Alan Dudkiewicz

The association of antithyroid antibodies in euthyroid nonpregnant women with recurrent first trimester abortions in the next pregnancy

OBJECTIVE To evaluate the prognostic value of antithyroid antibodies in euthyroid women with a history of recurrent first trimester abortions on future pregnancy loss. DESIGN The sera of 42 euthyroid women with a history of three or more consecutive first trimester abortions were evaluated for the presence of antibodies to thyroglobulin and thyroid peroxidase before pregnancy and again as soon as the diagnosis of pregnancy was made. SETTING Medical school-affiliated private infertility center. PATIENTS Forty-two women with a history of three or more consecutive first trimester abortions who were planning to conceive again. MAIN OUTCOME MEASURE The presence of antithyroid antibodies in the nonpregnant state and their association with pregnancy loss in the next gestation. RESULTS Thirteen of 42 women (31%) were positive for the presence of antithyroid antibodies at the initial screening before pregnancy. All 13 maintained positivity by the time their next pregnancy was diagnosed. Only 12 of those 42 women (29%) experienced a first trimester abortion. Eight of these 12 women (67%) were positive for one or more antithyroid antibody. In contrast, among 30 nonaborting women, only 5 of 30 (17%) exhibited thyroid antibody positivity. The detection of thyroid antibodies before conception carried an increased risk of pregnancy loss in the next pregnancy (8 of 13, 62% versus 4 of 29, 14%). CONCLUSION The presence of antithyroid antibodies in nonpregnant women with a history of recurrent abortion identifies a subgroup of women at significantly increased risk for yet another pregnancy loss in their next gestation. Because organ-specific autoantibodies thus demonstrate similar prognostic significance to nonorgan-specific autoantibodies, it is tempting to conclude that peripheral autoantibody abnormalities seen in habitual aborters only reflect an underlying T-lymphocyte defect, which may be the actual cause of pregnancy loss.

Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.

OBJECTIVES The purpose of our study was to evaluate the incidence of antithyroid antibodies and non-organ-specific antibodies in women who have had three or more recurrent spontaneous abortions. STUDY DESIGN Sera from 45 women for the presence of antithyroid antibodies to thyroglobulin and thyroid peroxide and for the non-organ-specific autoantibodies to 6 phospholipids, 5 histones, and 4 polynucleotides were analyzed. Sera from 100 apparently health blood donors served as controls. RESULTS The test results of 14 (31%) of 45 study subjects were positive for one or both antithyroid antibodies compared with 19 (19%) of controls. Five (11%) of 45 patients had positive test results for one or more non-organ-specific antibodies, and 4 (8%) of 45 had positive test results for the lupus anticoagulant by either activated partial thromboplastin, tissue thromboplastin time, or both. Only 3 (21%) of 14 subjects whose test results were positive for thyroid antibodies also demonstrated non-organ-specific autoantibodies. COMMENTS The incidence of antithyroid antibodies in women who have had recurrent abortions appears not to be significantly increased compared with a normal random control population. Antithyroid antibodies do occur, however, with significantly greater frequencies in women with recurrent spontaneous abortions than non-organ-specific autoantibodies (p = 0.02). Organ-specific and non-organ-specific autoantibodies may serve as independent markers of risk for repeated pregnancy loss in patient populations where pregnancy loss is associated with abnormal autoimmune function.

Clinical significance of β2-glycoprotein I-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: Correlation with conventional antiphospholipid antibody detection systems

