The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage

OBJECTIVE:To investigate the association between the C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR), serum homocysteine levels, and idiopathic recurrent miscarriage in a Middle-European white population.METHODS:In a case control study, we investigated 133 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 74 healthy controls with at least two live births and no history of pregnancy loss. A DNA extraction and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the MTHFR C677T polymorphism. Serum homocysteine levels were assessed by a fluorescence polarization immunoassay.RESULTS:The MTHFR allele frequencies in women with idiopathic recurrent miscarriage and controls were 34.6% and 21.6%, respectively, for the T allele (mutant) and 65.4% and 78.4%, respectively, for the C allele (wild type) (P =.007, odds ratio 1.9, 95% confidence interval 1.2, 3.1). The MTHFR genotype frequencies in women with idiopathic recurrent miscarriage and controls were: 17.3% (T/T), 34.6% (C/T), 48.1% (C/C) and 5.4% (T/T), 32.4% (C/T), 62.2% (C/C), respectively (P =.03, odds ratio 3.7, 95% confidence interval 1.2, 11.8 [T/T versus C/T and C/C]). Serum concentrations of homocysteine were significantly higher in carriers of a MTHFR mutant allele compared with women with no mutant allele (mean 7.4 +/- 2.4 micromol/L [T/T + C/T] versus 6.5 +/- 2.6 micromol/L [C/C], P =.05).CONCLUSION:Carriage of the mutant allele of the MTHFR C677T polymorphism is associated with elevated serum levels of homocysteine and idiopathic recurrent miscarriage.     

Tryptophan hydroxylase gene polymorphism (A218C) and idiopathic recurrent miscarriage

OBJECTIVE: To investigate the frequency of a polymorphism in intron 7 of the tryptophan hydroxylase gene among women with idiopathic recurrent miscarriage and healthy controls. METHODS: In a case control study, we studied 125 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 137 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the A218C polymorphism in intron 7 of the tryptophan hydroxylase gene. RESULTS: Allele frequencies among women with idiopathic recurrent miscarriage and controls were 32.4% and 38.7%, respectively, for allele A (wild type) and 67.6% and 61.3%, respectively, for allele C (mutant). No association between the presence of allele C and idiopathic recurrent miscarriage was found (P = .3; odds ratio 1.31; 95% confidence interval 0.93, 1.87). Genotype frequencies also were not significantly different between the study group (C/C: 44.8%; A/C: 45.6%; A/A: 9.6%) and the control group (C/C: 37.2%; A/C: 48.2%; A/A: 14.6%; P = .2). Between women with primary and women with secondary idiopathic recurrent miscarriage, no statistically significant differences with respect to allele frequencies were observed (63% vs 62% for allele C and 31% vs 38% for allele A; P = .3). CONCLUSION: The A218C polymorphism in intron 7 of the tryptophan hydroxylase gene is not associated with idiopathic recurrent miscarriage.     

The PROGINS progesterone receptor gene polymorphism and idiopathic recurrent miscarriage.

OBJECTIVE: Progesterone inhibits lymphocyte cytotoxicity, natural killer cell degranulation, and release of proinflammatory cytokines and has been shown to protect against spontaneous miscarriage. We investigated the association between idiopathic recurrent miscarriage (IRM) and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor gene, which is known to segregate with progesterone-dependent neoplasms. METHODS: In a case-control study we investigated 125 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 79 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: Allele frequencies among women with IRM and controls were 85.2% and 89.2%, respectively, for allele T1 (wild type) and 14.8% and 10.8%, respectively, for allele T2 (mutant). No association between allele T2 and the occurrence of IRM was found (P =.3; odds ratio [OR] 0.69; confidence interval [CI] 0.34, 1.40). Genotype frequencies were not significantly different between the study group (T1/T1 73.6%, T1/T2 23.2%, T2/T2 3.2%) and the control group (T1/T1 79.7%, T1/T2 19%, T2/T2 1.3%) (P =.4). Between women with primary and secondary IRM, there were no statistically significant differences with respect to allele frequencies (82% versus 87%, P =.4 for allele T1 and 12% versus 13%, P =.6 for allele T2). CONCLUSIONS: We found that the PROGINS polymorphism in the progesterone receptor gene was not associated with IRM in white women.     

Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis

OBJECTIVE: Vulvar vestibulitis is a chronic inflammatory syndrome of unknown cause and pathogenesis. We examined the relation between vulvar vestibulitis and polymorphisms in the gene coding for the interleukin 1 receptor antagonist, a naturally occurring down-regulator of proinflammatory immune responses. STUDY DESIGN: Cells from the lower genital tract of 68 women with vulvar vestibulitis, 343 women with no history of vulvodynia, and 40 women with human papillomavirus cervical infection were tested by polymerase chain reaction for the different alleles of the gene encoding for interleukin 1 receptor antagonist. The presence of human papillomavirus in the specimens was determined by polymerase chain reaction with the use of degenerate consensus primers to the conserved L1 gene. RESULTS: Allele 2 of the gene encoding the interleukin 1 receptor antagonist was present in homozygous form in 52.9% of women with vulvar vestibulitis. In marked contrast only 8. 5% of the control women and 2.5% of women with human papillomavirus were homozygous for this allele (P 相似文献   

Angiopoietin-2 polymorphism in women with idiopathic recurrent miscarriage

OBJECTIVE: To investigate the relationship between idiopathic recurrent miscarriage and a polymorphism of the gene encoding for angiopoietin-2 (ANGPT2), an autochthonous modulator of angiogenesis during pregnancy. DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred thirty-one women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation, and 125 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. INTERVENTION(S): Peripheral venous puncture. MAIN OUTCOME MEASURE(S): Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify the different ANGPT2 alleles. RESULT(S): No association between mutant (mt) allele and the occurrence of idiopathic recurrent miscarriage was found. Between women with primary and secondary idiopathic recurrent miscarriage, no statistically significant differences with respect to allele frequencies were observed. CONCLUSION(S): This is the first report on the ANGPT2 gene polymorphism in women with idiopathic recurrent miscarriage, demonstrating that the investigated polymorphism is not associated with idiopathic recurrent miscarriage in a white population.     

Interleukin-1 receptor antagonist and interleukin-1 beta polymorphisms in women with recurrent miscarriage

Genotypes and allele distributions for the interleukin (IL)-1beta -511 C/T and the IL-1 receptor antagonist gene intron 2 tandem repeat polymorphisms were compared in 206 women with recurrent miscarriage and a control population. No significant differences were observed between the distributions of IL-1beta or IL-1 receptor antagonist gene alleles in either the recurrent miscarriage group as a whole or when divided according to the cause of recurrent miscarriage compared with controls, which suggests that variation in the IL-1 receptor antagonist gene and IL-1beta genes individually does not play a role in susceptibility to recurrent miscarriage.     

Ethnic differences of polymorphisms in cytokine and innate immune system genes in pregnant women

OBJECTIVE: Investigations of the possible role of polymorphic genes in pregnancy outcome may be influenced by ethnic variations in genotype or allele frequencies. Differences in allelic carriage of immune system-related genes among white, black, and Hispanic pregnant women living in New York City and Boston were evaluated. METHODS: DNA was extracted from buccal or vaginal epithelial cells collected from 198 white, 75 black, and 114 Hispanic pregnant women who delivered at term and who had no history of a preterm birth. Genetic polymorphisms in the immunoregulatory genes encoding interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-4, IL-10, IL-1 receptor antagonist (IL-1ra), mannose-binding lectin, toll-like receptor-4, and the 70-kDa heat shock protein were determined. RESULTS: Allele 2 of the IL-1ra gene (IL1RN*2) and IL-4 -590C homozygosity were 4-fold less common in blacks than in whites or Hispanics (P <.001). The IL-4 -590T allele was almost 2-fold more common in Hispanics than in whites (P <.001). The frequency of the 70-kDa heat shock protein 1267G allele was at least 1.4 times greater in blacks compared with whites (P <.001) or Hispanics (P =.002), whereas the homozygous mannose-binding lectin codon 54G allele was observed at least 4.5 times more often in Hispanics compared with whites (P =.007) or blacks (P =.02). CONCLUSION: Investigations of the role of genetic factors affecting pregnancy outcome must be cognizant of ethnic variations when enrolling case and control subjects for studies on allele and genotype frequencies.     

