Thrombophilias and recurrent miscarriage

Inherited and acquired thrombophilias have been associated with recurrent pregnancy loss. Over recent years our ability to detect protein and genetic abnormalities responsible for thrombotic tendency has improved. We are now left with the task of deciphering which of these thrombophilias carries an increased risk for recurrent pregnancy loss. Acquired thrombophilias including lupus anticoagulant and anticardiolipin antibodies have been linked to recurrent pregnancy loss. However the evidence for the role of inherited thrombophilias such as, heterozygosity for the factor V Leiden, prothrombin G20210A mutation, the methylenetetrahydrofolate reductase (C677T MTHFR) mutation, as well as deficiencies of antithrombin, protein C and protein S is less clear. The methods for diagnosis and the evidence for their associations are discussed in this paper. Treatment modalities independent of those needed to prevent thrombotic events in pregnancy have generally not been studied. Given the present available data, there is insufficient evidence to include inherited thrombophilias in the initial evaluation of RPL. It is important to look for other, more common, causes of recurrent miscarriage in the evaluation of these patients.     

Sporadic pregnancy loss and recurrent miscarriage

Progesterone is essential for the maintenance of pregnancy, and progesterone deficiency is associated with miscarriage. The subject of whether progesterone supplementation in early pregnancy can prevent miscarriage has been a long-standing research question and has been investigated and debated in the medical literature for over 70 years. During this time, several different progestogens have been synthesised and tested for the prevention of miscarriage. In this chapter, we describe the prior evidence alongside the latest research using micronized natural progesterone as well as synthetic progestogens, which were used to treat both recurrent and threatened miscarriage. The totality of evidence indicates that women with a past history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone. The clinical implications of the findings are discussed.     

Recurrent fetal aneuploidy and recurrent miscarriage

OBJECTIVE: Some investigators have found a high frequency of abortus aneuploidy in women with recurrent miscarriage, suggesting the possibility of recurrent aneuploidy as a cause of recurrent miscarriage. Others contend that aneuploidy is not a cause of recurrent miscarriage. The purpose of this study was to investigate the relationship between fetal aneuploidy and recurrent miscarriage by estimating whether fetal aneuploidy is more common in patients with recurrent miscarriage than in patients with sporadic miscarriage METHODS: Recurrent miscarriage cases (n = 135) included women who had a subsequent miscarriage in which an abortus karyotype was obtained. Controls (n = 150) were patients experiencing a sporadic miscarriage who had fetal karyotypes performed as part of a study to assess the utility of abortus tissue for transplantation. Karyotype analysis was performed using standard G-banding techniques. RESULTS: Abortuses from 122 cases and 133 controls were successfully karyotyped. Thirty-one (25.4%) abortuses from cases and 56 (42.1%) from controls were aneuploid (odds ratio 0.47, 95% confidence interval 0.27-0.80). Aneuploid abortuses occurred in 20% of cases and 25% of controls, aged 20-29 years, 19% of cases and 24% of controls, aged 30-34 years, 35% of cases and 47% of controls, aged 35-39 years, and 50% of both cases and controls, aged 40 years or older (not significant). Of 30 cases in whom 2 or more miscarriages were karyotyped, 3 (10%) had aneuploidy in each abortus. CONCLUSION: In our population of recurrent miscarriage patients, abortus aneuploidy occurred significantly less often than in sporadic miscarriages. The rate of aneuploidy in this study was considerably lower than reported in other studies. If recurrent aneuploidy contributes to recurrent miscarriage, it does so in only a small number of patients. LEVEL OF EVIDENCE: II-2     

Evidence-based care of recurrent miscarriage

Between 0.5 and 1.0% of couples experience recurrent pregnancy loss (RPL), which is defined as three or more consecutive miscarriages. Losses are classified as pre-embryonic (<5 weeks), embryonic (5-10 weeks) or fetal (>10 weeks). Genetic abnormalities are responsible for RPL in 2-4% of these couples. Inadequate progesterone production has been proposed a cause of RPL and progesterone is given to prevent miscarriage, despite a lack of supportive evidence. The factor V Leiden and prothrombin G20210A mutations are common inherited thrombophilias also associated with RPL. Antenatal thromboprophylaxis is sometimes recommended although no data exist regarding efficacy. Antiphospholipid syndrome is known to cause RPL and antenatal thromboprophylaxis reduces the risk of miscarriage. Uterine abnormalities might also result in RPL. About 50% of cases of RPL have no identifiable cause. Alloimmune incompatibility has been proposed as a cause for RPL in these women. The concept of alloimmune-related RPL has not been scientifically validated.     

