Recurrent early pregnancy loss and antiphospholipid antibodies: where do we stand?

Evidence from basic science studies supports a causative relationship between antiphospholipid antibodies (aPL) and recurrent early miscarriage (REM) (prior to 10 weeks of gestation). However, human studies have not consistently found a relationship between aPL and REM. Members of the Obstetric Task Force of the 14th International Congress on Antiphospholipid Antibodies performed a literature review of the association of aPL and REM and searched for clinical trials in women with REM who tested positive for aPL. Of the 46 studies that investigated the relationship between aPL and REM, 27 found a positive association, seven found no association, and the remaining 12 papers could not report an association (lack of control group). The main identified problems for such conflicting results were varying definitions of REM (two or three abortions, not necessarily consecutive; different gestational age at which pregnancy losses occurred); analysis of patients with previous fetal death (>10 weeks) in the same group of REM; and different definitions of "positive aPL" (cutoffs not following international recommendations; small number of studies confirmed persistence of positive aPL after six to 12 weeks). The 10 identified randomized trials with proposed treatments for women with REM who test positive for aPL also had heterogeneous inclusion criteria, with only one trial limited to subjects who would meet the current criteria for antiphospholipid syndrome (APS) by both clinical and laboratory criteria. Against this background, we conclude that the association between REM and aPL remains inconclusive and that the findings of treatment trials are at best inconsistent and at worst misleading. More convincing data are critically needed. Studies that identify, or at least stratify, according to international consensus criteria and include standardized core laboratory testing results are crucial if we are to establish an evidence-based association between aPL and REM and treatment recommendations.

A risk stratification model to predict adverse neonatal outcome in labor.

OBJECTIVE: The development and evaluation of a labor risk model consisting of a combination of antepartum risk factors and intrapartum fetal heart rate (FHR) characteristics that can reliably identify those infants at risk for adverse neonatal outcome in labor. STUDY DESIGN: A nested case-control study of term singleton deliveries at the nine hospitals between March 2007 and December 2009. Eligibility criteria included: gestational age ≥ 37.0 weeks; singleton pregnancy; documented continuous FHR monitoring for ≥ 2 h before delivery; assessment of FHR tracing at least every 20 min; and, available maternal and neonatal outcomes. Adverse neonatal outcome was defined as nonanomalous infants admitted to the newborn intensive care unit with either a 5 minute Apgar score <7 or an umbilical artery pH<7.1. Initial risk score was determined using data available at 1 h after admission. Patients with an initial risk score between 7 and 15 were considered high risk. Intrapartum risk scores were then created for these patients using FHR tracing data and labor characteristics. RESULT: A total of 51 244 patients were identified meeting study criteria. Of the antepartum variables evaluated (n=31), 10 were associated with an adverse outcome. The high-risk group made up 28% of the population and accounted for 59.8% of the adverse outcomes. Intrapartum characteristics were then evaluated in this high-risk group. Intrapartum evaluation identified the highest risk group with a C/S rate of 40% and adverse outcome rate of 11.3%. CONCLUSION: Incorporation of maternal and antepartum risk factors with FHR analysis can improve the ability to identify the fetus at risk in labor.

Obstetric antiphospholipid syndrome: current uncertainties should guide our way.

The subject of obstetric antiphospholipid syndrome (APS) has been reviewed dozens of times, and there is little doubt that the international APS community has done well in bringing APS to the attention of clinicians around the world. However, the evolution of clinical practice, at least in the US, also has convinced us that our field would benefit from further clinical study. For example, the number of women diagnosed with 'APS', but who do not meet the revised Sapporo criteria, seems to have increased. It is now common practice for women with recurrent miscarriage or prior fetal death to be treated with heparin, even in the presence of indeterminate or low titer antiphospholipid antibody (aPL) levels and even after only one positive test. In part, this common practice derives from confusion on the part of many clinicians and patients regarding the diagnosis of APS as well as the clinical and laboratory criteria for the syndrome. In part, this derives from the common practice of so-called 'empiric treatment' in US reproductive medicine, often driven as much by patients as by clinicians. This brief commentary focuses on areas of uncertainty that we see as deserving of new or renewed study for the sake of improving our understanding of APS and best patient care.

Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress.

