Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage.

OBJECTIVE: To assesses the live birth rate without treatment in women with hereditary thrombophilia who have recurrent miscarriage and women without thrombophilia who have recurrent miscarriage. DESIGN: Prospective observational study. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One hundred twenty women with thrombophilia and 65 women without thrombophilia. MAIN OUTCOME MEASURE(S): Number of live births or repeated miscarriages. RESULTS: Of the 185 patients, 44 with thrombophilia and 26 without thrombophilia have conceived. Nineteen of the 44 pregnancies (43.2%) in thrombophilia patients have terminated in live births, compared with 8 of 26 pregnancies (30.8%) in patients without thrombophilia. This difference is not statistically significant. CONCLUSIONS: Hereditary thrombophilia did not seem to affect the live birth rate in women with recurrent miscarriage.

Human chorionic gonadotropin supplementation in recurring pregnancy loss: a controlled trial.

OBJECTIVES: To investigate the efficacy of hCG in the management of recurrent early pregnancy loss. DESIGN: A prospective, randomized, controlled trial. SETTING: Miscarriage Clinic, Women's Hospital, Liverpool, United Kingdom. SUBJECTS: Eighty-one women attending the miscarriage clinic with idiopathic recurrent pregnancy loss were randomized to receive hCG supplementation or placebo in early pregnancy. MAIN OUTCOME MEASURE: The success rate or live birth rate. RESULTS: In women with regular menstrual cycles it was found that hCG had no beneficial effect, the pregnancy success rate being 86% in both groups. However, women with oligomenorrhea had a pregnancy success rate of 40% in the placebo group but a statistically significant improvement to 86% if hCG was given. CONCLUSIONS: Human chorionic gonadotropin can be recommended for idiopathic recurrent pregnancy loss in women with oligomenorrhea.

Association of anticardiolipin antibodies and pregnancy loss in women with systemic lupus erythematosus.

OBJECTIVE: To analyze the pregnancy history in relation to the presence or absence of anticardiolipin antibodies in women who had been diagnosed with systemic lupus erythematosus (SLE). DESIGN: One-hundred twenty-five women of reproductive age who were diagnosed with SLE and attended the Lupus Clinic at Parkland Memorial Hospital or Southwestern Medical Center were selected for this study. A retrospective review of patient histories, including anticardiolipin antibody test results and pregnancy histories, was conducted. Women who had therapeutic pregnancy terminations were excluded from this study. A chi 2 analysis was used to evaluate the significance of the data. RESULTS: In women with SLE of childbearing age with anticardiolipin antibodies, a 39% pregnancy loss rate occurred, compared with an 11% loss rate in anticardiolipin antibody-negative women. In women with at least two pregnancies who had anticardiolipin antibodies, 27% experienced two or more losses, whereas only 3% of antibody-negative women had recurrent pregnancy loss. CONCLUSION: We conclude that women with SLE and the presence of anticardiolipin antibodies are at increased risk for pregnancy loss.

Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters?

OBJECTIVE: To examine the possible association between factor XII (FXII) deficiency and an elevated number of abortions. DESIGN: Factor XII activity, FXII antigen concentration, other blood clotting parameters, and phospholipid antibodies were examined in venous blood from 43 women with repeated (3 to 7) abortions before the 28th week of gestation but without gynecological and chromosomal abnormalities. The data were compared with those obtained from 49 age-matched women without fetal loss. RESULTS: Eight cases with moderately reduced FXII activity (35% to 68% of normal) could be identified in the abortion group, whereas among controls no abnormalities in FXII activity and antigen concentration were found. The relative occurrence of reduced FXII level was higher among patients with more than three abortions as compared with those with three abortions. CONCLUSION: Repeated abortions may be associated with reduced level of FXII activity of unknown origin.

beta2-Glycoprotein 1 as a marker of antiphospholipid syndrome in women with recurrent pregnancy loss.

