Diagnostic value of screening tests in subgroups of women with recurrent pregnancy loss.

OBJECTIVE: To evaluate the diagnostic value of screening laboratory tests in women who had recurrent pregnancy loss (RPL). METHODS: A total of 252 women with RPL managed in our tertiary referral research and education hospital were included in the study. Risk factors recorded involved age, gravidity, parity, number of prior live births, number of pregnancy losses, and thrombophlia tests. The cases were divided into three different groups and each group was analyzed separately. RESULTS: There was no statistically significant difference between the first and second groups in terms of clinical and laboratory parameters (p > 0.05). In the third group, there was a statistically significant difference among cases in terms of parity, gravidity, number of pregnancy losses, serum AT III levels, APCR, and age of the women. According to the logistic regression model, odds ratios (95% CI) were 6.116 (3.797-9.852), 5.665 (2.657-12.079), 4.763 (3.099-7.321), 4.729 (3.080-7.260), 2.820 (1.836-4.333), and 1.911 (1.232-2.965), respectively. CONCLUSIONS: We do not recommend the screening of all women with RPL, but in women with high parity and those who had prior live birth pregnancies, increased AT III, and APCR may be diagnostic markers for subsequent pregnancy loss.

Recurrent first trimester pregnancy loss: revised definitions and novel causes.

PURPOSE OF REVIEW: First trimester pregnancy loss affects up to 15% of clinically recognized pregnancies. Whereas most couples will proceed to have successful subsequent pregnancies, 2-4% will suffer recurrent losses, often with no identifiable cause. In fact, up to 40-50% of patients suffering recurrent pregnancy loss (RPL) will have no identifiable cause for their losses. Whereas the high incidence of spontaneous fetal aneuploidy will ensure that this number will never fall to zero, its level suggests that additional causes and appropriate diagnostic testing await discovery. The definition, diagnostic work-up and appropriate interventions among patients with RPL remain controversial. Here, we will review those papers published in the last 1-2 years that improve our understanding of the definition of RPL, that confirm the utility of present testing paradigms or that pose novel causes and diagnostic approaches to patients with a history of RPL. RECENT FINDINGS: Standard definitions of RPL have been suggested by the American Society of Reproductive Medicine. Suggested potential diagnostic testing for RPL has been expanded to include male factors and new paradigms that address placental function, including the role of vascular endothelial growth factor, thrombosis and maternal-fetal immunology. SUMMARY: Standardized definitions for RPL and standardized approaches to initiating the RPL work-up will aid in study design and improve the applicability and implications of published findings. Appropriate investigation of novel causes for RPL may decrease the percentage of patients carrying the diagnosis of unexplained RPL.

Definitions of infertility and recurrent pregnancy loss.

The American Society for Reproductive Medicine has recently revised its definitions of infertility and recurrent pregnancy loss.

[Early pregnancy: revision of the Dutch terminology for clinical and ultrasound findings]. / De jonge zwangerschap: revisie van de Nederlandse benamingen voor klinische en echoscopische bevindingen.

The nomenclature used to describe findings during early pregnancy in The Netherlands needs to be revised. Various terms, like 'abortion' and 'miscarriage', are used to describe the same phenomenon, which is confusing for both patients and doctors. In addition, the meaning of some terms, like 'missed abortion', has changed over time. In accordance with the revision of the European nomenclature in the English language by the Special Interest Group for Early Pregnancy of the European Society for Human Reproduction and Embryology (ESHRE), a revision of the nomenclature in the Dutch language is needed as well. An unambiguous Dutch terminology pertaining to early pregnancy is recommended that corresponds to the English terminology; this includes the Dutch terms 'embryo' [embryo], 'foetus' [foetus], 'biochemische zwangerschap' [biochemical pregnancy], 'zwangerschap met onbekende lokalisatie' [pregnancy of unknown location], 'miskraam' [miscarriage], 'lege vruchtzak' [empty sac], 'gestopte hart-activiteit' [fetal loss], 'herhaalde miskraam' [recurrent miscarriage], 'extra-uteriene zwangerschap' [ectopic pregnancy], and 'trofoblast-ziekte' [gestational trophoblastic disease], because these are based on well-defined clinical and ultrasonographic concepts.