OBJECTIVE Our purpose was to determine whether beta 2-glycoprotein I-dependent anticardiolipin antibodies may represent a superior marker of reproductive risk than do conventional antiphospholipid antibodies. STUDY DESIGN The incidence of beta 2-glycoprotein I-dependent and beta 2-glycoprotein I-independent anticardiolipin antibodies and of six conventional antiphospholipid antibodies was statistically compared between study groups with and without autoantibody-associated features of reproductive failure. Sera from 356 women were randomly selected from the frozen sera bank at the Center for Human Reproduction, Chicago. They included sera from 259 patients with autoantibody-associated features of reproductive failure such as unexplained infertility, endometriosis, and repeated pregnancy loss and 97 infertile controls. Autoantibody levels by a modified enzyme-linked immunosorbent assay for beta 2-glycoprotein I-dependent and beta 2-glycoprotein I-independent anticardiolipin antibodies and a standard enzyme-linked immunosorbent assay for anticardiolipin antibody and five other antiphospholipid antibodies were then compared. RESULTS Patients demonstrated a significantly higher incidence of beta 2-glycoprotein I-dependent anticardiolipin antibodies (5.4%) than did controls (0%) in a modified enzyme-linked immunosorbent assay (p = 0.01). No such difference was, however, noted for beta 2-glycoprotein I-independent anticardiolipin antibodies or any one of six antiphospholipid antibodies. Two or more among six antiphospholipid antibodies, especially if involving anticardiolipin antibodies, antiphosphatidylserine and antiphosphatidylinositol, as assayed by standard enzyme-linked immunosorbent assay, were significantly more often (p = 0.02) positive in the patients (5.0%) than in the controls (0%). Moreover, positivity in two of those three antiphospholipid antibodies correlated in 59% of cases to positivity in the beta 2-glycoprotein I-dependent anticardiolipin antibody. CONCLUSIONS As a single test beta 2-glycoprotein I-dependent anticardiolipin antibody appears to be superior to cofactor-independent anticardiolipin antibody or any other single conventional antiphospholipid antibody for the detection of autoantibody-associated conditions of reproductive failure. A broadly based panel of conventional antiphospholipid antibodies, especially if inclusive of anticardiolipid antibody, antiphosphatidylserine, and antiphosphatidylinositol, may, however, achieve similar results.

WHAT DO WE REALLY KNOW ABOUT AUTOANTIBODY ABNORMALITIES AND REPRODUCTIVE FAILURE: A CRITICAL REVIEW

CONDENSATION The diagnosis and treatment of autoantibody-associated forms of reproductive failure is critically reviewed. OBJECTIVE To critically evaluate the published literature in reference to autoantibody-associated forms of reproductive failure. LOCATION Medical School-affiliated private Infertility Center. MATERIALS A review of over 200 published papers reflecting on the topic. RESULTS Autoantibody associated reproductive failure, characterized by a decrease in fecundity and an increase in the risk of pregnancy loss, appears established. Autoantibody abnormalities, as routinely detected by standard laboratory assays, are, however, neither immunologically nor biologically specific since cross reactivities between autoantibodies are frequent and a specific autoantibody may cause a biological effect in one but not in another affected individual. CONCLUSIONS The evaluation of autoantibody abnormalities in all cases of suspected autoimmune-associated reproductive failure is valuable and will improve clinical care of affected patients. Clinicians need, however, to recognize the limitations of autoantibody testing and have to adjust their clinical management to the degree and quality of autoantibody evaluation available to them in their community.

Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success

OBJECTIVE Our aim was to determine the predictive value of autoantibody and immunoglobulin determinations as indicators of the success of in vitro fertilization. STUDY DESIGN This was a blinded study in which laboratory evaluations were performed on coded samples obtained from another institution. Codes were broken and data were analyzed after results of all laboratory tests had been reported out. One hundred five infertility patients who had undergone in vitro fertilization were randomly chosen. Among those, 46 were considered low responders (six or fewer oocytes were retrieved) and 59 as high responders (13 to 30 oocytes were retrieved). Total immunoglobulin G, M, and A levels and 15 autoantibody levels (6 antiphospholipids, 5 antihistones, and 4 antipolynucleotides) were determined separately for immunoglobulin G, immunoglobulin M, and immunoglobulin A isotypes. RESULTS High and low responders demonstrated an unusual incidence of autoantibody (25% and 30%, respectively) and immunoglobulin (46% and 48%, respectively) abnormalities. They did not differ from each other, however, in either immunoglobulin or autoantibody parameters. Autoantibody and immunoglobulin abnormalities alone or in combination did not predict pregnancy success (24% vs 16%), incidence of chemical pregnancies (15% vs 24%), or clinical pregnancy loss (9% vs 11%) when such women were compared with those without either abnormality. However, the occurrence of hypergammaglobulinemias, in contrast to hypogammaglobulinemias, was associated with a significant decrease in the clinical pregnancy rate (6% vs 24%, p = 0.05). CONCLUSIONS Neither autoantibody abnormalities nor total immunoglobulin abnormalities allow differentiation between high and low responders in in vitro fertilization cycles. The presence of autoantibody and total immunoglobulin abnormalities also does not predict low clinical pregnancy rates. Within a group of women with immunoglobulin abnormalities, those with hypergammaglobulinemias appear, however, at significant risk for low pregnancy rates with in vitro fertilization. This observation suggests that high total immunoglobulin levels may serve as a marker for an as yet to be determined immunologic factor that adversely affects the chance of conception. The evaluation of total immunoglobulin levels may be indicated as part of a routine infertility workup.