OBJECTIVE: To determine if beta2-glycoprotein 1 (beta2-GP1) antibodies are a better marker of the antiphospholipid antibody syndrome (APS) in women with recurrent pregnancy loss (RPL). DESIGN: Evaluation and testing of sera from women with RPL. SETTING: A university-affiliated reproductive endocrinology practice. PATIENT(S): 90 women with RPL; 45 women met criteria for APS and 45 women met criteria for RPL without antiphospholipid antibodies (APA). Both groups were of similar age and had a similar history of RPL. INTERVENTION(S): Patient sera were obtained from women with RPL and were tested for APA and beta2-GP1. MAIN OUTCOME MEASURE(S): A standard antiphospholipid antibody assay was employed to detect the presence of immunoglobulin (Ig)G, IgM, and IgA antibodies in serum against cardiolipin, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl serine, and phosphatidyl ethanolamine. Samples were also assayed with a commercial beta2-GP1 assay for IgG antibodies. RESULT(S): Among the 45 women with APS, 10 (22.2%) had positive IgG antibodies for beta2-GP1. Only 1 woman (2.2%) of 45 was positive for beta2-GP1 among the control group of women with RPL but negative APA. There was no correlation noted among the beta2-GP1-positive patients for a specific phospholipid antibody or isotype. CONCLUSION(S): These data suggest that IgG beta2-GP1 antibodies are less sensitive than antiphospholipid antibodies for the diagnosis of APS.

Midfollicular anticardiolipin and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome.

OBJECTIVE: To determine the prevalence of anticardiolipin and antiphophatidylserine antibodies in an IVF population and to correlate their presence and specific isotype with IVF cycle outcome. DESIGN: Retrospective clinical study using stored midfollicular sera for determination of antibody status. SETTING: University hospital infertility clinic. PATIENT(S): Women who underwent IVF treatment in 1991. INTERVENTION(S): Midfollicular sera were used to assess antibody status during the time of stimulation for IVF. MAIN OUTCOME MEASURE(S): Anticardiolipin and antiphosphatidylserine antibody titers and biochemical or sonographic documentation of IVF cycle outcome. RESULT(S): The overall prevalence of anticardiolipin and antiphosphatidylserine antibodies in IVF patients was 7.0% and 11.2%, respectively. There was no statistically significant difference in the prevalence of these antibodies in the groups of patients with a biochemical pregnancy (0 for anticardiolipin and 2.8% for antiphosphatidylserine), spontaneous miscarriage (11.4% for anticardiolipin and 20% for antiphosphatidylserine), ongoing pregnancy (7.3% for anticardiolipin and 11.6% for antiphosphatidylserine), and patients who failed to conceive (7.2% for anticardiolipin and 10.8% for antiphosphatidylserine). There was no correlation between outcome and the antibody isotype expressed. CONCLUSION(S): Anticardiolipin and antiphosphatidylserine antibodies are poorly predictive of the IVF cycle outcome. Routine testing of IVF patients for the presence of these antibodies is of limited clinical utility.

Thrombophilia-associated pregnancy wastage.

OBJECTIVE: To critically review the literature regarding inherited thrombophilia and recurrent fetal loss. DESIGN: English-language literature review. PATIENT(S): Women who experienced repeated pregnancy wastage. INTERVENTION(S): Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage. MAIN OUTCOME MEASURE(S): Live birth, miscarriage, preeclampsia, and pregnancy loss. RESULT(S): Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia. CONCLUSION(S): Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.

Factor XII deficiency is strongly associated with primary recurrent abortions.

