subcutaneous and myometrial resistance arteries from women who had preeclampsia, normal pregnancy, and nonpregnant women were obtained at the time of cesarean section or hysterectomy. Arteries were mounted on an isometric myograph and loaded with the Ca 2+ indicator, fura-2AM, to permit simultaneous measurement of force and [Ca 2+ ] i . Reponses to endothelium-dependent relaxants (acetylcholine and substance P) and vasoconstrictors (depolarizing potassium solution, phenylephrine, and angiotensin II) were examined. RESULTS: The fall in [Ca 2+ ] i and relaxation in response to acetylcholine was significantly inhibited in both myometrial and subcutaneous arteries from preeclamptic women compared with arteries from nonpregnant or normal pregnant women. However, responses to substance P did not differ between the 3 groups. There were no significant differences in [Ca 2+ ] i or force responses to high potassium, phenylephrine, or angiotensin II in myometrial and subcutaneous resistance vessels in women with preeclampsia compared with normal pregnant women. However, force, but not [Ca 2+ ] i responses to angiotensin II, in subcutaneous vessels from normal pregnant and preeclamptic women were reduced compared with subcutaneous arteries from nonpregnant women, indicating that pregnancy is associated with a reduction in Ca 2+ sensitization in this tissue. A similar effect was not seen in myometrial arteries. CONCLUSION: Endothelial function is altered in preeclampsia, with loss of effect of acetylcholine, but not substance P. Vasoconstrictor reactivity is not increased in preeclampsia compared with uncomplicated normal pregnancy, and this is unlikely to be an explanation for the increased peripheral vascular resistance seen in preeclampsia.

Adult↗
PubMed2005

Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure.

OBJECTIVE: Live birth rates are increased by treatment with heparin and aspirin in cases of poor pregnancy outcome such as antiphospholipid syndrome. Both drugs may attenuate miscarriage by inhibiting aberrant coagulation or by modulating trophoblast apoptosis. Here we assessed their roles in trophoblast apoptosis in vitro. STUDY DESIGN: BeWo cells and placental villi were cultured in sera from women with successful or failing in vitro fertilization, with and without heparin or aspirin. Apoptosis was assessed by using DNA laddering, cytokeratin 18 neoepitope formation, Bcl-2, and caspase 7 expression. RESULTS: In BeWo cells, sera from in vitro fertilization failure increased trophoblast apoptosis, whereas heparin and aspirin reversed these effects. In villous trophoblast, heparin increased Bcl-2 and cytokeratin 18 protein expression. Heparin and aspirin inhibited DNA laddering. CONCLUSION: Heparin and aspirin modulate trophoblast apoptosis suggesting a direct impact on trophoblast biology, thus providing an additional mechanism to explain the clinical benefits of heparin and aspirin on recurrent pregnancy loss.

Abortion, Habitual↗
PubMed2005

Recurrent miscarriage: pathophysiology and outcome.

PURPOSE OF REVIEW: This article reviews new concepts in the aetiology of recurrent miscarriage, presents new outcome data and evaluates new modalities of treatment for unexplained recurrent miscarriage. RECENT FINDINGS: Preimplantation genetic diagnosis has been considered an option for couples who have structural chromosomal abnormalities or unexplained recurrent miscarriage. The association between thrombophilias and adverse pregnancy outcome is further reviewed. In relation to this, there is increasing support for the use of thromboprophylaxis in improving pregnancy outcome in women with inherited thrombophilias. Nonrandomized studies have shown that the reduction in insulin levels with metformin in insulin-resistant individuals may reduce miscarriage risk by restoring normal haemostasis and improving the endometrial milieu. With respect to immunological concepts there is now evidence to suggest that, in addition to a suppression of maternal cell-mediated immunity, some elements of the innate immune system are activated in successful pregnancies. SUMMARY: With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.

Abortion, Habitual↗
PubMed2005

Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis.

Laboratory testing for the identification of heritable thrombophilia in high-risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost-effectiveness of universal and selective history-based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta-analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost-effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost-effective (ICER 6824 pounds). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER 202,402 pounds). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost-effective than universal screening in all the patient groups evaluated.

