Primary Recurrent Miscarriage Research Articles

Association between G1733A (rs6152) polymorphism in androgen receptor gene and recurrent spontaneous abortions in Mexican population.

Recurrent spontaneous abortion (RSA) is a multifactorial condition that occurs with a frequency of 0.2-5% in women of reproductive age. Among genetic factors, the single nucleotide polymorphism (SNP) G1733A in the androgen receptor (AR) gene has been associated with its presence in Greek and Iranian populations. Therefore, the aim of this study is to determine its possible association with RSA in this population. A total of 156 Mexican RSA (with at least 2 consecutive abortions) unrelated patients and 152 unrelated healthy women were included, the presence of karyotype anomalies in the parents as well as uterine anomalies as well as antiphospholipid antibodies was excluded in patients; while all the controls presented at least two healthy pregnancies and no abortion. In all the included women, the presence of the SNP G1733A was determined by restriction fragment length polymorphism (RFLP) technique. No significant differences were observed in age between groups. The genotype GG, GA, and AA had a frequency of 0.70, 0.27, and 0.03 in patients and of 0.89, 0.10, and 0.01 in controls [corrected] (p<0.001); while the A allele frequency was of 0.06 and 0.16 in controls and patients, respectively (p<0.0001). The difference in allele frequency increased 10-15% when patients with primary RSA (with no live births) and with at least three abortions were included. The SNP G1733A of the AR gene is significantly associated with RSA in Mexican patients. These results coincide with previous reports in other populations.

The Importance of Cytogenetics and Associated Molecular Techniques in the Management of Patients Carrying Robertsonian Translocation and Their Pregnancy Outcome by Intracytoplasmic Sperm Injection

The present study outlines three cases of a Robertsonian translocation and the consequences for the initiation of pregnancy by intracytoplasmic sperm injection (ICSI). Three case histories are presented documenting structural chromosome abnormalities in infertile males. Semen analysis was performed according to the World Health Organization guidelines. Chromosome analysis was performed using G-banding. Y chromosome microdeletions were detected by multiplex polymerase chain reaction assays. Cytogenetic analysis revealed Robertsonian translocation 45,XY,der(14;21)(q10;q10) in a male with severe oligoasthenoteratozoospermia (SOAT) after three subsequent ICSI treatments were unsuccessful. The second case involved a Robertsonian translocation 45,XY,der(13,14)(q10;q10) with SOAT detected in a male after one pregnancy loss. Third case involved a Robertsonian translocation 45,XY,der(13,14)(q10;q10) with SOAT. This case series emphasize the necessity of cytogenetic analysis of couples with primary infertility and recurrent miscarriages before any assisted reproductive technology is performed. For couples in whom one or more partners have atranslocation, prenatal genetic diagnosis/preimplantation genetic diagnosis is recommended.

Expression level of TNF-α in decidual tissue and peripheral blood of patients with recurrent spontaneous abortion.

ObjectiveThis study aimed to determine the express level of tumour necrosis factor α (TNF-α) in the decidual tissue and peripheral blood of patients with recurrent spontaneous abortion (RSA).Material and methodsEighty RSA patients and 100 control women were recruited in this study. Enzyme-linked immunosorbent assay (ELISA) was applied to determine the expression level of TNF-α in peripheral blood and decidual tissues from both groups. Additionally, the expression level of TNF-α was compared between RSA patients with different numbers of abortions, as well as primary and secondary RSA patients.ResultsThe expression level of TNF-α in peripheral blood and decidual tissues of RSA patients was significantly higher compared to the controls (p < 0.001). Patients who had undergone RSA twice expressed TNF-α in peripheral blood and decidual tissues at a similar level to patients who had experienced RSA three times (p > 0.05), but significantly lower than patients who had experienced RSA more than three times (p < 0.001). The expression level of TNF-α in peripheral blood and decidual tissues was significantly higher in the secondary RSA patients, when compared with primary RSA patients (p < 0.001).ConclusionsTaken together, the relatively high expression level of TNF-α in decidual tissue and peripheral blood may be one of the causes of RSA and therefore could be used as a clinical indicator.