OBJECTIVE: To evaluate factor XII deficiency in women with primary and secondary recurrent abortion. DESIGN: Prospective case-control study. SETTING: University hospital. PATIENT(S): Sixty-seven women with primary and 33 women with secondary recurrent abortion of unexplained nature and 49 healthy controls with no history of thrombotic disease or adverse pregnancy outcomes. MAIL OUTCOME MEASURE(S): Plasma factor XII activity, activated protein C resistance, factor V Leiden mutation analysis, protein C, protein S, antithrombin III, karyotyping, and anticardiolipin antibodies. RESULT(S): Ten of 67 women with primary recurrent abortion (14.9%) and 4 of 33 women (12.1%) with secondary recurrent abortion had reduced factor XII activity (<60%). These results are highly significant in the former group and showed a tendency toward significance in the latter group. All controls had normal factor XII activity. CONCLUSION(S): Factor XII deficiency is strongly associated with primary recurrent abortion, and women with secondary recurrent abortion show a tendency toward factor XII deficiency.

Impairment of the protein C anticoagulant pathway in a patient with systemic lupus erythematosus, anticardiolipin antibodies and thrombosis.

We have identified an inhibitor of the protein C anticoagulant pathway in the plasma of a patient with systemic lupus erythematosus and a history of recurrent deep vein thrombosis, fetal wastage, and seizures. The patient's plasma contained anticardiolipin antibodies as well as a weak lupus anticoagulant. Examination of this patient's plasma revealed normal levels of protein C and protein S antigen, normal levels of functional protein C, as well as essentially normal levels of every blood coagulation factor. In a modified prothrombin time assay, the activated protein C-mediated prolongation of the clotting time observed in normal plasma was not observed in this patient's plasma. Gel permeation chromatography of the patient's plasma revealed that the inhibitory material was a high molecular weight protein that coeluted with the IgM peak. The inhibitor did not appear to circulate as a complex with protein C, since the inhibitor could easily be separated from protein C during fractionation procedures, and did not interfere with the activation of protein C in plasma as assessed by a functional amidolytic assay. Our findings suggest that the recurrent thrombotic episodes observed in this patient may have occurred as a result of the patient's antiphospholipid antibody neutralizing specific phospholipids essential for the full expression of the anticoagulant activity of activated protein C.

IgA antiphospholipid and adrenal insufficiency: is there a link?

We present two females with antiphospholipid antibody (APA) syndrome who came with adrenal insufficiency (Addison's disease), recurrent abortions and extensive deep vein thrombosis (DVT). Both cases were positive for lupus anticoagulant (LA), global antiphospholipid test (APA), and IgG, IgA, IgM APA antibodies. Seventeen other cases with documented lupus anticoagulant and various clinical associations were tested for APA IgG, IgA, IgM. Only two were positive for IgA as well as IgG and IgM APA. Thirty volunteer blood donors (24 males and 6 females, aged 19-35 years) were taken as a control group. One person was moderately positive for LA and showed low positivity for IgG APA. These data suggest that the presence of IgA APA may signify a severe disease. Further studies are needed to confirm this observation.

Effect of thrombophylaxis on uterine and fetal circulation in pregnant women with a history of pregnancy complications.

PURPOSE: The aim of this study was to investigate the effect of thromboprophylactic therapy on fetal and maternal Doppler flow parameters in pregnant women with severe complications in previous pregnancies and evidence of acquired or congenital thrombophilia in the current pregnancy. METHODS: Sixty-five patients with a history of recurrent abortions, intrauterine fetal death, intrauterine growth restriction (IUGR), and severe early-onset preeclampsia were tested for the presence of acquired or congenital thrombophilia. Those with positive findings were prescribed low-dose aspirin plus low-molecular-weight heparin (LMWH) (enoxaparin); the remainder received low-dose aspirin only. A Doppler flow study was performed before and after treatment and in the third trimester of pregnancy. RESULTS: Of the 65 pregnancies, four ended in spontaneous abortion and were excluded from the analysis. Of the 61 women with completed pregnancies, 37 (61%) had evidence of acquired or congenital thrombophilia: 22 (36%) protein S deficiency; 1 (2%) protein C deficiency; 2 (3%) activated protein C resistance (APC-R); 2 (3%) IgG for antiphospholipid antibodies; 1 (2%) circulating anticoagulant; and 9 (15%) a combined defect. This group showed a significant decrease in mean uterine artery pulsatility index (PI) before and after treatment (1.32+/-0.36 vs. 1.04+/-0.23, P=.006), whereas the remaining 24 patients treated with low-dose aspirin only had nonsignificant changes. Pearson's correlation test yielded no correlations of the pregnancy outcome parameters with Doppler flow values in the umbilical or uterine arteries. CONCLUSIONS: Thromboprophylactic therapy transiently improves maternal circulation parameters in patients with thrombophilia at risk of fetal loss and other severe complications of pregnancy, but not in correlation with their pregnancy outcome. Therefore, Doppler examination of maternofetal circulation in the second trimester is not predictive of pregnancy outcome.