Adult↗
PubMed2005

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Adult↗
PubMed2004

Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro.

OBJECTIVE: Lupus anticoagulant poses a significant risk factor for obstetric complications, whereas heparin improves live birth rates in those pregnancies. Pathophysiology of antiphospholipid antibodies on placental function involves coagulopathies and thrombosis but also dysregulated trophoblast turnover. STUDY DESIGN: With the use of placental explant cultures, we assessed the effect of lupus anticoagulant positive sera (LA + sera) on apoptosis, mitosis, and invasion of trophoblast and determined the role of unfractionated heparin in regulating these functions. RESULTS: LA + sera were associated with increased placental apoptosis (TUNEL, M30 formation, DNA laddering). LA + sera decreased villous trophoblast proliferation and reduced extravillous trophoblast invasion through matrigel. Heparin attenuated LA + sera-induced apoptosis and facilitated trophoblast invasion. CONCLUSION: Lupus anticoagulant may impair placentation by increasing apoptosis, attenuating mitosis and reducing invasion of the trophoblast. The direct effects on trophoblast viability by heparin demonstrate an alternative biologic function for this anticoagulant and raise the possibility that anomalous trophoblast development may be therapeutically regulated.

Abortion, Spontaneous↗
PubMed2004

MRI guidance of focused ultrasound therapy of uterine fibroids: early results.

OBJECTIVE: The purpose of this study was to explore our hypothesis that MRI-guided focused ultrasound therapy for the treatment of uterine fibroids will lead to a significant reduction in symptoms and improvement in quality of life. We describe focused ultrasound therapy applications and the method for monitoring the thermal energy deposited in the fibroids, including the MRI parameters required, in a prospective review of 108 treatments. MATERIALS AND METHODS: Patients presenting with symptomatic uterine fibroids who attained a minimal symptom severity score and who would otherwise have been offered a hysterectomy were recruited. Thermal lesions were created within target fibroids using an MRI-guided focused ultrasound therapy system. The developing lesion was monitored using real-time MR thermometry, which was used to assess treatment outcome in real time to change treatment parameters and achieve the desired outcome. Fibroid volume, fibroid symptoms, and quality-of-life scores were measured before treatment and 6 months after treatment. Adverse events were actively monitored and recorded. RESULTS: In this study, 79.3% of women who had been treated reported a significant improvement in their uterine fibroid symptoms on follow-up health-related quality-of-life questionnaires, which supports our hypothesis. The mean reduction in fibroid volume at 6 months was 13.5%, but nonenhancing volume (mean, 51 cm(3)) remained within the treated fibroid at 6 months. CONCLUSION: This early description of MRI-guided focused ultrasound therapy treatment of fibroids includes follow-up data and shows that, although the volume reduction is moderate, it correlates with treatment volume and the symptomatic response to this treatment is encouraging.

Adult↗
PubMed2003

Risk factors for macrosomia and its clinical consequences: a study of 350,311 pregnancies.

OBJECTIVES: To identify demographic risk factors for either birthweight >4kg or over the 90th centile and to quantify the obstetric risks. STUDY DESIGN: Data from 350,311 completed singleton pregnancies in the North West Thames Region between 1988 and 1997 were analysed using logistic regression. Predisposing factors and pregnancy outcome were compared by birthweight 2.5-4kg (n=259,902) and >4kg (n=36,462) and 10th-90th centile (n=279,780) and >90th centile (n=34,937). RESULTS: Macrosomia defined as birthweight >90th centile was more likely in women whose BMI >30 (kg/m(2)) (odds ratio (OR) 2.08; confidence intervals (CI) 1.99, 2.17), parity >4 (OR 2.20; CI 2.02, 2.40), age >40 (OR 1.22; CI 1.11, 1.35) and in women with pre-existing diabetes (OR 6.97; CI 5.36, 8.16) or who developed gestational diabetes (OR 2.77; CI 2.51, 3.07). Macrosomia defined by birthweight >4kg was better than birthweight >90th centile at predicting morbidity and was associated with a prolonged first and second stage of labour (OR 1.57; CI 1.51, 1.63) and (OR 2.03; CI 1.88, 2.19), respectively, an increased risk of instrumental vaginal delivery (OR 1.76; CI 1.68, 1.85), third degree perineal trauma (OR 2.73; CI 2.30, 3.23), emergency caesarean section (OR 1.84; CI 1.75, 1.93), postpartum haemorrhage (OR 2.01; CI 1.93, 2.10), Apgar score <4 (OR 1.35; CI 1.03, 1.76), and admission to the special care baby unit (OR 1.51; CI 21.38, 1.68). CONCLUSION: Macrosomia is more common in mothers who are obese, older or diabetic and is associated with significant obstetric morbidity.