The “killer cell story” in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells

Peripheral and uterine NK cells (pNK, uNK) can be distinguished according to their receptor expression. Recent studies indicate an association of elevated pNK and uNK with recurrent miscarriage (RM). This study aimed to analyze pNK and uNK in patients with RM and healthy controls. Out of n=590 RM patients screened according to a standard diagnostic protocol, n=268 couples with ≥3 consecutive RM were identified. Subgroups consisted of n=151 primary RM (pRM), n=85 secondary RM (sRM), n=32 tertiary RM (tRM) and n=42 healthy controls. Finally, n=147 idiopathic RM (iRM) and n=121 non-iRM patients were identified. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined in non-pregnant patients and controls in the mid-luteal phase by FACS. In n=129 RM patients a uterine biopsy was taken to evaluate CD56+ NK cells by immunohistochemistry. PRM showed higher absolute pNK than sRM (median/μl (Q1;Q3): 234 (147;306) vs 176 (128;245), p=0.02). Further a trend towards higher pNK percentages in pRM was detected. UNK numbers did not differ between RM subgroups and did not correlate with pNK. However, the rate of highly elevated uNK was increased in iRM compared to non-iRM patients (p=0.04). Further, higher numbers of CD45+CD3-DR+ (p<0.01) and CD45+CD3+CD8+DR+ (p=0.04) peripheral lymphocytes were associated with higher uNK numbers. In conclusion, elevated pNK were present in pRM patients. Although pNK and uNK numbers did not correlate, the association between high CD45+CD3-DR+ and CD45+CD3+CD8+DR+ peripheral lymphocytes and uNK might indicate that activated NK, B and T cells provide cytokines for the differentiation of uNK.

Higher levels of peripheral natural killer cells in patients with primary recurrent miscarriage are associated with altered cytokine profile

Higher levels of peripheral natural killer cells in patients with primary recurrent miscarriage are associated with altered cytokine profile

Higher levels of peripheral natural killer cells in patients with primary recurrent miscarriage are associated with altered cytokine profile

Higher levels of peripheral natural killer cells in patients with primary recurrent miscarriage are associated with altered cytokine profile

Higher Levels of Peripheral Natural Killer Cells in Patients with Primary Recurrent Miscarriage are Associated with Altered Cytokine Profile

Higher Levels of Peripheral Natural Killer Cells in Patients with Primary Recurrent Miscarriage are Associated with Altered Cytokine Profile

Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.

Abnormalities in peripheral blood natural killer (NK) cells have been reported in women with primary infertility and recurrent spontaneous abortion (RSA) and several studies have been presented to define cutoff values for abnormal peripheral blood NK cell levels in this context. Elevated levels of NK cells were observed in infertile/RSA women in the presence of thyroid autoimmunity (TAI), while no studies have been carried out, to date, on NK cells in infertile/RSA women with non-autoimmune thyroid diseases. The contribution of this study is two-fold: (1) the evaluation of peripheral blood NK cell levels in a cohort of infertile/RSA women, in order to confirm related data from the literature; and (2) the assessment of NK cell levels in the presence of both TAI and subclinical hypothyroidism (SCH) in order to explore the possibility that the association between NK cells and thyroid function is not only restricted to TAI but also to SCH. In a retrospective study, 259 age-matched women (primary infertility [n = 49], primary RSA [n = 145], and secondary RSA [n = 65]) were evaluated for CD56+CD16+NK cells by flow cytometry. Women were stratified according to thyroid status: TAI, SCH, and without thyroid diseases (ET). Fertile women (n = 45) were used as controls. Infertile/RSA women showed higher mean NK cell levels than controls. The cutoff value determining the abnormal NK cell levels resulted ⩾15% in all the groups of women. Among the infertile/RSA women, SCH resulted the most frequently associated thyroid disorder while no difference resulted in the prevalence of TAI and ET women between patients and controls. A higher prevalence of women with NK cell levels ⩾15% was observed in infertile/RSA women with SCH when compared to TAI/ET women. According to our data, NK cell assessment could be used as a diagnostic tool in women with reproductive failure and we suggest that the possible association between NK cell levels and thyroid function can be described not only in the presence of TAI but also in the presence of non-autoimmune thyroid disorders.

Female third party lymphocytes are effective for immunotherapy of patients with unexplained primary recurrent spontaneous abortion: A retrospective analysis of outcomes

