Isaac Kligman

Differentiating clinical profiles: predicting good responders, poor responders, and hyperresponders

OBJECTIVE To describe the different clinical and laboratory diagnostic methods (basal and dynamic tests) available to identify poor-, good-, and high-responder patients undergoing treatment with in vitro fertilization (IVF). DESIGN Analytical review. SETTING IVF program. PATIENTS Women in different age groups undergoing IVF treatment. INTERVENTION(S) Assessment of clinical and laboratory parameters and correlation with outcomes. MAIN OUTCOME MEASURE(S) Response to ovarian stimulation and success of the assisted reproductive technologies (ART). RESULT(S) Age, basal follicle-stimulating hormone (FSH), estradiol and inhibin-B levels, and dynamic testing serve to predict individual response to ovarian stimulation for ART. CONCLUSION(S) Markers of ovarian reserve (day 3 FSH, inhibin B and E(2)) are particularly predictive and useful in guiding the choice of the optimal protocol for ART. However, no tests are absolutely predictive of a successful outcome. For the younger individual, and for the patient at risk of developing ovarian hyperstimulation syndrome (OHSS), assessment and identification of clinical and laboratory parameters predictive of a high response to ovarian stimulation should guide the clinician in choosing an appropriate stimulation protocol, thus attenuating the risk of OHSS.

Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome

OBJECTIVE To evaluate the outcomes of IVF and the incidence of ovarian hyperstimulation syndrome (OHSS) after discontinuing gonadotropin therapy in patients at risk of developing OHSS by delaying hCG administration until a drop in serum E2 levels was observed. DESIGN Retrospective study. SETTING IVF program at a university center. INTERVENTIONS Gonadotropin administration was withheld in 22 patients (group 1) when their serum E2 level was > or = 3,000 pg/mL (conversion factor to SI unit, 3.671). Patients continued GnRH analogue injections daily, and hCG was administered when serum E2 levels dropped to < or = 3,000 pg/mL. Outcomes were compared with 26 patients (group 2) in whom embryo transfer was canceled and all embryos cryopreserved for transfer during a subsequent unstimulated cycle. MAIN OUTCOME MEASURES Outcomes of IVF and incidence of OHSS were compared in both groups of patients. In group 1, follicular and hormonal parameters before and after the coasting interval were compared in pregnant versus nonpregnant patients. In addition, serum hormonal profiles were evaluated daily during the coasting period to determine the effects of gonadotropin withdrawal. RESULTS Although the mean number of oocytes retrieved was significantly higher in group 2, fertilization rates, miscarriage rates, delivery rates/stimulation cycle, and the incidence of OHSS did not differ significantly between the two groups. CONCLUSION Withholding gonadotropin administration is an effective alternative to prevent the development of severe OHSS in a high-risk population. Although the risk of cancellation cannot be completely eliminated, this strategy can provide a high pregnancy rate without the need to repeat multiple frozen-thawed cycles.

In vitro fertilization versus tubal surgery: is pelvic reconstructive surgery obsolete?

OBJECTIVE To compare the results of pelvic reconstructive surgery with cumulative success rates of IVF for couples with tubal factor infertility. DATA RESOURCES Outcomes of pelvic surgery were obtained from a review of articles from the literature identified by directed Medline searches. Cumulative pregnancy rates of 771 couples with tubal factor infertility treated at the Cornell IVF program between December 1989 and December 1992 were calculated by life-table analysis. RESULTS Overall delivery rate per transfer for patients with tubal factor was 28.9% (303 deliveries per 1,048 transfers) and did not appear to be affected significantly by the presence of a secondary diagnosis. A significant decline in pregnancy rates was observed with advancing age: age < 30 years, 48.4%; 30 to 34 years, 44%; 35 to 38 years, 28%; 39 to 40 years, 20%; 41 to 42 years, 9%; and > 42 years, 4.3%. Cumulative pregnancy rates for cycles 1 to 4 were 32%, 59%, 70%, and 77%, respectively, in patients with only tubal factor, and 28%, 55%, 62%, and 75% in patients with tubal combined with other associated infertility factors. CONCLUSIONS Our experience suggest that > 70% of women with tubal factor infertility will have a live birth within four cycles of treatment with IVF. These results compare favorably with the best outcomes after tubal reconstructive surgery. In older women, because of the rapid decline of fertility potential with advancing age, efforts should be directed toward the treatment method that provides the highest likelihood of success within the shortest time interval.

Preimplantation genetic diagnosis of human congenital heart malformation and Holt-Oram syndrome.