BACKGROUND AND PURPOSE: Inflammation is associated with oxidative stress and local generation of lipid peroxidation-derived aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). In most tissues, HNE is readily conjugated with glutathione and presently it is unknown whether glutathionyl-HNE (GS-HNE) plays a functional role in inflammation. Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1). EXPERIMENTAL APPROACH: GS-HNE was administered intraperitoneally to mice and peritoneal lavages were assessed for leukocyte infiltration and lipid mediators were targeted by mediator-lipidomics. RvD1 was administered to mice treated with GS-HNE and leukocyte infiltration was assessed in the peritoneum. Superoxide production and CD11b modulation were measured in isolated human polymorphonuclear leukocytes incubated with GS-HNE. KEY RESULTS: GS-HNE (1-10 microg) evoked infiltration of Gr-1(+) leukocytes into the peritoneum to form an inflammatory exudate. With isolated human polymorphonuclear leukocytes, GS-HNE stimulated both superoxide generation and CD11b expression. Among the lipid mediators, both cyclooxygenase- and lipoxygenase-derived pro-inflammatory eicosanoids, including prostaglandin E(2), leukotriene B(4) and cysteinyl leukotrienes, were generated in exudates of mice injected intraperitoneally with GS-HNE. RvD1, given i.v. in doses as low as 0.01-10.0 ng, sharply reduced GS-HNE-stimulated leukocyte infiltration ( approximately 30-70%). CONCLUSIONS AND IMPLICATIONS: Glutathione conjugates of HNE, derived during oxidative stress, are pro-inflammatory in vivo. RvD1 protects against this oxidative stress-initiated inflammation.

Optimal management strategies for placenta accreta.

OBJECTIVE: To determine which interventions for managing placenta accreta were associated with reduced maternal morbidity. DESIGN: Retrospective cohort study. SETTING: Two tertiary care teaching hospitals in Utah. POPULATION: All identified cases of placenta accreta from 1996 to 2008. METHODS: Cases of placenta accreta were identified using standard ICD-9 codes for placenta accreta, placenta praevia, and caesarean hysterectomy. Medical records were then abstracted for maternal medical history, hospital course, and maternal and neonatal outcomes. Maternal and neonatal complications were compared according to antenatal suspicion of accreta, indications for delivery, preoperative preparation, attempts at placental removal before hysterectomy, and hypogastric artery ligation. MAIN OUTCOME MEASURES: Early morbidity (prolonged maternal intensive care unit admission, large volume of blood transfusion, coagulopathy, ureteral injury, or early re-operation) and late morbidity (intra-abdominal infection, hospital re-admission, or need for delayed re-operation). Results Seventy-six cases of placenta accreta were identified. When accreta was suspected, scheduled caesarean hysterectomy without attempting placental removal was associated with a significantly reduced rate of early morbidity compared with cases in which placental removal was attempted (67 versus 36%, P=0.038). Women with preoperative bilateral ureteric stents had a lower incidence of early morbidity compared with women without stents (18 versus 55%, P=0.018). Hypogastric artery ligation did not reduce maternal morbidity. CONCLUSIONS: Scheduled caesarean hysterectomy with preoperative ureteric stent placement and avoiding attempted placental removal are associated with reduced maternal morbidity in women with suspected placenta accreta.

Immunotherapy for recurrent miscarriage.

BACKGROUND: Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss. OBJECTIVES: The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immune globulin on the live birth rate in women with previous unexplained recurrent miscarriages. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2004, Issue 3), MEDLINE (1966 to September 2004) and EMBASE (1980 to September 2004). SELECTION CRITERIA: Randomized trials of immunotherapies used to treat women with three or more prior miscarriages and no more than one live birth after, in whom all recognised non-immunologic causes of recurrent miscarriage had been ruled out and no simultaneous treatment was given. DATA COLLECTION AND ANALYSIS: The review author and the two co-authors independently extracted data and assessed study quality for all studies considered for this review. MAIN RESULTS: Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; intravenous immune globulin, Peto OR 0.98, 95% CI 0.61 to 1.58. AUTHORS' CONCLUSIONS: Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no significant beneficial effect over placebo in improving the live birth rate.

Obstetric uses of intravenous immunoglobulin: successes, failures, and promises.

