Sage Journals: Discover world-class research

Abstract

Hypercoagulation has been reported in some studies to be associated with reproductive failures, such as unexplained infertility, IVF implantation failure and recurrent fetal losses. Many pregnancy-related disorders have been interpreted as consequences of impaired microvascular function and might be viewed as a mild form of venous thromboembolic disease. In the absence of clinical guidelines, there is a need for an evidence base regarding thrombophilic screening and antithrombotic therapy in cases of reproductive failure. This article will focus on the controversial effect of congenital and acquired thrombophilia on human fertility, and will review the English literature for relevant studies identified by searching PubMed® results between January 1966–November 2010 using the key words: ‘thrombophilia‘, ‘fertility’ and ‘infertility‘.

Keywords

assisted reproduction fertility infertility thrombophilia

The coagulation system plays a role in embryogenesis and reproduction as well as in placental development and function. The main organ for the physiological interaction between the reproductive system and the coagulation system is the placenta [1]. The human placenta has a microvascular coagulation milieu generated by the interaction of systemic factors with local activation mechanisms. During extravascular trophoblast invasion of the decidua, thrombin generated from decidual cell-expressed tissue factor forms a hemostatic envelope that protects against hemorrhage during the initial breaching of capillaries by extravascular trophoblasts, and subsequent invasion and remodeling of the spiral arteries and arterioles. The uteroplacental circulation resembles venous circulation in terms of its low pressure and low velocity, and may be particularly susceptible to thrombotic complications [1]. Trophoblast cells of the placenta are procoagulant through the expression of tissue factor and membrane phosphatidylserine. They are counterbalanced by fibrin formation inhibitors, including: tissue-factor pathway inhibitor-1 and −2, thrombomodulin, annexin V and the fibrinolytic inhibitors. The placenta expresses and produces coagulation components, which participate in placental vascular development and differentiation [1]. Genes that encode for proteins labeled as thrombogenic have been shown to be involved not only in coagulation and fibrinolysis but also in fertilization, embryonic development and tissue remodeling [2], as well as recurrent implantation failure [3], recurrent fetal loss [4 –6] and congenital abnormalities [7]. However, it should be remembered that a single genetic polymorphism is hardly ever the sole determinant of venous thromboembolic disease [8].

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Genetic thrombophilic polymorphisms are suspected to be associated with approximately 30% of obstetrical complications, such as: intrauterine growth retardation, placental abruption or placental infarction, pre-eclampsia, pregnancy induced hypertension and stillbirth, although a causal relationship has not been proven [9,10]. Congenital and acquired coagulation defects have been found in some studies to be more prevalent in women with reproductive failure, such as IVF implantation failure and recurrent fetal losses, but evidence remains limited and inconclusive. In a prospective evaluation of the prevalence of thrombophilia in women with unexplained infertility (n = 31), implantation failure (n = 26), or recurrent fetal loss (n = 30), no association between isolated or combined thrombophilia and reproductive failure has been observed [11,12]. However, some researchers argue that the introduction of thrombophilia screening in clinical practice should be more evidence based [13]. The major limitation in reviewing the literature is the heterogeneity of studies. Large cohorts are discussed along with much smaller ones that have a significantly lower statistical power.

Recurrent fetal loss

Fetal losses frequently occur in women planning to conceive, with rates of up to 50% of all conceptions [14]. The reported early loss rates in clinically detected pregnancies range from 12 to 15%, with an even greater subclinical embryonic loss rate. Most losses occur in early pregnancy, before 19 weeks of gestation. At least 2% of women of reproductive age suffer two or more consecutive fetal losses and approximately 1% of women have at least three fetal losses. Three or more consecutive spontaneous fetal losses with or without previous live births are defined as ‘recurrent fetal loss‘, although some authors accept two fetal losses as recurrent. This difference in definition may cause heterogeneity in studies, making interpretation somewhat difficult. Clinical factors associated with recurrent fetal loss include advanced maternal age, chromosomal abnormalities, anatomical alterations of the uterus, endocrine abnormalities, autoimmune syndromes, environmental factors and antiphospholipid antibody syndrome (APLAS) [14]. Approximately 30–40% of recurrent fetal losses remain unexplained after standard gynecological, hormonal and karyotype investigations [15], and this may lead to clinical depression and anxiety [16]. A significant association exists between consecutive recurrent abortions and pregnancy complications such as placental abruption, hypertensive disorders and Cesarean section. This association persists after controlling for variables considered to coexist with recurrent abortions [17].

