Sperm DNA fragmentation index and pregnancy outcome after IVF or ICSI: a meta-analysis

PurposeThe purpose of this study was to carry out a meta-analysis for a comprehensive understanding and estimation of the association between sperm DNA Fragmentation Index (DFI) and pregnancy outcome after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment.MethodsStudies concerning the link of DFI with pregnancy outcome were included after literature search of database PUBMED, EMBASE, MEDLINE. Related information was extracted from the eligible studies by two independent authors and a meta-analysis was conducted by using STATA 12.0 software. Pregnancy outcomes consisted of biochemical pregnancy (BP), clinical pregnancy (CP) and pregnancy loss (PL). The studies included for meta-analysis were divided into three groups according to the DFI threshold value (DFI >27 %, 15–27 %, ≤15 % group). The odds ratio (OR ) and their 95 % confidence intervals (95 % CIs) were used to evaluate the association between DFI and pregnancy outcome.ResultsTwenty articles were included in our meta-analysis. The results indicated that infertile couples were more likely to get pregnant if DFI was less than threshold value (For threshold value > 27 % and 15–27 % group, combined overall OR (95 % CI) = 1.437 (1.186–1.742), 1.639 (1.093–2.459) respectively). However, when stratified by DFI detection methods, using sperm chromatin structure assay (SCSA) as the DFI test method, the results indicated a similar CP rate between groups with a high DFI or a lower DFI value (SCSA, For threshold value >27 % and 15–27 % group, combined overall OR (95 % CI) = 1.242(0.978–1.577), 1.480(0.921–2.377) respectively). The meta-analysis based on BP (overall OR (95 % CI) = 0.952 (0.697–1.302)) and PL((For DFI >27 %, 15–27 %, ≤15 % group, OR (95 % CI) = 0.786 (0.491–1.258), 1.509 (0.655–3.476), (0.538 (0.264–1.097) respectively) outcome yielded nonsignificant results.ConclusionsThe predication value of DFI for IVF or ICSI outcome is not confirmed in our meta-analysis. Further better designed studies with larger subjects involved are needed to better address this issue.     

Ischemia-modified albumin as an oxidative stress biomarker in early pregnancy loss

Background/aims: This study aimed to determine the association between early pregnancy loss and serum ischemia-modified albumin (IMA) concentrations.

Methods: Serum samples of 180 women that included healthy pregnant women, women admitted for termination of pregnancy due to the absence of fetal cardiac activity or absence of fetal pole on ultrasonographic examination, and healthy non-pregnant women attending for gynecological examination. Each group included 60 patients. Serum concentrations of IMA were compared among the groups, and the correlations with patients’ age, gravidity, BMI, gestational age and total serum albumin concentrations were calculated.

Results: When the groups were compared with respect to IMA concentrations, the group with early pregnancy loss was found to have significantly higher IMA concentrations (p?<?0.001). An IMA threshold of >163?ng/mL had a sensitivity of 75%, specificity of 55% to discriminate between healthy pregnant patients and patients with early pregnancy loss in first trimester.

Conclusion: Our findings support the theory that possible oxidative stress, a more hypoxic environment and defective placentation lead to increased serum IMA concentrations. These findings may help to shed light on the complicated pathogenesis of early pregnancy loss.     

Sperm aneuploidy and recurrent pregnancy loss

Experiments of double target in-situ hybridization were performed separately for chromosomes 1-17, 8-18 and sex chromosomes on sperm samples from 20 couples suffering from three or more recurrent first trimester abortions. For a subset of this study population, additional experiments of multicolour fluorescence in-situ hybridization for chromosomes 4, 7, 12, 13, 15, 18, 21, and 22, were performed on the bases of the available data from abortive tissue karyotyping. A markedly high rate of sperm disomy (14.5-15.5%) was scored in only two cases. For three other patients, the cumulative disomy rates for chromosomes 1, 17, 8, 18, X and Y also increased but at a lower level (7.8-9.5%). For the remaining 15 patients, the frequency of sperm aneuploidy was moderately increased or normal. Men with recurrent pregnancy loss (RPL) and poor semen quality had baseline sperm aneuploidy and diploidy rates higher than men with normal semen parameters (with or without RPL). Using probes for chromosomes 1, 17, 8, 18, X and Y, significantly elevated frequencies of sperm aneuploidy (not diploidy) were found in 10% of men with a history of RPL. Their rate of sperm aneuploidy was 30-34%. For the other men, changes in sperm aneuploidy were not thought to affect RPL. Poor semen quality per se impacted negatively on sperm aneuploidy and diploidy, thus making the interpretation of clinical data more difficult.     

