Recurrent In Vitro Fertilization Research Articles

Low-molecular-weight heparin in the treatment of recurrent IVF–ET failure and thrombophilia: A prospective randomized placebo-controlled trial

BackgroundIntroduction: Recently, thrombophilia (acquired and inherited) has been implicated in recurrent IVF–ET failure. The objective of this study was to determine the effect and safety of thromboprophylaxis using low-molecular-weight heparin (LMWH) in women with recurrent in vitro fertilization (IVF)–embryo transfer (ET) failure and thrombophilia. Methods: Eighty-three women with history of three or more previous IVF failures and who had at least one thrombophilic defect were eligible for this study. Patients were randomly allocated into two groups: Group A (n = 42) received enoxaparin 40 mg/day, and group B (n = 41) received placebo (NaCl 0.9%). Both treatments started on the day of ET and continued until delivery or foetal demise was diagnosed. The primary outcomes were the implantation, pregnancy and live birth rates. Results: Patients who received LMWH for thromboprophylaxis had a significant increase in the implantation and pregnancy rates compared with the placebo group (20.9% vs. 6.1% and 31% vs. 9.6%, respectively; p < 0.001 and p < 0.05, respectively). A significant increase in the live birth rate was observed in the heparin-treated group compared with placebo (23.8% vs. 2.8%, respectively; p < 0.05). The abortion rate was significantly higher in the placebo-treated group compared to the heparin-treated group (p < 0.05). The frequency of treatment complications did not differ between the two study groups. Conclusions: LMWH is a safe and effective thromboprophylactic treatment for women with thrombophilia and recurrent IVF–ET failures. The implantation rate, pregnancy and live birth rates are significantly increased with such treatment.

Does the prevalence of individual chromosomal aneuploidy vary with respect to day 3 embryo morphology?

Preimplantation genetic diagnosis (PGD) has been increasingly utilized in conjunction with embryo morphology grading to select embryos for transfer. Our group previously reported that High Implantation Potential (HIP) embryos are more likely to develop to the blastocyst stage, but a significant proportion of those are aneuploid. We aim to compare proportions of aneuploidy among individual chromosomes in HIP and non-HIP embryos that develop to the blastocyst stage by day 5. Retrospective analysis. We identified all women who underwent in vitro fertilization (IVF) with their first PGD cycle for recurrent miscarriage, recurrent IVF failure, advanced maternal age, or other indications between January 1 and December 31, 2006. Embryos were scored as HIP if they had ≥4 cells on day 2 and ≥7 cells on day 3, with <20% fragmentation and no multinucleation. Fluorescence in situ hybridization was utilized to analyze 9 or 12 chromosomes. P values were adjusted to account for lack of independence among embryos from the same woman. A total of 364 embryos from 88 cycles in 88 patients were analyzed. Non-HIP embryos were more likely to be aneuploid for chromosomes XY, 8, 15, 16, 18, and 22 compared to HIP embryos, with similar trends for chromosome 14 and 17. There were no significant differences between HIP and Non-HIP embryos in the aneuploidy rates of chromosomes 13, 20, and 21. TableAneuploidy Prevalence by ChromosomeChromosomeHIPNon-HIPPXY18/205 (9%)25/148 (17%)0.04811/63 (17%)12/34 (35%)0.011343/204 (21%)36/149 (24%)0.491417/68 (25%)15/35 (43%)0.091538/198 (19%)48/143 (34%)0.0011637/200 (19%)40/149 (27%)0.0471720/200 (10%)26/149 (17%)0.051838/204 (19%)45/149 (30%)0.012016/63 (25%)9/34 (26%)0.902146/206 (22%)34/150 (23%)0.942236/199 (18%)39/147 (27%)0.02No Nucleus4/210 (2%)4/154 (3%)0.64 Open table in a new tab Aneuploidy is common in embryos that develop to the blastocyst stage. Non-HIP embryos are associated with increased aneuploidy for most screened chromosomes, suggesting an association between morphology and chromosomal status. Interestingly, HIP embryos are no less likely to have abnormal numbers of chromosomes 13, 20, and 21. Our data suggest that PGD is a useful tool to detect embryos with potentially viable but detrimental chromosomal abnormalities that are not detected by embryo morphology alone.

