The Use of the Colposcopically Directed Punch Biopsy in Clinical Practice: A Survey of British Society of Colposcopy and Cervical Pathology (BSCCP)-Accredited Colposcopists.

OBJECTIVES: The colposcopically directed punch biopsy has been an integral component of colposcopic practice. In light of the changing landscape of the cervical screening programme, a study was conducted to investigate the current practice of British Society of Colposcopy and Cervical Pathology-accredited colposcopists on technique and rationale for performing a punch biopsy. MATERIALS AND METHODS: A web-based questionnaire survey was e-mailed to all British Society of Colposcopy and Cervical Pathology-accredited colposcopists. Questions included selection criteria for performing a punch biopsy, number of biopsies, and technique. Results were analyzed by specialty, experience, and workload. RESULTS: A total of 749 colposcopists responded, 50.2% of the 1,493 total. The respondents were obstetrician and gynecologists (42.9%), gynecologists/oncologists (33.6%), and nurse colposcopists (19.8%). Most colposcopists (78.3%) had more than 5-year colposcopy experience and saw in excess of 11 new cases (73.4%) of abnormal cervical cytology/month. Most colposcopists (56%) aimed to take 2 biopsies to diagnose cervical intraepithelial neoplasia, and very few (16.2%) reported routinely taking random biopsies from normal areas of cervix. Looking at the trends in management in the case scenarios, there was a lower threshold for performing punch biopsy before large loop excision of the transformation zone in younger (age, <25 years) or nulliparous women versus older women (age, >40 years; p < .05). Colposcopists were more likely to take biopsies in women with low-grade cytology/colposcopic findings (71.2%, always or most of the times) as compared with high-grade cytology/colposcopic findings (40.3%, never or rarely). CONCLUSIONS: Colposcopically directed punch biopsy is routinely used by colposcopists; however, techniques, number of biopsies taken, and rationale for performing a biopsy vary greatly between colposcopists.

How to manage an adolescent girl presenting with features of polycystic ovary syndrome (PCOS); an exemplar for adolescent health care in endocrinology.

Polycystic ovary syndrome (PCOS), or the potential diagnosis of PCOS, is one of the most common reasons for adolescent girls to present to endocrinology clinics. A diagnosis of PCOS has the potential to affect the young person, not only physically, but psychologically and socially. It is important we have the knowledge, skills and attitudes to work effectively with young people to address their concerns and meet their information needs. Successful engagement and management of adolescents with PCOS may have implications in adult life. In this article, the challenges of making the diagnosis of PCOS and introducing lifestyle change and the necessary skills for working with young people are discussed.

Oocyte vitrification in the 21st century and post-warming fertility outcomes: a systematic review and meta-analysis.

Oocyte cryopreservation is a rapidly developing technology, which is increasingly being used for various medical, legal and social reasons. There are inconsistencies in information regarding survival rate and fertility outcomes. This systematic review and meta-analysis provides evidence-based information about oocyte survival and fertility outcomes post warming to help women to make informed choices. All randomized and non-randomized, controlled and prospective cohort studies using oocyte vitrification were included. The primary outcome measure was ongoing pregnancy rate/warmed oocyte. Sensitivity analysis for donor and non-donor oocyte studies was performed. Proportional meta-analysis of 17 studies, using a random-effects model, showed pooled ongoing pregnancy and clinical pregnancy rates per warmed oocyte of 7%. Oocyte survival, fertilization, cleavage, clinical pregnancy and ongoing pregnancy rates per warmed oocyte were higher in donor versus non-donor studies. Comparing vitrified with fresh oocytes, no statistically significant difference was observed in fertilization, cleavage and clinical pregnancy rates, but ongoing pregnancy rate was reduced in the vitrified group (odds ratio 0.74), with heterogeneity between studies. Considering the age of women and the reason for cryopreservation, reasonable information can be given to help women to make informed choices. Future studies with outcomes from oocytes cryopreserved for gonadotoxic treatment may provide more insight.

A Case of Oligoasthenoteratozoospermia Following Genital Tucking: Transgender Fertility Preservation.