Objectives Allogeneic lymphocytes of paternal origin or supplied by a male third party have been used for the treatment of recurrent spontaneous abortion. Few studies, however, have examined the use of female third party lymphocytes. Our purpose was to determine whether female third party lymphocytes could be used for immunotherapy of women with recurrent spontaneous abortion.Methods In this retrospective non-randomised cohort-controlled study, the medical records of patients with three or more spontaneous abortions who received immunotherapy with lymphocytes from their partner, a male third party or a female third party, as well as those who received no immunotherapy, from 1996 to 2012 were reviewed. All patients were negative for mixed lymphocyte culture reaction (MLR)-blocking antibodies. Immunotherapy was performed in 302 patients in two courses, while 53 patients received no immunotherapy.Results The pregnancy rates in patients who received lymphocytes from their partners, a male third party or a female third party, and in those not immunised, were 85.6%, 87.3%, 89.7%, and 79.3%, respectively (p = 0.523);the live birth rates were 87.3%, 75.8%, 84.6%, and 40.5%, respectively (p < 0.001).Conclusions We conclude that female third party lymphocytes can be used for immunotherapy in patients with recurrent spontaneous abortion.Chinese 摘要目的 父源同种异体淋巴细胞或第三方男性供给淋巴细胞用于复发性自然流产的治疗。少数研究调查了女性第三方淋巴细胞的应用。我们的目的是验证女性第三方淋巴细胞是否可以用于复发性自然流产的免疫治疗。方法 在这项回顾性非随机队列对照研究中回顾了自1996年至2012年,接受配偶淋巴细胞,男性第三方淋巴细胞或接受女性第三方淋巴细胞免疫治疗,或未接受免疫治疗的三次或更多次自然流产的患者病历资料。所有患者的混合淋巴细胞培养反应(MLR)-封闭抗体均为阴性。302名患者接受了两个疗程的免疫治疗,而53名患者未接受免疫治疗。结果 接受配偶淋巴细胞,男性第三方淋巴细胞,女性第三方淋巴细胞和未接受免疫治疗的患者妊娠率分别为85.6%，87.3%，89.7%，和79.3% (p = 0.523)。活产率分别为87.3%, 75.8%, 84.6%和40.5% (p < 0.001) 。结论 我们推断,女性第三方淋巴细胞可用于复发性自然流产患者的免疫治疗。关键词免疫疗法；淋巴细胞；反复自然流产

Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: a retrospective cohort study.

Is a history of three or more miscarriages associated with adverse perinatal outcomes in a subsequent pregnancy? Recurrent miscarriage is associated with an increased risk of adverse perinatal outcomes, including preterm birth, very preterm birth and perinatal death, in a subsequent pregnancy. Published data are conflicting with some studies reporting an increase in adverse perinatal outcomes in association with prior recurrent miscarriage while others report little or no increase. Large-scale population-based studies have been lacking. We performed a retrospective cohort study of 30 053 women with a singleton pregnancy who booked for antenatal care and delivery between January 2008 and July 2011. All women who attended a university affiliated hospital in Ireland had a detailed obstetric history taken, recording the outcome of all previous pregnancies. We compared the obstetric and perinatal outcomes of 2030 women (6.8%) who had a history of three or more miscarriages (recurrent miscarriage) with the outcomes of 28 023 women (93.2%) who did not. Logistic regression analyses were performed, adjusting for potential confounding factors. Women with a history of recurrent miscarriage were more likely to be obese, to have undergone assisted conception, to have had a previous perinatal death, and to be delivered by scheduled Caesarean section. Recurrent miscarriage was associated with an increased incidence of preterm birth (<37 weeks gestation, 8.1 versus 5.5%, adjOR 1.54; 95% CI 1.29-1.84), very preterm birth (<32 weeks gestation, 2.2 versus 1.2%, adjOR 1.80; 95% CI 1.28-2.53), and perinatal death (1.2 versus 0.5%, adjOR 2.66; 95% CI 1.70-4.14). The results were similar for both primary and secondary recurrent miscarriage. This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, they were only confirmed to be consecutive in the primary RM group. The affected women have not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes differ according to aetiological subgroup. This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, particularly in relation to the risk of preterm delivery. There was no specific funding obtained for this study and there are no conflict of interests.

M2/ANXA5 haplotype as a predisposition factor in Malay women and couples experiencing recurrent spontaneous abortion: a pilot study

Recurrent spontaneous abortion (RSA) is a prevalent condition among the Malay population of Malaysia, where carriage risk of conventional hereditary thrombophilia factors has been generally ruled out. The contribution of M2/ANXA5, a common haplotype in the annexin A5 gene promoter, was evalauted for RSA in Malay. Seventy-seven women who had experienced two or more unexplained RSA and 41 available male partners were selected for study, with 360 population controls recruited from healthy Malay individuals. Incidence of M2 carriage and odds ratios were calculated between control and patient groups, and clinically defined subgroups and RSA risk was evaluated. M2/ANXA5, found in 42.2% of the general Malay population, was associated with greater risks for women with primary and secondary RSA with early (gestational week 5–15) losses. The risk was somewhat higher in Malay couples when both partners were carriers and a trend of higher prevalence was seen for the male partners patients who had experienced RSA. M2 carriage seems to be a risk factor with unusually high incidence in Malay women and couples with primary and secondary RSA with ‘early’ spontaneous abortions. The associated male partner risk confirms the proposed role of M2/ANXA5 as a genetic trait impeding embryonic anticoagulation.

