Recurrent miscarriage and long-term thrombosis risk: a case-control study

BACKGROUND: Recurrent miscarriage has been associated with antiphospholipid syndrome (APS) and other prothombotic conditions. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic recurrent miscarriage. METHODS: A retrospective case-control study was performed using validated questionnaires. A total of 141 women with recurrent miscarriage and APS alone were matched with 141 women with idiopathic recurrent miscarriage for age, number and type of pregnancy loss and number of years of follow-up. A subgroup of eight women included those who initially presented with recurrent miscarriage, thrombosis and APS. RESULTS: The mean length of follow-up was 7.3 years and response rate 74%. The incidence of thrombosis was similar in the recurrent miscarriage and APS women (6/1000 women-years) and in the idiopathic recurrent miscarriage women (2/1000 women-years) (P = 0.18). All eight women who presented with recurrent miscarriage, APS and thrombosis reported further thrombotic events. CONCLUSIONS: Both idiopathic and APS-associated recurrent miscarriage were associated with a similar long-term risk of thrombosis.     

Is endomyometrial injury during termination of pregnancy or curettage following miscarriage the precursor to placenta accreta?

AIMS: To determine the frequency with which myometrium is removed during vacuum terminations of pregnancy or dilatation and curettage after miscarriage, and to relate these findings to subsequent placenta accreta or its proxies. METHODS: Archival tissues from vacuum termination of pregnancy or dilatation and blunt curettage after miscarriage were examined for the presence of myometrium. The subsequent obstetric histories were scrutinised for manual removal of placenta, postpartum haemorrhage, or retained placenta. A retrospective study comparing the frequency of miscarriage and termination in women who had or did not have a manual removal was also performed. RESULTS: Myometrium was seen in the products of conception in 44% and 35% of termination and miscarriage tissues, respectively. One of nine women with myometrium at miscarriage had a postpartum haemorrhage in a subsequent pregnancy whereas, of the 21 women without myometrium at miscarriage, three required manual removal and seven had a postpartum haemorrhage afterwards. A past history of termination and/or miscarriage was more frequent in multigravid women who had a manual removal than those who did not. CONCLUSIONS: Endomyometrial injury is frequent at termination or dilatation and curettage after miscarriage, but the relation to subsequent placenta accreta remains unclear. Women requiring a manual removal of the placenta were likely to have had a past history of termination and/or miscarriage.     

Growth factors are markers of placental insufficiency in third-trimester miscarriage

The paper characterizes placental growth factors in the third trimester of pregnancy. The placental expression of vascular endothelial growth factor (VEGF) and transforming growth factor-beta2 (TGFbeta2) was studied in miscarriage after 34-37 weeks pregnancy and during term labor. Chronic placental insufficiency was diagnosed in miscarriage. The expression of VEGF and TGFbeta2 with trophoblast and decidual cells was decreased in miscarriage as compared with that during uncomplicated pregnancy. The growth factors under study are markers of chronic placental insufficiency in third-trimester miscarriage.     

Unresolved loss due to miscarriage: an addition to the Adult Attachment Interview

Abstract

Parental unresolved loss as assessed in the Adult Attachment Interview (AAI; George, Kaplan, & Main, 1985) is significantly associated with infant disorganized attachment. Lapses in the monitoring of both reasoning and discourse and reports of extreme behavioural reactions are evidence of the continuing presence of unresolved responses to loss. (Main, DeMoss, & Hesse, 1994). The original format of the AAI does not include a separate question concerning the experience of miscarriage. We added questions on this subject because, for many parents, miscarriage represents a significant loss. The questions and follow-up probes closely followed the format of the questions in the AAI about loss and were asked immediately after these questions. Answers to the questions about miscarriage were rated with the current classification system for unresolved loss. In a sample of 85 middle-class, non-clinical mothers of 1-year-old infants, thirty mothers (35%) reported that they had experienced a miscarriage. Scores on the 9-point rating scale for unresolved loss due to miscarriage were related to infant disorganized attachment behaviour, r(30) = .30, p = .05. Mothers' unresolved loss was not related to the amount of time that had passed since they had a miscarriage. Unresolved loss due to miscarriage was, however, related to the duration of the pregnancy before miscarriage, r(30) = .56, p = .004. Thus, including a question on miscarriage in the AAI may yield theoretically and clinically important information.     

A qualitative investigation into women's experiences after a miscarriage: implications for the primary healthcare team.

