Recurrent pregnancy loss is a complex health challenge with no universally accepted definition. Inconsistency in definitions involves not only the number of spontaneous abortions (two or three) that are accepted for recurrent pregnancy loss but the types of pregnancy and gestational age at miscarriage. Due to the heterogeneity of definitions and criteria applied by international guidelines for recurrent pregnancy loss, the true incidence of recurrent miscarriage, which is reported to range from 1% to 5%, is difficult to estimate. Moreover, the exact etiology of recurrent pregnancy loss remains questionable; thus, it is considered a polyetiological and multifactorial condition with many modifiable and non-modifiable factors involved. Even after thoroughly evaluating recurrent pregnancy loss etiology and risk factors, up to 75% of cases remain unexplained. This review aimed to summarize and critically analyze accumulated knowledge on the etiology, risk factors, relevant diagnostic options, and management approach to recurrent pregnancy loss. The relevance of various factors and their proposed roles in recurrent pregnancy loss pathogenesis remains a matter of discussion. The diagnostic approach and the management largely depend on the etiology and risk factors taken into consideration by a healthcare professional as a cause of recurrent miscarriage for a particular woman or couple. Underestimation of social and health consequences of recurrent pregnancy loss leads to compromised reproductive health and psychological well-being of women after miscarriage. Studies on etiology and risk factors for recurrent pregnancy loss, especially idiopathic, should be continued. The existing international guidelines require updates to assist clinical practice.

Glucocorticoids (GCs) exert their anti-inflammatory andimmunosuppressive effects by inhibiting the expression of cytokines andadhesion molecules. The molecular basis of GC action lies in theircapacity to diffuse through the cell membrane and bind their cytosolicGC receptor (GR), which subsequently undergoes nuclear translocationand modulates transcriptional activation through association withpromoter elements, GC response elements (GRE). GR also antagonized theactivity of transcription factors, including NF-κB, NF-AT, and AP-1,through direct and indirect mechanisms. GCs induced the genetranscription and protein synthesis of the NF-κB inhibitor, IκB. Activated GR antagonized transcription factor activity throughprotein:protein interaction. This involved complexing with andinhibition of transcription factor binding to DNA (simple model),association with factor bound at its DNA site (compositemodel), and/or through interaction of GRE-bound GR withDNA-bound transcription factor (transmodulation model). Finally, GRcompeted with transcription factors for nuclear coactivators(competition model), including CBP and p300. Remarkably, GR did notaffect the assembly of the preinitiation complex but acted proximallyin inhibiting transcription factor activity and thus transcriptionalinitiation.

Factor V G1691A (FV‐Leiden) and prothrombin G20210A mutations are major inherited risk factors for venous thrombosis. Recently, it was suggested that both mutations, through stimulation of venous and placental thrombosis events, were strongly associated with recurrent idiopathic miscarriages, although other studies disputed such a link. The aim of this study was to determine the prevalence of prothrombin G20210A and factor V G1691A (R506Q, FV‐Leiden) mutations in women with recurrent idiopathic abortions and to recommend management for high‐risk mutation carriers. One hundred ten women with two or more consecutive unexplained first‐trimester miscarriages (mean age ± SD, 32.3 ± 5.3) were compared to 67 parous women with uncomplicated pregnancies (mean age ± SD, 33.9 ±7.3) (P = 0.134) from the same ethnic background. The presence or absence of the prothrombin G20210A and FV‐Leiden mutations was assessed by PCR and RFLP analysis, using HindIII and MnlI digestion, respectively. In women with primary habitual abortion, 45 (40.91%) carried the FV‐Leiden mutation, of whom 7 were in the homozygote and 38 were in the heterozygote states, and 15 (13.64%) carried the prothrombin G20210A mutation all as heterozygotes, compared to 16.42% and 2.99% carrier rates among controls, respectively, all of whom were heterozygote carriers. Of the other risk factors analyzed, smoking (OR 1.76; 95% CI = 0.79–3.94) was more prevalent in habitual aborters compared to controls. Both FV‐Leiden and factor II G20210A mutations are major inherited risk factor associated with primary recurrent miscarriages. Women with a family or personal history of thrombosis should be screened before or early in the pregnancy for FV‐Leiden and factor II G20210A mutations. Am. J. Hematol. 71:300–305, 2002.

STUDY QUESTION Is recurrent spontaneous miscarriage (RSM) associated with changes in vascular endothelial growth factor (VEGF) serum levels, and with polymorphisms in the VEGFA gene? SUMMARY ANSWER Reduced serum VEGF levels, and VEGFA −460T/C (rs833061), 398G/A (rs833068), −583T/C (rs3025020) variants, were associated with RSM. WHAT IS KNOWN ALREADY Reduced expression of VEGF has been linked with spontaneous miscarriage, likely due to defective fetal and placental angiogenesis. Since VEGF production is in part inherited, VEGFA polymorphisms associated with altered VEGF secretion have been investigated for their association with RSM, often with variable conclusions. STUDY DESIGN, SIZE, DURATION A retrospective case–control study, which was conducted between January 2011 and April 15, 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects comprised 296 women with RSM (mean age: 31.6 ± 5.4 year), and 305 age-matched (mean age: 31.6 ± 4.9 year) control Arab women, who had attended outpatient obstetrics and gynecology clinics in two teaching hospitals in Bahrain. VEGFA −2578C/A (rs699947), −460T/C (rs833061), −1154G/A (rs15703060), −634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), −583T/C (rs3025020) and 936C/T (rs3025039) genotyping was done by real-time PCR, with defined clusters; VEGF serum levels were measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE Higher minor allele frequency (MAF) and genotype distribution of −460T/C [corrected P (P_c) = 0.003], 398G/A (P_c = 0.016) and −583T/C (P_c < 0.001) single nucleotide polymorphisms (SNPs) were seen in RSM cases than control women. Increased RSM risk was seen with homozygous −460T/C and 398G/A SNPs and with heterozygous −583T/C, which had a stronger effect when homozygous. Serum VEGF levels were significantly reduced in RSM cases compared with control women (P = 0.016), and correlated with −460T/C, 398G/A and −583T/C genotypes. Haploview analysis revealed heterogeneity in linkage disequilibrium between VEGFA variants, and two blocks were identified: Block 1 comprising −2578C/A, −460T/C and −1154G/A, while Block 2 contained −634G/C, 398G/A, 497G/A, −583T/C and 936C/T. Both negatively and positively RSM-associated 3-locus (Block 1) and 5-locus (Block 2) VEGFA haplotypes were identified, after controlling for a number of covariates. LIMITATIONS, REASONS FOR CAUTION The study was retrospective and can only demonstrate association and not a cause–effect relationship. Furthermore, it was limited to Bahraini Arabs,thereby necessitating parallel studies on other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Reduced VEGF secretion, and specific VEGFA variants may contribute to the pathogenesis of RSM. However, the association of VEGFA SNPs with RSM appears to be independent of their association with altered VEGF serum levels. The differential association of VEGFA variants with RSM is in line with previous findings on the contribution of ethnicity/racial background to genetic association studies.

Background: Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs) that confer type 2 diabetes (T2D) risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia. Methods: A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in KCNJ11/Kir6.2, K121Q in ENPP1, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in TCF7L2 encoding transcription factor 7-like2, and rs7923837 in HHEX encoding the homeobox, hematopoietically expressed transcription factor. Results: TCF7L2-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], P = 0.006) in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], P = 0.002). No allelic or genotypic association with T2D was detected for the other studied polymorphisms. Conclusion: In the Tunisian population, TCF7L2-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.