A polymorphism of the interleukin-1beta gene and idiopathic recurrent miscarriage

OBJECTIVE: Proinflammatory cytokines have been described to be involved in the pathogenesis of idiopathic recurrent miscarriage (IRM). We investigated the association between IRM and a polymorphism in exon 5 of the interleukin-1beta gene (IL1B) and interleukin-1beta (IL-1beta) serum levels. DESIGN: Case control study. SETTING: Academic research institution. SUBJECTS: One hundred thirty-one women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 68 healthy controls with at least two live births and no history of pregnancy loss. INTERVENTIONS: Peripheral venous puncture. MAIN OUTCOME MEASURES: An IL1B exon 5 (position +3953) gene polymorphism was analyzed by PCR amplification followed by restriction fragment length polymorphism analysis. IL-1beta serum levels were analyzed by a commercially available ELISA. RESULTS: Allele frequencies in women with IRM and controls were 77.9% and 80.8%, respectively, for the E1 allele (wild type), and 22.1% and 19.2%, respectively, for the E2 allele (mutant). No association between the E2 allele and the occurrence of IRM was found (P=.57, odds ratio =.83). Genotype frequencies and IL-1beta serum levels were not significantly different between the study group and the control group. CONCLUSIONS: This is the first report on an IL1B polymorphism in IRM. Although known to alter IL-1beta expression, the investigated IL1B polymorphism is not associated with IRM and increased serum levels in a large Caucasian population.     

Differential characterization of women with vulvar vestibulitis syndrome

OBJECTIVE: We differentiated women with vulvar vestibulitis syndrome into subgroups on the basis of the time of symptom onset, a history of recurrent vulvovaginal candidiasis, and the interleukin-1 receptor antagonist gene polymorphism. STUDY DESIGN: One hundred sixty-two consecutive patients with strictly defined vulvar vestibulitis syndrome were asked to fill out a questionnaire with the assistance of their gynecologist. A buccal sample was collected from each subject for the analysis of interleukin-1 receptor antagonist gene polymorphism; vaginal and vestibular microbial investigations were performed. RESULTS: Symptoms began with the first act of coitus in 20.4% of patients. A history of a recurrent Candida vulvovaginal infection was reported in 42.6% of patients; 25.9% of the patients were positive for the homozygous interleukin-1 receptor antagonist 2,2 genotype. Women with primary vulvar vestibulitis syndrome differed from women with secondary vulvar vestibulitis syndrome; women with primary vulvar vestibulitis syndrome were younger at the time of the onset of the symptoms (23.8 vs 31.2 years, P <.0001) and had never been pregnant (84.8% vs 61.2%, P <.0001). Women with a history of recurrent Candida vulvovaginitis differed from the other subjects by having a higher frequency of constant vestibular pain (40.6% vs 20.4%, P =.005), a vaginal discharge (79.7% vs 45.2%, P <.0001), and dysuria (62.3% vs 29.0%, P =.0001). Women who were homozygous for interleukin-1 receptor antagonist 2,2 genotype had an earlier onset of symptoms (26 years) than did women who were allele 1 homozygotes (31.3 years, P <.05). They also had a shorter duration of symptoms (4.1 vs 5.9 years, P <.05) and a higher frequency of allergy (47.6% vs 23.4%, P =.002). Human papillomavirus in the vaginal vestibule occurred at a greater frequency in women who were homozygous for interleukin-1 receptor antagonist 2,2 genotype. CONCLUSION: Subgroups of women with vulvar vestibulitis syndrome may be differentiated by symptomatic and genetic variables.     

