The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization.

PROBLEM: The effect of mini-dose heparin/aspirin (H/A) alone vs. combined intravenous immunoglobulin G (IVIg) and H/A on in vitro fertilization (IVF) birthrates in women who test seropositive for antiphospholipid antibodies (APA+) was evaluated, as was the question of whether outcome is influenced by the gammaglobulin isotype(s) or the phospholipid (PL) epitope(s) to which the APAs are directed. METHOD OF STUDY: A case-control study was conducted in three phases, spanning a 4-year period, in a multicenter clinical research environment. Six hundred eighty-seven APA+ women, who were younger than 40 years and who each, completed up to three consecutive IVF/embryo transfer cycles within a 12-month period, were given either H/A alone or H/A in combination with IVIg. Birthrates relative to the type of immunotherapy (i.e., H/A alone and H/A with IVIg) and APA profile were the main outcome measurements. RESULTS: In phase I, 687 women who tested APA+ to one or more PL epitopes underwent two or fewer IVF attempts for a total of 1050 IVF cycles. Four hundred seventy-seven (46%) births occurred in 923 IVF cycles in which H/A alone was administered. Twenty-two (17%) births occurred after 127 IVF cycles in which H/A was not administered. In phase II, 322 of 687 women tested positive for a single APA subtype. These subjects underwent up to two consecutive IVF attempts for a total of 521 IVF cycles while receiving H/A alone. The birthrate was significantly lower for women whose APAs were directed toward phosphatidylethanolamine (PE) or phosphatidylserine (PS) involving IgG or IgM isotypes than for women who had any other APA (17% vs. 43%). In phase III, 121 women who did not achieve live births after two consecutive IVF attempts in which H/A alone was administered received IVIg in combination with H/A during their third consecutive IVF cycle. The birth rate was 41% after these IVF cycles when anti-PS or anti-PE involving IgG or IgM isotypes were present, as compared with 17% when H/A alone was administered. The IVF outcome did not improve when IVIg was administered in association with any other single APA. CONCLUSIONS: The treatment of APA+ women with H/A alone improves IVF birthrates. This benefit is selective in that it does not apply in cases in which IgG- or IgM-related APAs are directed against PE or PS. In such cases, the addition of IVIg significantly improves the outcome.

A rational basis for the use of combined heparin/aspirin and IVIG immunotherapy in the treatment of recurrent IVF failure associated with antiphospholipid antibodies.

PROBLEMS: 1) Does the administration of heparin and aspirin (H/A) in combination with intravenous immunoglobulin G (IVIG) improve in vitro fertilization (IVF) implantation and birth rates in patients with recurrent IVF failure? 2) Is the effect of such treatment related to the antiphospholipid antibody (APA) status of the patients concerned? METHOD OF STUDY: Subjects consisted of 89 women younger than 36 years of age whose infertility was a result of causes other than male infertility and who had experienced four or more failed IVF/embryo transfer procedures. Fifty-two women were APA+ (group A), and 37 were APA- (group B). All patients, regardless of their APA status, received H/A (5000 U sq bid), aspirin (81 mg po qd) from the inception of menotropin therapy along with IVIG (20 g) through a single infusion 3 to 10 days before egg retrieval. RESULTS: Twenty-two (42%) of group A and 7 (19%) of group B patients achieved live births (P = 0.020). CONCLUSIONS: IVF outcome is significantly improved when H/A and IVIG are administered to APA+ women with repeat IVF failures. APA- women do not seem to benefit from such treatment.

The use of combined heparin/aspirin and immunoglobulin G therapy in the treatment of in vitro fertilization patients with antithyroid antibodies.

PROBLEM: To compare the effect of heparin/aspirin therapy alone vs. heparin/aspirin in combination with intravenous immuno-globulin (IVIg) immunotherapy on in vitro fertilization (IVF) outcome of patients who test positive for antithyroid antibodies (ATAs). METHOD OF STUDY: Eighty-two women younger than 40 years of age whose infertility was related exclusively to female causes were evaluated. All tested positive for organ-specific antithyroid antibodies (antimicrosomal and/or antithyroglobulin antibodies), but negative for antiphospholipid antibodies. Thirty-seven of these women (group A) received H/A alone, whereas 45 (group B) received heparin/aspirin in combination with IVIg. RESULTS: Ten (27%) of women in group A and 23 (51%) of women in group B achieved live births after completion of a single IVF/embryo transfer cycle (P = 0.027). CONCLUSION: We conclude that IVIg therapy significantly improves IVF success rates in ATA+ women.

Infertility treatment in women over 40 years of age.

Women experience a sharp decline in fecundity after the age of 40. Most research points to decreasing oocyte competency and ovarian function as the main causes of this downward trend. Aggressive treatment with in vitro fertilization, laboratory techniques that improve the implantation ability of embryos, and ovum donation can help many of these women achieve healthy pregnancies. Such medical advances are accompanied by new ethical challenges.

'Prolonged coasting': an effective method for preventing severe ovarian hyperstimulation syndrome in patients undergoing in-vitro fertilization.

Over a 4 year period ending 1 January 1995, 51 women scheduled for in-vitro fertilization (IVF) and embryo transfer were inadvertently severely overstimulated with menotrophins, as evidenced by the development of > 29 ovarian follicles in association with peak plasma oestradiol concentrations of > 6000 pg/ml. Accordingly, these women were at great risk of developing life-endangering complications associated with severe ovarian hyperstimulation syndrome (OHSS). Treatment involved withholding the administration of both menotrophins and human chorionic gonadotrophin for a number of days, while continuing gonadotrophin-releasing hormone agonist until the plasma oestradiol concentration fell to < 3000 pg/ml ('prolonged coasting'). The mean number of oocytes retrieved was 21.0, while the mean number of embryos transferred per procedure was 5.4. There were 21 clinical pregnancies (i.e. pregnancy rate of 41% per oocyte retrieval), 19 of which resulted in live births (i.e. a live birth rate of 37% per oocyte retrieval). Two pregnancies miscarried and there were four multiple gestations (three sets of twins and one set of triplets). None of the women developed severe OHSS. Prolonged coasting is an effective method of preventing the occurrence of severe OHSS without necessitating the cancellation of the IVF cycle or compromising success rates.

A mucin-like glycoprotein identified by MAG (mouse ascites Golgi) antibodies. Menstrual cycle-dependent localization in human endometrium.

Human endometrial glands synthesize and secrete a high molecular weight mucin-like glycoprotein in a menstrual cycle-dependent fashion. A novel moiety within this Golgi-associated glycoprotein is strongly reactive with IgG antibodies in numerous murine ascites, and has been termed MAG (mouse ascites Golgi). Immunohistochemical staining of 201 endometrial biopsies revealed the following patterns: MAG first appeared in the Golgi on cycle day 5, peaked on day 15, was present on the surface of the luminal epithelium between days 17 and 19, and was no longer detectable after day 19. MAG was also present in cervical, prostate, seminal vesicle, and lacrimal glands, pancreatic acinar cells, gall bladder and bile duct epithelium, and certain cells of the salivary and sweat glands. Interestingly, only tissues from blood group A individuals exhibited this staining. As a common link among all these cell types is the expression of mucins, we speculated that the MAG epitope could be a mucin-associated blood group A-related epitope. This hypothesis was tested by absorption experiments with a variety of glycoconjugates and erythrocytes and by immunoblots of MAG-rich material. The absorption studies demonstrated that only type III porcine mucin (< 1% sialic acid) and blood type A or AB erythrocytes were able to absorb the anti-MAG antibody. Inasmuch as N-acetyl-galactosamine alone, the terminal blood group A carbohydrate, did not block MAG antibody binding, the MAG epitope appears to involve N-acetylgalactosamine plus other determinants. Immunoblots of endometrial extracts and saliva from blood type A individuals revealed MAG-reactive material with a molecular weight > 200 kd under reducing conditions. Because the MAG epitope appears on the endometrial surface during the purported implantation window, we speculate that mucin-like epitopes could play a role in the earliest apposition phases of conceptus-endometrial interaction.

Subacute bacterial endocarditis with polyarthritis mimicking thrombotic thrombocytopenic purpura: a case report.

Thrombotic thrombocytopenic purpura (TTP) is a serious multisystem disorder that is usually rapidly progressive and often fatal if not diagnosed or treated. Unfortunately, the clinical and laboratory features of TTP are not specific and can also be seen in both autoimmune and infectious diseases. We describe a case where the rapid institution of therapy for a TTP-like syndrome masked a culture-negative infectious endocarditis. The diagnosis of this unique patient was established at valvulotomy, necessitated by acute aortic insufficiency.

High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin.

This study was undertaken to explore whether intervention with heparin and aspirin (H/A) in selected patients undergoing in-vitro fertilization (IVF) and embryo transfer could improve fecundity rates. Specifically, it explored the possibility that women diagnosed with organic pelvic disease who demonstrated antiphospholipid antibodies (APA) could benefit from H/A administration in a similar manner to that used in patients with recurrent pregnancy loss. We used an enzyme-linked immunosorbent assay for six different phospholipids to identify patients who expressed APA before they underwent IVF/embryo transfer. This study was confined to the first IVF/embryo transfer cycle that followed assessment of APA status and accordingly, the number of IVF/embryo transfer cycles corresponds with the number of patients treated. APA seropositive patients were treated with aspirin, 81 mg orally q.d., and heparin 5000 IU s.c. b.i.d., beginning on day 1 of controlled ovarian stimulation. The endpoint for success was a live birth or an ultrasound confirming fetal cardiac activity (a viable pregnancy). The prevalence of APA in patients diagnosed with organic pelvic disease (53%) was much higher than in those without female pathology (14%). The administration of H/A to APA seropositive patients significantly (P < 0.05) improved the viable pregnancy rate (49%) compared to the untreated APA seropositive group (16%). The viable pregnancy rate for APA seropositive women treated with H/A was also significantly (P < 0.001) higher than for untreated APA seronegative patients (27%). We conclude that all women undergoing IVF/embryo transfer should be tested for APA prior to initiating ovarian stimulation and those with APA seropositivity should be treated with H/A.

High fecundity rates in donor oocyte recipients and in-vitro fertilization surrogates using parenteral oestradiol valerate.

Ovum donation and in-vitro fertilization (IVF) surrogacy can help couples with difficult infertility problems achieve pregnancy. Most centres using oral oestrogens and oestradiol patches report pregnancy rates in the range of 30% per cycle. Parenteral oestradiol valerate has pharmacological properties that make it an attractive option for preparing the endometrium in the recipients undergoing these procedures. When the egg providers were under age 35 years, and using oestradiol valerate in the recipients, we achieved a 61% clinical pregnancy rate in 62 cycles. These improved results suggest that parenteral oestradiol valerate should be used to prepare the endometrium in recipients, and that the hormonal milieu of the endometrium plays an important role in the higher implantation rates obtainable in ovum donor and IVF surrogate cycles.

Eliminating the risk of life-endangering complications following overstimulation with menotropin fertility agents: a report on women undergoing in vitro fertilization and embryo transfer.

OBJECTIVE: To evaluate a new method for preventing the life-endangering complications associated with inadvertent menotropin-induced severe ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS: Seventeen women each underwent a single cycle of controlled ovarian hyperstimulation with menotropins in preparation for IVF-ET. The indications for IVF-ET were tubal occlusion in nine, endometriosis in six, and unexplained infertility in two. The peak plasma estradiol (E2) concentration before hCG administration was greater than 6000 pg/mL and more than 30 ovarian follicles were detected by transvaginal ultrasound. Thus, life-endangering complications associated with severe ovarian hyperstimulation syndrome were highly likely to occur following hCG administration. Rather than cancel the cycle of treatment, menotropin therapy was discontinued and hCG administration was deferred for a number of days until the plasma E2 concentration fell below 3000 pg/mL ("prolonged coasting"), whereupon hCG was administered and egg retrievals and ETs were duly performed. RESULTS: None of the women developed severe ovarian hyperstimulation syndrome. There were six viable pregnancies (35.2%), which proceeded normally. CONCLUSION: This study indicates that "prolonged coasting" prevents severe ovarian hyperstimulation syndrome in severely overstimulated women undergoing IVF-ET, without necessitating cycle cancellation.

Central nervous system herpesvirus infection in systemic lupus erythematosus: diagnosis by endoretinal biopsy.

A 31-year-old woman with systemic lupus erythematosus (SLE) developed meningoencephalitis, followed by transverse myelitis. The clinical picture was otherwise not consistent with a lupus flare. Extensive diagnostic evaluation was unrevealing. Acute visual loss ensued, associated with an unusual pattern of retinitis. Endoretinal biopsy established the diagnosis of herpesvirus infection. Reinstitution of antiviral therapy, and optic nerve sheath decompression, led to resolution of neurologic deficits and partial return of vision. Our report is the first that describes a patient with SLE with herpes meningoencephalitis, transverse myelitis, and rapidly progressive outer retinal necrosis, diagnosed antemortem by endoretinal biopsy, and successfully treated with acyclovir and optic nerve fenestration.

Management of suboptimal sonographic endometrial patterns in patients undergoing in-vitro fertilization and embryo transfer.

A total of 816 women who underwent 1332 cycles of ovarian stimulation for in-vitro fertilization and embryo transfer (IVF/ET) had sonographic assessments of the endometrium within 2 days of oocyte retrieval. Endometrial linings were classified on the basis of thickness and echogenicity, using a grading system described previously. Grades I and IIB ('poor') were associated with a 6% viable pregnancy rate (advanced beyond 12 weeks' gestation) compared with a 29% rate for Grade IIA ('optimal'). In a subset of 112 women with poor endometrial linings during natural cycles, eight out of 21 women (38%) under 40 years of age developed optimal linings following ovarian stimulation with menotrophins, while 19 out of 91 women (21%) aged 41-45 years converted to optimal linings. Twenty-two out of 47 women (44%) who failed to develop optimal endometrial linings following ovarian stimulation converted to Grade IIA during subsequent cycles of exogenous oestrogen replacement. The financial, emotional, and physical burden associated with IVF/ET demands that patients with poor endometrial linings following ovarian stimulation with menotrophins be counselled with regard to either cancelling their cycles of treatment, or having their embryos cryopreserved for transfer to the uterus during a subsequent hormonal replacement cycle.

Systemic herpetic infection diagnosed by retinal biopsy.

We describe a patient with systemic lupus erythematosus who developed myelopathy, optic neuropathy, retinopathy, and aseptic meningitis unresponsive to immunosuppressive and antimicrobial therapy. Although cultures and brain biopsy were unrevealing, a Herpes virus was suggested by retinal biopsy. The patient recovered dramatically after institution of acyclovir therapy and optic-nerve-sheath decompression. This case demonstrates that herpetic retinitis can occur in an iatrogenically suppressed host and underscores the value of tissue diagnosis.

The use of two-component fibrin sealant for embryo transfer.

This is a report of our preliminary experience using fibrin sealant with a series of 38 patients undergoing IVF and ET. We used a two-component fibrin sealant to create a fibrin plug in the uterine cavity at the time of ET to decrease the possibility of embryo expulsion and also ectopic pregnancy. Our preliminary report proves that it is possible to obtain 26% pregnancies using this two-component biological glue instead of serum or culture medium for uterine embryo replacement. A prospective randomized study will be undertaken to evaluate whether the use of fibrin sealant could significantly improve IVF and ET results.