Plasmapheresis with intravenous immunoglobulin G is effective in patients with elevated panel reactive antibody prior to cardiac transplantation.

BACKGROUND: Patients with a PRA >10% are considered to be at greater risk for the development of not only acute cellular and humoral rejection but also increased mortality when compared to nonsensitized patients following transplantation. All patients with a PRA >10% at our institution are treated with plasmapheresis and intravenous immunoglobulin G immediately prior to cardiac transplantation. METHODS: Sixteen (Group 1) of 118 patients awaiting cardiac transplantation were found to be sensitized. These patients underwent plasmapheresis followed by 20 gm of intravenous immunoglobulin G (IVIG) immediately prior to cardiac transplantation. Group 1 was compared to the remaining 102 patients with a PRA <10% (Group 2). RESULTS: Despite more patients in Group 1 having a positive crossmatch, pulmonary hypertension, and requiring mechanical circulatory support, there was no statistically significant difference in length of stay or mortality at a mean follow-up of 21.6+/-15.0 months. There was no difference in the occurrence of mild, moderate or severe cellular rejection or humoral rejection in these sensitized patients when compared to Group 2. CONCLUSIONS: Pretransplant plasmapheresis followed by intravenous immunoglobulin G may be an effective therapy that obviates the need for a prospective crossmatch and allows sensitized patients to undergo cardiac transplantation. There is no increase in the post transplant length of stay, occurrence of rejection or short term mortality. Long term follow up is necessary to evaluate whether there is a difference in the development of late rejection, transplant vasculopathy and survival.

Analysis of risk factors for the development of bronchiolitis obliterans syndrome.

Chronic rejection after lung transplantation, manifesting as bronchiolitis obliterans syndrome (BOS), has become the dominant challenge to long-term patient and graft survival. In order to elucidate risk factors for development of BOS we utilized the 1995 revision of the working formulation for the classification of lung allograft rejection (), and devised a quantitative method to retrospectively study lung transplant biopsies from all patients who survived at least 90 d. All transbronchial biopsies were regraded 0 to 4 for acute perivascular rejection and lymphocytic bronchitis/bronchiolitis (LBB), and the grades were totaled over a period of time to give two scores, respectively, for each patient. Also examined were timing of acute rejection and LBB episodes and decreased immunosuppression defined as two or more cyclosporine A levels < 200 ng/ml. Sixty-six patients with BOS and 68 with no BOS (NBOS) satisfied our criteria for inclusion in the study. Demographics including age, sex, and primary diagnoses were similar. The mean perivascular score for BOS was 6.2 over a mean follow-up of 822 d (range, 113 to 2,146) compared with 3.2 for NBOS over 550 d (range, 97 to 1,734) mean follow-up. Airway scores were 5.3 and 1.7, respectively, for the same follow-up periods. There was no correlation between length of follow-up and rejection or LBB scores, although mean length of follow-up for the two groups was significantly different. Late acute rejection and LBB were significantly associated with BOS as was decreased immunosuppression. In addition to perivascular rejection, LBB, late acute rejection, and decreased immunosuppression are significant risk factors for the development of BOS. Analysis of the current data leads us to believe that LBB, in the absence of infection, is in fact a manifestation of acute rejection, with similar implications for graft function as acute perivascular rejection.

A phase II trial of interleukin-2 in myelodysplastic syndromes.

Patients with myelodysplastic syndromes (MDS) show a decrease in the number and function of natural killer (NK) cells, including lymphokine activated killer (LAK) cell activity. Interleukin-2 (IL-2) stimulates the proliferation and activity of these lymphocytes. Anecdotal clinical experience has shown haematological and cytogenetic improvement in myelodysplasia by low-dose IL-2 treatment. A total of 10 patients with MDS were treated with 1 million units of IL-2 subcutaneously daily for 12 weeks. Even though improvement in CD16+/CD56+ cell numbers was seen in a majority of the patients, the haematological status and transfusion requirements remained unchanged. There was minimal toxicity from this therapy.

Plasmapheresis followed by intravenous immunoglobulin in presensitized patients awaiting thoracic organ transplantation.