Genital tucking is a behavioural practice facilitating gender expression by genitalia concealment. Genital tucking can be achieved by either pushing the testicles into the inguinal canal and/or securing the scrotum and penis between the legs towards the buttocks. Genital tucking has a negative impact on spermatogenesis, and therefore can result in a suboptimal sample and impaired sperm parameters. Fertility cryopreservation is recommended prior to hormone therapy or elective surgery, and therefore, the practice of genital tucking prior to fertility preservation could result in lesser quality and fewer samples being stored for future use. This case study presents a transwoman, aged 20-30, displaying severe oligoasthenoteratozoospermia derived from genital tucking. The case discusses how the cessation of genital tucking resulted in improved semen parameters, and therefore improved the quality and quantity of samples stored for future use. Fundamentally, the case highlights the necessity for health professionals to broaden their understanding and awareness of genital tucking, the impact it has on fertility, and how to better advise patients prior to fertility cryopreservation.

Early pregnancy complications including recurrent pregnancy loss and obesity.

This review on early pregnancy complications and obesity will focus on the known pregnancy complications such as miscarriage (whether spontaneous or after fertility treatment), polycystic ovaries and risk of miscarriage, recurrent pregnancy loss, ectopic pregnancy, hyperemesis gravidarum and birth defects. Evidence will be assessed and mechanistic pathways for the outcomes will be described. We know that obesity is now a pandemic and has an impact on early pregnancy complications. The evidence has been summarised to provide the reader with a comprehensive overview and advice for pregnant women with obesity in early pregnancy.

Nelson syndrome and perinatal challenges: A case report and systematic review of the literature.

Nelson syndrome is a rare and potentially life-threatening complication of treatment with total bilateral adrenalectomy for women with Cushing disease. A successful term pregnancy following fertility treatment in a patient with Nelson syndrome is presented. Our study provides guidance in the prenatal and intrapartum management of this condition. A case report and a systematic review of 14 papers describing 50 pregnancies are presented. An electronic database search included Medline (1946 to September 2022), Embase (1980 to September 2022), Cochrane Library, and UKOSS. A small number of pregnancies in women with Nelson syndrome are reported in literature, but there are no guidelines. Some authors detail the prenatal care provided to their patients. Four studies report prenatal monitoring with visual field checks and two report monitoring with X-rays. Five studies report the use of parenteral hydrocortisone at the time of delivery. Where described, women delivered appropriately grown newborns at term, with timing and mode of delivery dictated by obstetric indications. Preconception counseling and optimization of maternal health status improve pregnancy outcomes in women with Nelson syndrome. Multidisciplinary review in a combined obstetric-endocrine prenatal clinic is ideal. Awareness about potential complications during pregnancy and the postnatal period is crucial in providing optimal care to the mother and baby.

Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis.

Mechanical endometrial injury (biopsy/scratch or hysteroscopy) in the cycle preceding ovarian stimulation for IVF has been proposed to improve implantation in women with unexplained recurrent implantation failure (RIF). This is a systematic review and meta-analysis of studies comparing the efficacy of endometrial injury versus no intervention in women with RIF undergoing IVF. All controlled studies of endometrial biopsy/scratch or hysteroscopy performed in the cycle preceding ovarian stimulation were included and the primary outcome measure was clinical pregnancy rate. Pooling of seven controlled studies (four randomized and three non-randomized), with 2062 participants, showed that local endometrial injury induced in the cycle preceding ovarian stimulation is 70% more likely to result in a clinical pregnancy as opposed to no intervention. There was no statistically significant heterogeneity in the methods used, clinical pregnancy rates being twice as high with biopsy/scratch (RR 2.32, 95% CI 1.72-3.13) as opposed to hysteroscopy (RR 1.51, 95% CI 1.30-1.75). The evidence is strongly in favour of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained RIF. However, large randomized studies are required before iatrogenic induction of local endometrial injury can be warranted in routine clinical practice. Some women undergoing IVF treatment fail to conceive despite several attempts with good-quality embryos and no identifiable reason. We call this 'recurrent implantation failure' (RIF) where the embryo fails to embed or implant within the lining of the womb. Studies have shown that inducing injury to the lining of the womb in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy. Injury can be induced by either scratching the lining of the womb using a biopsy tube or by telescopic investigation of the womb using a camera. We performed a collective review of the available good-quality studies that used the above two methods in the cycle prior to starting ovarian stimulation for IVF. We pooled results from seven studies, which included 2062 women with RIF and assessed the difference in clinical pregnancy rates for those undergoing injury to the womb lining compared with no injury prior to IVF. The results suggest that inducing injury is 70% more likely to result in a clinical pregnancy as opposed to no treatment. Furthermore, scratching of the lining was 2-times more likely to result in a clinical pregnancy compared with telescopic evaluation of the lining of the womb. This study suggests that in women with RIF, inducing local injury to the womb lining in the cycle prior to starting ovarian stimulation for IVF can improve pregnancy outcomes. However, large studies are required before this can be warranted in routine clinical practice.