Holt–Oram syndrome (HOS) is a multiple malformation syndrome associated with congenital heart malformation (CHM) and caused by mutations in the TBX5 transcription factor. Effective prenatal genetic diagnosis of HOS is limited by factors that modify clinical manifestations and confound prediction of an individuals phenotype. Although preimplantation genetic diagnosis (PGD) has been applied to complex disorders with some cardiovascular manifestations, its utility in Mendelian CHM has not been previously demonstrated. We tested whether PGD and in vitro fertilization (IVF) technology, including oocyte donation, can identify fertilized eggs affected by HOS for potential embryo selection. Five donor oocytes were fertilized in vitro with sperm from a HOS patient heterozygous for a Glu69ter‐TBX5 mutation and then underwent embryo biopsy and genotyping. One carried the Glu69ter‐TBX5 mutation; all others had wildtype genotypes. Two wildtype blastocysts were transferred to the mother, and the resulting singleton pregnancy was successfully delivered. Mutational analysis of fetal amniocytes and postpartum umbilical cord blood confirmed PGD. Fetal ultrasonography as well as postpartum electrocardiography and echocardiography also validated accurate prediction of normal skeletal and cardiac phenotypes. We conclude that PGD is an effective reproductive strategy for HOS patients. As more genetic etiologies for CHM are identified, application of PGD as adjunctive therapy to IVF will be increasingly available to prevent transmission of such diseases from affected parents to their children. Clinical application of PGD must balance the benefits of avoiding disease transmission with the medical risks and financial burdens of IVF.

Heterotopic cervical pregnancy successfully treated with transvaginal ultrasound-guided aspiration and cervical-stay sutures.

OBJECTIVE To present a case of a heterotopic cervical pregnancy successfully treated with transvaginal ultrasound-guided aspiration and cervical-stay sutures. DESIGN Case report. SETTING Tertiary academic IVF program. PATIENT(S) A 35-year-old woman who conceived from IVF-ET treatment at 5.5 weeks of gestation. INTERVENTION(S) Transvaginal ultrasound-guided aspiration of the cervical pregnancy followed by cervical-stay sutures to control hemorrhage after aspiration. MAIN OUTCOME MEASURE(S) Recovery of the patient, preservation of the intrauterine pregnancy, and sequelae. RESULTS(S) The cervical pregnancy was successfully aborted, and the intrauterine pregnancy progressed to term. CONCLUSION(S) Transvaginal ultrasound-guided aspiration in combination with hemostatic cervical-stay sutures can be safely used to manage heterotopic cervical pregnancies.

An Analysis of the Effect of Age on Implantation Rates

AbstractPurpose: To evaluate implantation rate as a function of age. Methods: A total of 1621 consecutive cycles of IVF wereevaluated for implantation as a function of age at The NewYork Hospital/Cornell Medical Center. Results: An overall implantation rate of 23.3% (1328/5691)was found. The implantation rate as a function of agedecreased in a nonlinear fashion. Implantation remainedconstant until the age of 35 and then decreased in a significantly,linear fashion by 2.77% per year (P < 0.001, R2 =0.975). A formula to predict implantation rates for a givenage was developed: Implantation rate = −119.352 + (9.985× Age − (0.164 × Age2)). Conclusions: We have demonstrated that implantation ratesremain constant until the age of 35 at which time a lineardecrease of 2.77% per year is observed.

Immune Recognition of the 60kD Heat Shock Protein: Implications for Subsequent Fertility

The 60kD heat shock protein (hsp60) is a highly conserved protein and a dominant antigen of most pathogenic bacteria. In some women, chronic or repeated upper genital tract infections with Chlamydia trachomatis, and possibly with other microorganisms, induces immune sensitization to epitopes of hsp60 that are present in both the microbial and human hsp60. Once a woman becomes sensitized to these conserved epitpes, any subsequent induction of human or bacterial hsp60 expression will reactivate hsp60-sensitized lymphocytes and initiate a pro-inflammatory immune response. Hsp60 is expressed during the early stages of pregnancy, by both the embryo and the maternal decidua. We examined, therefore, whether women who were sensitized to hsp60 experienced less successful pregnancy outcomes compared to women who were not sensitized to this antigen. In women undergoing in vitro fertilization (IVF), the presence of cervical IgA antibodies reactive with the C. trachomatis hsp60 correlated with implantation failure after embryo transfer. Further analysis revealed that an immunodominant epitope for these IgA antibodies was an hsp60 epitope shared between C. trachomatis and man. In subsequent studies of women not undergoing IVF, cervical IgA antibodies to the human hsp60 were identified in 13 of 91 reproductive age women. This antibody was most prevalent in those women with a history of primary infertility (p = 0.003). In addition, cervical anti-hsp60 IgA correlated with the detection of the pro-inflammatory cytokines interferon-γ (p = 0.001) and tumor necrosis factor-α (p = 0.02) in the cervix. Conversely, women with proven fertility had the highest prevalence of the anti-inflammatory cytokine, interleukin 10, in their cervices (p = 0.001). In an analysis of serum samples in a third study, women with a history of two or more consecutive first trimester spontaneous abortions had a higher prevalence (p = 0.01) of IgG antibodies to the human hsp60 (36.8%) than did age matched fertile women (11.1%) or women with primary infertility (11.8%). Immune sensitization to epitopes expressed by the human hsp60 may reduce the probability of a successful pregnancy outcome due to reactivation of hsp60-reactive lymphocytes, induction of a pro-inflammatory cytokine response and interference with early embryo development and/or implantation.