Intrauterine inseminations with washed human spermatozoa

The success of intrauterine inseminations with washed human spermatozoa was evaluated in four groups of patients. The first two groups were couples in whom either the man or the woman had detectable circulating sperm-agglutinating antibodies. The third group included couples where the woman exhibited hostile or absent cervical mucus, whereas the fourth group represented couples with oligozoospermic males. The couples underwent 3.7 +/- 2.1 insemination cycles, with a 30% overall pregnancy rate for all four groups. Intrauterine inseminations of women with hostile cervical mucus yielded a 68% conception rate. Couples with either male or female serum sperm-agglutinating antibodies showed 25% and 40% pregnancy rates, respectively. However, none of the couples with oligozoospermic males achieved pregnancy. Intrauterine inseminations with washed human spermatozoa thus represent a satisfactory method of achieving pregnancy in women with hostile cervical mucus and in couples with circulating sperm agglutinating antibodies. Couples in whom oligozoospermia has been identified as the principal cause of infertility do not seem to benefit from this therapy.

Ovarian stimulation protocol for in vitro fertilization with gonadotropin-releasing hormone agonist widens the implantation window*†

Pregnancy rates vary considerably with the type of ovarian stimulation used for in vitro fertilization and embryo transfer (IVF-ET). The window of implantation may represent one of the rate-limiting steps in IVF success. We therefore investigated estimated implantation times of 10 consecutive IVF singleton pregnancies, achieved using pituitary suppression with gonadotropin-releasing hormone agonist (GnRH-a) before and during ovarian stimulation with human menopausal gonadotropins (hMG), and compared those with 9 consecutive IVF pregnancies achieved by hMG stimulation only. Estimated implantation times were calculated by regression analysis of serial human chorionic gonadotropin (hCG) measurements between days 7 and 16 after ET. The GnRH-a/hMG pregnancies implanted between days 7 and 11, whereas hMG pregnancies implanted between days 7 and 9 after ET. The hCG regression curve for the GnRH-a/hMG pregnancies revealed a delay of 1.5 days in estimated implantation time compared with the hMG only group. There were no significant differences in pretransfer in vitro embryos development between the two groups. Thus, the delay in hCG rise probably reflects a delay in embryo implantation. We therefore conclude that a GnRH-a/hMG stimulation protocol appears to widen the implantation window in comparison with a hMG only protocol. This observation may at least in part explain the improved IVF pregnancy success with GnRH-a/hMG stimulation protocols.

Octreotide is not useful for clomiphene citrate resistance in patients with polycystic ovary syndrome but may reduce the likelihood of ovarian hyperstimulation syndrome