BACKGROUND: Approximately 16% of clinically confirmed pregnancies end in miscarriage. However, there is frequently no routine follow-up by the primary healthcare team (PHCT) to identify psychiatric morbidity after miscarriage. AIM: To explore women's experiences of miscarriage care that may impact on the ability of the PHCT to detect psychiatric morbidity after a miscarriage. DESIGN OF STUDY: Qualitative study using questionnaires, semi-structured interviews of patients, and interviews of healthcare professionals in focus groups. SETTING: Patients who had experienced a miscarriage were recruited from the gynaecology wards of a district general hospital. The healthcare professionals were recruited from 14 local general practices. METHOD: Post-miscarriage 'psychiatric cases' were identified using the hospital anxiety and depression (HAD) scale. A theoretical sampling technique was used to identify patients for semi-structured interviews. Interviews with healthcare professionals were conducted in three focus groups. RESULTS: Seven themes emerged from the interviews and focus groups that characterised the experience of patients and the perception of health professionals after a miscarriage. These were a need and desire for formal follow-up plans, poor recall and understanding of initial events, a need for more information and answers, normalisation of miscarriage by the PHCT, guilt and false assumptions, variable standards of care and skills deficiencies, and suggestions for further improvements. CONCLUSION: Themes that emerged from interviews, questionnaires, and focus groups indicate that there are deficiencies and inconsistencies in current care provision that are likely to impact on the ability of the PHCT to identify psychiatric morbidity following a miscarriage.     

Affective disorders in the aftermath of miscarriage: a comprehensive review

We review the research literature regarding affective symptomatology and disorders following miscarriage, with an emphasis on controlled studies and those that have been published since the last review article in 1996. The current review draws a sharp distinction between controlled and uncontrolled designs and clarifies the proper inferences that may be drawn from each, as only with an appropriate comparison group can it be determined whether the affective reactions following miscarriage are a specific consequence of the reproductive loss or of other life events common in women of reproductive age. In addition to providing an update of the literature on depression in the aftermath of miscarriage and associated risk factors, we also discuss reproductive loss in the context of attachment theory and grief, and present information on topics that were not covered extensively (or at all) by prior reviews, such as issues related to a pregnancy subsequent to miscarriage and the impact of miscarriage on the partners of miscarrying women. In the final section, treatment options relevant to miscarriage are presented.     

Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage

Activated protein C (APC) resistance, both in its congenital form, due to the factor V Leiden mutation, and in its acquired form, are important risk factors for systemic venous thrombosis. In view of the suspected thrombotic aetiology of some cases of recurrent miscarriage, the prevalence of APC resistance was determined among 1111 consecutive Caucasian women with a history of either recurrent early miscarriage (three or more consecutive pregnancy losses at <12 weeks gestation; n = 904) or a history of at least one late miscarriage (>12 weeks gestation; n = 207). A control group of 150 parous Caucasian women with no previous history of adverse pregnancy outcome was also studied. Acquired APC resistance was significantly more common among both women with recurrent early miscarriage (8.8%: 80/904; P = 0.02) and those with late miscarriage (8.7%: 18/207; P = 0.04) compared with controls (3.3%: 5/150). In contrast, the frequency of the factor V Leiden allele was similar among (i) women with recurrent early miscarriage (3.3%:60/1808; 58 heterozygotes and one homozygote), (ii) those with late miscarriage (3.9%:16/414; 14 heterozygotes and one homozygote) and (iii) the control group (4.0%:12/300; 12 heterozygotes). Acquired but not congenital APC resistance (due to the factor V Leiden mutation) is associated with both early and late miscarriage.     

Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study

BACKGROUND: Reproductive loss carries immeasurable human costs as well as being costly to the health care system. The objectives of this study were to determine the frequency and distribution of cytogenetically abnormal miscarriages from couples with recurrent miscarriage and to compare the results with the general population. METHODS: A total of 420 specimens, including 29 pre-clinical, 237 embryonic and 154 fetal, were successfully karyotyped from 285 couples with recurrent miscarriage. The results were stratified according to maternal age and compared with controls. RESULTS: In all, 225 specimens (54%) were euploid. A total of 195 specimens (46%) were cytogenetically abnormal, of which 131 (66.5%) were trisomic, 37 (19%) were polyploid, 18 (9%) were monosomy X, eight (4%) were unbalanced translocations and one was a combination of trisomy 21 and monosomy X. The frequency of euploid miscarriages was significantly higher in women <36 years of age with recurrent miscarriage compared with controls. The distribution of cytogenetic abnormalities in the recurrent miscarriage group was not significantly different from controls, when stratified by maternal age. CONCLUSIONS: Women <36 years of age with recurrent miscarriage have a higher frequency of euploid miscarriage. When stratified for maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with recurrent miscarriage compared with controls.     

