Cytokine polymorphisms in women with recurrent pregnancy loss: meta-analysis

BACKGROUND: Inflammatory cytokine cascades have been implicated in the pathogenesis of recurrent pregnancy loss (RPL). Polymorphisms in cytokine genes may affect the risk of RPL, but genetic association studies are often limited by small sample sizes. Meta-analysis of all available studies can increase the precision of these estimates. AIMS: To assess and synthesise the available data from association studies of inflammatory cytokine polymorphisms with RPL. METHODS: Systematic review and random effects meta-analysis of genetic association studies. RESULTS: Sixteen reports of genetic association studies of cytokine polymorphisms with RPL were identified. Meta-analyses did not identify any significant associations with tumour necrosis factor (-308A, or -238A), interferon-gamma (+874T), interleukin (IL)-1beta (-511T), IL-6 (-174G), or IL-10 (-1082A, or -819T, or -592A). Significant associations were found with IL-1B (-31T) (two studies: pooled odds ratio (OR) 2.12 (95% confidence interval (CI) 1.04 to 4.33)) and IL-6 (-634G) (one study: OR 0.22 (95% CI 0.09 to 0.57)). CONCLUSIONS: The available data are not consistent with more than modest associations between these candidate cytokine polymorphisms and RPL. Data from future association studies may be added to the meta-analyses to obtain more precise estimates of effect sizes.     

Thrombophilic genes alterations as risk factor for recurrent pregnancy loss

Objective: The important polymorphisms leading to inherited thrombophilia are Factor V Leiden (FVL), Prothrombin G20210A and MTHFR C677T and A1298C. The frequencies also the correlation among these polymorphisms and RPL have been reported controversially in various populations. Our clinic is one of the referral centers in reproductive biomedicine in which patients in all over Iran refer to; thus the results of this study could be considered clinically beneficial. Besides, in the present study, not only the frequency of specific but also multiple thrombophilic gene alterations were compared in Iranian women with RPL and a control group.

Methods: The patients group comprised 330 women with three or more consecutive RPLs. The control population included 350 women with at least one child and no history of pregnancy loss. FVL, Prothrombin G20210A and MTHFR C677T polymorphisms were analyzed by Strip assay kit. MTHFR A1298C was genotyped by PCR-RFLP.

Results: The frequencies of FVL, Prothrombin G20210A, MTHFR C677T and MTHFR A1298C mutations in patients were 8.48, 4.24, 45.45 and 59.39%, and in controls were 2.86, 2.86, 34.28 and 6%, respectively.

Conclusions: The present data showed that FVL, MTHFR polymorphisms also combined with thrombophilic gene mutations have a strong association with RPL.     

Clinical approach to recurrent pregnancy loss

Recurrent pregnancy loss is a topic that most trainee obstetricians and gynaecologists are likely to find themselves confronted with on a regular basis during their roles in early pregnancy assessment unit. We examine the current guidelines from the RCOG and ESHRE on the management of this patient group. The investigation and management of recurrent pregnancy loss is subdivided into the areas of first trimester (5–13 weeks) and second trimester (14–24 weeks) pregnancy loss. These two areas have some overlap but generally reveal differing pathophysiology and treatment. The setting of a recurrent miscarriage clinic is the perfect opportunity to optimise patient's underlying medical co-morbidities and encourage a healthy lifestyle to improve obstetric outcomes. It is also essential to offer psychological support to couples who suffer significant mental health problems and to address factors that are known to be associated with recurrent miscarriage. There are exciting developments in treatment since the last RCOG guideline was published and research is ongoing.     

High basal estradiol level and FSH/LH ratio in unexplained recurrent pregnancy loss

Background The potential role of diminished ovarian reserve in unexplained recurrent pregnancy loss (RPL) in a retrospective comparative analysis. Methods Eighty women with RPL underwent routine work-up to exclude known associations of RPL. Serum FSH, LH and E₂ levels were assessed on the 3rd day of the menstrual cycle. Following investigation, 58 women failed to reveal an identifiable cause and are therefore classified as unexplained RPL. Control group consisted of women in whom the cause of abortions was known such as uterine septum and parental chromosomal abnormalities. Mean age, gravidity, parity, presence of infertility, previous number of miscarriages, duration of marriage were similar in both groups. Day 3 serum levels of FSH, E₂ and FSH: LH ratios were compared in the two groups. Results Elevated FSH concentrations were equally distributed in the unexplained RPL and control groups. Both day 3 E₂ and FSH:LH ratio were elevated in the unexplained RPL group compared with the control group (p=0.0066 and p=0.0187 respectively). The percentage of women with elevated FSH and/or E₂ levels on day 3 were significantly higher in the unexplained RPL group than in controls (p=0.0045). Conclusions Unexplained RPL may be associated with diminished ovarian reserve and should be considered in the workup of RPL.     