A study of sixty pregnancies in patients with the antiphospholipid syndrome.

OBJECTIVE: To study the maternal and fetal outcome in treated antiphospholipid syndrome (APS) pregnancies. METHODS: Sixty pregnancies in 47 APS patients (11 primary and 36 secondary) were followed in a multidisciplinary clinic. Patients testing antiphospholipid antibody positive and having a history of recurrent miscarriages were treated with low-dose aspirin (75 mg) daily. Patients with APS and a previous history of thrombotic events were treated with subcutaneous unfractionated or low molecular weight heparin and low-dose aspirin (75 mg) daily. RESULTS: The live birth rate increased from 19% of their previous non-treated pregnancies to 70% despite a high incidence of obstetric and fetal complications: pre-eclampsia (18%), prematurity (43%), fetal distress (50%) and intrauterine growth retardation (31%). Two predictors of fetal outcome were observed: the previous obstetric history and the presence of thrombocytopenia. Seven pregnancies (12%) were complicated by thrombotic events during pregnancy or during the puerperium. There were no thrombotic events in those receiving a low molecular weight heparin regimen. CONCLUSION: Close obstetric monitoring by a multidisciplinary team and the use of antithrombotic therapy was effective in reducing the fetal wastage in APS pregnancies despite a high incidence of obstetric and fetal complications.

The effect of sera from women with systemic lupus erythematosus and/or antiphospholipid syndrome on rat embryos in culture.

Women with systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (APLA) suffer from a high rate of recurrent abortions perhaps as a result of specific antibodies that may damage the conceptus. We studied the effects of sera from women with SLE--with or without--APLA and recurrent abortions on 10.5-d-old rat embryos in culture. This was compared to the results of culture on sera from control women and on rat sera. In addition, we studied sera from women with SLE with or without APLA after treatment with low doses of aspirin and glucocorticosteroids. Seventy-three percent of embryos cultured in sera from women with SLE with or without APLA were malformed in comparison to only 10.2% in embryos cultured on control sera and 5.4% in embryos cultured on rat sera. The rate of anomalies was reduced to 37.5% in embryos cultured on sera from women with SLE with or without APLA after treatment, as in 6 of 13 sera, the treatment reduced or prevented the occurrence of embryonic anomalies. When sera were divided in to low- and high-risk sera, the effect of treatment was even more significant, as the average percentage of embryonic anomalies per serum was reduced from 81.7 to 44.7%. Specific ultrastructural changes were found in the yolk sacs of the embryos cultured on the sera from women with SLE with or without APLA by transmission electron microscopy and by scanning electron microscopy. It seems that the rat embryo culture system may be an important clinical diagnostic tool to identify women with recurrent abortions in whom the etiology may be immunologic rejection of the embryo and to assess the efficacy of various treatment modalities.

The antiphospholipid symdrome in a teenage with miscarriages, thromboses, and diabetes mellitus.