The Factor VIII:C plasma activity level in females with primary unexplained infertility and recurrent miscarriage

The Factor VIII:C plasma activity level in females with primary unexplained infertility and recurrent miscarriage

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.

Microchimerism in recurrent miscarriage.

Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnancy. We conducted studies to ask whether microchimerism that a woman acquired from her own mother is detectable before or during pregnancy in women with recurrent miscarriage. Fetal microchimerism was also assayed. Women with primary idiopathic recurrent miscarriage (n=23) and controls (n=31) were studied. Genotyping was conducted for probands, their mothers and the fetus, a non-shared polymorphism identified and quantitative polymerase chain reaction performed to measure microchimerismin peripheral blood mononuclear cells. Preconception comparisons were made between recurrent miscarriage subjects and controls, using logistic regression and Wilcoxon rank sum. Longitudinal microchimerism in subsequent pregnancies of recurrent miscarriage subjects was described. There was a trend toward lower preconception detection of microchimerism in recurrent miscarriage versus controls, 6% vs. 19% (1/16 vs. 6/31, P=0.2). During pregnancy, 3/11 (27%) of recurrent miscarriage subjects who went on to have a birth had detection of microchimerism from their own mother, whereas neither of two subjects who went on to miscarry had detection (0/2). This initial data suggest that microchimerism from a woman's own mother, while detectable in women with recurrent miscarriage, may differ from controls and according to subsequent pregnancy outcome. Further studies are needed to determine the cell types, quantities and any potential functional role of microchimerism in recurrent miscarriage.

Prevalence of coagulation factor XIII and plasminogen activator inhibitor-1 gene polymorphisms among Egyptian women suffering from unexplained primary recurrent miscarriage

Recurrent miscarriage (RM) is an obstetric challenge. Polymorphisms of factor XIII (FXIII) and plasminogen activator inhibitor-1 (PAI-1) may cause an imbalance between coagulation and fibrinolysis that can end in RM. The aim of the work was to determine the prevalence of FXIII Val34Leu and PAI-1 4G/5G gene polymorphisms in Egyptian women presenting with unexplained primary first trimester RM. Genotyping of 120 unexplained primary first trimester RM patients and 130 healthy controls by polymerase chain reaction (PCR) amplification of target genes followed by the allele-specific restriction enzyme digestion (RFLP technique). Among the cases, 67.5% of individuals had wild-type FXIII; 21.7% were heterozygous and 10.8% were homozygous for the FXIII Val34Leu polymorphism. Among controls, the proportions were 89.2%, 8.5% and 2.3% respectively. In addition, comparison between the two groups regarding Leu and 4G allele frequencies showed statistically significant differences (P values=0.0001 and 0.027 respectively). RM is more frequent in women with combined polymorphisms than in women with a single gene polymorphism (RR=3.91; OR=4.51; 95% CI=1.79–11.38; P=0.002). FXIII Val34Leu and PAI-1 4G/5G polymorphisms are prevalent in Egyptian women, with unexplained primary first trimester RM and combined polymorphisms statistically increasing the risk.

Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage

Are non-visualized pregnancy losses (biochemical pregnancy loss and failed pregnancy of unknown location combined) in the reproductive history of women with unexplained recurrent miscarriage (RM) negatively associated with the chance of live birth in a subsequent pregnancy? Non-visualized pregnancy losses contribute negatively to the chance for live birth: each non-visualized pregnancy loss confers a relative risk (RR) for live birth of 0.90 (95% CI 0.83; 0.97), equivalent to the RR conferred by each additional clinical miscarriage. The number of clinical miscarriages prior to referral is an important determinant for live birth in women with RM, whereas the significance of non-visualized pregnancy losses is unknown. A retrospective cohort study comprising 587 women with RM seen in a tertiary RM unit 2000-2010. Data on the outcome of the first pregnancy after referral were analysed for 499 women. The study was conducted in the RM Unit at Rigshospitalet, Copenhagen, Denmark. We included all women with unexplained RM, defined as ≥3 consecutive clinical miscarriages or non-visualized pregnancy losses following spontaneous conception or homologous insemination. The category 'non-visualized pregnancy losses' combines biochemical pregnancy loss (positive hCG, no ultrasound performed) and failed PUL (pregnancy of unknown location, positive hCG, but on ultrasound, no pregnancy location established). Demographics were collected, including BMI, age at first pregnancy after referral and outcome of pregnancies prior to referral. Using our own records and records from other Danish hospitals, we verified the outcome of the first pregnancy after referral. For each non-visualized pregnancy loss and miscarriage in the women's reproductive history, the RR for live birth in the first pregnancy after referral was determined by robust Poisson regression analysis, adjusting for risk factors for negative pregnancy outcome. Non-visualized pregnancy losses constituted 37% of reported pregnancies prior to referral among women with RM. Each additional non-visualized pregnancy loss conferred an RR for live birth of 0.90 (95% CI 0.83; 0.97), which was not statistically significantly different from the corresponding RR of 0.87 (95% CI 0.80; 0.94) conferred by each clinical miscarriage. Among women with ≥2 clinical miscarriages, a reduced RR for live birth was also shown: 0.82 (95% CI 0.74; 0.92) for each clinical miscarriage and 0.89 (95% CI 0.80; 0.98) for each non-visualized pregnancy loss, respectively. Surgically treated ectopic pregnancies (EPs) were significantly more common for women with primary RM and no confirmed clinical miscarriages, compared with women with primary RM and ≥1 clinical miscarriage (22 versus 6%, difference 16% (95% CI 9.1%; 28.7%); RR for ectopic pregnancy was 4.0 (95% CI 1.92; 8.20). RM was defined as ≥3 consecutive pregnancy losses before 12 weeks' gestation, and we included only women with unexplained RM after thorough evaluation. It is uncertain whether the findings apply to other definitions of RM and among women with known causes for their miscarriages. To our knowledge, this is the first comprehensive investigation of prior non-visualized pregnancy losses and their prognostic significance for live birth in a subsequent pregnancy in women with unexplained RM. We show that a prior non-visualized pregnancy loss has a negative prognostic impact on subsequent live birth and is thus clinically significant. None. N/A.

Influenza A virus infection during pregnancy: an impaired interaction between dendritic cells and the adaptive immune system reduces specific killing of infected cells in mice

s / Journal of Reproductive Immunology 101–102 (2014) 40–60 41 lowing etiological factors: genetic, anatomical, hormonal, thrombophilia (inherited and acquired) and autoimmune. The pregnancy outcomes have also been described. The characteristics of the study population are shown as median and range for continuous variables and in numbers (%) for categorical variables. The data were transferred to an Excel 2007 spreadsheet (Microsoft Corp., Redmond,WA, USA) and the statistical software package SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Results: The mean age of patients was 32.0 +5.1 (range of 18–45). Themean number of previous pregnancies, previous deliveries, and previous miscarriages in all patients was2.73+0.8, 0.19+0.4 and2.54+0.6 respectively.Ninetynine out of 120 patients had a history of primary recurrent miscarriage. The most frequent etiological factors associated with alloimmunity were: MTHFR C677T, thyroid peroxidase antibody, antiphospholipid syndrome (12.5%), anatomical (10%), antithyroglobulin antibody (9.2%), hormonal (9.2%), and antinuclear antibody (8.3%). Genetic alterations were: 8 cases of mosaicism and 2 cases of balanced translocation. The anatomical findings included 6 cases of adhesions, 3 cases of bicornuate uterus, and 3 endometrial polyps. Conclusion: The presence of multiple etiological factors associated with the alloimmune factor reinforces the need to investigate and treat all possible causesof recurrent miscarriage.

Recurrent miscarriage and birth sex ratio

ObjectiveTo examine the relationship between birth sex ratio and unexplained recurrent miscarriage (RM). Study designRetrospective, observational study including a total of 138 women with primary recurrent miscarriage (PRM) and 170 women with secondary recurrent miscarriage (SRM) in a tertiary referral recurrent miscarriage clinic between 1992 and 2010. The sex ratio of the first birth and subsequent birth were the main outcome measures. ResultsIn women with SRM: (i) The male:female sex ratio of the first stillbirth was 10:2, significantly (OR=4.76) higher than the male:female sex ratio of 1.05 among all births in UK. (ii) When the first born was a male, the male:female sex ratio of the subsequent birth was 21:35, significantly (OR=0.57) lower than the sex ratio among the general population. (iii) A male firstborn did not affect the chance of a subsequent live-birth. The findings did not apply to sex ratio in primary RM. ConclusionThere was a subtle relationship between the sex of the first and subsequent births and secondary recurrent miscarriage, but not primary recurrent miscarriage.

The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study.

BackgroundHistidine-rich Glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage.MethodsThe study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP.ResultsThe results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p < 0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p < 0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p < 0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p < 0.05).ConclusionsWomen who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Histidine‐rich glycoprotein gene polymorphism in patients with recurrent miscarriage

Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage.