Inherited thrombophilia and pregnancy with fetal loss

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism (TE), but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. If the acquired thrombophilia is a well-established factor in etiology of fetal loss, the contribution of specific inherited thrombophilic genes is still controversial. The most common inherited traits are deficiency of antithrombin, protein C or protein S; Factor V Leiden; prothrombin G20210A; MTHFR C677T This review focuses on association of recurrent fetal loss with specific gene thrombophilic defects. Overall 52% of women with obstetric complication other than TE carry thrombophilic gene defects. The role of specific genes is different in etiology of early and late pregnancy loss. Inherited thrombophilia is now view as multicausal model; clinical manifestation can be heterogeneous result of gene-gene and gene-environment interactions. Therefore the criteria for genetic screening affected women with history of fetal loss should not be very stringent. The implication of screening for thrombophilic mutations allow to find women at risk of thrombosis and vascular gestational abnormalities in which antithrombotic drugs may have potential therapeutic benefit.     

Inherited thrombophilia in women with recurrent miscarriages and pregnancy loss in anamnesis--own experience

Single nucleotide polymorphisms of the genes coding for coagulation factors are the cause of congenital thrombophilia which might lead to recurrent miscarriages and fetal loss in advanced pregnancy. The most frequent reasons of thrombophilia are the following: factor V Leiden (1691G>A), mutation 20210G>A of prothrombin gene, and 677C>T of 5, 10-methylenetetrahydrofoliate reductase gene. The following article briefly summarizes the administration of antithrombotic prophylaxis (low-molecular weight heparin, acetylsalicylic acid) which seems to be an effective course of action to prevent complications in next pregnancies. What is more, adverse events after long-term usage of low-molecular weight heparin and acetylsalicylic acid in prophylactic doses have not been observed. Due to lack of complete randomized investigation about the inclusion of antithrombotic prophylaxis in this group of pregnant women, common scheme of administration and optimal dosage is yet to be established.     

Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss

Purpose: To evaluate the prevalence of thrombophilic disorders in polycystic ovarian syndrome (PCOS) women with history of recurrent pregnancy loss (RPL). Materials and methods: This study was carried out in 184 women with history of RPL, of which 92 of them were diagnosed with PCOS and 92 patients were without known PCOS. The prevalence of thrombophilic disorders was compared between the two mentioned groups. Results: According to the findings, 70.7% of PCOS women with history of RPL had thrombophilic disorders. The prevalence of protein C deficiency was significantly higher in PCOS group compared to the non-PCOS group (21.7% vs. 10.9%, p = 0.04). There was a trend toward higher prevalence of protein S deficiency in PCOS group compared to the control group, but the difference did not reach statistical significance (23.9% vs. 13%, p = 0.05). The prevalence of other thrombophilic disorders such as antithrombin III deficiency, homocysteine elevation, antiphospholipid antibody and Factor V Leiden was comparable between groups. Conclusion: The prevalence of thrombophilic disorders was more common in PCOS women than the normal group. The protein C deficiency is associated with PCOS in women with history of RPL. There was a trend toward higher prevalence of protein S deficiency in PCOS women, which needs further study.     

Acquired and inherited thrombophilia in women with unexplained fetal losses

OBJECTIVE: The purpose of this study was to investigate the possible role of inherited and acquired thrombophilia in women with unexplained abortions and intrauterine fetal death. STUDY DESIGN: We included 75 women with >/=1 unexplained fetal loss, and 75 control subjects with at least 1 healthy term infant and without gestational complications. All of these women were tested for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; deficiencies of antithrombin-III, protein C, and protein S; and the presence of antiphospholipid antibodies and fasting homocysteine concentration. A placental histologic study was also carried out. RESULTS: Thirty-five percent of the 75 patients had thrombophilia (control subjects, 16%; P =.008; odds ratio, 2.78). This prevalence was more prominent in second and third trimesters (P =.0002; odds ratio, 6.3), and the presence of combined genetic defects was associated with intrauterine fetal death (P =.04; odds ratio, 12; 95% CI, 1.44-102). When we analyzed the overall gestations of the patients, we observed an increase of intrauterine fetal death in patients with thrombophilia (P =.01) and early pregnancy loss in patients without thrombophilia (P =.02). The analysis of the correlation between extensive placental infarctions and thrombophilic defects rendered values in the boundaries of significance (P =.05). CONCLUSION: The significant high prevalence of biologic causes in patients with late fetal loss suggests that a study of thrombophilia should be carried out, together with an assessment of a preventive treatment.     

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.     