The preterm prediction study: cervical lactoferrin concentration, other markers of lower genital tract infection, and preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

OBJECTIVE: This study was undertaken to determine the relationship among cervical lactoferrin concentration, other cervical markers potentially related to infection, and spontaneous preterm birth. STUDY DESIGN: Cervical lactoferrin concentrations obtained at 22 to 24 weeks' gestation among 121 women who had a spontaneous preterm birth <35 weeks' gestation were compared with cervical lactoferrin concentrations among 121 women matched for race, parity, and center who were delivered at >/=37 weeks' gestation. Results were compared against levels of cervical interleukin 6, fetal fibronectin, and sialidase, against cervical length according to ultrasonography, and according to the bacterial vaginosis Gram stain score. RESULTS: Cervical lactoferrin concentrations ranged from not measurable (19% of the concentrations were below the threshold for this assay) to a titer of >/=1:64. There was no significant difference in the overall distributions of lactoferrin concentrations between the case patients and control subjects (P =.18). Only when the highest titers of lactoferrin were considered were there more women in the spontaneous preterm birth group (6/121 vs 0/121; P =.03). According to Spearman correlation analyses the cervical lactoferrin concentrations were strongly related to interleukin 6 concentration (r =.51; P =.0001), sialidase activity (r =.38; P =.0001), and bacterial vaginosis (r =.38; P =.0001), were weakly related to fetal fibronectin (r =. 16; P =.01), and were not related to cervical length. With the 90th percentile (a dilution of 1:32) used as a cutoff to establish a dichotomous variable, lactoferrin concentration had the following odds ratios and 95% confidence intervals for associations with other potential markers of infection: bacterial vaginosis odds ratio, 4.8 (95% confidence interval, 2.2-10.3); interleukin 6 concentration odds ratio, 2.8 (95% confidence interval, 1.2-6.5); sialidase activity odds ratio, 5. 5 (95% confidence interval, 2.2-13.7); fetal fibronectin concentration odds ratio, 0.6 (95% confidence interval, 0.2-2.0); chlamydiosis odds ratio, 2.3 (95% confidence interval, 0.8-6.9); and short cervix odds ratio, 0.5 (95% confidence interval, 0.2-1.4). CONCLUSIONS: Lactoferrin found in the cervix correlated well with other markers of lower genital tract infection. High lactoferrin levels were associated with spontaneous preterm birth but had a very low predictive sensitivity.     

Single nucleotide polymorphisms in the promoter region of the interleukin-6 gene and the risk of recurrent pregnancy loss in Japanese women

OBJECTIVE: To investigate the relationships between recurrent pregnancy loss and single nucleotide polymorphisms (-634C-->G and -174G-->C genotypes) in the promoter region of the interleukin (IL)-6 gene in the Japanese population. DESIGN: A case-control study. SETTING: Obstetrics and gynecology department of a university hospital. PATIENT(S): Cases were 76 women with recurrent pregnancy loss; controls were 93 fertile women. INTERVENTION(S): Determination of IL-6 promoter gene polymorphisms performed by polymerase chain reaction and gel electrophoresis. MAIN OUTCOME MEASURE(S): Frequency and distribution of the promoter region of the IL-6 gene allele. RESULTS: There was a significant difference in the -634C-->G genotype frequency (CC vs. CG/GG) between women with recurrent pregnancy loss and controls. The risk of recurrent pregnancy loss was lower in the carriers of the G allele than in women with the wild type (CC) (odds ratio = 0.46; 95% confidence interval = 0.24-0.91). On the other hand, we did not detect any carrier of -174C among the 169 subjects. CONCLUSION(S): The results suggest that, in the Japanese population, women carrying the -634G allele of the IL-6 gene might have a decreased risk of recurrent pregnancy loss.     