Embryo culture to the blastocyst stage does not select for gender

Reports of increased developmental rates in male embryos have resulted in concerns that day 5 blastocyst transfer may lead to gender selection. We compared blastocyst development and prevalence of euploidy in XX vs. XY embryos. Retrospective analysis. We identified all women who underwent in vitro fertilization (IVF) with their first preimplantation genetic diagnosis (PGD) cycle for recurrent miscarriage, recurrent IVF failure, advanced maternal age, or other indications between January 1 and December 31, 2006. Fluorescence in situ hybridization was utilized to analyze 9 or 12 chromosomes. Embryos with abnormal sex chromosomes were excluded. P values were adjusted to account for lack of independence among embryos from the same woman. A total of 481 embryos from 99 cycles in 99 patients with complete results for the 9-chromosome panel were analyzed. 235 (49%) were XX and 246 (51%) were XY. The prevalence of euploidy was similar between the XX and XY embryos (30% vs. 32%, P=0.73). XX and XY embryos were equally likely to develop to the blastocyst stage by day 5 (59% vs. 60%, P=0.84), and those that became blastocysts had similar proportions of euploidy (41% vs. 37%, P=0.43). Results were similar in a subset of embryos in which all 12 chromosomes were analyzed. Abnormal numbers of individual autosomes were no more likely to occur in XX than XY embryos. XX and XY embryos are equally likely to develop to the blastocyst stage by day 5. Moreover, XX and XY blastocysts are equally likely to be euploid. There is no predilection for aneuploidy of any single autosome to occur with greater frequency in XX vs. XY embryos. Our data suggest that day 5 blastocyst culture does not result in gender selection and that euploidy and aneuploidy are not gender dependent.

Differential Delivery Rates Between Infertility Diagnosis in a PGD/FISH Program

In the majority of patients undergoing IVF, competent embryos are identified using cumulative morphology grading. However, specific populations of patients exist that fail to conceive or continue to miscarry despite multiple attempts at IVF with the same embryo grading criteria. It has been hypothesized that these patients have less chromosomally normal embryos making the option of PGD desirable to identify euploid embryos for transfer. PGD as a treatment for infertility is often indicated in patients suffering from recurrent pregnancy loss (RPL), advanced maternal age, multiple failed in-vitro fertilization (IVF) attempts, and repeat biochemical pregnancies after IVF. However, this application of PGD has demonstrated varying reports of success. The goal of this study is to analyze the relationships between embryo morphology and aneuploidy and pregnancy outcomes in each patient population. Retrospective data analysis All patients over a 15-month period who had PGD with FISH for aneuploidy were included. Patients undergoing PGD for translocation or single gene defects were excluded. The clinical pregnancy rates (CPR) and ongoing/delivery rates were recorded by age and euploidy by indication. Embryo data was recorded by pronuclear and day three morphology and percent euploid by indication. A significant difference was observed in ongoing pregnancy rates between PGD patients of specific diagnosis groups. With the exception of the advanced maternal age group, there was no difference in the percent of euploid embryos between groups. In addition, there was no significant difference between embryo morphology in any of the diagnosis groups. Tabled 1 Tabled 1 These data suggest that PGD results in high pregnancy success rates for recurrent miscarriage patients. When a previous pregnancy rate of zero percent prior to PGD is considered, PGD proves to increase pregnancy rates by a significant amount for all of the diagnosis populations. However, the large discrepancy in success rates and the lack of significantly different morphology and aneuploidy data between groups suggests the existence of other unknown factors responsible for the majority of infertility in patients with recurrent IVF failure and repeat biochemical pregnancies.

Rezidivierende Aborte und frustrane In-vitro-Fertilisation

Antibodies against annexin-V, a potent anticoagulant abundant in placental tissues, were recently controversially reported to be associated with recurrent miscarriages or failures of in-vitro-fertilization (IVF) attempts. We screened 56 women (34.7 +/- 4.3 years of age: mean +/- 1 SD) with recurrent IVF failures and/or early pregnancy losses for resistance against activated protein C, lupus anticoagulant and antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. Among them the prevalence of APC-R (8/56, 14%) and elevated levels of IgG- or IgM-anti-cardiolipin antibodies (7/56, 12%) were more common than elevated levels of (IgG or IgM) antibodies against beta(2)-glycoprotein-1 (3/56, 5%) or annexin-V (1/56, 2%). 42 (75%) of the women had another IVF-attempt after this haemostaseological evaluation and received low molecular weight heparin and/ or acetylsalicylic acid in the case of positivity for APC-resistance, lupus anticoagulant or antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. The outcome of these IVF-attempts were 19 pregnancies (34%): 4 early miscarriages (7%) and 15 so far uncomplicated pregnancies (27%). The only woman with an elevated anti-annexin V (IgG) level had had 7 IVF before and received 40 mg Enoxaparin (Lovenox) subcutaneously once daily during the 8(th) IVF, which resulted in a healthy pregnancy. Our findings suggest that among women with recurrent IVF failures anti-annexin V antibody positivity is less prevalent than APC-resistance, lupus anticoagulant (LA) or elevated levels of antibodies against cardiolipin, beta(2)-glycoprotein-1 and that the IVF-result of women with APC-R, LA or with elevated levels of antibodies against annexin V, cardiolipin or beta(2)-glycoprotein might be positively influenced by low molecular weight heparin.