A comprehensive screening analysis of antiphospholipid antibodies in Indian women with fetal loss

OBJECTIVE: The present study was aimed at a comprehensive analysis of acquired thrombophilia in a large series of Indian women with fetal loss. STUDY DESIGN: Four hundred and thirty women (median age 26 years, range 18-39 years) with unexplained fetal loss (median number of abortions 3, range 1-13) were screened for the presence of antiphospholipid antibodies (APA), i.e. lupus anticoagulant (LA), IgG/M antibodies for cardiolipin (ACA), beta 2 glycoprotein 1 (beta2 GP1) and annexin V. We also studied 100 normal healthy women (median age 24 years, range 18-30 years) who had at least one healthy child and did not have any miscarriage or other obstetric complications. RESULTS: The prevalence of persistently positive LA was 8.1% and 1% in the patients and controls, respectively (OR 8.7; 95% CI, 1.4-51; P<0.05). The overall prevalence of IgG and/or IgM antibodies for cardiolipin, beta 2 GP1 and annexin V were as follows-ACA 27.9% (OR 18.9; 95% CI, 5-70; P<0.05), beta 2 GP1 12.2% (OR 6.8; 95% CI, 1.8-25; P<0.05) and annexin V 14.6% (OR 17; 95% CI, 2.9-98; P<0.05). The conventional LA and ACA tests were positive 23.2% of the cases as against 1% in the controls (OR 14.8; 95% CI, 3.9-55; P<0.05). The prevalence of LA, ACA, beta 2 GP1 and annexin V antibodies as independent risk factors were observed in 0.5%, 16.5%, 5.4% and 7.8% in the patients as against 1% each in the controls. The overall positivity for any one of the APA studied was 42.6% (OR 10.2; 95% CI, 4.5-23; P<0.05). CONCLUSION: The present study thus indicates the importance of APA in women experiencing fetal loss where all the conventional causes of miscarriages have been ruled out. It also suggests that conventional APA assays (LA and ACA) are effective in the detection of a majority of APA positive cases and by the addition of other cofactor-dependent (beta 2 GP1 and annexin V) APA assays, there is a considerable increase in the diagnostic efficiency in the detection of APA.     

Genetic variant C677T in the MTHFR in women with recurrent early fetal loss

The aim of this study was to evaluate correlation of carrier status for thrombophilic gene mutation--C677T in the methylenetetrahydrofolate reductase (MTHFR) and recurrent early pregnancy loss. Recently inherited thrombophilia was discussed as a predisposed factor for early recurrent fetal loss (ERFL). We investigated carrier status for C677T genetic variant in 54 women with ERFL before 10 week of gestation and 67 women with one or more successful pregnancy. It was found significant prevalence of C677T genetic variant in MTHFR in women with ERFL compared with controls (p = 0.005). The significant high prevalence of C677T genetic variant in women with ERFL suggests that thrombophilia have an increased risk of early pregnancy loss and possibly, although the definition of the magnitude of risk will require prospective longitudinal studies.     

Obstetric implications of fetal inherited thrombophilia in thrombophilic women

ObjectivesThe relationship between fetal thrombophilic polymorphism and adverse pregnancy outcomes is still unclear. The aim of this study is to evaluate if fetal thrombophilia may affect obstetric and perinatal outcomes in thrombophilic women.Study designFrom 2007 to 2011 all patients with a known inherited thrombophilic mutation consecutively admitted to our labor ward at ⩾25 weeks of gestation with a singleton viable pregnancy were considered eligible for the purpose of the study. At the age of 1 year, the infants were tested for inherited thrombophilic mutations. Patients were then divided into two groups according to the presence or absence of any neonatal mutation.Main outcome measuresThe following outcome variables were then compared between the two groups: gestational age at delivery, birth weight, incidence of hypertensive disorders of pregnancy and SGA neonates.ResultsOverall, 67 pregnancies of 49 women were studied. Among them, the G20210A Prothrombin (32/67 or 47.7%) mutation and the Factor V Leiden mutation (31/67 or 46.3%) were the commonest findings, with a single patient presenting both. A thrombophilic mutation was found in 38 mother–infant pairs. The risk of all maternal and perinatal events including the incidence of hypertensive disorders disorders (5/29 or 17.2% vs 6/38 or 15.7% p = 1.00) and of SGA neonates (3/29 or 10.3% vs 7/38 or 18.4%, p = 0.49) was comparable between the two groups irrespective of the associated fetal thrombophilia.ConclusionsOur data suggest that women with inherited thrombophilia carrying a thrombophilic fetus are not at increased risk of adverse pregnancy outcomes.     

Chemical abortion in patients with recurrent fetal loss.