Evidence that patients with inherited thrombophilic disorders run a higher risk for recurrent fetal loss has prompted many investigators to study the frequency of thrombophilic abnormalities in patients with recurrent fetal loss [18]. Fetal loss in women with thrombophilia can be explained by excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency [19]. An anecdotal observation published showed a higher rate of spontaneous fetal loss when the fetus was a carrier of factor V Leiden (FVL; G1691A) than when it was not [20]. However, other pathophysiological pathways are likely to be involved, since adverse pregnancy outcome can occur in women with thrombophilia in the absence of placental thrombosis [21]. Proposed mechanisms include prevention of conceptus implantation by damage to decidual or chorionic vessels or reduction in trophoblast invasiveness [22].

The FVL mutation and the prothrombin mutation (PTM; G20210A), the two most commonly studied thrombophilias among patients experiencing venous thromboembolism, have been investigated in patients with recurrent fetal loss and have shown inconsistent results. A meta-analysis established an association between FVL mutation and recurrent fetal loss, with a cumulative odds ratio of two. In other words, carriers of the FVL mutation have double the risk of recurrent fetal loss when compared with noncarriers. This association was confirmed by several methods of analysis. Carriers of the PTM were also found to have a double risk of recurrent fetal loss when compared with noncarriers. However, statistical significance of the association between PTM and recurrent fetal loss was dependent on the technique of analysis [23]. Another meta-analysis showed that some, but not all, of the thrombophilias examined are associated with fetal loss [24]. First trimester recurrent fetal loss is associated with FVL, activated protein C resistance, and PTM. This meta-analysis suggests that the assessment of women with early recurrent fetal loss should include screening for FVL, activated protein C resistance, PTM and protein S deficiency, whereas women with late fetal loss should be tested for FVL, PTM, and protein S deficiency. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) mutation were not found to be at increased risk of fetal loss. In a recent retrospective Danish cohort of 363 women with a minimum of three consecutive pregnancy loses, FVL and PTM had no prognostic value for achieving live birth [25], but in a recently published more established systematic review of prospective cohort studies, the absolute risk of loss in women with FVL was small (4.2 vs 3.2% in noncarriers), and there was no significant association between fetal loss and PTM [26]. In the recently published Anticoagulants for Living Fetuses (ALIFE) trial, either combination therapy with aspirin and low molecular weight heparin (LMWH) or aspirin alone improved the chance of a live birth for women with unexplained recurrent fetal loss [27]. Another recent multicenter randomized trial that was prematurely ended because of slow recruitment is the Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion (HABENOX) trial [28]. In the whole study group the live birth rate was 65% (95% CI: 58.66–71.74) for women with three or more miscarriages (n = 204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage. No significant difference in the live birth rate was found among the three groups. The British Committee for Standards in Haematology has recently recommended against antithrombotic therapy in pregnant women with a history of loss based on the results of testing for inherited thrombophilia [29]. Thus, the controversy is still ongoing, and inherited thrombophilia is probably a contributing factor in the multifactorial pathogenesis of fetal loss [30]. Since the association of recurrent fetal loss with inherited thrombophilia merely stems from meta-analyses, coupled with a small potential for harm, LMWH should be considered an experimental drug for these indications until data from controlled trials are published. At present, women with a history of placenta-mediated pregnancy complications, with or without a thrombophilia, should be followed closely without routine prophylactic LMWH other than for prevention of venous thromboembolism in limited circumstances [31].

The APLAS is defined by the persistent presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapy is the mainstay of treatment, given the high risk of recurrent thromboembolism that characterizes this condition [32]. The guidelines for lupus anticoagulant detection have been recently updated by the Committee of the International Society on Thrombosis and Haemostasis [33]. The APLAS is the only consensus-defined syndrome associated with recurrent early and late fetal losses. In a systematic review of 25 case–control studies exploring the risk of recurrent loss in women with APLAS, statistically significant associations were found between lupus anticoagulant or anticardiolipin moderate-high titers and recurrent fetal loss. The strongest association was seen in patients with lupus anticoagulant and late recurrent loss [34]. There is strong high-quality evidence (Grade 1A) and a recommendation for screening all women with recurrent fetal loss for antiphospholipid antibodies: lupus anticoagulant (IgM + IgG), anticardiolipin (IgM + IgG) and anti-β 2-glycoprotein 1 (IgM + IgG) [35].