Intravenous immune globulin (IVIG) is approved for use in a number of conditions that may occur in obstetrical patients, including autoimmune thrombocytopenia and immune deficiency syndromes. IVIG also is widely used in obstetrics for nonapproved indications, such as fetal-neonatal alloimmune thrombocytopenia, antiphospholipid syndrome, and recurrent miscarriage. This review critically analyzes the use of IVIG for these indications based on the best available information. The authors conclude IVIG is effective in the management of fetal-neonatal alloimmune thrombocytopenia. IVIG appears promising as a treatment for severe fetal-neonatal alloimmune hemolysis due to antierythrocyte antibodies. A prospective multicenter trial should be undertaken. IVIG is no more effective than heparin and low-dose aspirin in the treatment of pregnancies complicated by antiphospholipid syndrome but has not been adequately evaluated in refractory cases. Finally, pending convincing studies, IVIG is not effective and should not be used for the management of recurrent miscarriage.

Antiphospholipid antibodies in women at risk for preeclampsia.

OBJECTIVE: The aim of this study was to determine whether positive results of tests for any of 5 antiphospholipid antibodies are associated with recurrent preeclampsia among women with a history of preeclampsia in a previous pregnancy. STUDY DESIGN: Second-trimester serum samples were obtained from 317 women with preeclampsia in a previous pregnancy who were being followed up in a prospective treatment trial. The serum samples were measured by enzyme-linked immunoassay for immunoglobulin G and immunoglobulin M antibodies against 5 phospholipids. Positive results were analyzed with regard to preeclampsia, severe preeclampsia, intrauterine growth restriction, and preterm delivery. RESULTS: Sixty-two of the 317 women (20%) had recurrent preeclampsia develop, 19 (6%) had severe preeclampsia, and 18 (5.8%) were delivered of infants with growth restriction. Positive results of tests for immunoglobulin G or immunoglobulin M antiphospholipid antibodies were not associated with recurrent preeclampsia. Positive results for immunoglobulin G or immunoglobulin M antibodies at the 99th percentile were also not associated with preterm delivery. Positive results at the 99th percentile for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results at the 99th percentile for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. The positive predictive values for these outcomes all were approximately 30%. CONCLUSION: Positive results of testing for antiphospholipid antibodies in the second trimester were not associated with recurrent preeclampsia among women at risk because of a history of preeclampsia. Positive results for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. However, the positive predictive values for all these associations were modest. Testing for antiphospholipid antibodies during pregnancy is of little prognostic value in the assessment of the risk for recurrent preeclampsia among women with a history of preeclampsia.

Coumarin derivatives and breast-feeding.

Coumarin derivatives are the anticoagulants most widely used in the United States. These agents are relatively contraindicated during pregnancy, and the use of these drugs in breast-feeding women remains controversial. Much of the confusion regarding the passage of these agents into breast milk might stem from the fact that different agents possess significantly different chemical properties. A review of the chemical structure of different coumarin derivatives, as well as available clinical evidence, suggests that warfarin sodium is not excreted into breast milk, and can be safely given to women requiring therapeutic anticoagulation postpartum. For the rare patient who cannot tolerate warfarin sodium, the use of dicumarol, rather than anisindione, is preferred.

Neonatal alloimmune thrombocytopenia: antenatal management.

OBJECTIVE: The optimal management of pregnancies at risk for neonatal alloimmune thrombocytopenia is debated. Proposed management includes the administration of intravenous immunoglobulin and serial determination of the fetal platelet count. The aims of our study were to determine the effectiveness and likely mechanism of action of intravenous immunoglobulin and to evaluate the safety of cordocentesis in cases of neonatal alloimmune thrombocytopenia. STUDY DESIGN: Eighteen mother-infant pairs were studied. All were at risk for neonatal alloimmune thrombocytopenia on the basis of delivery of a previously affected infant and confirmation of specific maternal antiplatelet antibodies. The pertinent antigen was HPA-1a in 13 cases, HPA-3a in 2 cases, and undetermined in 3 cases. Serial cordocenteses were used to determine fetal platelet counts. If the platelet count was <50,000/microL before 37 weeks' gestation, treatment was initiated with intravenous immunoglobulin administered to either the fetus (n = 2) or the mother (n = 8). In 3 cases fetal and maternal immunoglobulin G levels were determined before and after treatment. RESULTS: Seven (39%) fetuses had adequate platelet counts, were not treated, and were delivered of infants with normal platelet counts. Eleven (61%) fetuses were thrombocytopenic. Eight thrombocytopenic infants were treated with maternally administered intravenous immunoglobulin. In 6 (75%) of 8 cases the fetal platelet count increased after administration of intravenous immunoglobulin, but 2 fetuses remained severely thrombocytopenic. Two thrombocytopenic fetuses were treated with intravenous immunoglobulin infusion directly into the umbilical vein; both remained thrombocytopenic. Moreover, fetal immunoglobulin G levels did not correlate well with the response to intravenous immunoglobulin. Two (5.3%) of 38 cordocenteses were complicated by hemorrhagic complications, necessitating immediate cesarean delivery despite the use of prophylactic platelet transfusion in one case. CONCLUSION: Severe fetal alloimmune thrombocytopenia does not always occur in subsequent fetuses. Thus either fetal antigen status or platelet counts or both of these are necessary to determine whether treatment is needed. The effect of intravenous immunoglobulin on raising the fetal platelet count is inconsistent and appears to be caused by maternal or placental factors rather than a direct inhibition of fetal platelet destruction by immunoglobulin. The risk of hemorrhagic complications from cordocentesis in pregnancies complicated by neonatal alloimmune thrombocytopenia is higher than generally appreciated and is not always avoided by platelet transfusion at the time of the procedure.