Four highly sensitized patients awaiting thoracic organ transplantation were treated immediately preceding transplantation with 1 plasmapheresis and infusion of high dose intravenous immunoglobulin (IVIG). All 4 underwent successful surgery and have had minor to no rejection episodes over a range from 5 1/2 to 12 months. All panel reactive antibodies (PRA) were dithiotheitol (DTT) resistant, and 1 patient had IgG specific alloantibodies to a donor alloantigen. All 4 patients had positive donor cross matches prior to transplantation, and 3 of the 4 patients remained PRA negative for up to 9 months after allografting. Possible mechanisms of this therapy include inhibition of proliferating alloreactive B cells or suppression by antiidiotypic antibodies. Further study is warranted.

Immunomodulatory effect of beta-carotene on T lymphocyte subsets in patients with resected colonic polyps and cancer.

Results from a number of studies suggest that beta-carotene-containing foods prevent the initiation or progression of various cancers. One possible mechanism for this effect could be enhancement of the immune response. The aim of this study was to determine whether beta-carotene modulates T lymphocyte subsets in patients affected with colonic polyps or cancerous lesions. Patients with previous adenomatous colonic polyps (n = 18) or colon cancers (n = 19) were randomized to receive placebo or beta-carotene (30 mg/day) for three months. Percentages of T lymphocyte subsets were determined using flow cytometry in blood samples collected before randomization and at three months. T lymphocyte subsets of 14 normal control subjects were also determined for comparison. Initially, there was no difference in total leukocyte counts, percentage of lymphocytes, and various subsets of lymphocytes among the three groups, although in cancer patients there was a lower percentage of CD4 and interleukin-2 (IL-2) receptor-positive (IL-2R+) cells than in patients with polyps and in controls. After supplementation with beta-carotene, a significant increase in IL-2R+ T lymphocytes (from 12.7 +/- 3.0% to 26.0 +/- 1.9%) and CD4+ lymphocytes (from 40.9 +/- 3.1% to 45.6 +/- 3.2%) was seen only in the cancer patients. These percentages remained unchanged in patients with adenomatous polyps receiving placebo or beta-carotene. We concluded that beta-carotene increased the number of IL-2R+ T lymphocytes and CD4+ lymphocytes, which in turn may produce IL-2 only in patients with cancer who may already have some deficiency in their immune system. This increase in activated T lymphocytes may mediate cytotoxic reactions to cancer cells via cytokine production.

Polyclonal lymphoid tumor of the choroid plexus presenting as an intraventricular mass in a young gorilla.

An unusual lymphoid lesion with reactive germinal centers, occurring in the choroid plexus of a young gorilla, is reported. It presented as a large mass in the lateral ventricle with hydrocephalus and neurological symptoms. A work-up did not reveal any underlying cause for this lesion. No similar lesion of the choroid plexus has been reported in either human or veterinary literature. Histological work-up, including flow cytometry, gene rearrangement studies and T and B cell markers, favored the lesion being a non-neoplastic lymphoid proliferation of unknown etiology. The prognosis is unknown, although, following complete removal, the animal is well and free of tumor at the time of this report.

Characterization of postcardiac transplant lymphomas. Histology, immunophenotyping, immunohistochemistry, and gene rearrangement.

OBJECTIVE: Between 2% and 9% of cardiac transplant recipients develop posttransplant lymphoproliferative disease, which includes lymphomas. These are usually aggressive Epstein-Barr virus-associated B-cell proliferations similar to those seen in other immunodeficiency states. A retrospective pathologic study of the tumor tissue from 21 cardiac transplant recipients with posttransplant lymphoproliferative disease was undertaken. DESIGN: Tumor histology, immunohistochemistry, immunophenotyping, and DNA analysis for clonal gene rearrangement and the presence of Epstein-Barr virus DNA were performed. PATIENTS: The mean patient age was 53.4 +/- 10.2 years (range 33-67 years); 33% of the patients were alive at the time of study. RESULTS: Histologically, the samples comprised one Burkitt's lymphoma, three diffuse mixed lymphomas, eight diffuse large-cell lymphomas, and nine immunoblastic lymphomas. Thirteen (93%) of 14 samples were infiltrated by small reactive T cells; five of the lymphomas qualified as T-cell rich. Of 14 cases studied, 12 had clonal immunoglobulin gene rearrangements, 1 had oligoclonal bands, and 1 exhibited only a germline pattern. The B cells were CD10+, CD19+, and CD20+, and the reactive T cells were CD2+, CD3+, CD5+, CD7+, CD8+, and CD57+ by immunophenotyping. CONCLUSIONS: In this patient series, morphologically aggressive lymphomas and disseminated disease occurred early as well as late after transplantation. Most of the tumors showed a reactive T-cell component, which may represent a host attempt at controlling the B-cell proliferation.