Serotonin receptor 1A C(-1019)G polymorphism associated with premenstrual dysphoric disorder

OBJECTIVE: To assess whether the G allele of the serotonin receptor 1A C(-1019)G polymorphism is associated with premenstrual dysphoric disorder. METHODS: The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range 27-46 years, mean 37.7 years) and 51 healthy control subjects (age range 22-48 years, mean 36.2 years). The serotonin receptor 1A C(-1019)G polymorphism was genotyped and compared between the two groups. RESULTS: In contrast to the postulated "high-risk" G/G genotype, there was a marked overrepresentation of the C/C genotype in the premenstrual dysphoric disorder group (P=.034; odds ratio 3.63, 95% confidence interval 1.22-10.78). The presence of at least one C allele was associated with a 2.5-fold increased risk of premenstrual dysphoric disorder (P=.053; odds ratio 2.46, 95% confidence interval 1.03-5.88). CONCLUSION: Our hypothesis that the high-risk G allele is associated with the occurrence of premenstrual dysphoria was not proved in this study. However, due to the increased prevalence of the C variant, we suggest that the C(-1019) allele may contribute to the risk of premenstrual dysphoria. LEVEL OF EVIDENCE: II.     

Pregnancy outcome in recurrent miscarriage patients with skewed X chromosome inactivation

OBJECTIVE: To analyze X inactivation in women with recurrent miscarriage to estimate whether skewed X inactivation is associated with recurrent miscarriage and whether it predicts next pregnancy outcomes. METHODS: A multicenter study was performed. A power calculation determined that 101 patients were needed to detect a difference in skewed X inactivation between patients and controls. Patients were entered into a prospective trial of mononuclear-cell immunotherapy and subsequently tested for skewed X inactivation. Age-matched controls had one live birth and no prior miscarriages. Results from our X inactivation assay were compared with those from an independent genetics laboratory. RESULTS: Greater than 75% skewing was seen in 22.6% of patients and 26.5% controls (P =.52). Greater than 90% skewing was seen in 6.6% of patients and 3.9% of controls (P =.77). There were 19.8% of primary aborters and 32% of secondary aborters with greater than 75% skewed X inactivation (P =.38). There were 4.9% of primary aborters and 12.0% of secondary aborters with greater than 90% skewed X inactivation (P =.27) Neither greater than 75% nor greater than 90% skewed X inactivation impacted next pregnancy outcomes (odds ratios = 0.87 [95% confidence interval (CI) 0.34, 2.3] and 1.4 [95% CI 0.27, 7.5], respectively). Results of the exchange of samples with an independent laboratory were highly correlated (alpha = 0.987, P <.001, coefficient of variation = 5.5%). CONCLUSION: Skewed X chromosome inactivation is not associated with recurrent miscarriage. A patient's X chromosome inactivation status does not predict next pregnancy outcome. Our assay correlates with another experienced laboratory.     

Prevalence and incidence of gynecologic disorders among women infected with human immunodeficiency virus

OBJECTIVE: Our purpose was to ascertain the prevalence, incidence, and predictors of gynecologic disorders among women infected with human immunodeficiency virus. STUDY DESIGN: We serially assessed 292 women infected with human immunodeficiency virus and 681 uninfected women. Outcomes were incidence and prevalence of sexually transmitted diseases, viral shedding, findings of Papanicolaou smears, fungal infections, and menstrual disorders. RESULTS: Women infected with the virus were more likely to have prevalent vulvovaginal candidiasis (odds ratio 1.80, 95% confidence interval 1. 0-3.25, P =.05), oncogenic human papillomavirus (odds ratio 3.79, 95% confidence interval 2.43-5.91, P =.001), abnormal Papanicolaou smears (odds ratio 5.40, 95% confidence interval 3.35-8.78, P =.001), amenorrhea (4.8% vs 0%, P =.05), positive results on Treponema pallidum hemagglutination assay (odds ratio 1.83, 95% confidence interval 1.16-2.88, P =.01), infection with cytomegalovirus (odds ratio 4.2, 95% confidence interval 1.82-10.62, P =.001), and genital warts (odds ratio 6.93, 95% confidence interval 3.16-16.30, P =.001) but were less likely to have Chlamydia trachomatis infection (odds ratio 0.28, 95% confidence interval 0.10-0.66, P =.01). Annual incidence rates among women infected with human immunodeficiency virus were 4.0% for candidiasis, 22.0% for oncogenic human papillomavirus, 11.4% for genital warts, 1.7% for infection with C trachomatis, 1.7% for infection with Neisseria gonorrhoeae, 10.3% for Trichomonas vaginalis, 1.1% for positive results on T pallidum hemagglutination assay, 7.4% for an abnormal Papanicolaou smear, and 10.9% for infection with herpes simplex virus. Overall, 46.9% had at least 1 incident condition. Women infected with human immunodeficiency virus were more likely to have incident oncogenic human papillomavirus infection (odds ratio 2.0, 95% confidence interval 1.01-3.8), abnormal Papanicolaou smears (odds ratio 7.76, 95% confidence interval 2.08-42.8), and genital warts (odds ratio 9. 32, 95% confidence interval 3.04-38.0). Incidence and prevalence of sexually transmitted diseases and oncogenic human papillomavirus infection increased with increased CD4(+) cell counts. CONCLUSIONS: Women infected with the human immunodeficiency virus are significantly more likely to have prevalent and incident gynecologic disorders but not disorders related to risk taking (eg, incident sexually transmitted diseases). The latter disorders increased in women with CD4(+) cell counts >500 cells/mm3. Clinicians should be aware of these patterns so that they can provide appropriate evaluation and treatment of gynecologic disorders.     