Spontaneous Coronary Artery Dissection Associated With Infertility Treatment.

Assisted conception involving hormonals is a risk factor for spontaneous coronary artery dissection (SCAD), and pregnant women with spontaneous coronary artery dissection are more likely to have had treatment for subfertility. Increasingly, there is a risk of maternal death in women after assisted conception, and so, the need to assess the cardiovascular sequelae after assisted conception is imperative. This is an illustrative case of spontaneous coronary artery dissection shortly after a repeat cycle of in vitro fertilisation (IVF). The aetiology of spontaneous coronary artery dissection is believed to be multi-factorial, affecting mostly young women, a population similar to women requiring assisted conception. The oestrogen and progesterone used in in vitro fertilisation are believed to trigger structural weakening in the coronary blood vessels, leading to vascular rupture. Repeat in vitro fertilisation cycles and successful conception are thought to increase spontaneous coronary artery dissection risk by increasing hormonal exposure. The management of spontaneous coronary artery dissection is dependent on if pregnancy has been achieved or not, and a multi-disciplinary approach to its management is essential. More research is needed to identify women at higher risk of this life-threatening event.

Fertility preservation decisions in young women with breast cancer: a qualitative study of health care professionals' views and experiences.

Fertility preservation (FP) discussions prior to breast cancer treatment are an important aspect of care and considered routine practice. However, studies show that women diagnosed with breast cancer have unmet needs about FP discussions. To better understand them, a qualitative study was conducted to explore the perceptions of healthcare professionals (HCPs) regarding FP for young women diagnosed with breast cancer. Semi-structured interviews were performed in a University teaching hospital to explore the knowledge, attitudes and reported behaviours of HCPs (oncologists, breast surgeons, breast care specialist nurses and fertility specialists) who offer FP discussions (n = 20). Data were analysed thematically. HCPs in this study were aware of the need to discuss FP with patients but were not confident in their knowledge and were unsure of their role in the discussion. Patient characteristics of younger age, nulliparity and ethnicity appeared to influence if and how HCPs discussed FP, in addition to the personal attitudes and knowledge of HCPs. Specialist nurses were identified as having an important role in FP discussions. Raising awareness of the essential components of FP discussions by a checklist or algorithm may help in addressing ambiguity and promoting consistent FP discussions by HCPs.

Caffeine intake during pregnancy, late miscarriage and stillbirth.

Caffeine is a commonly consumed drug during pregnancy with the potential to affect the developing fetus. Findings from previous studies have shown inconsistent results. We recruited a cohort of 2,643 pregnant women, aged 18-45 years, attending two UK maternity units between 8 and 12 weeks gestation from September 2003 to June 2006. We used a validated tool to assess caffeine intake at different stages of pregnancy and related this to late miscarriage and stillbirth, adjusting for confounders, including salivary cotinine as a biomarker of smoking status. There was a strong association between caffeine intake in the first trimester and subsequent late miscarriage and stillbirth, adjusting for confounders. Women whose pregnancies resulted in late miscarriage or stillbirth had higher caffeine intakes (geometric mean = 145 mg/day; 95% CI: 85-249) than those with live births (103 mg/day; 95% CI: 98-108). Compared to those consuming < 100 mg/day, odds ratios increased to 2.2 (95% CI: 0.7-7.1) for 100-199 mg/day, 1.7 (0.4-7.1) for 200-299 mg/day, and 5.1 (1.6-16.4) for 300+ mg/day (P (trend) = 0.004). Greater caffeine intake is associated with increases in late miscarriage and stillbirth. Despite remaining uncertainty in the strength of association, our study strengthens the observational evidence base on which current guidance is founded.