Preimplantation genetic diagnosis by fluorescence in situ hybridization: clinical possibilities and pitfalls.

Preimplantation genetic diagnosis using the fluorescence in situ hybridization technique (FISH) is being used widely to prevent the transmission of sex-linked diseases, to screen for translocations, and for aneuploidy screening in specific in vitro fertilization (IVF) patient groups, along with FISH analysis of spermatozoa in infertile men. In this study, we aim to critically analyze our clinical results in patients at risk of transmitting sex-linked diseases (n = 55), in carriers of translocations (n = 43), in women who have recurrent miscarriage (two or more miscarriages) (n = 128), recurrent IVF failure (three or more failed IVF attempts) (n = 47), and patients of advanced maternal age (37 years old or older) (n = 79). The use of the FISH technique in carriers of sex-linked diseases and translocation patients prevents transmission of these conditions and provides good IVF outcome. In patients with recurrent miscarriage, implantation failure, and advanced maternal age, a high incidence of embryos with abnormal chromosomes 13,16,18,21,22, X, and Y was observed (range 69-75%), as expected. In those three groups of patients, the selection of euploid embryos for transfer resulted in good pregnancy rates with a low incidence of miscarriage. Limitations and pitfalls of this technique are also discussed.

Does in vitro fertilization (IVF) influence the levels of sperm and zona pellucida (ZP) antibodies in infertile women?

The levels of sperm and zona pellucida antibodies in 250 women divided into four groups according to number of recurrent IVF failures (1-4) were analysed and compared with results of a control group of 211 unexplained infertile women never treated by IVF. Sperm antibodies in serum and in ovulatory cervical mucus were determined by mixed antiglobulin reaction (MAR) test, serum zona pellucida antibodies were detected using passive haemagglutination and ELISA. These tests showed increased occurrence of zona pellucida antibodies in women after repeated IVF. Zona pellucida antibodies were found in 20% after on unsuccessful IVF (similarly to 27% in the control group), but in 64% after two, in 91% after three and in 4 of 5 cases after four IVF failures. Sperm IgG, A, M, and E antibodies in serum and in ovulatory cervical mucus do not seem to be influenced by IVF procedure. The results show evolution of autoimmune process due to repeated ovarial intervention during oocyte collections. Presence of zona pellucida antibodies, on the other hand, may become a cause of IVF failure.

Effect of paternal leukocyte immunization on implantation after biochemical pregnancies and repeated failure of embryo transfer.

It is unclear how paternal leukocyte immunization prevents pregnancy loss. We investigated whether immunization affects early pregnancy, and whether it increases the rate of implantation and early embryonic development at the time of implantation. Three groups of women with possible implantation failure were immunized: (1) recurrent biochemical pregnancies (> 3), (2) three or more failed in vitro fertilization (IVF) cycles, and (3) IVF after immunization for recurrent abortion (> 3). Patients were immunized if antipaternal complement-dependent antibody (APCA) was negative, and mixed lymphocyte culture hyporeactive to husbands lymphocytes. Immunizations were prepared from 100 ml paternal blood separated by Ficoll Hypaque density centrifugation. IVF was attempted after APCA was produced. In the women with biochemical pregnancies, 10 to 12 subsequent pregnancies developed normally. Seventy-nine subsequent IVF cycles in 33 patients resulted in 20 pregnancies, 16 of which developed normally. Six pregnancies followed 30 cycles in recurrent failed IVF, and 14 pregnancies from 49 cycles in 23 patients with previous habitual abortion. This treatment may prevent further biochemical pregnancies if control studies confirm this preliminary observation, but was not shown to affect recurrent failed embryo transfer.

Immunolologic investigation of in vitro fertilization (IVF) pregnancy early loss and consequences of immunization with husband's leukocytes in recurrent IVF pregnancy

Immunolologic investigation of in vitro fertilization (IVF) pregnancy early loss and consequences of immunization with husband's leukocytes in recurrent IVF pregnancy