Obesity is a risk factor for early pregnancy loss after IVF or ICSI

BACKGROUND: Experience with polycystic ovary syndrome shows that insulin resistance is related to early pregnancy loss. This association was examined by comparing pregnancy outcome in obese and lean women. METHODS: A cohort of 383 patients conceiving after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was studied. Ovarian stimulation was achieved by GnRHa and FSH or hMG (n=362), by FSH or hMG alone (n=16), or by clomiphene citrate and FSH or hMG (n=5). Luteal phase was supported with progesterone. Pregnancies were defined by >10 IU/l plasma beta-hCG on day 14. Ultrasound scan on week 6 and week 12 confirmed fetal viability. RESULTS: Lean group (body mass index [BMI]<25 kg/m2; n=304) and obese group (BMI > or =25 kg/m2; n=79) were established. Obese patients had fewer oocytes collected (median: 8 vs 10 p=0.03), they had higher abortion rate during the first 6 weeks (22% vs 12%; p=0.03) and lower live-birth rate (63% vs 75%; p=0.04). The relative risk of abortion before week 6 was 1.77 (95% CI: 1.05 to 2.97). Multivariate logistic regression analysis revealed that obesity and low oocyte count were independently associated with spontaneous abortion. In the obese group, low oocyte number was associated with a more profound increase in the risk of abortion than among lean patients. The effect of age, history of past pregnancies, or infertility diagnosis on the probability of miscarriage were not significant. CONCLUSIONS: Obesity is an independent risk factor for early pregnancy loss. This risk is, in part, related to the lower number of collected oocytes in obese women.     

Thrombophilia and early pregnancy loss

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol.     

Antiphosphatidylethanolamine antibodies in recurrent early pregnancy loss and mid-to-late pregnancy loss

AIM: Associations have been reported between antiphospholipid antibodies (aPL), mainly anticardiolipin antibodies (aCL) and/or the lupus anticoagulant, and recurrent pregnancy losses (RPL). However, relatively few studies describing antiphosphatidylethanolamine antibodies (aPE) have been reported. We describe the prevalence of aPL to both cardiolipin and phosphatidylethanolamine in patients with RPL. METHODS: Patients with recurrent early pregnancy losses (n = 145) and mid-to-late pregnancy loss(es) (n = 26) were screened for aPE and aCL. RESULTS: In patients with recurrent early pregnancy losses, prevalence of immunoglobulin G (IgG) aPE (17.9%, P = 0.001) and immunoglobulin M (IgM) aPE (12.4%, P = 0.01) was significantly higher than in the control group. In patients with mid-to-late pregnancy loss(es), prevalence of IgM aPE (19.2%, P = 0.008) and IgG aCL (23.1%, P = 0.02) was significantly higher than in the control group. CONCLUSION: Our data suggest that aPE may be a risk factor in patients with mid-to-late pregnancy loss(es) as well as recurrent early pregnancy losses.     

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.     

Endocrinology and recurrent early pregnancy loss

Endocrine disorders have been frequently linked to recurrent pregnancy loss (RPL). Because embryo attachment and early implantation are exquisitely controlled by the local hormonal milieu, endocrine-related pregnancy failures are likely to occur early in gestation. Thyroid disorders, luteal phase defects, and polycystic ovary syndrome are the endocrine abnormalities most commonly associated with RPL. In this review we discuss new concepts in the pathophysiology and treatment of these diseases with the ultimate goal of improving pregnancy maintenance. We have also included our recommendations on testing and treatment of women with isolated and repeated pregnancy failure that is believed to be at least partially mediated by newly defined hypothyroidism, thyroid autoimmunity, luteal phase defects, obesity, and polycystic ovary syndrome.     