Interlaboratory comparison of methodologies for the measurement of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine.

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is widely used as a marker of oxidative stress. Here we report the comparison of two, distinct chromatographic assays with an enzyme-linked immunosorbent assay (ELISA). The chromatographic assays displayed good agreement (r =:0.89, p < 0.0001), whereas there was markedly worse, albeit still significant, agreement with the ELISA (high-pressure liquid chromatography followed by gas chromatography (HPLC-GC/MS), r = 0.43; HPLC with electrochemical detection (HPLC-EC), r = 0.56; p < 0.0001). Mean values differed significantly between the chromatographic assays and the ELISA (HPLC-GC/MS 3.86, HPLC-EC 4.20, ELISA 18.70 ng mg(-1) creatinine; p < 0.0001). While it is reassuring to note good agreement between chromatographic assays, this study reveals significant short-comings in the ELISA, which brings into question its continued use in its present form.

Prediction of miscarriage in women with viable intrauterine pregnancy-A systematic review and diagnostic accuracy meta-analysis.

Both ultrasound and biochemical markers either alone or in combination have been described in the literature for the prediction of miscarriage. We performed this systematic review and meta-analysis to determine the best combination of biochemical, ultrasound and demographic markers to predict miscarriage in women with viable intrauterine pregnancy. The electronic database search included Medline (1946-June 2017), Embase (1980-June 2017), CINAHL (1981-June 2017) and Cochrane library. Key MESH and Boolean terms were used for the search. Data extraction and collection was performed based on the eligibility criteria by two authors independently. Quality assessment of the individual studies was done using QUADAS 2 (Quality Assessment for Diagnostic Accuracy Studies-2: A Revised Tool) and statistical analysis performed using the Cochrane systematic review manager 5.3 and STATA vs.13.0. Due to the diversity of the combinations used for prediction in the included papers it was not possible to perform a meta-analysis on combination markers. Therefore, we proceeded to perform a meta-analysis on ultrasound markers alone to determine the best marker that can help to improve the diagnostic accuracy of predicting miscarriage in women with viable intrauterine pregnancy. The systematic review identified 18 eligible studies for the quantitative meta-analysis with a total of 5584 women. Among the ultrasound scan markers, fetal bradycardia (n=10 studies, n=1762 women) on hierarchical summary receiver operating characteristic showed sensitivity of 68.41%, specificity of 97.84%, positive likelihood ratio of 31.73 (indicating a large effect on increasing the probability of predicting miscarriage) and negative likelihood ratio of 0.32. In studies for women with threatened miscarriage (n=5 studies, n=771 women) fetal bradycardia showed further increase in sensitivity (84.18%) for miscarriage prediction. Although there is gestational age dependent variation in the fetal heart rate, a plot of fetal heart rate cut off level versus log diagnostic odds ratio showed that at ≤110 beat per minutes the diagnostic power to predict miscarriage is higher. Other markers of intra uterine hematoma, crown rump length and yolk sac had significantly decreased predictive value. Therefore in women with threatened miscarriage and presence of fetal bradycardia on ultrasound scan, there is a role for offering repeat ultrasound scan in a week to ten days interval.

Strategies to improve fertilisation rates with assisted conception: a systematic review.