Is vaginal birth after cesarean less expensive than repeat cesarean delivery?

OBJECTIVE: This study was undertaken to compare total medical costs of trial of labor after cesarean with those of elective repeat cesarean without labor, with both short- and long-term neonatal costs associated with such procedures taken into account. STUDY DESIGN: Costs associated with All Patient Refined diagnosis-related groups and Current Procedural Terminology for a large not-for-profit health care system were applied to an algorithm describing maternal and neonatal outcomes of trial of labor. Perinatal morbidity rates and cost estimates for long-term neurologic damage associated with uterine rupture were derived from published literature. RESULTS: If a 70% vaginal birth rate for women undergoing a trial of labor and delivery in a tertiary center with a mean uterine rupture to delivery time of 13 minutes is assumed, the net cost differential ranged from a saving of $149 to a loss of $217, depending on morbidity assumptions. For vaginal birth after cesarean success rates <70%, trial of labor in the presence of two previous scars, and institutional factors increasing the perinatal morbidity rate by just 4% with respect to that seen in tertiary centers, trial of labor resulted in a net financial loss to the health care system regardless of all other assumptions made. CONCLUSIONS: When costs as opposed to charges are considered and the cost of long-term care for neurologically injured infants is taken into account, trial of labor after previous cesarean is unlikely to be associated with a significant cost saving for the health care system. Recent government-mandated length-of-stay requirements are likely to make the economic benefit of vaginal birth after cesarean even less favorable. Factors other than cost must govern decisions regarding trial of labor or repeat cesarean.

Alloimmune causes of recurrent pregnancy loss.

Recurrent pregnancy loss is a vexing problem facing many couples. Some authorities have suggested that idiopathic recurrent pregnancy loss is alloimmune in nature. Suggested mechanisms include the presence of cytotoxic antibodies, absence of maternal blocking antibodies, inappropriate sharing of human leukocyte antigens, and disturbances in natural killer cell function and distribution. Proposed therapies for so-called alloimmune-related pregnancy loss include leukocyte immunization and intravenous immune globulin. Unfortunately, neither has been successful in well-designed trials and both are expensive. Although alloimmune disturbances may be responsible for some idiopathic recurrent pregnancy loss, the pathophysiology is far from certain and there is currently no clinical indication for immunotherapy.

Vibroacoustic and scalp stimulation.

Both VAS and scalp stimulation are useful in the evaluation of fetal compromise by decreasing the number of falsely abnormal FHR tests and limiting the number of unnecessary interventions, thus improving the efficiency of antepartum and intrapartum FHR monitoring. As is true for all types of fetal assessment using FHR monitoring, VAS and scalp stimulation have limitations, and a lack of response to these methodologies does not necessarily indicate fetal acidemia. When either VAS or scalp stimulation is employed, one must take into consideration their respective predictive values (see Table 1). Fetal VAS or scalp stimulation should be considered as one facet of comprehensive fetal evaluation. When these techniques are used in this manner, the clinician evaluating the fetus in the antepartum or intrapartum period may prevent unnecessary intervention and improve maternal and neonatal outcome.

Deep venous thrombosis: prophylaxis in gynecology.