The antiphospholipid syndrome has been associated with many clinical conditions since its description by GRV Hughes in 1983. The linkage to Type 1 diabetes mellitus has not been established. There have been no reports of deep venous thrombosis in association with antiphospholipid syndrome and diabetes mellitus. We present the case of an African-American teenager with multiple miscarriages, diabetic ketoacidosis, deep venous thromboses, and elevated immunoglobulin M and G anticardiolipin antibodies. We urge that clinicians consider testing for antiphospholipid antibodies when diabetic patients present with multiple miscarriages or deep venous thrombosis.

Prognosis of a new pregnancy following previous spontaneous abortions.

The risk for a clinical spontaneous abortion in a pregnancy following 0 to 4 consecutive spontaneous abortions was estimated in a large, unselected, Danish population, including approximately 300,500 pregnancies. The overall risk for spontaneous abortion was 11% and the risk for a spontaneous abortion was 16, 25, 45 and 54% after 1 to 4 previous consecutive spontaneous abortions, respectively. For women over 35 years, the risk for spontaneous abortion was significantly increased, but the almost identical abortion rates after repeated abortions in both young and old women indicate a risk factor which is not age-related.

Ovarian pregnancy: association with IUD, pelvic pathology and recurrent abortion.

Six cases of ovarian pregnancy were reviewed and their relationship with the IUD, fibromyoma of the uterus and previous spontaneous abortion was examined. In fact, 5 patients had an IUD in situ, in 2 women fibroids were found; 4 of the women had spontaneous abortions in their past history. The latter fact has been discussed, and it is suggested that this association may possibly contribute to an early diagnosis of ectopic pregnancy resulting in improved chances for conservative microsurgery. Attention is drawn to the fact that the diagnosis of ovarian pregnancy is often made only on microscopic examination. Thus, it is concluded that the true incidence of ovarian pregnancy may be higher than is apparent.

PIP: 6 cases of ovarian pregnancy were reviewed and their relationship with the IUD, fibromyoma of the uterus, and previous spontaneous abortion was examined. 5 of the patients had in situ IUDs, and 1 patient was treated in conjunction with a 20 week size fibroid uterus. 1 of the patients with an IUD also had a fibroid uterus. 4 of the women had spontaneous abortions in their past history. All cases met Spiegelberg's requirements for the diagnosis of ovarian pregnancy. The 6 cases are summarized in table form. During the 4 year period that these 6 patients were treated, a total of 59 ectopic pregnancies were treated at the Hasharon Hospital in Petah-Tikva, Israel. 18 or 30.5% occurred in patients with in situ IUDs. Ovarian pregnancies constituted 10.2% of all the ectopic pregnancies and 20% of the ectopic pregnancies in the group of patients using IUDs. The possibility that the IUD may potentiate ovarian nidation must be considered. It has been suggested that the IUD causes changes in the synthesis of prostaglandins so that tubal peristalsis is increased, and this could increase the incidence of both tubal and ovarian pregnancies. 2 of the patients were initially treated for vaginal bleeding and pelvic pain by removal of their IUDs, and the proper treatment was delayed for 14 days. The ovarian pregnancy in the patient with the fibroid uterus was diagnosed only after histological examination of an incidental hemorrhagic mass found at laparotomy. The series of 6 cases of ovarian ectopic pregnancy seems to confirm the association, and it must also be noted that mild chronic salpingitis was reported on histopathological examination in only 1 case. No conclusion can be reached on the basis of such a small group of patients.

Clinical significance and outcome of preterm prelabor rupture of membranes: population-based study.