Two pilot studies comparing the safety and efficacy of LMWH as an alternative to unfractionated heparin for the treatment of recurrent fetal loss in APLA showed equivalence between the options [36,37]. In a randomized clinical trial including patients with a history of recurrent fetal loss and at least one of the following: antiphospholipid antibody, inherited thrombophilia, or antinuclear antibody, patients were treated with LMWH plus aspirin or aspirin alone [38]. LMWH plus aspirin did not confer incremental benefit compared with aspirin alone for this population. Regardless of the treatment regimen, number of prior losses or antiphospholipid positivity, almost 80% of women with recurrent fetal loss had a successful pregnancy outcome. These findings contribute to the growing body of evidence that the emerging standard of care for this population includes LMWH/aspirin.

A recent first-reported multicenter, randomized controlled trial of LMWH and low-dose aspirin in women with recurrent fetal loss found no reduction in fetal loss rate with antithrombotic intervention in pregnant women with two or more consecutive previous fetal losses not associated with APLAS [39]. In this randomized trial, women were excluded if they were already known to have a thrombophilic disorder or the previous loss was associated with an anatomic, chromosomal, endocrine or immunologic cause. Despite the fact that there is no evidence from randomized trials that LMWH is equivalent to unfractionated heparin in preventing recurrent fetal loss, most centers now use LMWH because of greater safety and convenience. Results from randomized trials do not define an optimum treatment for women with fetal death or previous early delivery (<34 weeks gestation) owing to severe pre-eclampsia or placental insufficiency.

At present, anticoagulant or antiplatelet drugs should not be given routinely to pregnant women in order to prevent recurrent fetal loss [27,31]. However, clinicians should also be aware of thromboprophylaxis in this group of patients, especially during childbirth.

IVF implantation failure

Artificial reproductive techniques have become part of the routine care, with the prevalence ranging from 0.1 to 3.9% of all live born children in Europe [40] and an average of 2% in some parts of the USA [41].

Live birth rates as a consequence of assisted reproduction therapy have remained relatively constant, limited by the step of the pre-embryo implantation. According to the 2006 statistics of the Society for Assisted Reproductive Technology, 80–90% of IVF cycles resulted in embryo transfer (ET), but only 30–40% resulted in pregnancy [101]. The mechanisms responsible for the high rate of failure of the assisted reproductive procedures are largely unclear, and involve unsuccessful implantation or placentation [101]. Failure to implant in assisted reproduction is relatively common, and in fact, it is the main cause of IVF failure, despite transferring morphologically normal embryos. Factors affecting IVF-ET success include age, previous pregnancy, parity, basal hormonal levels, number of antral follicles before stimulation, endometrial thickness, embryo grading, position and length of the uterus, and the transfer technique [42 –49]. Implantation failure may recur, and three or more IVF cycles without pregnancy are usually regarded as repeated IVF-ET failures. This frustrating event has been attributed to many factors as mentioned before; however, for most, the causal relationship has not been established. Although not all studies concur, congenital and acquired coagulation defects have been found to be more prevalent in women with recurrent implantation failures [50 –54]. It has been postulated that invasion of maternal vessels by syncytiotrophoblast may be affected by local microthrombosis at the site of implantation, leading to implantation failure [55]. In a case–control study conducted on 45 patients with repeated IVF-ET failures and 44 controls, thrombophilia was more prevalent in the group of repeated implantation failure (26.7 vs 9.1% with p = 0.003) [55]. In another case–control study comprising 90 women with three or more IVF-ET failures, 90 women with a successful pregnancy after their first IVF-ET cycle and 100 women who conceived spontaneously with at least one uneventful pregnancy and no previous fetal loss, thrombophilia was much more prevalent in the first group. The incidence of thrombophilia was 68.9, 25.6 and 25%, respectively (p < 0.01) [56]. Conversely, in a case–control study of 234 women undergoing IVF and intracytoplasmic sperm injection compared with 234 women who conceived naturally, maternal thrombophilia was not associated with failure to achieve pregnancy after assisted reproductive procedures [57]. A survey done in the UK found that anticardiolipin antibodies and lupus anticoagulant were the most common investigations suggested for repeated IVF-ET failures [58]. A recent study looked at whether the FVL mutation is a cause of in vitro fertilization failure. FVL is the most common hereditary thrombophilia, and in the USA, the overall prevalence of this mutation is between 3 and 7% [59]. In a cohort of 182 women undergoing IVF, screening for this mutation in the general IVF population found no association between the FVL mutation and nonpregnancy after IVF, perhaps because of the low prevalence of the mutation in the study population [60]. In a cohort of 51 consecutive women with three or more failed IVF-ET cycles, no increased prevalence of FVL, PTM and MTHFR was found compared with the control group [61]. Some experts suggest thrombophilia screening prior to embarking on the fourth ET, as intervention with heparin may be required [62].