The association between polymorphisms of genes related to inflammation and recurrent pregnancy loss

Aim: Recurrent pregnancy loss (RPL) occurs in 1–2% of pregnant women and about 50% of RPL cases are unexplained. Previous studies have shown that genetic variation in immune response genes can contribute to the risk in pregnancy maintenance during pregnancy. The aim of the present study was to evaluate the relationship between RPL and genes those have previously been associated with an inflammatory process on 107 RPL cases and 187 healthy controls.

Methods: In this work, the single-nucleotide polymorphisms was examined by utilizing the direct sequencing and the Sequenom MassARRAY system.

Results: The FAU rs769440?G allele had higher frequencies in patients with RPL (p?=?.019). No association was observed between other polymorphisms and RPL.

Conclusion: The results showed an association between FAU rs769440 polymorphism and RPL in Chinese Han population.     

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.     

Ongoing pregnancies in patients with unexplained recurrent pregnancy loss: adverse obstetric outcomes

To investigate the incidence of adverse pregnancy outcomes in couples with an unexplained Recurrent Pregnancy Loss (RPL) history, a retrospective cohort study was conducted between 2014 and 2015. The study group (A) included couples with an unexplained RPL, and the control group (B) was composed of couples who attended the Low-Risk Antenatal Unit during the same period. On the other hand, 53 couples were included in the study group (A) and on the other hand, 65 in the control group (B). Women with previous unexplained recurrent pregnancies loss had a significantly increased risk of gestational diabetes with 12 cases (22.6%) in the study group and 3 cases (4.6%) in the control (OR: 6.048; 95% CI: 1.607–22.762; p?=?0.007). A slight increase in the risk of preterm delivery and hepatic cholestasis was observed in the study group (6 cases, 11.3%, in study group and 1 case, 1.5% in the controls (OR: 8.170; 95% CI: 0.951–70.158; p?=?0.0555). Women with a history of RPL delivered more frequently by caesarean section (OR: 3.252; 95% CI: 1.460–7.241; p?=?0.0039). Women with a history of RPL were at an increased risk for adverse pregnancy outcomes, mainly gestational diabetes. Therefore, a closer surveillance during the antenatal period is recommended in this group of patients.     

Index pregnancy versus post-index pregnancy in patients with recurrent pregnancy loss

Objective: To compare pregnancy outcomes of two consecutive pregnancies in a cohort of women with recurrent pregnancy loss (RPL), in order to determine the long-term prognosis of women with RPL managed in a dedicated RPL clinic.

Methods: A retrospective cohort study including 262 patients with two or more consecutive pregnancy losses followed by two subsequent pregnancies – index pregnancy (IP) and post-index pregnancy (PIP). All patients were evaluated and treated in the RPL clinic in the Soroka University Medical Center.

Results: Comparing IP with PIP, no significant difference in perinatal outcome was observed. The perinatal outcome remained encouraging with approximately 73% birth rate (73.7% versus 72.5%; p?=?0.83). Only 11% of the women with RPL continued to experience pregnancy losses for two subsequent pregnancies. In a multivariate logistic regression analysis, number of miscarriages pre-Index was the only factor independently associated with birth in the PIP.

Conclusion: There is no significant difference between IP and PIP regarding perinatal outcome. Appropriate management in the RPL clinic conferred a significant beneficial effect on long-term pregnancy outcome of a cohort of women with RPL.     

Association of IL-10, IL-18, and IL-33 genetic polymorphisms with recurrent pregnancy loss risk in Iranian women

Recurrent pregnancy loss (RPL) is a heterogeneous disease with three or more consecutive abortions before 20?weeks of pregnancy. Recently, inflammatory factors such as interleukins (IL) have been found to be a significant factor in the RPL. The objective of this study was to investigate the association between RPL and IL-10 (rs1800896), IL-18 (rs1946518) and IL-33 (rs1929992) genes polymorphisms in Iranian women. The study participants consisted of 300 women with RPL and the control group comprised of 300 healthy women with successful delivery. Genomic DNA was extracted from peripheral blood, and genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). There were no significant differences in the frequencies of genotype and allele in IL-10 gene polymorphism (rs1800896) between patients and control group (p?>?.005). In contrast, there were significant differences in the frequencies of CC genotype in IL‐18 gene polymorphism (rs1946518) between patients and the control groups (p?=?.004; OR =0.990; 95% CI: 0.320–8.855). Also, there were significant differences in the frequencies of GA genotype in IL‐33 gene polymorphism (rs1929992) between patients and the control groups (p?=?.001; OR =0.955; 95% CI: 0.239–9.807). Present study showed that the rs1800896 polymorphism (IL-10) might not play role in RPL in the Iranian population; whereas rs1946518 (IL-18) and rs1929992 (IL-33) polymorphisms may be associated with the risk of RPL in the Iranian women.     