Recurrent fetal aneuploidy and recurrent miscarriage

OBJECTIVE: Some investigators have found a high frequency of abortus aneuploidy in women with recurrent miscarriage, suggesting the possibility of recurrent aneuploidy as a cause of recurrent miscarriage. Others contend that aneuploidy is not a cause of recurrent miscarriage. The purpose of this study was to investigate the relationship between fetal aneuploidy and recurrent miscarriage by estimating whether fetal aneuploidy is more common in patients with recurrent miscarriage than in patients with sporadic miscarriage METHODS: Recurrent miscarriage cases (n = 135) included women who had a subsequent miscarriage in which an abortus karyotype was obtained. Controls (n = 150) were patients experiencing a sporadic miscarriage who had fetal karyotypes performed as part of a study to assess the utility of abortus tissue for transplantation. Karyotype analysis was performed using standard G-banding techniques. RESULTS: Abortuses from 122 cases and 133 controls were successfully karyotyped. Thirty-one (25.4%) abortuses from cases and 56 (42.1%) from controls were aneuploid (odds ratio 0.47, 95% confidence interval 0.27-0.80). Aneuploid abortuses occurred in 20% of cases and 25% of controls, aged 20-29 years, 19% of cases and 24% of controls, aged 30-34 years, 35% of cases and 47% of controls, aged 35-39 years, and 50% of both cases and controls, aged 40 years or older (not significant). Of 30 cases in whom 2 or more miscarriages were karyotyped, 3 (10%) had aneuploidy in each abortus. CONCLUSION: In our population of recurrent miscarriage patients, abortus aneuploidy occurred significantly less often than in sporadic miscarriages. The rate of aneuploidy in this study was considerably lower than reported in other studies. If recurrent aneuploidy contributes to recurrent miscarriage, it does so in only a small number of patients. LEVEL OF EVIDENCE: II-2     

Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review

Obesity has become an epidemic in developed societies. Retrospective studies suggest that obesity is associated with miscarriage in assisted reproduction. The objective of this study was to evaluate whether obesity is associated with miscarriage in spontaneous conception. We conducted a systematic review of published studies with pooled analysis. A literature review was performed. Studies in which fertility drugs or in vitro fertilization were used were excluded, unless data could be extracted for spontaneous conception. Data were compared for obese (body mass index [BMI]: ≥28 or 30 kg/m (2)), overweight (BMI: 25 to 29 kg/m (2)), and normal-weight (BMI: <25 kg/m (2)) women, with pooled odds ratios (ORs). Recurrent miscarriage data were analyzed separately. Six studies met the criteria for a cohort of 28,538 women. Pooled analysis revealed a higher miscarriage rate of 13.6% in 3800 obese versus 10.7% in 17,146 normal-BMI women (OR: 1.31; 95% confidence interval [CI], 1.18 to 1.46). Although the cohort was small, there was a higher prevalence of recurrent early miscarriage in obese versus normal-BMI women (0.4% versus 0.1%; OR: 3.51; 95% CI, 1.03 to 12.01). In women with recurrent miscarriage, there was a higher miscarriage rate in the obese versus nonobese women (46% versus 43%; OR: 1.71; 95% CI, 1.05). Based on retrospective studies, we concluded that obesity is associated with a higher miscarriage rate in women who conceive spontaneously. Larger prospective studies are urgently needed to verify these preliminary results.     