Recurrent miscarriage: a defect in nature's quality control?

Recent data on recurrent miscarriage (RM) is discussed in the framework of the selection failure hypothesis which states, 'Recurrent miscarriage is the result of failure of the prevention of 'poor quality' embryos implanting, allowing embryos that are destined to fail to implant and present clinically as recurrent miscarriage. Thus, recurrent miscarriage is a failure of nature's quality control.' The assumption that RM results from the maternal rejection of normal fetuses is challenged and evidence reviewed regarding the contribution of abnormal embryos and endometrial receptivity. Further research is needed to understand the mechanisms of maternal tract-embryo interaction and move towards improved management of recurrent pregnancy loss.     

Spontaneous abortion in multiple pregnancy: focus on fetal pathology

Multiple pregnancy with its wide array of medical consequences poses an important condition during pregnancy. We performed perinatal autopsy in 49 cases of spontaneous abortion resulting from multiple pregnancies during the study period. Twenty-seven of the 44 twin pregnancies ending in miscarriage were conceived naturally, whereas 17 were conceived through assisted reproductive techniques. Each of the 5 triplet pregnancies ending in miscarriage was conceived through assisted reproductive techniques. There was a positive history of miscarriage in 22.4% of the cases. Monochorial placentation occurred more commonly in multiple pregnancies terminating with miscarriage than in multiple pregnancies without miscarriage. A fetal congenital malformation was found in 8 cases. Three of these cases were conceived through assisted reproductive techniques, and 5 were conceived naturally. Miscarriage was due to intrauterine infection in 36% of the cases. Our study confirms that spontaneous abortion is more common in multiple than in singleton pregnancies. Monochorial placentation predicted a higher fetal morbidity and mortality. In pregnancies where all fetuses were of male gender, miscarriage was more common than in pregnancies where all fetuses were female. Assisted reproductive techniques do not predispose to the development of fetal malformations.     

Microchimerism in recurrent miscarriage

Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnancy. We conducted studies to ask whether microchimerism that a woman acquired from her own mother is detectable before or during pregnancy in women with recurrent miscarriage. Fetal microchimerism was also assayed. Women with primary idiopathic recurrent miscarriage （n=23） and controls （n=31） were studied. Genotyping was conducted for probands, their mothers and the fetus, a non-shared polymorphism identified and quantitative polymerase chain reaction performed to measure microchimerismin peripheral blood mononuclear cells. Preconception comparisons were made between recurrent miscarriage subjects and controls, using logistic regression and Wilcoxon rank sum. Longitudinal microchimerism in subsequent pregnancies of recurrent miscarriage subjects was described. There was a trend toward lower preconception detection of microchimerism in recurrent miscarriage versus controls, 6% vs. 19% （1/16 vs. 6/31, P=0.2）. During pregnancy, 3111 （27%） of recurrent miscarriage subjects who went on to have a birth had detection of microchimerism from their own mother, whereas neither of two subjects who went on to miscarry had detection （0/2）. This initial data suggest that microchimerism from a woman＇s own mother, while detectable in women with recurrent miscarriage, may differ from controls and according to subsequent pregnancy outcome. Further studies are needed to determine the cell types,quantities and any potential functional role of microchimerism in recurrent miscarriage.     

Psychological sequelae of miscarriage: a controlled study using the general health questionnaire and the hospital anxiety and depression scale.

This study was carried out to assess whether psychiatric morbidity after a miscarriage is higher than that associated with early pregnancy. A total of 60 consecutive women admitted to a Swansea hospital with a miscarriage were compared with 62 consecutive women who attended an antenatal clinic at the same hospital, using the 28-item general health questionnaire and the hospital anxiety and depression scale. These were completed both at initial contact and six weeks later. Women who had had a miscarriage were found to be significantly more anxious and scored higher on the subscale for severe depression than the pregnant women, both at initial assessment and six weeks later. At the six week assessment more somatic symptoms were also experienced by the group who had had a miscarriage. This study highlights the psychological disturbance associated with miscarriage. The primary health care team and hospital staff need to take this into consideration when organizing follow up for women who have had a miscarriage.     