Prepregnancy weight and antepartum insulin secretion predict glucose tolerance five years after gestational diabetes mellitus.

OBJECTIVE: To identify phenotypic, genotypic, and metabolic parameters measured at the time of antepartum diagnosis of gestational diabetes mellitus that can indicate the risk of diabetes mellitus at early postpartum (< or = 6 mo after delivery) and at a 5-yr follow-up. RESEARCH DESIGN AND METHODS: The recommendations from the National Diabetes Data Group and International Workshop Conferences on Gestational Diabetes Mellitus were used for screening, diagnosing, and subclassifying gestational diabetes mellitus. National Diabetes Data Group criteria were also used for classification of glucose tolerance postpartum. Plasma glucose, insulin, and free fatty acids were measured after an overnight fast. Plasma glucose and insulin were measured 15, 30, 60, 120, and 180 min after the 100-g oral glucose load. Postpartum glucose tolerance was evaluated at 3-6 mo (early), 1 yr, and annually thereafter. RESULTS: The 5-yr cumulative incidence of diabetes during follow-up after gestational diabetes mellitus was nearly 50%. Among those who had diabetes within 5 yr, a history of diabetes in only the mother was nearly threefold more common than a history of diabetes in only the father (30 vs. 11%, P < 0.01). Those who displayed diabetes at early postpartum (< or = 6 mo) testing had significantly higher antepartum glucose levels at 60, 120, and 180 min compared with those whose early postpartum results were normal. They were also relatively insulinopenic at antepartum testing. Their fasting, acutely stimulated (15 and 30 min), and integrated 3-h response to oral glucose were all significantly lower relative to women who remained normal or had impaired glucose tolerance at early postpartum testing. Women who developed diabetes between 6 mo and 5 yr postpartum were more obese before the index pregnancy, and they had lower fasting, acutely stimulated (15 and 30 min), and integrated (1-3 h) insulin levels compared with women who remained normal or displayed impaired glucose tolerance at 5 yr postpartum. A multiple logistic regression model showed that diabetes present at early postpartum testing was independently associated with higher 2-h glucose and lower basal and total integrated insulin level. Later (> or = 6 mo-5 yr postpartum) development of diabetes was independently associated with prepregnancy weight and impaired insulin secretion at diagnosis of gestational diabetes mellitus. CONCLUSIONS: Impaired beta-cell function and obesity at diagnosis of GDM were associated with the development of diabetes during a 5-yr, follow-up period. Studies designed to prevent diabetes in this high-risk group should examine strategies to maintain both optimal beta-cell function and maximum insulin sensitivity.

HLA-DR incompatibility predicts heart transplant rejection independent of immunosuppressive prophylaxis.

To determine whether immunosuppressive prophylaxis reduces the effect of HLA-DR incompatibility on rejection, we compared clinical and immunologic variables of patients given horse antithymocyte globulin, OKT3, or no immunosuppressive prophylaxis. Median follow-up was 27 months. Groups were similar in race; preoperative HLA reactivity; ABO matching; number of HLA-A, -B, -C, and -DR mismatches; and rejection severity. Patients given immunosuppressive prophylaxis were younger (p = 0.04), had a greater frequency of preoperative ischemic disease (p = 0.03), and had a higher 6-month rejection rate (p = 0.02). A highly significant association was found between the number of mismatches at the HLA-DR locus and rejection severity (p = 0.005). Within the OKT3-based immunosuppressive prophylaxis group and the no immunosuppressive prophylaxis group a significant association was found between the number of HLA-DR mismatches and rejection severity (p = 0.01 and p = 0.009, respectively). A similar trend was identified in the group given horse antithymocyte globulin-based immunosuppressive prophylaxis. Logistic regression, used to identify independent predictors of rejection, showed that the number of HLA-DR mismatches and not the use or type of immunosuppressive prophylaxis is significantly associated with rejection (p = 0.0009). One-year patient survival was 83% in the group with two HLA-DR mismatches and 85% in the group with one or no HLA-DR mismatch. Thus the lower rejection rates in patients with one or no HLA-DR mismatch were not associated with a 1-year survival, which was better than that of patients with two HLA-DR mismatches. The potential benefit of HLA-DR matching on rejection and patient survival must be confirmed by larger prospective studies.

Role of humoral immunity in acute cardiac allograft dysfunction.