Endocrinological and endometrial factors in recurrent miscarriage

Objective To investigate the endocrinological and endometrial factors in women with unexplained recurrent miscarriage
Design Prospective, case study
Setting Recurrent miscarriage clinic, Jessop Hospital for Women, Sheffield
Participants One hundred and forty-four women with unexplained recurrent (≥ 3) miscarriages
Methods A blood sample was obtained in early follicular phase (day 3–5) to measure follicle stimulating hormone, luteinising hormone, prolactin, androgens and thyroid function; daily blood/urine samples were obtained from mid-follicular phase to measure luteinising hormone until the luteinising hormone surge was identified; endometrial biopsy and a further blood sample for progesterone measurement were obtained in the mid-luteal phase. A transvaginal ultrasonography was performed to evaluate ovarian morphology.
Results Hypersecretion of luteinising hormone or ultrasonographic features of polycystic ovarian disease was present in 8% and 7.8% of women, respectively. The free androgen index was elevated in 14.6% of subjects. In the mid-luteal phase, low progesterone level was found in 17.4% and delayed endometrial development was noted in 27.1% of women. Although women with recurrent miscarriage women and delayed endometrium had significantly lower progesterone levels than those with normal endometrial development, only 8/24 had mid-luteal progesterone levels below 30 nmol/L. Recurrent miscarriage was not associated with hyperprolactinaemia or abnormal thyroid function test.
Conclusions Endocrinological and endometrial abnormalities are present in about a quarter of women with unexplained recurrent miscarriage.     

The epidemiology of recurrent miscarriage: a descriptive study of 1214 prepregnant women with recurrent miscarriage

AIMS: To describe the characteristics of the prepregnant population attending the Recurrent Miscarriage Clinic (RMC) at the National Women's Hospital (NWH), Auckland, between 1986 and 2003, and to compare them with the overall obstetric booking population of the hospital. METHODS: The identifying details of 1214 prepregnant women attending the RMC were obtained. Both hospital and RMC records, which were kept separately, were retrospectively reviewed for demographic information and results of diagnostic investigations. Data from Auckland residents who attended the clinic were compared with data from all Auckland women booking or delivering at NWH. RESULTS: RMC attendees were older than the general NWH population, but had similar parity. Clinic attendees had a higher incidence of personal and family history of antepartum haemorrhage, fetal abnormalities, stillbirths and neonatal deaths than reported rates for the general population. Chromosomal anomalies were detected in 86 women, reproductive tract anomalies were found in 142 women, and polycystic ovarian syndrome was detected in 49 women. The majority (52.7%) of women had no identifiable cause for recurrent miscarriage detected. CONCLUSIONS: These data support the concept of women with recurrent miscarriage being at high risk for adverse obstetric outcomes including fetal abnormalities, stillbirths and neonatal deaths, even when the pregnancies are ongoing. We conclude that recurrent miscarriage is different from subfertility, and provide information of use in planning care for such women.     

