Religiosity is an important part of coping with grief in pregnancy after a traumatic second trimester loss.

Women (n = 15) who were pregnant after a traumatic late pregnancy loss (termination because of fetal death or serious anomalies) completed psychometric screening tests and scales, including the Perinatal Grief Scale (PGS), the Impact of Event Scale (IES), the Duke Depression Inventory (DDI), the Generalized Anxiety Disorder-7 (GAD), and the Hoge Scale for Intrinsic Religiosity (IR). Despite a mean elapsed time since the prior loss of 27 (range, 7-47) months, half (7/15, 47%) of the combined groups had high levels of grief on the PGS. Multiple positive scores on psychometric tests were frequent: Sixty percent (9/15) had high scores on the PGS Active Grief subscale or on the IES. Forty percent (6/15) had a high score on the DDI, and 17% (3/15) on the GAD. IR scores significantly and negatively correlated with scores on the Despair subscale of the PGS. The results from this pilot study suggest that high levels of grief and PTS symptoms are significant problems for pregnant women who have suffered late loss of a wanted pregnancy. Religiosity may play an important part in maternal coping during these stressful pregnancies.

Religious beliefs affect grieving after pregnancy loss.

Religious beliefs and practices may aid in coping with bereavement and grief after pregnancy loss. Data from 103 women enrolled in the original Lehigh Valley Perinatal Loss Project, and who were followed-up for at least 1 year, were evaluated for the impact of initial religious practices and beliefs on the course and severity of grief. Religious practices corresponding to standard scales of religiosity and agreement with specific beliefs were rated by the women on a Likert scale of 1-5. Neither agreement with statements corresponding to extrinsic and intrinsic religiosity or to positive religious coping, nor frequency of religious service attendance was predictive of follow-up scores on the Perinatal Grief Scale. Religious struggle, agreement with statements classified as negative religious coping, and continued attachment to the baby were all associated with more severe grief.

Placental pathology and antiphospholipid antibodies: a descriptive study.

We described placental pathology in antiphospholipid antibody (APL) syndrome, APL and no history of recurrent pregnancy loss, and in treated and untreated pregnancies of APL syndrome. Thirty-nine pregnancies of 28 patients were studied: 23 placentas delivered from 23 women with APL (13 with APL syndrome and 10 with serological APL); 8 untreated miscarriages before APL diagnosis from 6 of the 13 patients with APL syndrome and 1 of 10 with serological APL; and 8 miscarriages by 5 additional women before APL syndrome diagnosis. Histopathology was reviewed by a pathologist blinded except to gestational age. Contingency tables and analysis of variance (ANOVA) considered p < 0.05 significant. Comparing the placentas delivered at > 18 weeks' gestation, excessive perivillous coagulation, avascular terminal villi, and chronic villitis/uteroplacental vasculitis tended to be more common in treated APL syndrome than serological APL cases (p = 0.07). Of the 16 miscarriages before diagnosis of APL, 11 were lost at < 18 weeks' gestation. None had pathology typical of APL, but 4 of 11 (36%) had chronic intervillositis. Five of 16 miscarriages before the diagnosis of APL were miscarried between 18-22 weeks. Three of 5 (60%) miscarried after 18 weeks had multifocal uteroplacental thromboses, compared to 6 of 13 (46%) treated pregnancies with APL syndrome and 0 of 10 cases with serological APL.

Management of immune thrombocytopenic purpura associated with the antiphospholipid antibody syndrome.

Our two patients had "primary" antiphospholipid antibody syndrome without underlying systemic lupus erythematosus or other systemic autoimmune process, as well as symptomatic immune thrombocytopenic purpura (ITP). The thrombocytopenia did not respond to prolonged courses of corticosteroids and/or immune globulin infusions, but was controlled following splenectomy. The presence of serum antibodies to platelet surface glycoproteins, typical of ITP, could be helpful in the confirmation of both of these disorders in the same patient, rather than secondary thrombocytopenia. Management of such cases is confounded by an increased risk for both bleeding and thrombosis, including fetal death. To reduce the risk of fetal loss and thrombosis, both patients were advised to take aspirin 80 mg daily. The frequency and clinical significance of this association would suggest that patients with ITP should be tested for antiphospholipid antibodies, particularly before pregnancy or surgical procedures. Patients with coexistent antiphospholipid antibody syndrome would be at increased risk for thrombosis in the post-operative period following splenectomy and should be given prophylactic anticoagulation.

Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population.