Numerous interventions have been published to increase the IVF success rate [63], but only few are evidence based and can be offered to couples with infertility [64]. These interventions include hysteroscopy [65,66], removal of hydrosalpinx [67], thromboprophylaxis for thrombophilia [68] and assisted hatching [69]. In a first reported prospective cohort study of 273 women undergoing a protocol combining the aforementioned evidence-based interventions [70], the pregnancy rate was 47% and the clinical pregnancy rate was 41%.

The notion that coagulation disorders may lead to implantation failure led to the use of anticoagulants, mainly heparin, during assisted reproduction. Several studies have examined the effect of heparin on the outcome of IVF in women with antiphospholipid antibodies [51,71 –73]. Despite the heterogeneity of studies, results suggest a potential improvement in pregnancy outcomes with anticoagulant therapy.

More recently, heparin has been proposed to play a role in the complicated process of implantation beyond its anticoagulant effects [62,74]. Several lines of evidence from in vivo and in vitro studies suggest a beneficial effect of heparin on embryo implantation through interactions with several adhesion molecules, growth factors, cytokines and enzymes such as matrix metalloproteinases [62]. In a cohort of 150 women with two or more failed assisted reproduction treatment cycles, who were randomly assigned to receive 1 mg/kg/day of LMWH or no treatment from oocyte retrieval to 12th week, implantation rates were 24.5 and 19.8% in the LMWH and control groups, respectively (p = 0.33), and live births were 34.7 versus 26.7%, respectively (p = 0.29) [75]. Despite the lack of statistical significance, the relative increase by 30% in live births with LMWH may be regarded as a clinically significant trend, necessitating further research. Failure to demonstrate statistical significance may be due to the limited sample size.

The first placebo-controlled, randomized trial to evaluate the efficacy of thromboprophylaxis using enoxaparin 40 mg/day in a cohort of 83 women with a history of three or more previous IVF failures, who had at least one thrombophilic defect, was recently published [68]. Patients who received LMWH for thromboprophylaxis had a significant increase in the implantation and pregnancy rates compared with the placebo controls (20.9 vs 6.1% and 31 vs 9.6%, respectively; p < 0.001 and p < 0.05, respectively). A significant increase in the live birth rate was observed in the heparin-treated group compared with placebo (23.8 vs 2.4%, respectively; p < 0.01). This study was criticized for its “methodological weakness”, and for heparin being used prior to demonstration of its efficacy in carefully designed randomized controlled clinical trials [76].

Unexplained infertility

Unexplained infertility is a diagnosis made after a complete workup, excluding hormonal and anatomical abnormalities (by transvaginal ultrasonography, hysterosalpingogram and/or hysteroscopy), as well as normal semen analysis according to the 2000 WHO criteria (>2 ml volume, >20,000,000 sperm/ml, >40,000,000 total sperm count, >50% progressive motility, >30% normal morphology) [77]. If no pregnancy is achieved after 1 year of sexual intercourse without contraception, unexplained infertility can be asserted. The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, clomiphene citrate, intrauterine insemination, controlled ovarian hyperstimulation with intrauterine insemination and IVF.

The frequencies of inherited thrombophilias (including FVL, factor V H1299R [R2], PTM, factor XIII V34L, β-fibrinogen 455G>A, PAI-1 4G/5G, HPA1 a/b [L33P], MTHFR, and MTHFR A1298C) among 92 women with unexplained infertility, were compared with those among 60 fertile control women [78]. In another cohort of 32 women with unexplained infertility compared with 130 women with recurrent fetal loss, the only statistical association between the two groups was for factor V H1299R mutation heterozygosity and for MTHFR homozygosity [79]. It has been found that MTHFR was the only specific gene to show a significant difference between women with a history of unexplained infertility and control subjects. The exact mechanisms of how abnormalities in folic acid metabolism cause reproductive problems are unclear. Insufficient methylation of critical metabolites has been suggested as a possible mediator of problems in cell division [80]. It has also been shown in another study that MTHFR affects follicular estradiol synthesis [81].

Conversely, in a case–control study including 100 women with unexplained infertility compared with a control group of 200 apparently healthy women, no association was found with the presence of the most common thrombophilia traits (FVL, PTM and MTHFR) [82].