OBJECTIVE To determine whether octreotide is effective for ovulation induction in patients with polycystic ovary syndrome (PCOS) and clomiphene citrate resistance or for reduction of the risk of ovarian hyperstimulation syndrome (OHSS) with gonadotropin therapy. DESIGN Prospective, double-blind, placebo-controlled, crossover trial. SETTING Private infertility practice. PATIENT(S) Twelve patients with PCOS undergoing therapy for infertility. INTERVENTION(S) The patients were assigned randomly to receive either octreotide or placebo. Those with clomiphene citrate-resistant PCOS received clomiphene citrate, 150 mg. Patients at risk for the development of OHSS received urinary FSH for ovulation induction. MAIN OUTCOME MEASURE(S) Ovulation, pregnancy, the development of OHSS, and levels of fasting insulin, insulin-like growth factor 1, insulin-like growth factor binding proteins 1 and 3, testosterone, androstenedione, DHEAS, E2, LH, and FSH. RESULT(S) Octreotide significantly reduced levels of fasting insulin, insulin-like growth factor 1, and LH in both clomiphene citrate- and urinary FSH-stimulated cycles. Levels of insulin-like growth factor binding protein 3 were increased. Two of six clomiphene citrate-stimulated cycles reached ovulation with the use of either octreotide or placebo. In urinary FSH-stimulated cycles, patients who received octreotide had significantly lower E2 levels at the time of hCG administration and fewer mature follicles. No cases of OHSS occurred in either group. One pregnancy occurred in each group. CONCLUSION(S) Octreotide was no more effective than placebo for clomiphene citrate resistance in patients with PCOS, but it did reduce E2 levels and follicle numbers when combined with urinary FSH. Thus, octreotide may reduce the incidence of OHSS in patients with PCOS.

A managed care provider's approach toward mandated infertility coverage: The Illinois Family Building Act

In January of 1992 a new state law, the so-called Family Building Act (House Bill 1470, Public Act 87-681) took effect in Illinois. This law provided most Illinois citizens with comprehensive mandated infertility treatment coverage. Insurance companies were obligated to provide infertility coverage inclusive of up to four cycles of assisted reproductive technology (ART) that reached oocyte retrieval, such as in vitro fertilization (IVF), for any first child and up to two such cycles after a live birth. Excluded from this mandate was the state itself, in that recipients of public assistance did not receive such coverage. Religious organizations were given the option not to provide such coverage to their employees, as were companies with less than 25 employees or companies that were self-insured. Also not covered by the mandate were Illinois citizens whose medical insurance was bought out of state. The law thus covered a majority of individuals employed and/or living in Illinois, but excluded by different estimates between 25% and 40% of couples who were in their reproductive years and otherwise might have benefited from the mandate. Up to 1993, infertility coverage in Illinois was unregulated. Most insurance plans offered coverage

Effect of Ejaculation Frequency on Sperm Quality

Sixty-four normozoospermic and 19 oligozoospermic males underwent sperm analyses of two successive specimens obtained at 1-, 2-, and 3-day intervals. The first specimen was produced after 3 days of abstinence. Sperm volume of normozoospermic males declined from 2.3 +/- 1.0 to 1.6 +/- 1.0 ml, 2.6 +/- 1.0 to 2.0 +/- 0.9 ml, and 2.1 +/- 0.9 to 1.9 +/- 1.0 ml at 1-, 2-, and 3-day intervals, respectively. Similarly, oligozoospermic males showed declines from 2.3 +/- 1.2 to 1.7 +/- 1.5 and 2.3 +/- 1.1 to 1.8 +/- 1.2 and an increase from 1.2 +/- 1.2 to 1.5 +/- 0.7 ml, respectively. Sperm counts of normozoospermic males declined from 65 +/- 54 to 55 +/- 34, 83 +/- 57 to 69 +/- 47, and 97 +/- 51 to 81 +/- 46 million spermatozoa/ml at 1-, 2-, and 3-day intervals, respectively. Oligozoospermic males showed declines from 5.1 +/- 5.4 to 3.8 +/- 4.1 and 8.2 +/- 8.6 to 7.2 +/- 5.2 and an increase from 3.8 +/- 0.6 to 5.7 +/- 2.1 million spermatozoal/ml at 1-, 2-, and 3-day intervals, respectively. Sperm motility of normozoospermic males varied from 41 +/- 20 to 38 +/- 18, 55 +/- 14 to 56 1/3 pm 14, and 52 +/- 15 to 52 +/- 20% at 1-, 2-, and 3-day intervals, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)