Semantics and pitfalls in the diagnosis of cornual/interstitial pregnancy.

OBJECTIVE(S): To clarify the respective definitions of cornual and interstitial pregnancy and to explore the difficulties in diagnosing these entities, particularly in the context of Müllerian fusion defects. DESIGN: Case study. SETTING: Community and tertiary-care hospitals. PATIENT(S): Female with recurrent pregnancy loss initially diagnosed with an interstitial pregnancy but subsequently found to have a cornual pregnancy in a bicornuate/septate uterus. INTERVENTION(S): Imaging with two-dimensional and three-dimensional ultrasound, hysterosalpingogram, serial beta-hCG measurement, administration of methotrexate and misoprostol, and aspiration and curettage. MAIN OUTCOME MEASURE(S): Measurement of beta-hCG levels and pathologic evaluation of aspiration and curettage material. RESULT(S): Correct diagnosis and eventual termination of cornual pregnancy and identification of a uterine anomaly were achieved. The process led to the development of an enhanced understanding of diagnostic modalities and their limitations with regard to the entities under discussion. CONCLUSION(S): Accurate diagnosis of an interstitial pregnancy requires that those reading and reporting ultrasounds use consistent, precise nomenclature. Clinicians must remain cognizant of the limitations of ultrasound in distinguishing cornual (intrauterine) from interstitial (ectopic) pregnancies and the influence of uterine anomalies on this distinction.

Management of recurrent early pregnancy loss.

Recurrent pregnancy loss is a devastating health problem that affects many couples who are trying to establish a family. Evaluation depends on a number of factors, including the pattern of pregnancy loss, underlying medical disease and life-style issues. A detailed obstetric history, including gestational age at the time of death, ultrasound, pathology and cytogenetic results, is key in the evaluation and management of recurrent pregnancy loss. This complex reproductive disorder requires a multidisciplinary approach since genetic, endocrinologic, anatomic, immunologic, infectious, thrombophilic and iatrogenic factors may require evaluation and management. Monitoring of subsequent pregnancies requires close supportive care.

Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work?

Immunological disturbances play a role in the majority of patients with recurrent miscarriage (RM) and therefore treatment with intravenous immunoglobulin (IvIg) has been tested in patients with RM in several trials. Seven placebo-controlled trials that were extremely heterogeneous with respect to patient characteristics and treatment procedures were carried out. One trial found that IvIg significantly improved pregnancy outcome in all patients whereas the remaining trials could either detect no treatment effect at all or only an effect in subsets of patients. In a meta-analysis, the pooled odds ratio for a new live birth in IvIg- versus placebo-treated patients with RM after a birth (secondary RM) was 1.60 (95% CI = 0.70-3.66). IvIg seems to be efficacious in patients with repeated second trimester intrauterine fetal deaths since it significantly (p < 0.01) increased the live birth rate in this subset compared with placebo. In most trials the design was suboptimal with regard to detecting any treatment effect of IvIg in RM due to low doses or starting the treatment late. A new large placebo-controlled trial should be conducted in RM patients with secondary RM or repeated second trimester fetal deaths and sufficient IvIg doses should be given with optimal timing.

Updated and revised nomenclature for description of early pregnancy events.

The nomenclature used to describe clinical events in early pregnancy has been criticized for lack of clarity and promoting confusion. There is no agreed glossary of terms or consensus regarding important gestational milestones. In particular there are old and poorly descriptive terms such as 'missed abortion' and 'blighted ovum', which have persisted since their introduction many years ago (Robinson, 1975) and have not undergone revision despite the widespread application of ultrasound for accurate clinical assessment and diagnosis. The authors are aware of these shortcomings in terminology and are keen to provide an updated glossary. We hope that this paper will facilitate the introduction of a revised terminology in an attempt to provide clarity and to enhance uptake and use in the literature as well as clinical assessment and documentation.

Differences in number and activity of peripheral natural killer cells in primary versus secondary recurrent miscarriage.