Thromboembolism remains a serious concern for women undergoing surgery for benign and malignant gynecologic conditions. Attempts at perioperative thromboprophylaxis have probably reduced the incidence of DVT considerably. Both heparin and mechanical devices offer effective and safe treatment. However, even though unfractionated heparin and LMWH compounds are easy to administer and are well tolerated by patients, mechanical compression devices avoid the bleeding complications that may be encountered with anticoagulation therapy. Individual patient risks and circumstances should be taken into consideration when choosing which therapy to use (Table 1). Those patients at greatest risk may benefit from aggressive combination therapy.

Institutional influences on the primary cesarean section rate in Utah, 1992 to 1995.

OBJECTIVES: Our purpose was to evaluate institutional and organizational influences on cesarean section rates in Utah and to adjust such rates for differences in patient acuity. STUDY DESIGN: Data on cesarean section rates were derived from the Utah Hospital Discharge Database and adjusted for patient acuity by correcting raw cesarean rates for those patients undergoing cesarean section meeting regional gestational age transport criteria. RESULTS: When analyzed by means of 1-way analysis of variance, the following factors had a significant negative correlation (P < .05) with cesarean section rate: presence of a newborn intensive care unit and maternal-fetal medicine subspecialists, presence on the medical staff of obstetrician-gynecologist(s) as opposed to family physicians only, delivery volume >1500/y, urban location, and 24-hour in-house anesthesiology. When cesarean rates were corrected for acuity, facilities with maternal-fetal medicine specialists and a newborn intensive care unit had significantly lower rates (P < .001) and more uniform rates than otherwise similar institutions. CONCLUSIONS: More medically sophisticated physicians and institutions have lower cesarean rates when patient acuity is taken into account.

The risk of preterm birth across generations.

OBJECTIVE: To examine the risk of preterm birth for mothers who themselves were born before term. METHODS: Data were taken from a linked data base of birth certificates composed of two cohorts: 1) a parental cohort of women born between 1947 and 1957 and 2) their offspring born between 1970 and 1992. "Preterm mothers" were women in the parental cohort who were born at less than 37 weeks' gestation. "Term mothers" were women in the parental cohort born at or after 38 weeks' gestation. Preterm mothers and term mothers were matched for birth year, county of birth, marital status, parity, and age. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the risk of preterm delivery in preterm mothers. Multiple logistic regression was used to assess the interaction of concomitant variables with the risk of premature delivery. RESULTS: The risk of preterm birth was significantly higher in preterm mothers than in term mothers (OR 1.18; 95% CI 1.02, 1.37). The risk increased as the gestational age at the mothers' birth decreased (less than 30 weeks'; OR 2.38; 95% CI 1.37, 4.16). The interaction between maternal age and parity increased the risk of preterm delivery at less than 34 weeks in some age and parity strata. CONCLUSION: An increased risk of preterm delivery exists for women who themselves were born before 37 weeks' gestation. The risk is inversely correlated with the maternal gestational age at birth and is influenced by maternal age and parity.

Potential of immunotherapeutic treatment for recurrent pregnancy loss.

The problem of recurrent pregnancy loss frustrates couples and physicians alike. One major reason for these frustrations is that the precise aetiology of recurrent pregnancy loss is rarely determined during the routine clinical evaluation. In at least 50% of couples, no obvious aetiology is ascertained, and this fact has led many investigators to suggest an immunological cause for the disorder. Various immunotherapeutic regimens have been developed, including paternal leucocyte immunisation and intravenous immunoglobulin. Thus far, properly randomised and blinded trials have shown only a modest benefit from immunotherapy for recurrent pregnancy loss. One major problem is that there are no reliable and reproducible tests to identify any subsets of women with recurrent pregnancy loss who might potentially benefit from immunotherapy. Until there is a better understanding of the basic pathophysiology of recurrent pregnancy loss, all immunotherapies for the disorder will be empirical. Therefore, new immunotherapeutic regimens should be tested in randomised prospective trials prior to general acceptance by the medical community.

Intravenous immune globulin in the management of severe Rh D hemolytic disease.

Although intrauterine fetal transfusion has improved dramatically perinatal outcome in Rh D alloimmunization, in some cases the fetus is affected before transfusion is possible. Immune globulin (IVIG) administration is being increasingly used to successfully treat a variety of immune-mediated diseases, such as pregnancies affected by platelet alloimmunization. Although only a limited number of pregnancies have been reported, favorable outcomes with IVIG treatment of severe Rh disease have been described. We present a case report, review the published experience with IVIG treatment in severe, early-onset anti-D sensitization, and propose that IVIG may have an adjunctive role in the treatment of severe Rh isoimmunization.