To elucidate the pathogenic mechanisms of acute allograft dysfunction that is not caused by acute cellular rejection, we have studied the clinical and immunopathologic characteristics of 11 heart transplant recipients who had acute allograft dysfunction in the absence of interstitial mononuclear cell infiltrates on endomyocardial biopsy samples. Six of eleven patients (54%) had a striking increase in levels of anti-HLA antibodies in close temporal proximity with the episode of acute allograft dysfunction. Cardiac allograft function improved in all patients with intensification of immunosuppression.

Hand mirror variant of adult acute lymphoblastic leukemia. Evidence for a mixed leukemia.

Blast cells from a female patient with acute lymphoblastic leukemia-hand mirror variant were examined using various techniques, including light and ultrastructural morphologic examination, cytochemical analysis, surface antigen characterization, cytogenetic analysis, and gene rearrangement studies. The blast cells were found to be pre-B cells (CD19+ and Tdt+) that also expressed the myeloid antigens CD13 and CD33 and demonstrated a heavy chain immunoglobulin gene rearrangement. Cytogenetic studies revealed a t(11;19) translocation previously described in biphenotypic leukemias. A subset of acute lymphoblastic leukemia-hand mirror cells has been previously defined and includes predominately female patients with an indolent course. The authors' findings place this case, a mixed leukemia, within that subgroup. The possibility of mixed lineage should be considered in future cases of hand mirror variants of adult acute lymphoblastic leukemia. Furthermore, hand mirror morphologic features in any case of acute leukemia should alert the hematopathologist/hematologist to the possibility of mixed lineage.

Acute leukemia and related entities. Impact of new technology.

Twenty-seven cases of acute leukemia and related entities were evaluated by morphologic examination, cytochemical study, terminal deoxynucleotidyltransferase study, immunophenotyping, cytogenetic analysis, ultrastructural cytochemical study, and gene rearrangement analysis to determine the impact on the determination of the French-American-British (FAB) classification and the definitive diagnosis. The definitive diagnosis contained prognostic, diagnostic, and treatment information beyond the FAB classification that affected the disease course and patient management. All diagnostic variables were evaluated in each case and were labeled essential, ambivalent, supportive, or noncontributory. Except for gene rearrangement analysis, all variables we studied contributed essential data to establish the definitive diagnosis. Ambivalent findings were rare but could be explained with the knowledge of the total data. All variables, except cytochemical study, whose results were almost always essential, contributed supportive data. Noncontributory data only occurred with cytogenetic analysis in cases that demonstrated normal karyotypes. The FAB classification was established in 20 (74%) of the cases by use of morphologic examination, cytochemical study, and terminal deoxynucleotidyltransferase study. With use of the same variables, however, the definitive diagnosis, whose determination required all data, was established in only 15 (55.5%) of the cases. The addition of immunophenotyping increased the definitive diagnosis to 25 (92.5%) of the cases. The use of ultrastructural myeloperoxidase and platelet peroxidase analysis enabled us to definitively diagnose the remaining two cases (27 cases [100%]). Cytogenetic analysis revealed four cases in which essential information was added to the diagnosis. However, because the cytogenetic information usually was not immediately available, the result did not affect the immediate diagnosis or treatment. Surprisingly, the gene rearrangement studies did not yield essential data in any case and in a few cases contributed ambivalent data. This finding should not exclude gene rearrangement analysis in selected cases; however, the data should always be interpreted in light of all clinical and laboratory findings. This study clearly demonstrates the importance of a multifaceted approach to the understanding of the acute leukemias and related entities and shows the impact of newer technologies on reaching a definitive diagnosis.

Lymphoblastic crisis of chronic myelogenous leukemia. Hand mirror variant.

We present, to our knowledge, the first extensively studied case of lymphoid L2 blast crisis of chronic myelogenous leukemia with a hand mirror cell (HMC) variant. Special stains revealed the leukemic cells to be terminal deoxynucleotidyl transferase positive by immunofluorescence and cytochemically positive for alpha-naphthyl acetate esterase and acid phosphatase (diffuse granular). Immunophenotyping identified the major leukemic cell population as B-cells that expressed CD10+, CD19+, and HLA-DR+. It was not possible to separate the HMC and the non-HMC leukemic population by gating various cell populations, dual staining, cytochemistry, or by terminal deoxynucleotidyl transferase. Gene rearrangements were observed in both Ig heavy-chain alleles and one T-cell antigen receptor gamma-subunit allele. The rearrangements occupied all of the cells, indicating that the HMC and non-HMC were of a common clonal origin. The patient had a mosaic karyotype, with 90% of the cells having t(9;22), t(8;14), and t(9;15) translocations, an additional chromosome 8, and deleted chromosomes 9 and 15. Antibodies to simian sarcoma-associated virus and baboon endogenous virus were isolated in the patient's peripheral blood plasma.