Rubinstein-Taybi syndrome (RTS) is a well delineated multiple congenital anomaly syndrome characterised by mental retardation, broad thumbs and toes, short stature, and specific facial features. The recent localisation of the disorder to 16p13.3 and subsequent identification of a submicroscopic deletion of this region in RTS patients led us to screen a large cohort of affected subjects using the RT1 probe. Among 64 patients with clinical evidence of RTS, seven (11%) had a deletion. Another patient had a translocation of the region without evidence of a deletion. The features of coloboma, growth retardation, naevus flammeus, and hypotonia have a positive predictive value for the presence of an RT1 deletion. Because of the relatively low frequency of deletions in RTS, the RT1 probe is useful in diagnostic confirmation, but has limited use as a screening tool.

Evaluation of the prethrombotic state in pregnancy and in women using oral contraceptives.

The purpose of this study was to determine the effects of pregnancy and oral contraceptive use on in vivo coagulation by measurement of plasma levels of prothrombin fragment 1 + 2 and thrombin antithrombin III complex. Fifty-four women with uncomplicated singleton gestations, 34 women using oral contraceptives and 45 non-pregnant controls were the subjects of this study. Levels of prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were measured using enzyme linked immunoassays. In uncomplicated pregnancies, levels of prothrombin fragment 1 + 2 and thrombin antithrombin III complex increased significantly with advancing gestational age. Women using oral contraceptives had significantly higher levels of prothrombin fragment 1 + 2 and thrombin antithrombin III complex compared to non-pregnant controls. The significant increase in levels of prothrombin fragment 1 + 2 and thrombin-antithrombin III complex throughout gestation and in women using oral contraceptives provided evidence of thrombin activation during these clinical conditions.

Fertility among women with recurrent spontaneous abortions--the effect of paternal cell immunization treatment.

PROBLEM: The risk of women whose chief complaint is recurrent spontaneous abortions (RSA) for secondary infertility (infecundability) has not been evaluated prospectively. The effect of paternal mononuclear cell immunization on conception rates is unknown. METHOD: Two hundred women whose chief complaint was RSA were randomly assigned to be immunized with paternal mononuclear cells either before or after (up to 6 postmenstrual weeks) conception. Fertility rates (both conception and live birth) were evaluated for the group immunized before conception and compared to those for the control group, who were not immunized until after conception, using life table and multiple logistic regression analyses. RESULTS: Prospectively ascertained, age-related conception rates for nonimmunized RSA controls appeared to be similar to those for general populations. Immunization before pregnancy had no significant effect (power +/- 14%) on rates of conception (66% before, 77% after) or time to conceive (median weeks before 19.5, after 27.0). Live birth rates (before 59%, after 63%) were also similar for both groups (P = 0.7). CONCLUSION: Women whose only prior complaint was RSA were not at high risk for secondary infecundability, and immunization did not alter either conception rates or time to conceive. Postponement of immunization until after conception did not affect live birth rates for women selected for study because they did not have a history of prior infecundability or early repeated miscarriages.

Alloantibody responses to antigens recognized by rabbit antitrophoblast antisera in trophoblast and mononuclear cell (MNC) membranes by primary aborting women before and after paternal leukocyte immunization.

PROBLEM: Because shared allogeneic antigens are expressed on peripheral blood lymphocytes, as well as trophoblasts, it has been proposed that lymphocyte transfusions may appropriately sensitize recurrent spontaneous aborters (RSA) to trophoblast and lead to pregnancy conservation. The degree to which these responses are affected by this treatment, however, has not been defined. METHOD: SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analyses were used to study the alloantibody responses in RSA patients both before and after immunization with paternal leukocytes (MNC) against membrane proteins isolated from peripheral blood mononuclear cells (MNC), first trimester and full term chorionic villi (CV). RESULTS: A distinct set of antigens with apparent molecular weights of 32, 36, 41, 63, 65, and 85 kDa was identified in both MNC and trophoblast membranes by rabbit anti-trophoblast antisera. In addition, a 55 kDa protein was recognized by MNC membranes. Thirty-eight percent of primary RSA sera recognized this 55 kDa protein. After paternal MNC immunization, all primary RSA samples displayed increased reactivity or produced antibodies to this 55 kDa protein when compared with preimmunization sera. The protein was identified as MCP using a rabbit polyclonal anti-MCP antisera. In contrast, reactivity to the other antigens present in the membrane preparations decreased after paternal MNC immunization. CONCLUSION: Changes in immune reactivity in RSA patients after paternal MNC immunization suggest that immunization alters serum immune reactivity to MNC and trophoblast shared antigens.

Can tests for IgA, IgG, or IgM antibodies to cardiolipin or phosphatidylserine substitute for lupus anticoagulant assays in screening for antiphospholipid antibodies?

Antiphospholipid antibodies (APL) are detected by both ELISA and tests for lupus anticoagulants (LA). We evaluated ELISA tests for IgG, IgM, and IgA isotopes of antibodies binding cardiolipin (CL) and phosphatidylserine (PS) in samples from LA patients presenting with recurrent miscarriages. All values were expressed in multiples of the normal median (MOM). In 32% (11/34) of cases, not only were all ELISA values at or below 2.5 MOM, but the distribution of these ELISA MOM values within the normal range was similar to distribution of values from LA negative controls with the same history. Neither the use of PS as the antigen nor the addition of IgA assays improved the correlation of ELISA results with the presence of LA. ELISAs are inadequate as the sole screening test for these separate, but often associated, families of APL.