Massive deep vein thrombosis in a patient with antithrombin III deficiency undergoing ovarian stimulation for in vitro fertilization

OBJECTIVE To present the first report of a thromboembolic complication in early pregnancy after ovarian hyperstimulation for IVF in a patient with AT III deficiency who was treated successfully and subsequently delivered a healthy male infant at 32 weeks of gestation. DESIGN Case report. SETTING Hospital-based clinic for reproductive medicine. PATIENT A 28-year-old woman who consulted our IVF clinic with a 3.5-year history of primary infertility. INTERVENTIONS Intravenous heparin therapy. RESULTS The patient responded adequately to heparin therapy and was discharged home on SC heparin. A primary cesarean section was performed at 32 weeks of gestation because of poor fetal growth and transverse lie. CONCLUSIONS We stress the importance of obtaining a thorough personal and family history before initiation of ovarian hyperstimulation. Measuring activity of AT III, protein C, and protein S in patients with a suspicious history of thromboembolic episodes occurring at an early age may lead to the implementation of appropriate prophylactic measures, preventing potentially life-threatening complications.

Ureaplasma urealyticum and Mycoplasma hominis detected by the polymerase chain reaction in the cervices of women undergoing in vitro fertilization : prevalence and consequences

PurposeThe prevalence of Ureaplasma urealyticumand Mycoplasma hominisin the endocervix at the time of oocyte collection in women undergoing in vitrofertilization (IVF) was examined using the polymerase chain reaction (PCR).MethodsAll women were treated with tetracycline following sample collection.ResultsU. urealyticumwas identified in 56 (17.2%) of 326 women while M. hominiswas present in only 5 (2.1%) of 235 women. U. urealyticumwas detected at a higher frequency (P =0.01) in those women whose IVF cycle failed prior to embryo transfer. This organism was present in 8 of 19 (42.1%) women with either no fertilization or no embryo transfer, 19 of 148 (12.8%) who had no evidence of pregnancy following embryo transfer, 6 of 30 (20,0%) who had only a transient (biochemical) pregnancy, 5 of 14 (35.7%) with a spontaneous abortion, and 18 of 115 (15.6%) with a term birth. Of the eight women with U. urealyticumwho had no embryos transferred, male factor was the cause of infertility in five cases, two women had tubal occlusions while in one woman the diagnosis was idiopathic. Therefore, poor sperm quality, and not a U. urealyticuminfection, might explain the failure of most of these cases to proceed to the stage of embryo transfer. Analysis of all patients revealed no association between male factor infertility and U. urealyticumin the cervix.ConclusionsU. urealyticum,but not M. hominis,is present in the cervices of many culture-negative women. Its presence, however, does not influence IVF outcome subsequent to embryo transfer in women treated with tetracycline after oocyte retrieval.

Stimulation of the young poor responder: comparison of the luteal estradiol/gonadotropin-releasing hormone antagonist priming protocol versus oral contraceptive microdose leuprolide.

OBJECTIVE To evaluate in vitro fertilization (IVF) cycle outcomes in young poor responders treated with a luteal estradiol/gonadotropin-releasing hormone antagonist (E(2)/ANT) protocol versus an oral contraceptive pill microdose leuprolide protocol (OCP-MDL). DESIGN Retrospective cohort. SETTING Academic practice. PATIENT(S) Poor responders: 186 women, aged <35 years undergoing IVF with either E(2)/ANT or OCP-MDL protocols. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Clinical pregnancies, oocytes retrieved, cancellation rate. RESULT(S) Patients in the E(2)/ANT group had a greater gonadotropin requirement (71.9 ± 22.2 vs. 57.6 ± 25.7) and lower E(2) level (1,178.6 ± 668 vs. 1,627 ± 889), yet achieved similar numbers of oocytes retrieved and fertilized, and a greater number of embryos transferred (2.3 ± 0.9 vs. 2.0 ± 1.1) with a better mean grade (2.14 ± .06 vs. 2.7 ± 1.8) compared with the OCP/MDL group. The E2/ANT group exhibited a trend toward improved implantation rates (30.5% vs. 21.1%) and ongoing pregnancy rates per started cycle: 44 out of 117 (37%) versus 17 out of 69 (25%). CONCLUSION(S) Poor responders aged <35 years may be treated with the aggressive E(2)/ANT protocol to improve cycle outcomes. Both protocols remain viable options for this group. Adequately powered, randomized clinical comparison appears justified.