Prospective randomized trial of OKT3- versus horse antithymocyte globulin-based immunosuppressive prophylaxis in heart transplantation.

To compare monoclonal anti-T3-receptor antibody (OKT3) and horse antithymocyte globulin (HATG) immunoprophylaxis, 23 heart transplant recipients were randomized to OKT3 (N = 12) 5 mg IV x 14 days of HATG (N = 11) 5 mg/kg IV x 10 days and followed up for 216 +/- 137 days receiving triple immunosuppression. Recipient groups were demographically and clinically similar. First rejection occurred later in OKT3 recipients vs HATG recipients (31.7 +/- 18.3 vs 15.1 +/- 2.3 days; p less than 0.01), but the first rejection necessitating intensified immunosuppression occurred at similar times (30.9 +/- 14.6 vs 21.9 +/- 10.2 days; NS). Phenotypic characterization of peripheral blood lymphocytes by flow cytometry revealed that OKT3 and HATG recipients had similar decreases in total T lymphocytes and lymphocyte subpopulations. During the follow-up period rejection rates in the OKT3- and in the HATG-treated patients were 3.4 +/- 2.7 and 5.9 +/- 4.7, respectively (NS). The number of rejection episodes per recipient treated with intensified immunosuppression was 1.4 +/- 1.2 in the OKT3- and 2.0 +/- 3.1 in the HATG-treated patients (NS). Infection rates were 4.9 +/- 5.2 in the OKT3- and 2.7 +/- 1.7 in the HATG-treated patients (NS). The number of infection episodes that necessitated intravenous antimicrobial therapy was 2.7 +/- 2.3 in the OKT3- and 1.6 +/- 1.3 in the HATG-treated recipients (NS). The number and length of hospitalizations were similar in patients given OKT3-based or HATG-based immunoprophylaxis. We conclude that immunosuppressive prophylaxis with OKT3 vs HATG in heart transplant recipients is associated with a slightly lower incidence and severity of rejection and slightly higher infection rates.

Donor-specific transfusions. Donor-recipient HLA compatibility, recipient HLA haplotype, and antibody production.

HLA profiles of 25 donor-specific transfusion (DST) kidney donor-recipient pairs were analyzed for HLA antigen compatibility. Serum samples collected during and after DST were tested for cytotoxic antibodies against T and B lymphocytes of the donors and 30 normal individuals. Eleven recipients did not produce cytotoxic antibodies to the antigens of their DST donors, and eight produced cold and/or warm, broadly reactive B-cell antibodies. Six patients (24%) produced HLA-A, B, C, and/or DR antibodies. Three of these individuals produced antibodies after two immunizations, while others required three immunizations. Three of the 11 antibody nonproducers (17%) had not received previous transfusions, as compared to three of the eight antibody producers (43%). Comparison of HLA profiles revealed 22 percent of the HLA-A, B, DR identities between the transfusion donor and recipient in antibody nonproducers as compared to 9 percent of the HLA-A, B, DR identities in antibody producers. The HLA-A2, B40, DR4 haplotype and HLA-DRW6 antigen were more common among antibody producers than among nonproducers, who had an excess of the HLA-B8, DR3 haplotype. These results are consistent with the hypothesis that there may be high- and low-responder HLA haplotypes that control immunologic responsiveness to histocompatibility antigens.

Prenatal effects of maternal-fetal HLA compatibility.

Both retrospective studies of idiopathic aborters, as well as prospective studies of normal couples, have shown reduced fertility among couples sharing HLA antigens. However, the effects of maternal-fetal histocompatibility on surviving embryos are largely univestigated. We thus prospectively studied 53 healthy, fertile women whose timed pregnancies were verified within 21 days of conception. Maternal-fetal histocompatibility status was determined for HLA-A,-B, and -DR locus antigens. Fetal growth rates were monitored by ultrasound at 8, 12, and 20 weeks gestation. Neonates were weighed, measured (birthlength, chest circumference, head circumference), and examined within 72 h of delivery (116 major and minor anomalies) in standardized fashion by one of two geneticists. Although no significant differences were found between infants compatible and incompatible at the HLA-A or HLA-B locus, significant differences were observed between HLA-DR compatible and incompatible infants for sex ratios (p less than .003) and minor anomaly rates (p less than .05). Although differences in mean birthweights between HLA-DR compatible and incompatible infants were not significant in this sample, HLA-DR compatible infants were on average 200 grams smaller than HLA-DR incompatible infants. We interpret these findings as evidence for selection against histocompatible fetuses throughout gestation, particularly with respect to HLA-DR compatibility. Potential immunologic and genetic mechanisms are discussed.