Chromosome errors as a cause of spontaneous abortion: the relative importance of maternal age and obstetric history.

OBJECTIVE: To evaluate the likelihood of obtaining a chromosome diagnosis in cases of spontaneous abortion (SAB) and of the relative importance of maternal age versus obstetric history in predicting the fetal karyotype. DESIGN: Obstetric history was obtained from all 100 cases of miscarriage in 1 year when products of conception were sent for chromosome studies. Multiple logistic regression analysis was used to calculate odds ratio and statistical significance for correlations between historical factors and the probability of any chromosomal abnormality or trisomy. RESULTS: A chromosome diagnosis was made in 84% of cases. Maternal age was a more important predictor of chromosome abnormality, specifically trisomy, than history of previous livebirths or miscarriages. CONCLUSION: Results from chromosome studies using chorionic villi from SABs are diagnostically useful, even when the patient has a history of repeated miscarriages.

Predictors for live birth after unexplained spontaneous abortions: correlations between immunologic test results, obstetric histories, and outcome of next pregnancy without treatment.

Our objective was to determine whether results from tests for maternal serum antinuclear antibodies, cytotoxic antibodies to paternal lymphocytes, parental histocompatibility types, and blocking factors for maternal-paternal mixed lymphocyte reactions were predictive of pregnancy outcome without immunologic treatment. Pregnancy outcome data from 95 women with a history of unexplained recurrent spontaneous abortions who underwent immunologic tests at Jefferson Medical College were evaluated with multiple logistic regression analyses. The number of prior spontaneous abortions, history of another relevant diagnosis, parental sharing of one histocompatibility antigen, and maternal age were related to the outcome of the next pregnancy in women given no immunologic treatment (p = 0.05). No significant correlation was found between results from the immunologic tests or other history characteristics evaluated and outcome of the next pregnancy. The immunologic tests evaluated were not clinically useful predictors of pregnancy outcome.

The number of cells used for immunotherapy of repeated spontaneous abortion influences pregnancy outcome.

One hundred and sixty-eight women were immunized on a single occasion with paternal mononuclear cells (MNC) for recurrent spontaneous abortion (RSA) and pregnancy outcomes were analysed with respect to the number of MNC given. The study was done in a prospective sequential fashion using all MNC recoverable from a unit of the spouse's blood and both patients and investigators were blinded as to the number of cells injected. Women receiving low and mid-range doses of MNC (58-305 x 10(6) and 308-567 x 10(6), respectively) had a significantly higher pregnancy success rate (57%) than those receiving the high (568-2677 x 10(6)) dose of MNC (41%). In 77 consecutive patients the diameter of the largest immediate skin flare reaction at the site of subcutaneous injection was recorded. No correlation was found between the skin flare response and the number of MNC injected. Our data suggest that a blinded trial of paternal MNC immunization comparing what appears to be optimum numbers of cells (100-550 million) to a low dose inoculum (e.g., 10 million), again noting the sizes of the skin flare reactions, might answer questions about efficacy and placebo effects of immunotherapy for RSA.

Neonatal alloimmune thrombocytopenia after maternal immunization with paternal mononuclear cells: successful treatment with intravenous gamma globulin.

We report a case of neonatal alloimmune thrombocytopenia and intracranial hemorrhage in an infant whose mother received immunizations of paternal mononuclear cells. This therapy is designed to prevent unexplained first trimester miscarriages. No previous cases of platelet autoimmunization associated with maternal immunization with paternal mononuclear cells has been reported. Treatment with antenatal maternal infusions of intravenous gamma globulin (IVGG) did not prevent fetal thrombocytopenia, but IVGG may become the treatment of choice for postnatal, antibody-mediated thrombocytopenia of the newborn.

Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment.

OBJECTIVE: We attempted to compare the use of low-dose heparin with a standard dose of 40 mg prednisone daily (both plus low-dose aspirin) for treatment of pregnant women with antiphospholipid antibody-associated recurrent fetal loss with respect to maternal and perinatal morbidity and efficacy in prevention of fetal death. STUDY DESIGN: A multicenter randomized trial included 20 patients. Generalizability of results from randomized patients was evaluated by means of additional data from 13 women refusing and 12 women ineligible for randomization. Data from study groups were compared with Fisher's exact test, and generalizability was evaluated with a chi 2 test for trend. RESULTS: Live birth rates were the same (75%) with either treatment, but "serious" maternal morbidity and the frequency of preterm delivery were significantly higher among women randomly assigned to prednisone (p = 0.02 vs p = 0.006). Preterm delivery among prednisone-treated women was usually associated with premature rupture of the membranes or preeclampsia. These results could be generalized to the other groups of women ascertained during the course of the study. CONCLUSIONS: Low-dose heparin should be preferred to prednisone when treatment is indicated for high-risk pregnant women with antiphospholipid antibodies.