Interestingly, in men, increased sperm count may account for the high population frequency of FVL [83].

Thrombotic risk & assisted reproductive treatment

One of the risks in assisted reproductive treatment that should be considered is thrombosis. Thromboembolic disease, a complication of ovarian stimulation, is generally considered to be rare but life-threatening, occurring mainly during ovarian hyperstimulation syndrome (OHSS) or following a treatment cycle that results in pregnancy. OHSS is one of the most serious complications of assisted reproductive technologies, and is characterized by massive outflow of intravascular fluid into third space resulting in hemoconcentration, leukocytosis oliguria and electrolyte imbalance. OHSS can be complicated by renal insufficiency, hepatic failure or thromboembolic disease. The overall risk of venous thrombosis in women with OHSS is small, and estimated to be 0.1% per treatment cycle [84]. In a review of 54 cases of thromboembolism during assisted conception treatments reported in the literature, 66% were associated with OHSS and 84% with a pregnancy cycle [85]. Approximately three-quarters of patients had venous thrombosis, and surprisingly, 60% of them had it in the upper limb, neck and head veins, which are regarded as unusual sites of deep venous thrombosis. Most were not associated with central venous catheters. Although there may be some reporting bias in publishing cases of upper extremity thrombosis given its rarity, these reports suggest that upper extremity thrombosis, for unknown reasons, is not an uncommon site of thrombosis in this clinical situation.

The reason might be that in women with OHSS, peritoneal fluid containing high concentrations of estrogens is collected into the lymphatic system, and may even be concentrated during lymphatic passage, leading to extremely high hormone levels. Ultimately, this lymphatic fluid is drained into the upper extremity veins in close proximity to the internal jugular, the subclavian and the brachial veins. This in combination with approximately 1000-fold elevated estrogen levels in women with OHSS and, particularly, high levels in the peritoneal fluid, offers a plausible explanation for the specific occurrence of upper extremity thrombosis [86].

Arterial thromboses in this report affected 25% of patients and most commonly presented as stroke [85]. The reason why these individuals develop thrombosis is unclear. Typically used hormonal stimulation results in estradiol levels up to 10 times the normal basal levels [87]. OHSS can manifest by significant hemodilution associated with the development of pleural effusion and ascites, and compression of the pelvic veins from marked ovarian enlargement. Coagulation studies generally show increased coagulation factors, particularly fibrinogen and factor VIII, and decreased fibrinolysis [87]. OHSS is observed in approximately 2–6% of all IVF treatment cycles. If thrombosis occurs, it typically happens between the 7th and 10th weeks of gestation [88]. Underlying thrombophilias have not generally been detected in these women, although most patients were not tested for FVL and PTM. However, in a series of 54 cases [85], six had a personal history of thrombosis and two had a strong family history of thrombosis. Given the risks, it seems reasonable to institute thromboprophylaxis in a woman with a documented thrombophilia or a personal or familial history of prior thrombosis who is to receive assisted reproductive treatment, although the optimal drug and dosing regimen remain unknown [89]. In a cohort of 50 Czech women who had undergone controlled ovarian hyperstimulation for IVF complicated by severe OHSS, compared with women undergoing IVF without OHSS and healthy pregnant women with no history of infertility, no increased prevalence of FVL or MTHFR was found [90]. In the recent recommendations of the British Committee for Standards in Haematology [29], it is stated that testing asymptomatic women before assisted conception and those with OHSS is not indicated (1B; recommended based on moderate-quality randomized trials).

Future perspective

Controversies of thrombophilic screening and antithrombotic therapy in cases of reproductive failure are the future challenge. Ideally, women with reproductive failure should be enrolled in clinical studies, and evidence from these prospective trials would shed further light on the association between reproduction and coagulation. Until then, the introduction of recommendations regarding thrombophilic screening and antithrombotic therapy into clinical practice should be evidence-based, and the urge to use unproven treatments that could potentially cause harm should be avoided. Therapeutic decisions should be based on clinical circumstances and not on the results of (heritable) thrombophilia testing. Decisions regarding the use of antithrombotic therapy to prevent recurrent reproductive failure should be made after reviewing with the patient the current data and limitations of available studies, along with the potential benefits, harms and costs of any intervention.

Executive summary

The coagulation system has a role in normal reproduction.

Reproductive failure refers to unexplained infertility, IVF implantation failure and recurrent fetal loss.

Some studies found increased prevalence of heritable, as well as acquired, thrombophilias in women with reproductive failure.

Comparison between studies is complicated, because as more thrombophilias are checked the more likely it is to find an association.

Unfractionated heparin and low molecular weight heparin have been found in some studies to increase the rate of successful pregnancies in women with reproductive failure, but this should be proved in large randomized controlled trials.

The introduction of recommendations regarding thrombophilic screening and antithrombotic therapy into clinical practice should be evidence-based.

Anticoagulant or antiplatelet drugs should not be given routinely to pregnant women in order to prevent recurrent fetal loss.

Women with reproductive failure should be enrolled in clinical studies.

Therapeutic decisions should be based on clinical circumstances and not on the results of heritable thrombophilia testing.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Lanir

Aharon

Brenner

. Haemostatic mechanisms in human placenta. Best Pract. Res. Clin. Haematol. 16(2), 183–195 (2003).

Rawlings

Barrett

. Evolutionary families of peptidases. Biochem. J. 290(Pt 1), 205–218 (1993).

Coulam

Jeyendran

Fishel

Roussev

. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod. Biomed. Online 12(3), 322–327 (2006).

Coulam

Jeyendran

Fishel

Roussev

. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am. J. Reprod. Immunol. 55(5), 360–368 (2006).

Goodman

Coulam

Jeyendran

Acosta

Roussev

. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am. J. Reprod. Immunol. 56(4), 230–236 (2006).

Coulam

Wallis

Weinstein

DasGupta

Jeyendran

. Comparison of thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis. Am. J. Reprod. Immunol. 60(5), 426–431 (2008).

10.

Botto

Yang

. 5,10-methyl-enetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am. J. Epidemiol. 151(9), 862–877 (2000).

11.

Lane

Grant

. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 95(5), 1517–1532 (2000).

12.

Kupferminc

Eldor

Steinman

. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N. Engl. J. Med. 340(1), 9–13 (1999).

13.

Robertson

Langhorne

. Thrombophilia in pregnancy: a systematic review. Br. J. Haematol. 132(2), 171–196 (2006).

14.

The largest meta-analysis done on thrombophilia traits and the risk of pregnancy complications

15.

Bellver

Soares

Alvarez

. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum. Reprod. 23(2), 278–284 (2008).

16.

Ricci

Simeone

. Thrombophilic screening in clinical practice should be evidence-based. Hum. Reprod. 23(11), 2610–2601 (2008).

17.

Lindhoff-Last

Luxembourg

. Evidence-based indications for thrombophilia screening. Vasa 37(1), 19–30 (2008).

18.

Rai

Regan

. Recurrent miscarriage. Lancet 368(9535), 601–611 (2006).

19.

Branch

Silver

Blackwell

Reading

Scott

. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet. Gynecol. 80(4), 614–620 (1992).

20.

Craig

Tata

Regan

. Psychiatric morbidity among patients with recurrent miscarriage. J. Psychosom. Obstet. Gynaecol. 23(3), 157–164 (2002).

21.

Sheiner

Levy

Katz

Mazor

. Pregnancy outcome following recurrent spontaneous abortions. Eur. J. Obstet. Gynecol. Reprod. Biol. 118(1), 61–65 (2005).

22.

Brenner

. Inherited thrombophilia and pregnancy loss. Thromb. Haemost. 82(2), 634–640 (1999).

23.

Arias

Romero

Joist

Kraus

. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J. Matern. Fetal Med. 7(6), 277–286 (1998).

24.

Dizon-Townson

Meline

Nelson

Varner

Ward

. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am. J. Obstet. Gynecol. 177(2), 402–405 (1997).

25.

Mousa

Alfirevic

. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum. Reprod. 15(8), 1830–1833 (2000).

26.

Rand

Guller

Scher

Andree

Lockwood

. Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am. J. Obstet. Gynecol. 177(4), 918–923 (1997).

27.

Kovalevsky

Gracia

Berlin

Sammel

Barnhart

. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch. Intern. Med. 164(5), 558–563 (2004).

28.

Rey

Kahn

David

Shrier

. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet 361(9361), 901–908 (2003).

29.

Lund

Nielsen

Hviid

Steffensen

Nyboe Andersen

Christiansen

. Hereditary thrombophilia and recurrent pregnancy loss: a retrospective cohort study of pregnancy outcome and obstetric complications. Hum. Reprod. 25(12), 2978–2984 (2010).

30.