Lymphocyte subpopulation profiles and mitogen kinetics in immunological deficiency testing.

The correlation between lymphocyte proliferative responses to mitogens and T4/T8 ratios was analyzed in a cross section of patients who either were in a high-risk group for HTLV-III infection or fulfilled clinical criteria for acquired immune deficiency syndrome (AIDS). The patient results showed that, correlated with decreased T4/T8 ratios, there was a decrease in mitogen responsiveness first to pokeweed mitogen (PWM), followed by concanavalin A (Con A) and then phytohemagglutinin (PHA). Parallel to this decrease there was a shift toward higher concentrations of mitogens needed for optimal proliferation. In comparison, depletion of T4+ lymphocytes from normal healthy controls also decreased lymphocyte proliferative responses to all three mitogens but shifted the amount of mitogen needed for optimal proliferation toward lower concentrations. The differences in mitogen-induced proliferation between patients and healthy controls suggest a model whereby there is a functional defect(s) in mitogen responsiveness of the remaining T4- lymphocyte population that can be overcome when higher concentrations of mitogen are used.

The human sex ratio: increase in first-born males to parents with shared HLA-DR antigens.

Maternal-fetal HLA-DR antigen sharing has been reported to affect the sex ratio of first-born. We therefore studied offspring sex ratios and birth orders in 66 families in which parents shared one or more HLA-DR antigens as compared to 61 families with no parental HLA-DR sharing. A significant excess of males was found among first-born children who were HLA-DR compatible with their mothers compared to first-born HLA-DR incompatible children of couples sharing HLA-DR antigens and couples not sharing HLA-DR antigens. Increased numbers of males may persist among children of higher birth orders in families where parents share both HLA-DR antigens, but not among couples sharing only one HLA-DR antigen. We hypothesize that the presence of the H-Y antigen in the male fetus may provide the necessary stimulus for a successful pregnancy in HLA-DR compatible pregnancies and may explain the excess of male births in the general population.

Gestational diabetes mellitus: a syndrome with phenotypic and genotypic heterogeneity.

One hundred ninety-nine gravida with gestational diabetes mellitus (GDM) defined as "carbohydrate intolerance of varying severity with onset or first recognition during pregnancy" have been stratified into subgroups on the basis of fasting plasma glucose and evaluated for further phenotypic and genotypic heterogeneity. A significantly greater proportion of the women in all our groups were older and heavier than in a "control" population of 148 consecutive gravida with documented normal oral glucose tolerance. After correction for age and weight by covariate analysis, absolute insulinopenia in response to oral glucose could be demonstrated in all GDM groups, although exceptions were present in each. The incidence of diabetes in the mothers of our patients with GDM was 8-fold greater than in controls; the incidence in fathers did not deviate from control patterns. HLA-DR3 and DR4 antigens were more frequently present in GDM and the increase was statistically significant in blacks. At the time of diagnosis, cytoplasmic islet cell antibodies (ICA) were significantly more common in GDM associated with elevated fasting plasma glucose than in controls; the frequency of ICA was 18.4% (7/38) in women with fasting plasma glucose greater than or equal to 130 mg/dl. Our findings indicate that GDM entails genotypic as well as phenotypic diversity and may include patients with slowly-evolving Type I diabetes mellitus, as well as patients with Type II diabetes mellitus, and women with asymptomatic diabetes which antedated the pregnancy (i.e. pregestational diabetes mellitus). Appreciation of this heterogeneity should be incorporated into any evaluation of intervention strategies for women with GDM or into prognoses concerning their postpartum metabolic status.

Gestational diabetes mellitus. Heterogeneity of maternal age, weight, insulin secretion, HLA antigens, and islet cell antibodies and the impact of maternal metabolism on pancreatic B-cell and somatic development in the offspring.

We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into "lean" and "obese" indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e., A1 less than A2 less than B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of "markers" known to be associated with type I diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)