Biomedical subjects
Publications and source records attributed to D Feldberg.
The purpose of this article is to review the methods and evaluate the 'avenues' that are open to patients and physicians in their search for improvement of in vitro fertilization-embryo transfer (IVF-ET) treatment results. The option of egg donation, although very important and viable in the treatment of poor responders, is not described here.
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OBJECTIVE: To compare the effect of treatment with gonadotropin-releasing hormone agonist (GnRH-a) and human menopausal gonadotropins (hMG) with that of gonadotropins only, on the cumulative livebirth rate and miscarriage rate of pregnancies achieved in women with polycystic ovarian syndrome (PCOS). DESIGN: Retrospective analysis of the outcome of 97 pregnancies according to the treatment protocol, with or without GnRH-a. Calculation of miscarriage rate and cumulative livebirth rate by life-table analysis. SETTING: Infertility clinic and in vitro fertilization (IVF) unit. PATIENTS: Women with polycystic ovaries (n = 239) who were clomiphene citrate failures and received either GnRH-a/hMG (n = 110) or gonadotropins only (n = 129) for ovulation induction (n = 138) or superovulation for IVF (n = 101). INTERVENTIONS: For ovulation induction, hMG was given in a step-up, individually adjusted dose scheme. For IVF, three ampules of pure follicle-stimulating hormone were given for 3 days followed by three ampules per day hMG and then individual dose adjustment. Gonadotropin-releasing hormone agonist (Decapeptyl, D-Trp6, microcapsules, 3.75 mg) was given in a single dose 2 weeks before gonadotropin treatment. MAIN OUTCOME MEASURES: The rate of early miscarriages (< 12 weeks) per pregnancies achieved was analyzed, and the cumulative livebirth rate for each treatment group was calculated by life-table analysis. RESULTS: Miscarriage rates after treatment in ovulation induction with (16.7%) and without GnRH-a (39.4%) and in IVF with (18.2%) and without GnRH-a (38.5%) were almost identical and were therefore analyzed together. Of pregnancies achieved with GnRH-a, 17.6% miscarried compared with 39.1% of those achieved with gonadotropins alone. Cumulative livebirth rate after four cycles for GnRH-a was 64% compared with 26% for gonadotropins only. CONCLUSIONS: Cotreatment with GnRH-a/hMG for anovulatory women with PCOS reduces the miscarriage rate and improves the livebirth rate compared with treatment with gonadotropins alone.
Severe life-threatening complications as a result of ultrasonically guided ovum pick-up for IVF may rarely occur. We report 14 cases, out of 3,656 patients undergoing the procedure, presenting with a clinical picture of acute abdomen. In 9 patients tubo-ovarian and pelvic abscess were diagnosed; 3 were treated by laparotomy, whereas in the other 6, culdocentesis and drainage were performed. In 3 cases severe intra-abdominal bleeding occurred with 1 requiring laparotomy and hemostasis, whereas in the others laparoscopic drainage and hemostasis were sufficient. Ruptured endometriotic cystic masses caused acute abdomen in 2 patients; partial oophorectomy and drainage were essential operative procedures. We conclude that although severe postovum retrieval complications are rare, one has to be aware of their occurrence with the aim of accurate diagnosis and prompt intervention.