Rodger

Betancourt

Clark

. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 7(6), e1000292 (2010).

31.

Kaandorp

Goddijn

van der Post

. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N. Engl. J. Med. 362(17), 1586–1596 (2010).

32.

Visser

Ulander

Helmerhorst

. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb. Haemost. 105(2), 295–301 (2011).

33.

Baglin

Gray

Greaves

. Clinical guidelines for testing for heritable thrombophilia. Br. J. Haematol. 149(2), 209–220 (2010).

34.

Summary of the British recommendations regarding thrombophilia screening and management in pregnancy complications

35.

Bates

. Consultative hematology: the pregnant patient pregnancy loss. Hematology Am. Soc. Hematol. Educ. Program 2010, 166–172 (2010).

36.

Comprehensive, updated summary on the issue of recurrent pregnancy loss and thrombophilia

37.

Rodger

Paidas

McLintock

. Inherited thrombophilia and pregnancy complications revisited. Obstet. Gynecol. 112(2 Pt 1), 320–324 (2008).

38.

Lim

. Antiphospholipid antibody syndrome. Hematology Am. Soc. Hematol. Educ. Program 2009, 233–239 (2009).

39.

Pengo

Tripodi

Reber

. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J. Thromb. Haemost. 7(10), 1737–1740 (2009).

40.

Opatrny

David

Kahn

Shrier

Rey

. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J. Rheumatol. 33(11), 2214–2221 (2006).

41.

Bates

Greer

Pabinger

Sofaer

Hirsh

. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl.), 844S–886S (2008).

42.

The current official evidence-based recommendations of the American College of Chest Physicians on the issue of thrombophilia and pregnancy

43.

Noble

Kutteh

Lashey

Franklin

Herrada

. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil. Steril. 83(3), 684–690 (2005).

44.

Stephenson

Ballem

Tsang

. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J. Obstet. Gynaecol. Can. 26(8), 729–734 (2004).

45.

Laskin

Spitzer

Clark

. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J. Rheumatol. 36(2), 279–287 (2009).

46.

Clark

Walker

Langhorne

. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 115(21), 4162–4167 (2010).

47.

A first reported multicenter, randomized controlled trial on low molecular weight heparin and aspirin in women with two or more miscarriages

48.

Nyboe Andersen

Goossens

Bhattacharya

. Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum. Reprod. 24(6), 1267–1287 (2009).

49.

Centers for Disease Control and Prevention (CDC). Assisted reproductive technology and trends in low birthweight – Massachusetts, 1997–2004. MMWR Morb. Mortal. Wkly Rep. 58(3), 49–52 (2009).

50.

Templeton

Morris

Parslow

. Factors that affect outcome of in vitro fertilisation treatment. Lancet 348(9039), 1402–1406 (1996).

51.

Egbase

Al-Sharhan

Grudzinskas

. Influence of position and length of uterus on implantation and clinical pregnancy rates in IVF and embryo transfer treatment cycles. Hum. Reprod. 15(9), 1943–1946 (2000).

52.

Tang

. The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Hum. Reprod. 15(9), 1937–1942 (2000).

53.

Surrey

Schoolcraft

. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil. Steril. 73(4), 667–676 (2000).

54.

Schoolcraft

Surrey

Gardner

. Embryo transfer: techniques and variables affecting success. Fertil. Steril. 76(5), 863–870 (2001).

55.

Akande

Fleming

Hunt

Keay

Jenkins

. Biological versus chronological ageing of oocytes, distinguishable by raised FSH levels in relation to the success of IVF treatment. Hum. Reprod. 17(8), 2003–2008 (2002).

56.

Kovacs

Matyas

Boda

Kaali

. The effect of endometrial thickness on IVF/ICSI outcome. Hum. Reprod. 18(11), 2337–2341 (2003).

57.

Qublan

Malkawi

Tahat

. In vitro fertilisation treatment: factors affecting its results and outcome. J. Obstet. Gynaecol. 25(7), 689–693 (2005).

58.

Sher

Zouves

Feinman

. A rational basis for the use of combined heparin/aspirin and IVIG immunotherapy in the treatment of recurrent IVF failure associated with antiphospholipid antibodies. Am. J. Reprod. Immunol. 39(6), 391–394 (1998).

59.

Stern

Chamley

Norris

Hale

Baker

. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil. Steril. 80(2), 376–383 (2003).

60.

Stern

Chamley

. Antiphospholipid antibodies and coagulation defects in women with implantation failure after IVF and recurrent miscarriage. Reprod. Biomed. Online 13(1), 29–37 (2006).