Adolescent↗
PubMed2002

High serum luteinizing hormone and testosterone concentrations do not predict pregnancy outcome in women with recurrent miscarriage.

OBJECTIVE: To investigate the relationship between Day 8 serum luteinizing hormone (LH) and testosterone (T) concentrations, and body mass index (BMI) with pregnancy outcome in women with recurrent miscarriage. DESIGN: Prospective observational study. SETTING: National recurrent miscarriage clinic. PATIENT(S): Three hundred forty-four women (median age 32 years; range 18-44) with a history of recurrent first trimester miscarriage (median 4; 3-14; <12 weeks gestation) who conceived spontaneously and who received no pharmacological treatment during pregnancy were studied. All women were antiphospholipid antibody negative and had a normal peripheral karyotype as did their partners. INTERVENTION(S): Outcome of untreated pregnancies. MAIN OUTCOME MEASURE(S): Day 8 serum LH and T concentrations and BMI were correlated with pregnancy outcome. RESULT(S): One hundred and ninety-two (55.8%) women had a live birth and 152 (44.2%) women miscarried. Polycystic ovarian morphology was diagnosed in 174 women (50.6%). There was no significant relationship between follicular phase LH concentrations and pregnancy outcome. Pregnancy outcome was similar in women with normal and high serum T concentrations. BMI value was not significantly different between women who had a live birth and those who miscarried. CONCLUSION(S): The analysis of this large cohort of women with recurrent miscarriage demonstrates that prepregnancy Day 8 serum LH and T concentrations, and BMI do not have a statistically significant relationship with pregnancy outcome.

Abortion, Habitual↗
PubMed2002

Antiphospholipid antibodies and infertility.

Antiphospholipid antibodies (aPL) are an established cause of recurrent pregnancy loss. As defective embryonic implantation is a common link between unexplained infertility and recurrent miscarriage, interest has focused on the potential relationship between aPL and implantation failure after in vitro fertilization and embryo transfer (IVF-ET). This review critically examines the published data to determine whether women undergoing IVF-ET should be routinely screened for aPL. Although most studies have reported an increased prevalence of aPL among women undergoing IVF-ET, prospective studies examining the effect of aPL on the outcome of IVF-ET demonstrate that these antibodies do not significantly affect either the implantation or ongoing pregnancy rates. The increased prevalence of aPL among women with infertility is therefore likely to be part of a generalized autoimmune disturbance associated with infertility. Hence routine screening for aPL among women undergoing IVF-ET is not warranted and therapeutic interventions should be used only in well designed randomized controlled trials.

Abortion, Habitual↗
PubMedDate not supplied

Thrombophilia and pregnancy loss.

Thrombophilia is defined as a tendency to thrombosis. The association between specific thrombophilic defects--both inherited and acquired--and pregnancy loss is a rapidly developing field. However, apart from antiphospholipid antibodies (aPL), an acquired thrombophilic defect, the role of other defects in the haemostatic pathways remains to be established. In this invited review we discuss the recent advances in our understanding of aPL related pregnancy loss, the association between genetic thrombophilic mutations and pregnancy outcome and the role of whole blood haemostasis testing in the investigation of women with recurrent miscarriage.

Abortion, Habitual↗