Influence of thyroid autoimmunity and maternal age on the risk of miscarriage

OBJECTIVES: Recently, studies have shown an association between antiperoxidase for the detection of thyroid autoimmunity (TAI) and abortion. Another point to be considered is the association of high risk of abortion and maternal age. The aim of the present study was to evaluate if the association between TAI and miscarriage could also be verified whether a population of unselected pregnant young women who normally present a low risk of miscarriage. MATERIALS AND METHODS: We studied 534 pregnant women, by determining their serum thyroid antiperoxidase antibodies (TPO-Abs), thyrotropin (TSH) and free thyroxine (fT4) levels. Our end point was the pregnancy loss or live birth. RESULTS: Age ranged from 12 to 49 years (mean +/- S.D.; 23.5 +/- 5.9). Of 534 women, 29 (5.4%) were TPO-Ab positive. TSH levels were significantly higher in TPO-Ab-positive women compared with TPO-Ab negative women (median; 1.9 versus 1.1; P = 0.001). Elevated TSH levels were found in 13.8% (4 of 29) of the TPO-Ab-positive women compared with only 2.4% (12 of 505) in the TPO-Ab-negative women. There were no significant differences in fT4 levels in relation with autoimmunity and risk of miscarriage. The overall risk of miscarriage was 2.4% (13 of 534). Risk of miscarriage was significantly higher among women older than 35 years (7.7%), TPO-Ab positive (10.3%) and presenting high levels of TSH (12.5%). These factors remained independently associated with the risk of miscarriage in full multivariate analysis. CONCLUSIONS: We conclude that TAI is independently associated with is a higher risk of miscarriage in a population of unselected pregnant presenting a low risk of miscarriage.     

The Balance of the Immune System between T Cells and NK Cells in Miscarriage

Immunological dysfunction has been proposed to explain the etiology of recurrent pregnancy loss (RPL). The immunological environment differs between the decidua basalis and decidua parietalis, and also between RPL cases with normal fetal chromosomes and those with abnormal fetal chromosomes. The problem with analyzing decidual tissues from spontaneous abortions is that cause versus effect phenomena are difficult to distinguish. Recent data show that the immune system in a late‐stage miscarriage is completely different from that in an early‐stage miscarriage. If immunocompetent cells can cause RPL, the immunological environment may be a causative factor, especially in an early‐stage miscarriage, at the decidua basalis, and/or in cases of RPL with a normal embryo. Careful examination of the immune system at the decidua basalis in an early‐stage miscarriage in RPL cases with normal fetal chromosomes may reveal useful information. This paper aimed at finding a cause of RPL by analyzing the balance of the immune system between T cells and NK cells in an early‐stage miscarriage.     

Treatment options for threatened miscarriage

Threatened miscarriage, as demonstrated by vaginal bleeding with or without abdominal cramps, is a common complication of pregnancy. It occurs in about 20% of recognised pregnancies. Risk of miscarriage is increased in older women and those with a history of miscarriage. Low serum levels of progesterone or human chorionic gonadotrophin (hCG) are a risk factor for miscarriage. Other risk factors include heavy bleeding, early gestational age and an empty gestational sac of >15–17 mm diameter. Clinical history and examination, maternal serum biochemistry and ultrasound findings provide valuable information about the prognosis and are important to establish in order to determine potential treatment options. Although bed rest is the most common choice of treatment, there is little evidence of its value. Other options include luteal support with progesterone, dydrogesterone or hCG. There is some evidence from clinical studies indicating that progesterone or dydrogesterone may reduce the rate of miscarriage, although further data from double-blind, randomised-controlled trials are necessary to confirm efficacy.     

Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage

PROBLEM: Recurrent miscarriage is a heterogeneous condition. While the role of acquired thrombophilia has been accepted as an etiology of recurrent miscarriage, the contribution of specific inherited thrombophilic genes to this disorder has remained controversial. We compared the prevalence of 10 thrombophilic gene mutations among women with a history of recurrent miscarriages and fertile control women. METHOD OF STUDY: A total of 150 women with a history of two or more recurrent pregnancy losses and 20 fertile control women with no history of pregnancy losses had buccal swabs taken for DNA analyses of 10 gene mutations [factor V G1691A, factor V H1299R (R2), factor V Y1702C, factor II prothrombin G20210A, factor XIII V34L, beta-fibrinogen -455G>A, PAI-1 4G/5G, HPA1 a/b (L33P), MTHFR C677T, MTHFR A1298C]. The prevalence of these mutations was compared between women experiencing recurrent miscarriage and controls. RESULTS: No differences in the frequency of specific gene mutations were detected when women with recurrent miscarriage were compared with control women. However, the prevalence of homozygous mutations and total gene mutations among patients with recurrent miscarriage was significantly higher than among controls. Homozygous mutations were found in 59% of women with a history of recurrent pregnancy loss contrasted to 10% of control women. More than three gene mutations among the 10 genes studied were observed in 68% of women with recurrent miscarriage and 21% of controls. CONCLUSION: Inherited thrombophilias are associated with recurrent miscarriage. This association is manifest by total number of mutations rather than specific genes involved.     