Data analysis of two in vivo fertility studies using Sperm Chromatin Structure Assay-derived DNA fragmentation index vs. pregnancy outcome

The 2006 American Society for Reproductive Medicine Compendium of Practice Report found no significant effects of elevated sperm DNA fragmentation by using a 30% DNA fragmentation index (DFI) threshold for natural fertilization and SCSA data (odds ratio, 1.07; 95% confidence interval, 0.39-2.93). In contrast, it is shown in this article that these two in vivo studies showed significant odds ratios of 6.54 (95% confidence interval, 1.71, 24.91) and 7.58 (95% confidence interval, 2.54, 22.67), which resulted in the conclusion that the pregnancy (PG) rates are statistically significantly higher for the group with DFI below the thresholds of 30% and 40%, respectively. In addition, all the chi(2) statistics used to test the null hypotheses of no association between the pregnancy status and DFI for natural (normal) fertilization confirmed this conclusion that the probability of pregnancy for the group with <30% or <40% DFI was statistically significantly higher than that for the group with >30% or >40% DFI.     

Recurrent early pregnancy loss and consanguinity

The present authors have studied the possible relationship between recurrent miscarriage and consanguinity in the Qatari population, where the prevalence of first cousin marriage is 47%. The maternal of three or more early pregnancy losses were compared with those of 92 non-consanguineous women from the same population and with the same obstetrical history, matched for maternal age. The retrospective investigation showed no difference in the rate of previous pregnancy loss and maternal disorders, including diabetes, thyroid dysfunction and immunity, abnormal uterine and ovarian anatomy or thrombophilia. There was also no evidence of familial clustering of recurrent miscarriage in both groups. The prospective study showed no difference in the rate of subsequent pregnancy loss and the median gestational age and fetal weight at delivery in ongoing pregnancies. The absence of a relationship between recurrent miscarriage and consanguinity in Qatar could be due to the particular characteristics of the native Qatari population, in which rare recessive genes are uncommon, or overall to the absence of an association between recurrent miscarriage and consanguinity.     

Management of early pregnancy loss.

OBJECTIVES: In order to assess the available evidence on the management of early pregnancy loss, we performed a meta-analysis on the subject. METHODS: MEDLINE and EMBASE were searched for randomized studies reporting on the effectiveness of expectant management, misoprostol treatment or curettage. Outcomes considered were 'complete evacuation', complications, duration of bleeding, pain resulting from the procedure, side effects and women's satisfaction with the procedure. RESULTS: Thirteen studies were identified. Combined data in women with missed abortion managed expectantly or treated with misoprostol showed complete evacuation rates of 28% (49/173) (range 14-47%) and 81% (242/298) (range 60-83%), respectively. In women with incomplete abortion, these rates were 94% (31/33) (range 80-100%) and 99% (75/76) (range 99-100%), respectively. CONCLUSION: In the management of early pregnancy loss both expectant management and misoprostol treatment reduce the need for curettage, but misoprostol treatment seems to be more effective in women with missed abortion as compared to expectant management.     

Management of recurrent early pregnancy loss

Recurrent pregnancy loss is a devastating health problem that affects many couples who are trying to establish a family. Evaluation depends on a number of factors, including the pattern of pregnancy loss, underlying medical disease and life-style issues. A detailed obstetric history, including gestational age at the time of death, ultrasound, pathology and cytogenetic results, is key in the evaluation and management of recurrent pregnancy loss. This complex reproductive disorder requires a multidisciplinary approach since genetic, endocrinologic, anatomic, immunologic, infectious, thrombophilic and iatrogenic factors may require evaluation and management. Monitoring of subsequent pregnancies requires close supportive care.