First-trimester maternal serum alpha-fetoprotein and chorionic gonadotropin in aneuploid pregnancies.

First-trimester maternal serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels were measured in samples from 29 women with cytogenetically abnormal pregnancies and 145 women with cytogenetically normal pregnancies matched for gestational age, race, and sample storage time. All patients had a risk of fetal aneuploidy greater than or equal to that of a mother 35 years of age. AFP was significantly lower in samples from pregnancies affected with trisomy 21 (0.67 MoM; p less than 0.05), while HCG values were no different from those of matched controls. Trisomies 13 and 18 could not be distinguished from matched controls by AFP. However, levels of HCG were significantly lower in such pregnancy samples, with median values of 0.65 MoM in trisomy 13 and 0.32 MoM in trisomy 18 (p less than 0.05). Variations in AFP and HCG levels suggest that expressed differences between autosomal aneuploidies include differences in fetal and placental protein production in the first trimester.

Cell surface antigen expression of first trimester chorionic villus samples.

First trimester chorionic villi obtained by chorionic villus sampling at approximately 9 weeks of gestation were investigated by indirect immunofluorescence to demonstrate trophoblast cell surface antigen expression. Villous trophoblast expressing the trophoblast specific markers transferrin receptor, human placental lactogen, and cytokeratin was also found to express a monomorphic major histocompatibility complex class I determinant recognized by the monoclonal antibody W6/32. W6/32 positive regions included sparsely scattered regions of villous trophoblast and fanning outgrowths of trophoblast. The class I antigenic determinant expressed by first trimester trophoblast was found to be recognized exclusively by W6/32 when assayed with a panel of anti-class I determinant monoclonal antibodies. Trophoblast W6/32 determinant expression was not increased after 24 hour organ culture in the presence of 200 U of interferon gamma. Exposure to interferon gamma resulted in increased class I antigen expression by mesenchyme and low level de novo mesenchyme class II antigen expression. These data suggest that early gestational stage villous trophoblast express non-classical class I antigens which do not seem to be subject to the regulatory effects of interferon gamma.

Paternal mononuclear cell immunization therapy for repeated miscarriage: predictive variables for pregnancy success.

Pregnancy outcomes for 125 women with unexplained recurrent abortion conceiving after immunologic testing for possible paternal leukocyte immunization were analyzed. Pregnancy success was related to the number of previous miscarriages (relative risk 0.36 for each additional miscarriage after 3), a history of a late pregnancy loss (relative risk 0.18), any other relevant treated or untreatable diagnosis (relative risk 0.27), immunization with paternal mononuclear cells (relative risk 5.6), and time in weeks from test date to LMP of the next pregnancy (relative risk 0.93 for each additional week). The significant difference in pregnancy outcomes between women given a single immunization and nonimmunized women reflected a larger difference between those in each group conceiving within 12 weeks of initiating tests for inclusion in the treatment program. The latter observation suggests that any effect from a single immunization in prevention of recurrent miscarriage is of relatively short duration.

Association of HLA-DR5 with recurrent spontaneous abortion in women treated with paternal leukocytes. Possible subclinical autoimmune disease.

The incidence of pregnancy loss is higher in patients with various autoimmune diseases than in the general population. The causes of recurrent spontaneous abortions (RSA) are unknown; however, the presence of antinuclear antibodies and other antibodies in some women with RSA who are otherwise healthy suggests the possibility of underlying autoimmune disease. Because autoimmune diseases are often associated with an increased incidence of certain histocompatibility antigens, we examined the occurrence of specific HLA antigens in patients who had been treated for RSA. We found HLA-DR5 to be significantly overrepresented in the patients with RSA who aborted again after treatment with paternal mononuclear cell immunotherapy, compared with the incidence of this phenotype in a control population. Neither antinuclear antibodies nor antilymphocyte antibodies segregated with DR5. However, DR5+ patients who developed antilymphocyte antibodies after immunotherapy were more likely than all other treated patients to experience subsequent abortion (P less than 0.01). Our findings suggest the possibility of an underlying autoimmune disease in these women.

Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions.

In two women with antiphospholipid antibodies and recurrent fetal losses refractory to usual treatments, therapy consisting of aspirin, heparin, and intravenous gamma-globulin infusions was successful. Production of antiphospholipid antibodies was not suppressed. The transient decrease in anticoagulant activity noted in one case was not reproduced in vitro and was probably not physiologically important.