OBJECTIVE: To examine the outcome of treatment with IVF-ET of women with polycystic ovarian syndrome (PCOS) who failed to conceive on conventional treatment. DESIGN: Retrospective analysis with an age-matched control group. SETTING: University hospital infertility clinic and IVF unit. PATIENTS. INTERVENTIONS: Sixty-eight women with PCOS who had failed to conceive on treatment with clomiphene citrate and during six ovulatory cycles on gonadotropins underwent 208 cycles of IVF-ET. An age-matched group of 68 women with a tubal mechanical factor who received 143 treatment cycles during the same period served as controls. MAIN OUTCOME MEASURES: Cumulative conception rates, the cumulative livebirth rates, and IVF-ET data were compared between the two groups. Results of treatment with and without GnRH agonist (GnRH-a) within the groups were also compared. RESULTS: A comparison of PCOS and mechanical factor (control) groups showed almost identical results at 6 months for cumulative conception rate (82% versus 85%) and cumulative livebirth rate (69% versus 65%). Significantly more oocytes were retrieved but a smaller percentage fertilized in PCOS, and the pregnancy rate per ET did not differ between the two groups (23% versus 26%). Treatment with GnRH-a and gonadotropins as opposed to gonadotropins alone improved the cumulative conception rate, miscarriage rate, and cumulative livebirth rate in the PCOS but not in the control group and improved fertilization rates in both groups. CONCLUSIONS: For patients with PCOS who fail to conceive with gonadotropin treatment, IVF-ET is a successful treatment alternative, producing results equal to those for women with a mechanical tubal factor. Better results were achieved with GnRH-a in women with PCOS but made no difference to those with a mechanical tubal factor compared with treatment with gonadotropins alone.
This study was designed to investigate concurrently the psychological and hormonal changes at three critical points during in vitro fertilization (IVF) treatment. One hundred thirteen couples suffering from mechanical and unexplained infertility participated in the study and 23 of them conceived. Psychological evaluation included background questionnaires, Lubin's Depression Adjective Check List, and Spielberger's State Trait Anxiety inventory. Cortisol and prolactin levels were estimated by radioimmunoassay. The results showed that patients' anxiety and depression scores were significantly higher than the population norm. Psychological test scores and hormonal levels showed a similar pattern of change, increasing on oocyte retrieval day, decreasing on embryo transfer day, and rising again on pregnancy test day. Differences between these phases were generally significant. Differences in parameters' means between conceiving (C) and nonconceiving (NC) women were generally not significant. However, correlations between psychological measures and hormonal levels showed a clear disparity between C and NC women in the last phase. Whereas significant negative correlations were found in C patients, no relationship was found in NC patients. The findings suggest that success in IVF treatment may depend, in part, on differential modes of coping with anxiety and depression, involving hormonal or endorphin mediation.
Human interleukin-3-like activity (IL-3-LA), a factor possessing similar characteristics to interleukin-3 and having clony stimulating factor (CSF) activity, has recently been defined. In the present study, IL-3-LA levels in the sera of women before and after delivery were examined. The results indicate a significant increase in IL-3-LA levels in women before delivery as compared to IL-3-LA levels after delivery or to non-pregnant healthy women. The ability of mononuclear cells from women before and after delivery to produce IL-3-LA was similar to that of mononuclear cells from cord blood. In addition, the effect of progesterone on in vitro IL-3-LA production was examined and a stimulatory dose-dependent effect was observed. These observations point to the hypothesis that during pregnancy IL-3-LA levels are modulated by progesterone. With placental loss, the IL-3-LA in the sera decreases, although the mononuclear cells previously affected by the hormone continue to produce cytokines.
OBJECTIVE: To examine the relationship between endometriosis and preclinical abortions and to evaluate the effect of gonadotropin-releasing hormone analogue (GnRH-a) therapy on these pregnancies. DESIGN AND PATIENTS: Of 67 women with severe endometriosis referred to us for in vitro fertilization-embryo transfer (IVF-ET), 32 underwent ovarian stimulation for oocyte retrieval with menotropins (protocol A), whereas the other 35 were admitted for the procedure after a 6-month period of hormonal suppression with a GnRH agonist (protocol B). The clinical impact of the preclinical and clinical pregnancies in both treatment protocols were evaluated on the basis of oocyte classification and embryo quality score. SETTING: All patients were treated in our IVF Unit. MAIN OUTCOME MEASURE: Clinical pregnancy was used as our main outcome measure of success. RESULTS: A significantly higher number of preclinical pregnancies (P less than 0.0001) occurred in patients treated by protocol A. After GnRH-a treatment, the preclinical pregnancy rate declined significantly (P less than 0.0001), whereas the clinical pregnancy rate per cycle and per transfer rose significantly (P less than 0.0001 and P less than 0.0001, respectively). Furthermore, clinical pregnancies had a significantly better mean embryo quality score in comparison with preclinical pregnancies (P less than 0.0001). CONCLUSIONS: It is concluded that combining GnRH-a therapy before IVF-ET provides an improved treatment modality for preclinical abortions and infertility associated with severe endometriosis.