Menarcheal age and habitual miscarriage: evidence for an association

Among women who habitually miscarried (two or more miscarriages) we observed a modest association for increased risk of miscarriage of first pregnancies in those with younger (especially less than or equal to 11 years) and older (greater than or equal to 16 years) menarcheal age (quadratic G2 = 3.49, P = 0.062). No associations of menarcheal age with first pregnancy miscarriage were observed when analysed by age at first pregnancy, or with pregnancy number among women with only one miscarriage. Unusually early or late menarcheal age appears to increase the risk of miscarriage of the first pregnancy but only among women who will go on to habitually miscarry.     

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Chromosomal microarray analysis (CMA) has been used routinely in pediatric and prenatal genetic diagnosis in clinical practice, but it has rarely been applied to miscarriage analysis. In this study, we conducted a prospective study to evaluate the feasibility of CMA for genetic diagnosis of first‐trimester miscarriage specimens. We successfully analyzed 551 fresh miscarriage specimens using single‐nucleotide polymorphism (SNP) array. Among the specimens, 2.9% (16/551) had significant maternal cell contamination and were excluded from the study. Clinically significant chromosomal abnormalities were identified in 295 (55.1%) cases, including 214 (40%) with aneuploidy, 40 (7.5%) with polyploidy, 19 (3.6%) with partial aneuploidy, 12 (2.2%) with pathogenic microdeletion/microduplication, and 10 (1.9%) with uniparental isodisomy (isoUPD). Variants of uncertain significance were obtained in 15 cases (2.8%). Notably, isoUPD involving a single chromosome (chromosome 22) and two recurrent copy number variations, 22q11.2 microdeletion and 7q11.23 microdeletion, were identified as probably to be associated with miscarriage. The frequency and distribution of genetic aberrations in the spontaneous abortion group was not significantly different from those in the recurrent miscarriage group. Our study suggests SNP array is a reliable, robust, and high‐resolution technology for genetic diagnosis of miscarriage in clinical practice.     

Abnormal IL-2 receptor levels in non-pregnant women with a history of recurrent miscarriage

BACKGROUND: Immunological abnormalities have been found in pregnant women with a history of recurrent miscarriage. This study compared interleukin-2 receptor (IL-2R) levels in non-pregnant women with a history of recurrent miscarriage with those found in serum from a non-pregnant group with no such history. METHODS: Group 1 comprised 49 non-pregnant women with a history of recurrent miscarriage (at least three consecutive miscarriages). Group 2 comprised 22 non-pregnant women with no history of miscarriage. Serum IL-2R levels were measured in all patients. RESULTS: The results obtained showed that although all women were not pregnant at the time of sampling, IL-2R levels were significantly higher in women in Group 1 compared with those in Group 2 (1589 +/- 1289 versus 1082 +/- 823 pg/ml; P < 0.05). Follow-up data were available for 21 women from Group 1. The next pregnancy ended successfully for 14 of these women, while seven miscarried again. The IL-2R levels obtained pre-pregnancy were not significantly different between the two groups (1480 +/- 910 versus 1356 +/- 716 pg/ml). CONCLUSION: This study has shown that non-pregnant women with a history of recurrent miscarriage have raised IL-2R levels. These increased pre-pregnancy IL-2R levels did not necessarily predict miscarriage for the next pregnancy.     

Women's experiences of general practitioner management of miscarriage.

A study of 67 women one month after miscarriage identified significant levels of dissatisfaction with their medical care. There are particular problems in managing miscarriage which is very distressing for many women but a common clinical presentation for doctors. The reasons for women's dissatisfaction with their management are explained. Greater understanding of the experience of miscarriage should lead to better management and suggestions are made for better care for this common distressing experience.