OBJECTIVE: To compare peripheral natural-killer (NK) cell numbers and activity in women with primary recurrent miscarriage, secondary recurrent miscarriage and controls. DESIGN: Observational study. Academic medical center. PATIENT(S): Thirty-eight women with primary recurrent miscarriage, 29 women with secondary recurrent miscarriage, and 25 control women. INTERVENTION(S): None.[1] The proportion of NK cells in the total lymphocyte population, [2] the concentration of NK cells per microliter of blood, and [3] NK activity (NKA), using both standard and whole-blood assays. RESULT(S): Primary aborters had the highest proportion and concentration of NK cells and had the highest activity using the standard assay. Secondary aborters had an intermediate level of these NK cell indices, whereas the control patients had the lowest levels. Using the whole-blood NKA assay, the differences between primary and secondary aborters were most apparent: primary aborters had significantly higher NKA than did either secondary aborters or control women (72, 40, and 35 lytic units, respectively). Approximately 50% of the variability in NKA could be attributed to differences in concentrations of NK cell per microliter of blood. CONCLUSION(S): The higher NKA evident in primary recurrent miscarriage and the reported higher efficacy of immunotherapy in primary aborters support the involvement of NK cells in the etiology of primary recurrent miscarriage.

Types of pregnancy loss in recurrent miscarriage: implications for research and clinical practice.

BACKGROUND: In recurrent pregnancy loss, there is much debate about cause and association, as exact pathophysiological mechanisms have not been elucidated. The aim of this study was to assess whether recurrent pregnancy loss (RPL) patterns differ according to causal/associated conditions, suggesting differing disease processes. METHODS: Following investigation, 427 women with RPL were classified into the following 'diagnostic' groups: idiopathic, oligomenorrhoea, antiphospholipid syndrome (APS) and 'possible' APS. A total of 323 subsequently conceived, and underwent serial ultrasonography in early pregnancy; of these, 87 (26.9%) miscarried, and the types of pregnancy loss for the four diagnostic groups were allocated to either embryo loss (fetal heart never seen) and fetal loss (fetal heart seen prior to pregnancy loss). RESULTS: Overall, there were 75 embryonic losses and 12 fetal losses. The fetal loss rates in each group were similar: idiopathic 5.1%, oligomenorrhoea 3.4%, 'possible' APS 4.9% and APS 4.8%. CONCLUSIONS: Serial ultrasound helps to discriminate type of pregnancy loss and demonstrates that embryo loss is more common than fetal loss. More importantly, pregnancy loss patterns do not seem to differ between diagnostic groups in a treated population. The fetal loss rate in each of the diagnostic groups is similar to that in other reported populations.

Prevalence of embryotoxic factor in sera from women with unexplained recurrent abortion.

PROBLEM: The presence of embryotoxic factors in sera from women with recurrent spontaneous abortion (RSA) has been proposed as a basis for classification of unexplained RSA. To determine the prevalence of circulating embryotoxins among women with idiopathic RSA, sera from 160 women were studied using the mouse blastocyst assay. METHODS: Two-cell embryos were collected from superovulated mated (CB6F1/J mice and cultured in media supplemented with fetal bovine serum (FBS) or 10% serum at 37 degrees C with 5% CO2 and high humidity. Each assay was run in triplicate using three mice with at least five embryos from each mouse. Results were determined by calculating the average percentage atresia for each mouse. FBS, known to support embryo proliferation, was used to control in each assay. RESULTS: The prevalence of embryotoxic factors among women experiencing RSA was 24.4% (39/160). There is no correlation found between the presence of embryotoxicity and phospholipid antibodies, lupus anticoagulant, and thyroglobulin/microsomal antibodies. CONCLUSION: The embryotoxicity assay can serve as a basis for a new approach for classification of unexplained recurrent spontaneous abortion.

A new hysteroscopic classification of and nomenclature for endometrial lesions.