Five IDD patients achieved strict preconception glycemic control and then underwent nine IVF-ET cycles. All patients had high E2 response with an adequate number of preovulatory oocytes retrieved and normal fertilization and cleavage rates; one conceived. Follicular fluid analysis revealed similar E2, P, A, hCG, PRL, and IGF-I levels to non-IDD controls. The source of the insulin detected in the FF of IDD patients was probably from the insulin doses administered intensively during the tight diabetes management; insulin was absent in non-IDD participants. It seems that patients with IDD have conventional responses to gonadotropin stimulation for IVF and their follicular milieu resembles that of non-IDD patients. Nevertheless, in view of the significant advantages of preconceptional diabetes control in regard to pregnancy outcome, they should be allowed to participate in IVF programs only after tight preconception metabolic control has been obtained.
One hundred ten women with normal initial hysteroscopy who failed to conceive during three or more IVF-ET cycles underwent repeat hysteroscopic evaluation. In 20 patients (18.2%), visualization revealed uterine abnormalities, mainly newly added endometrial lesions, i.e., hyperplasia, polyps, endometritis, and synechiae. Our results indicate that repeat hysteroscopic evaluation, in cases of recurrent IVF-ET failure, is an important adjunctive method for further evaluating and possibly optimizing the IVF-ET procedure.
Frozen thawed semen has been associated with reduced semen quality and as a result diminished pregnancy rates. In vitro fertilization (IVF) can supply the true measure of the functional fertilizing capacity of fresh versus frozen-thawed semen. One hundred and six patients in an IVF program who underwent donor insemination were divided into two groups. Group I included 51 women in whom initial insemination with donor fresh or frozen semen was performed. They were compared to 65 group II women in whom late insemination with donor fresh or frozen semen was performed after initial insemination with husband semen had failed to fertilize the eggs. There was no statistically significant difference between groups I and II on initial insemination; however, statistically significant difference in fertilization (P less than 0.006) and pregnancy rates (P less than 0.001) between the two groups were achieved when late insemination was carried out. Consequently, we prefer initial insemination with frozen-thawed donor semen in cases indicated.
Preincubation of oocytes aspirated from follicles in IVF-ET programs is a controversial approach. While some investigators recommend this technique others doubt its necessity. We have studied the embryo quality in 100 women, undergoing IVF-ET, in whom ovulation was induced by the combination of GnRH agonists (GnRHa) and menotropins and compared to a control group in whom ovulation was induced with menotropins alone. No statistically significant difference was noted with regard to the fertilization and cleavage rates as well as to the preincubation period. Significantly higher pregnancy rates (P less than 0.001) were encountered in the first group in comparison with the control group.
Sixty-nine women were treated with a long-acting gonadotropin-releasing hormone analogue (GnRHa), D-Trp-6-LH-RH (DTRP6) 3.2 mg (Decapeptyl, Ferring, Kiel, F.R.G.) prior to induction of ovulation for in vitro fertilization (IVF) with human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories, Inc., Randolph MA). Three types of response were noted: Group I (18 patients) responded between days 1-3 of the treatment; Group II (30 patients) responded between days 4-6 of the therapy, and Group III (21 patients) responded after 7 days of treatment. Although a higher number of oocytes were encountered in Group I than in the latter two groups fertilization and clinical pregnancy rates were lower than in Group II (P less than 0.05), respectively, but higher than in Group III (P less than 0.07 and P less than 0.01), respectively. The best results were achieved by Group II patients, while Group III seemed to represent low responders as the number of embryos and pregnancy rate were significantly lower than in the other two groups. It seems that the level of ovarian suppression achieved by GnRH analogue results in a period of refraction of the ovary, and its duration has most probably an effect upon the results of the IVF cycles.