Successful fertilisation is one of the key steps determining success of assisted conception. Various factors including sperm or oocyte pathology and environmental factors have a significant impact on fertilisation rates. This systematic review is aimed to evaluate the existing evidence about factors affecting fertilisation and strategies to improve fertilisation rates. A literature search was performed using Ovid MEDLINE ® (Jan 1950-April 2016), EMBASE (Jan 1950-April 2016), Ovid OLDMEDLINE ®, Pre-MEDLINE (Jan 1950-April 2016) and the Cochrane Library. Relevant key words were used to combine sets of results and a total 243 papers were screened. Only qualitative analysis was performed, as there was major heterogeneity in study design and methodology for quantitative synthesis. Factors affecting fertilisation were divided into sperm- and oocyte-related factors. The methods to improve fertilisation rates were grouped together based on the approach used to improve fertilisation rates. Optimising laboratory condition and procedural effects in techniques is associated with improved fertilisation rates. Various techniques are described to improve fertilisation rates including assisted oocyte activation, physiological intracytoplasmic sperm injection (PICSI) and intracytoplasmic morphologically selected sperm injection (IMSI). This review highlights the promising strategies under research to enhance fertilisation rates. Adequately powered multicentre randomised trials are required to evaluate these techniques before considering clinical application.

Three-arm age-matched retrospective cohort study of obstetric outcomes of donor oocyte pregnancies.

OBJECTIVE: To evaluate and compare obstetric complications between women who conceived after oocyte donation and age-matched control women who conceived spontaneously or by autologous in vitro fertilization (IVF). METHODS: In a retrospective cohort study, data were assessed from all women who conceived after oocyte donation and delivered a live neonate after 24weeks of pregnancy between January 2007 and December 2014 at a UK hospital. Two age-matched control groups-one containing women who conceived after autologous IVF and the other containing women who conceived spontaneously-were used for comparison. The primary study outcome was hypertensive disorders of pregnancy (pregnancy-induced hypertension and pre-eclampsia). Multivariate analysis was performed by logistic regression. RESULTS: Each group included 45 women. Hypertensive disorders in pregnancy affected 15 (33%) women in the study group, 3 (7%) women who conceived after autologous IVF, and 3 (7%) who conceived spontaneously. The risk of hypertensive disorders in pregnancy was significantly higher in the donor oocyte group (odds ratio 5.85, 95% confidence interval 1.42-23.9; P=0.01). CONCLUSION: Women who conceived after oocyte donation had an increased risk of hypertensive disorders. Oocyte donation should be managed as an independent risk factor, and couples should be counselled appropriately.

Role of serum biomarkers in the prediction of outcome in women with threatened miscarriage: a systematic review and diagnostic accuracy meta-analysis.

BACKGROUND: Threatened miscarriage affects one in five women and is associated with significant emotional distress. The uncertainty around the prognosis of threatened miscarriage makes it equally challenging to the healthcare professionals. Various biochemical markers have been investigated in the past to predict the outcome of threatened miscarriage; however, the results have been conflicting. Therefore, we have conducted a systematic review and meta-analysis to determine the diagnostic accuracy of biochemical markers in predicting the outcome in women presenting with threatened miscarriage. METHODS: This is a systematic review and meta-analysis of prospective studies that investigated biochemical markers to determine outcomes for women with threatened miscarriage at 5-23 weeks gestational age. Electronic databases were searched up to June 2015 and study quality assessment was performed using QUADAS-2 (Quality Assessment for Diagnostic Accuracy Studies-2: A Revised Tool) for evaluating the diagnostic accuracy studies. Statistical analysis was performed using the Cochrane systematic review software. RESULTS: A total of 19 studies were included in the qualitative data synthesis of which 15 (including 1263 women) were eligible for the meta-analysis. The review highlights the role of biochemical markers serum progesterone, hCG, pregnancy associated plasma protein A, estradiol and cancer antigen 125 (CA 125) in the prediction of outcome in women with threatened miscarriage. Interestingly, serum CA 125 appears to be the most promising marker (n = 648 women in seven studies), whereas serum progesterone and hCG are less useful once fetal viability is established. The summary receiver operating characteristics for CA 125 showed a sensitivity of 90% (95% confidence interval (CI) 83-94%), specificity of 88% (95% CI 79-93%), positive likelihood ratio of 7.86 (95% CI 4.23-14.60) and negative likelihood ratio of 0.10 (95% CI 0.06-0.20). The inverse of negative likelihood ratio was 9.31 (95% CI 5-17.1) indicating that a negative test is likely to identify those who are likely to continue with the pregnancy. Serum estradiol was the next best marker with a sensitivity of 45% (95% CI 6-90%), a specificity of 87% (95% CI 81-92%), a positive likelihood ratio of 3.72 (95% CI 1.01-13.71) and a negative likelihood ratio of 0.62 (95% CI 0.20-1.84). CONCLUSIONS: In women with threatened miscarriage, serum CA 125 has high predictive value in identifying pregnancies that are 'likely to continue', whereas the most commonly used biomarkers of serum hCG and progesterone are not useful in predicting outcome of a pregnancy with a viable fetus. Other markers such as inhibin A and a combination of markers need to be investigated to hopefully improve the prediction of outcome in women with threatened miscarriage.