STUDY OBJECTIVE: To establish a hysteroscopic classification of endometrial lesions based on a combined score: DESIGN: A prospective study to grade four features of endometrial lesions (thickness, surface, color, vascularization) and subdivide them as mild (low risk) and severe (high risk). SETTING: Gynecologic endoscopy unit of an obstetric and gynecology clinic. PATIENTS: Two hundred twenty-nine women with hysteroscopically diagnosed endometrial lesions. INTERVENTIONS: Hysteroscopic inspection of endometriotic lesions, with grading performed on the four features. MEASUREMENTS AND MAIN RESULTS: The sensitivity and specificity of our system were 86.9% and 87.4% for mild pathology, and 96% and 92.9% for severe pathology. CONCLUSIONS: This hysteroscopic classification of endometrial pathology can be useful for a better definition of endometrial lesions. The method has good sensitivity and specificity.

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.

Systematization of clinical management for recurrent aborters by combined immunological testing.

The natural outcomes of successive new pregnancies of 66 recurrent aborters were analysed in relation to their immunological profiles. The data demonstrated that the presence of anti-phospholipid antibodies (success rate 6.7%), positive anti-paternal cytotoxicity (8.7%) and a negative mixed lymphocyte reaction (MLR)-blocking effect (33.3%) in the patients' sera were factors associated with a poor prognosis. By the combined evaluation of these testings, a rational scheme of clinical management for recurrent aborters was established.

Recurrent miscarriage.

On epidemiological evidence, the definition of recurrent miscarriage should be three or more consecutive pregnancy losses. Data should be collected to 28 weeks' gestation but analysis up to 20-22 weeks' or 500 g fetal weight should also be possible. General practitioners and gynaecologists should do what they feel is suitable for couples whose history does not meet these criteria but a diagnosis of recurrent miscarriage should not be made. Women meeting the definition can be subdivided into primary and secondary groups, respectively consisting of those who have lost all previous pregnancies and those who have had one successful pregnancy followed by consecutive losses.

Recurrent spontaneous abortion.

The laboratory diagnosis and clinical management of unexplained recurrent spontaneous abortion (RSA) patients is a controversial issue in contemporary obstetrics. In this report, the results of laboratory investigations and immunotherapy of RSA patients referred to our Center since 1986 are detailed. Our analyses have resulted in grouping RSA patients into primary (1 degree), secondary (2 degrees), and unexplained classifications. Laboratory evaluation criteria included assays for both complement-dependent and complement-independent antipaternal antibodies as well as histocompatibility antigen tissue typing for HLA, A, B, C, and DR antigens. In addition, mixed lymphocyte cultures (MLC) were performed to assess the degree of HLA-D locus compatibility between couples and to test for the presence of MLC inhibitors in maternal blood. Immunotherapy options and the rationale for their use are given and preliminary outcome data are presented from randomized double-blinded, placebo-controlled clinical trials.

Clinical value of research in chronic spontaneous abortion.

We have focused on comparisons of abnormal with normal pregnancies. Humoral and cellular aspects were studied in 50 couples with unexplained consecutive pregnancy failures and compared with 15 fertile couples. The results show that spontaneous aborters generally fall into two groups: Primary spontaneous aborters are those women who, by the same husband, never have carried a pregnancy beyond 20 weeks; secondary spontaneous aborters have had, by the same husband, either a normal pregnancy or a pregnancy failure beyond the 20th week. Primary spontaneous aborting couples tend to share a significantly greater number of HLA antigens than do secondary aborters or normally fertile mates. Secondary spontaneous aborters manifest cytotoxic non-HLA-dependent antibody to husbands' lymphocytes in complement-dependent assays; these are antibodies to trophoblast-lymphocyte cross-reactive (TLX) antigens. Secondary but not primary aborters have complement-independent antibody-dependent cell-mediated cytotoxicity reactions to their husbands' lymphocytes. Both exhibit diminished mixed lymphocyte culture reactions between mating partners if the tests are done in autologous plasma; only primary aborters show poor reactions if the assays are done in control sera. Immunotherapy with nonhusband lymphocytes in more than 20 primary spontaneous aborters has resulted in greater than 90% successful subsequent pregnancies. Leukocyte immunotherapy has not been useful for secondary aborters, but two of three women have had normal pregnancies following daily subcutaneous injections of heparin. The clinical relevance of these findings will be discussed.