The present studies were performed to establish the effects of the size and number of artificial holes produced in the zona pellucida (ZP) on hatching and trophoblast outgrowth in vitro. Limited partial zona dissection (PZD) produced small, narrow incisions, and zona drilling with acidic Tyrode's (AT) across a larger area in the ZP was used to produce bigger round holes. Some embryos were micromanipulated once; others were micromanipulated several times. Blastocysts hatched preferentially through the artificial gaps, but completion of hatching was dependent on the size of the hole. Only 16% (26/167) of PZD embryos migrating through narrow holes hatched completely; the remainder were trapped in a typical figure-eight shape. Seventy-two percent (43/60) of those migrating through larger PZD holes hatched, but trophoblast outgrowth was not observed. Significantly (P less than 0.001) more AT-blastocysts hatched (248/270; 92%) and showed trophoblast outgrowth (176/248; 70%). Simultaneous hatching through several openings was rarely observed in AT-embryos (14/167; 8%), but this did occur in 36% (73/201) of the PZD embryos. Trapping of PZD-embryos could be almost entirely avoided by drilling with AT elsewhere on the ZP. Embryos with multiple holes in their zonae preferentially hatched through the largest opening. The results suggest that the ability of microsurgically treated human embryos to fully hatch in vitro, should be carefully (re)assessed prior to application of clinical micromanipulation systems. Micromanipulated embryos with small holes in their zonae may be rescued by performing an additional more aggressive opening procedure elsewhere on the ZP.
The influence of women's age on the results of in vitro fertilization (IVF) was analyzed in 1801 women undergoing the procedure. Advancing age was found to be related to significant reduced success rates from an average of 30.1% per transfer below the age of 36 years to 15.9% per transfer at 37 years or more (P less than 0.001). The decrease was related to a reduction in oocyte production (five at 25 years or less, four below the age of 40 years, three at 40 years or more, and two in the 43 to 47-year group) and probably due to reduced implantation. It is concluded that a woman's age must be considered an important prognostic factor when IVF is suggested.
The occurrence and incidence of early pregnancy wastage in an in vitro fertilization and embryo transfer (IVF-ET) program have been studied in 750 patients. In 297 (39.6%) a pregnancy was diagnosed; of these, 14.8% were biochemical and 24.8% clinical pregnancies. In the latter group 23.6% aborted, while 75.8% had clinical ongoing pregnancies. The mean embryo quality score of the biochemical pregnancy group was similar to that of the clinical ongoing pregnancy group but statistically different from that of the clinical abortion group (P less than 0.005). Furthermore, the clinical ongoing pregnancy rate in women with previous biochemical pregnancy was 24.7%, a significantly higher percentage compared to clinical ongoing pregnancies achieved in IVF-ET cycles (P less than 0.05). It is possible that biochemical pregnancy does not represent an index for infertility but rather an intact stage of reproduction leading toward implantation. The high clinical pregnancy rate in subsequent cycles may probably serve as an encouraging sign or a marker for future clinical pregnancy.
Controversy still exists concerning the optimal treatment of endometriomata in endometriosis and its related infertility. Forty-one women with endometriomata who failed to conceive during previous in vitro fertilization and embryo transfer (IVF-ET) cycles (protocol A) were readmitted for ovum pickup following transvaginal ultrasonic needle-guided aspiration of the endometriomata (protocol B). Following aspiration a significantly higher number of oocytes was recovered (P less than 0.0006); subsequently, more embryos were transferred, and significantly higher clinical pregnancy rates per cycle (P less than 0.0001) were achieved. This difference may be directly related to the reduction of extensive ectopic endometrial tissue (endometriomata) with improved ovarian response, follicular accessibility, and, most probably, improved oocyte quality.
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