British Fertility Society Policy and Practice Committee: adjuvants in IVF: evidence for good clinical practice.

Optimisation of the environment favourable for satisfactory ovarian response to stimulation and successful embryo implantation remains at the core of assisted conception programmes. The evidence base for the routine use of different adjuvants, alone or in combination, for women undergoing their first in vitro fertilisation (IVF) treatment cycle and for those with poor prognosis is inadequate. The aim of this document is to update the last review of the available literature carried out by the British Fertility Society Policy and Practice Committee (BFS P&P) published in 2009 and to provide fertility professionals with evidence-based guidance and recommendations regarding the use of immunotherapy, vasodilators, uterine relaxants, aspirin, heparin, growth hormone, dehydroepiandrosterone, oestrogen and metformin as adjuvants in IVF. Unfortunately despite the lapse of 5 years since the last publication, there is still a lack of robust evidence for most of the adjuvants searched and large well-designed randomised controlled trials are still needed. One possible exception is metformin, which seems to have a positive effect in women with polycystic ovary syndrome undergoing IVF. Patients who are given other adjuvants on an empirical basis should always be informed of the lack of evidence and the potential side effects.

Definition and epidemiology of unexplained infertility.

The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.

Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis.

BACKGROUND Poor fertility outcomes in women with recurrent implantation failure (≥ RIF) present significant challenges in assisted reproduction, and various adjuncts, including heparin, are used for potential improvement in pregnancy rates. We performed this systematic review and meta-analysis to evaluate the effect of low-molecular-weight heparin (LMWH) on live birth rates (LBRs) and implantation rates (IRs) in women with RIF and undergoing IVF. METHODS Studies comparing LMWH versus control/placebo in women with RIF were searched for on MEDLINE, EMBASE, Cochrane Library, conference proceedings and databases for registered and ongoing trials (1980-2012). Statistical analysis was performed using Review Manager 5.1. The main outcome measure was LBR per woman. RESULTS Two randomized controlled trials (RCTs) and one quasi-randomized trial met the inclusion criteria. One study included women with at least one thrombophilia ( Qublan et al., 2008) and two studies included women with unexplained RIF ( Urman et al., 2009; Berker et al., 2011). Pooled risk ratios in women with ≥ 3 RIF (N = 245) showed a significant improvement in the LBR (risk ratio (RR) = 1.79, 95% confidence interval (CI) = 1.10-2.90, P = 0.02) and a reduction in the miscarriage rate (RR = 0.22, 95% CI = 0.06-0.78, P = 0.02) with LMWH compared with controls. The IR for ≥ 3 RIF (N = 674) showed a non-significant trend toward improvement (RR = 1.73, 95% CI 0.98-3.03, P = 0.06) with LMWH. However, the beneficial effect of LMWH was not significant when only studies with unexplained RIF were pooled. The summary analysis for the numbers needed to be treated with LMWH showed that approximately eight women would require treatment to achieve one extra live birth. CONCLUSIONS In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group; however, this is to be considered with caution, since the overall number of participants in the studies was small. Further evidence from adequately powered multi-centered RCTs is required prior to recommending LMWH for routine clinical use. This review highlights the need for future basic science and clinical research in this important field.