Antiphospholipid antibodies and the investigation of recurrent miscarriage

Recurrent miscarriage (three or more consecutive miscarriages) affects 1% of the female population and this causes severe psychological morbidity in both the sufferer and their partner. For many years the aetiology of recurrent miscarriage in the majority of cases has remained unclear. Treatment regiments to improve pregnancy outcome were based on poorly-designed studies, often without control cohorts, which have subsequently been shown to be of no proven benefit. Over the past 15 years accumulating evidence has implicated the presence of antiphospholipid antibodies (APAbs) in the aetiology of recurrent miscarriage. APAbs can be found in 15% of the recurrent miscarriage population, and are associated with first and second-trimester miscarriages as well as other obstetric complications. Aspirin and subcutaneous heparin administration are of clinically-proven benefit in lowering the miscarriage rate in women with this condition. Maternal side effects of aspirin and heparin are rare but include thrombocytopenia and osteoporosis. No direct teratogenic effects of aspirin and heparin have been demonstrated but pregnancies complicated by APAbs need to be monitored closely for evidence of pre-eclampsia and intrauterine growth restriction.     

Counterfactual thinking and psychological distress following recurrent miscarriage

Developing an understanding of the cognitive factors mediating the emotional response to recurrent miscarriage may help explain how women process and adjust to such an experience. Counterfactual thinking is a cognitive response in which individuals simulate an alternative outcome to an event, and has been found to be related to both positive and negative outcomes following trauma. This study aimed to investigate the relationship between counterfactual thinking, distress, future plans and search for meaning following recurrent miscarriage. Sixty‐two women attending the Recurrent Miscarriage Clinic completed measures of anxiety, depression and thought listing tasks. Findings indicated a positive association between upward counterfactual thoughts and anxiety. Contrary to predictions, there was no relationship between counterfactual thinking and positive outcomes. Future plans were not related to lower distress, but there was some evidence that search for meaning was inversely related to distress. Clinical implications and proposals for future research are discussed.     

The medical and surgical management of recurrent miscarriage

Recurrent miscarriage is suffered by 1% of couples. It is extremely distressing causing stress to the woman and her family. A careful history and investigation can elicit a cause in around 50% of cases. Early pregnancy support and targeted treatments can increase the likelihood of success to approximately 80% in the subsequent pregnancy. Possible treatments include psychological support, aspirin, hCG injections and cervical cerclage, but these need to be considered carefully and explained fully to the couple before being tried. Extravagant claims and inappropriate, potentially dangerous therapies must be avoided. Management is best performed in specialized units with experience in this area.     

Progesterone for recurrent miscarriage: truth and deceptions

Recurrent miscarriage is known to affect 0.5-2% of pregnant women, and the standard investigative protocol fails to identify a specific cause in 50% of cases. Progesterone, a key hormone in pregnancy maintenance, has been used to support early pregnancy for decades. A growing body of considerable evidence indicates that in addition to women with luteal phase defects, women with idiopathic recurrent miscarriage may benefit from progestogen treatment, as progesterone has been shown to be an essential immunomodulatory agent in early pregnancy. It plays a critical role in the expression, modulation and inhibition of various growth factors, cytokines, cell adhesion molecules and decidual proteins. Some studies have revealed a remarkable improvement in pregnancy outcome after progestogen supplementation in women suffering from recurrent miscarriage. As most studies on this topic are of unsufficient statistical power, further research on the efficacy of progestogen treatment in affected women is required.     

Maternal caffeine consumption and sine causa recurrent miscarriage

Objective

The objective of this study was to examine whether the risk of sine causa recurrent miscarriage is associated with caffeine consumption during the periconceptional period and early gestation after controlling for pregnancy-related symptoms.

Study design

A retrospective case–control study was conducted in the Department of Obstetrics and Gynecology, University of Turin between 2008 and 2009. Fifty-two sine causa recurrent miscarriers and 260 healthy pregnant women were assessed. Data were analyzed using SPSS 17 for Windows.

Results

Caffeine consumption during the periconceptional period and early gestation was higher in sine causa recurrent miscarriers compared to healthy pregnant women. Moreover, each caffeine intake of 100 mg/day was associated with an increased odds ratio for sine causa recurrent miscarriage of 2724 (p for trend 0.001; 95% confidence interval [CI], 2.715–2.733), after adjusting for relevant confounding covariates.

Conclusion

Caffeine intake may increase the risk of sine causa recurrent miscarriage regardless of pregnancy-related symptoms and relevant covariates (such as age and tobacco use).