The incidence of chemical, or pre-clinical, abortion was determined in 10 women on 3 occasions after Day 8 after ovulation with a highly sensitive enzyme immunoassay for beta hCG carboxyterminal peptide. Chemical abortion is defined as occurrence of 0.25 mIU hCG/ml on 3 occasions after Day 8 of ovulation on the basal body temperature chart, but menses occurs on schedule. The subjects were selected from a group of 1120 women with history of repeated spontaneous abortion who had been evaluated at the Keio University Hospital between 1984-1990. These women had an average of 3.22 pregnancies, of which on average 2.9 had ended spontaneously. In 4 of these 10 women hCG was 0.25 mIU/ml in first morning urine, but their menses arrived on schedule, and they had no clinical signs of pregnancy. Levels of hCG were 0.25, or 0.25 mIU/ml less than 3 times in the other 6 women. The normal level of hCG in nonpregnant women was reported to be 0.16 mIU/ml. This is the 1st report of documented chemical abortion in a habitually aborting population.     

Increased plasma adrenomedullin in women with recurrent pregnancy loss

OBJECTIVE: To evaluate vascular changes and uterine perfusion in women with recurrent pregnancy loss. METHODS: We measured plasma levels of adrenomedullin of 100 pregnant women in the midluteal phase of a nonpregnant cycle (control group: n = 62; recurrent pregnancy loss group: n = 38). We measured the pulsatility index (PI) in the uterine arteries by transvaginal pulsed Doppler ultrasonography at the same time. RESULTS: The plasma level of adrenomedullin in women with recurrent pregnancy loss (5.6 +/- 1.9, mean +/- standard deviation) was significantly higher (P >.001) than that in control women (3.6 +/- 1.7). Uterine arterial PI of women with recurrent pregnancy loss (2.70 +/- 0.47) was significantly higher (P >.001) than that in control women (2.09 +/- 0.39). Plasma level of adrenomedullin had a significant positive correlation with uterine arterial PI both in the control group (r =.58, P <.001) and in the recurrent pregnancy loss group (r =.78, P <.001). Both plasma adrenomedullin concentration (7.2 +/- 2.3) and uterine arterial PI (3.06 +/- 0.36) were significantly high in women with antiphospholipid antibodies. CONCLUSION: Plasma adrenomedullin may serve as a useful biochemical marker for recurrent pregnancy loss caused by impaired uterine perfusion.     

Basal hormone levels in women with recurrent pregnancy loss

The potential role of endocrine abnormalities during the follicular phase in women with unexplained recurrent pregnancy loss was investigated in a retrospective study. Eighty women with recurrent pregnancy loss underwent routine work-up to exclude known associations with the condition. Following investigation ,58 women failed to reveal an identifiable cause ,and were therefore classified as having unexplained recurrent pregnancy loss. The control group consisted of women with known causes of abortions ,such as uterine septum and parental chromosomal abnormalities. Mean age ,gravidity ,parity ,presence of infertility, previous number of miscarriages and duration of marriage were similar in both groups. Day-3 serum levels of follicle stimulating hormone (FSH) ,estradiol ,luteinizing hormone (LH) prolactin ,total testosterone, dehydroepiandrosterone sulfate (DHEAS) and thyroid stimulating hormone (TSH) were compared in the two groups. FSH ,estradiol ,LH ,prolactin and DHEAS concentrations were significantly higher in the unexplained recurrent pregnancy loss group than in the explained recurrent pregnancy loss group ,although serum concentrations of all hormones were within the normal range (p < 0.01). TSH and total testosterone levels were similar in the two groups (p > 0.05). There were no differences in the frequency of abnormal levels of hormones between the two groups (p > 0.05). We conclude that endocrine abnormalities in the follicular phase are not associated with recurrent pregnancy loss.     

Inherited thrombophilia in pregnancy: a systematic review

The purpose of this study was to conduct a systematic review of the literature of studies that examined the association between inherited thrombophilias and adverse pregnancy outcomes. We have evaluated developments in this area published since 1998. The published studies differ widely in design, mostly in patients and controls selection and in data analytic approach. Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia in pregnancy, specially regarding less prevalent thrombophilic defects, such as deficiencies in antithrombin, protein C, and S. Several studies on the association on factor V Leiden showed that it may play a role not only in second trimester losses, but also in pre-eclampsia, intrauterine growth-retardation, and placental abruption. Studies on the prothrombin gene mutation yielded conflicting results. Further large prospective studies are needed to asses the relative clinical and cost effectiveness of anticoagulant therapies in the prevention of pregnancy adverse outcomes.