A clinical approach to recurrent pregnancy loss

A diagnosis of recurrent pregnancy loss can be considered after the loss of two or more pregnancies before 24 weeks' gestation. In most couples no pathological cause is identified. The outcome can be improved for women with recurrent pregnancy loss and antiphospholipid syndrome with treatment with aspirin and/or heparin. Couples with unexplained recurrent pregnancy loss have an excellent prognosis with supportive care alone and to date no pharmacological intervention has been proven to be beneficial. This review describes the causes of recurrent pregnancy loss, the clinical work-up and an evidence-based approach to management.     

Fas and FasL genetic polymorphisms in women with recurrent pregnancy loss: a case-control study

Aberrant apoptosis at the trophoblast–maternal interface and abnormal expression of Fas and Fas ligand (FasL) have been reported in complicated pregnancies with recurrent pregnancy losses (RPL) and preeclampsia. We assessed the prevalence of Fas and FasL genetic polymorphisms in Korean women with RPL and in fertile controls. In total, 306 women with RPL and 298 fertile controls were enrolled. Genotype distributions of Fas and FasL in RPL patients versus fertile controls were examined under the Hardy–Weinberg equilibrium. Fas ?670 A/G genotype (AA versus AG versus GG, p?=?0.340) and allele frequencies (A versus G, p?=?0.412) were not different between the RPL and control groups. There was no difference in each Fas ?1377?G/A and FasL ?844 C/T genotype, and their allele frequencies. In addition, the unions of two zygosities of each genotype and their combined genotypes did not differ between two groups. No difference in the prevalence of Fas and FasL single-nucleotide polymorphisms (SNPs) was observed between women with RPL and fertile controls among Korean women. To determine the possibility of genetic polymorphisms in Fas and its ligand as risk factors for RPL, further studies in various races and a large study population are needed.     

Association of p53 polymorphism with ICSI/IVF failure and recurrent pregnancy loss

Background: The p53 tumour suppressor gene is a well-known factor regulating apoptosis in a wide variety of cells. Alterations in the p53 gene are among the most common genetic changes in human cancers. Several polymorphisms of the p53 tumour suppressor gene have been associated with recurrent pregnancy loss (RPL).
Aims: To evaluate the association of polymorphisms p53 codon 72 with the response to in vitro fertilisation (IVF) treatment and occurrence of repeated miscarriages.
Methods: The homozygous and heterozygous genotypes and allelic frequencies of Arg and Pro p53 at codon 72 were identified by using polymerase chain reaction–restriction fragment length polymorphism technique in 70 infertile women with more than two IVF failures. Each comparison was made with 97 women experiencing RPL and 32 fertile women each with at least two healthy children as the control group.
Results: The frequency of homozygous Pro/Pro genotypes was found significantly higher among the women with RPL than the other two groups ( P  = 0.041). Whereas, Arg/Arg genotype was significantly different in the recurrent implantation failure (RIF) group ( P  = 0.005).
Conclusion: It is concluded that p53 codon 72 polymorphism may serve as a susceptible factor affecting the chances of RPL and RIF.     

Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis

Objective: To quantify the risk of recurrent early pregnancy loss in the presence of elevated fasting or afterload homocysteine concentrations or homozygosity for the 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (T/T genotype).

Design: Case-control studies published between January 1992 and November 1999 were identified with a MEDLINE-search. These studies were combined with a recent case-control study performed by our own research group.

Setting: Academic research environment.

Patient(s): Studies published in the English language, concerning two or more pregnancy losses before 16 weeks’ menstrual age were included.

Intervention(s): Meta-analysis of all of the studies included.

Main Outcome Measure(s): The number of subjects with and without hyperhomocysteinemia or with the T/T genotype were derived, if necessary the study was supplemented by personal communication with the original authors.

Result(s): Pooled risk estimates of 2.7 (1.4 to 5.2) and 4.2 (2.0 to 8.8) were calculated for fasting and afterload plasma homocysteine concentrations, respectively. For the MTHFR T/T genotype a pooled risk estimate of 1.4 (1.0 to 2.0) was found.

Conclusion(s): These data support hyperhomocysteinemia as a risk factor for recurrent early pregnancy loss. Further research should be focused on the pathophysiology of this relationship and on the clinical efficacy of B vitamin supplementation.