Interleukin-1 receptor antagonist gene polymorphism and multifetal pregnancy outcome

OBJECTIVE: The purpose of this study was to determine whether interleukin-1 receptor antagonist and/or interleukin-1beta gene polymorphisms influence multifetal pregnancy outcome. STUDY DESIGN: Maternal and neonatal buccal swabs from 51 multifetal gestations were analyzed for interleukin-1 receptor antagonist and interleukin-1beta alleles. Outcome data were obtained subsequently. RESULTS: Fetal carriage of interleukin-1 receptor antagonist allele 1 was more than twice as prevalent as the carriage of allele 2. Preterm premature rupture of membranes was observed in 12 of 24 pregnancies (50.0%) in which 2 fetuses tested positive for interleukin-1 receptor antagonist allele 2, as opposed to only 3 of 27 pregnancies (11.1%) in which 1 or neither fetus tested positive for interleukin-1 receptor antagonist allele 2 (P=.005). Similarly, 20 of 26 neonates (76.9%) with documented morbidity tested positive for interleukin-1 receptor antagonist allele 2, as compared with 36 of 78 neonates (46.2%) without morbidity (P=.007). Fetal or maternal interleukin-1beta polymorphisms or maternal interleukin-1 receptor antagonist polymorphisms were unrelated to pregnancy outcome. CONCLUSION: Fetal carriage of interleukin-1 receptor antagonist allele 2 was associated with both preterm premature rupture of membranes and neonatal morbidity in women with multifetal pregnancies.     

Fibrinolytic defects and recurrent miscarriage: a systematic review and meta-analysis

OBJECTIVE: To systematically review evidence of the association between fibrinolytic defects and recurrent miscarriage. DATA SOURCES: MEDLINE, EMBASE, and references of retrieved articles (last update September 2006) were used. METHODS OF STUDY SELECTION: Studies comparing the prevalence of fibrinolytic defects in patients with recurrent miscarriage and control women were reviewed. Of 111 potentially relevant studies, data from 14 were integrated with meta-analytic techniques and were presented as odds ratios (ORs). TABULATION, INTEGRATION, AND RESULTS: Plasminogen activator inhibitor-1 4G/5G polymorphism (OR 1.65, 95% confidence interval [CI] 0.92-2.95) and increased plasminogen activator inhibitor activity were not significantly associated with recurrent miscarriage, although the latter showed profound heterogeneity across studies. Although factor XII C46T polymorphism is not associated with recurrent miscarriage (OR 1.07, 95% CI 0.52-2.22), factor XII deficiency is significantly associated (five studies, 1,096 women; OR 18.11, 95% CI 5.52-59.39), with minimal heterogeneity across studies. Factor XIII Val34Leu and Tyr204Phe polymorphisms were not associated with recurrent miscarriage (OR 1.24, 95% CI 0.46-3.34 and OR 2.61, 95% CI 0.45-15.16, respectively). There were no eligible studies found for the rest of the factors searched (urokinase-type plasminogen activator, tissue-type plasminogen activator, kallicrein, a2-antiplasmin, a2-macroglobulin, thrombin-activated thrombolysis inhibitor, and factor XI). Only a small minority of studies ascertained miscarriage according to specific criteria, and none of the studies provided equal examination for confounders in cases and controls. CONCLUSION: Factor XII deficiency is associated with recurrent miscarriage. Data on the other factors either fail to show association or are quite limited.