OBJECTIVE: To evaluate maternal characteristics and neonatal and maternal birth outcome in cases of prelabor rupture of membranes (PPROM) in a non-selected parturient population. STUDY DESIGN: The study population consisted of 5660 singleton preterm births (24-36 weeks gestation) occurring between 1988 and 1997 at the Soroka University Medical Center in Israel. Parturients with no prenatal care were excluded from the study. A cross-sectional study was designed between two groups. The study group consisted of patients with PPROM (n=968) and the comparison group consisted of patients without PPROM (n=4692). The data were analyzed by SPSS package. Information was obtained using a computerized database based on detailed obstetrical records. Logistic regression was used to assess the contribution of different risk factors to PPROM. RESULTS: PPROM was associated with a significantly lower gestational age (24-32 weeks) and birth weight (<2500 g) than those with intact membranes. The rates of chorioamnionitis and urinary infection were found significantly higher in the PPROM group compared with women without PPROM (16.5 vs. 2.7%; 5.1 vs. 3.3%, respectively) (P<0.001). The rate of endometritis and bacteremia in the postpartum period were significantly higher in women with PPROM compared with controls 2.8 vs. 1.4%, (P=0.003) and 9.4 vs. 5%, (P=0.001), respectively. Total perinatal mortality rates were significantly higher in the group without PPROM 10.5 vs. 7.2% (P=0.01), however, rates of postpartum death were higher in the PPROM group 5.5 vs. 4% (P<0.01). When adjusted for recognized risk factors using logistic regression analysis, infection of amniotic fluid (OR=6.6) and genito-urinary tract infection (OR=1.64) remained the independent risk factors associated with PPROM. CONCLUSIONS: Infectious morbidity in patients with preterm prelabor rupture of membranes and preterm delivery remained an important risk factor for obstetrical and neonatal complications.

Obstetric outcome in women after multiple spontaneous abortions.

Obstetric outcome in 88 women with a past history of three or more consecutive pregnancy losses was studied. The results were compared to those in our total obstetric population for the same period (control group). The incidence of small-for-gestational-age infants, prematurity, low-birth-weight infants and toxemia in the study group was not significantly different from that in the control group. Gestational diabetes and chronic hypertension, however, occurred more frequently in the study group than in the control group (P less than .001). These data could be helpful in counseling women with repeated pregnancy loss.

[Spontaneous fetal mortality. Role of maternal age, parity and previous abortions]. / La mortalité foetale spontanée. Rôle de l'âge de la mère, de la parité et des antécédents d'avortements.

Analysing the reproductive biographies of samples of women has made it possible to clarify the role of various factors in bringing about a risk of spontaneous fetal death during the reproductive life of the mother. However, attention must be paid to the difficulties in observing the cases and measuring parameters. To make the various features comparable it is necessary to distinguish between apparent intra-uterine mortality (the pregnancy being diagnosed by the woman), recognisable (the pregnancy is diagnosable clinically) and total (from the time of fertilisation). The effect of maternal age is definite and quite independent of parity. Apparent intra-uterine mortality rises from about 120 per 1,000 pregnancies at the age of 20-24 to 200 per 1,000 at 35-39 and 270 per 1,000 at 40-44. If there has been no previous abortion the risks generally are less than 150 per 1,000, but if there has been even one previous abortion they become practically double. This discontinuity can be interpreted as showing the existence of marked changes between women as far as this risk is concerned.

[A case of inflammatory myopathy worsened by miscarriage with autoimmune disorder-associated disease].

The patient was 42-year-old woman who had exhibited elevated levels of serum creatine kinase(CK) and intermittent weakness of proximal muscles since her thirties. She had a history of palmoplantar pustulosis, Mondor's disease and recurrent miscarriages. Basedow's disease, which had been treated with antithyroid drugs since 37 years of age, recurred during the fourth pregnancy. After the pregnancy was terminated in the sixth week, weakness and grasp pain in the proximal muscles developed. The biopsy of biceps brachii muscle showed necrosis and reconstruction of muscle fibers with equivocal inflammatory cells, which was compatible with the findings for inflammatory myopathy such as polymyositis(PM). She was treated with prednisolone and the weakness and grasp pain in the proximal muscles were resolved. PM beginning during a woman's reproductive period is rare, and few studies have examined the association between PM and pregnancy. In this case, pregnancy and her past diseases were considered to be linked to an autoimmune abnormality that might have contributed to the inflammatory myopathy.