61.

Geva

Amit

Lerner-Geva

Azem

Yovel

Lessing

. Autoimmune disorders: another possible cause for in vitro fertilization and embryo transfer failure. Hum. Reprod. 10(10), 2560–2563 (1995).

62.

Grandone

Colaizzo

Lo Bue

Checola

Cittadini

Margaglione

. Inherited thrombophilia and in vitro fertilization implantation failure. Fertil. Steril. 76(1), 201–202 (2001).

63.

Azem

Many

Ben Ami

. Increased rates of thrombophilia in women with repeated IVF failures. Hum. Reprod. 19(2), 368–370 (2004).

64.

Qublan

Eid

Ababneh

. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum. Reprod. 21(10), 2694–2698 (2006).

65.

Martinelli

Taioli

Ragni

. Embryo implantation after assisted reproductive procedures and maternal thrombophilia. Haematologica 88(7), 789–793 (2003).

66.

Tan

Vandekerckhove

Kennedy

Keay

. Investigation and current management of recurrent IVF treatment failure in the UK. BJOG 112(6), 773–780 (2005).

67.

Ridker

Miletich

Hennekens

Buring

. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 277(16), 1305–1307 (1997).

68.

Rudick

Sammel

Kovalevsky

Shaunik

Barnhart

. Is factor V Leiden mutation a cause of in vitro fertilization failure? Fertil. Steril. 92(4), 1256–1259 (2009).

69.

Simur

Ozdemir

Acar

. Repeated in vitro fertilization failure and its relation with thrombophilia. Gynecol. Obstet. Invest. 67(2), 109–112 (2009).

70.

Nelson

Greer

. The potential role of heparin in assisted conception. Hum. Reprod. Update 14(6), 623–645 (2008).

71.

Excellent review on the role of heparin in assisted conception

72.

Margalioth

Ben-Chetrit

Gal

Eldar-Geva

. Investigation and treatment of repeated implantation failure following IVF-ET. Hum. Reprod. 21(12), 3036–3043 (2006).

73.

Nap

Evers

. Couples with infertility belong to a very vulnerable group, they should not be exploited. Hum. Reprod. 22(12), 3262–3263; author reply 3263 (2007).

74.

Bosteels

Weyers

Puttemans

. The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review. Hum. Reprod. Update 16(1), 1–11 (2010).

75.

El-Toukhy

Sunkara

Coomarasamy

Grace

Khalaf

. Outpatient hysteroscopy and subsequent IVF cycle outcome: a systematic review and meta-analysis. Reprod. Biomed. Online 16(5), 712–719 (2008).

76.

Kontoravdis

Makrakis

Pantos

Botsis

Deligeoroglou

Creatsas

. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx. Fertil. Steril. 86(6), 1642–1649 (2006).

77.

Qublan

Amarin

Dabbas

. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum. Fertil. (Camb.) 11(4), 246–253 (2008).

78.

First placebo-controlled, randomized trial evaluating the efficacy of thromboprophylaxis in a cohort of women with thrombophilia and history of repeated IVF implantation failure

79.

Das

Blake

Farquhar

Seif

. Assisted hatching on assisted conception (IVF and ICSI). Cochrane Database Syst. Rev. (2), CD001894 (2009).

80.

Sharif

Ghunaim

. Management of 273 cases of recurrent implantation failure: results of a combined evidence-based protocol. Reprod. Biomed. Online 21(3), 373–380 (2010).

81.

Sher

Feinman

Zouves

. High fecundity rates following in vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum. Reprod. 9(12), 2278–2283 (1994).

82.

Kutteh

Yetman

Chantilis

Crain

. Effect of antiphospholipid antibodies in women undergoing in vitro fertilization: role of heparin and aspirin. Hum. Reprod. 12(6), 1171–1175 (1997).

83.

Sher

Matzner

Feinman

. The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am. J. Reprod. Immunol. 40(2), 74–82 (1998).

84.

Fiedler

Wurfel

. Effectivity of heparin in assisted reproduction. Eur. J. Med. Res. 9(4), 207–214 (2004).

85.

Urman

Ata

Yakin

. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum. Reprod. 24(7), 1640–1647 (2009).

86.

Ricci

Giolo

Simeone

. Heparin's “potential to improve pregnancy rates and outcomes” is not evidence-based. Hum. Reprod. Update 16(2), 225–227; author reply 227–228 (2010).

87.

Quaas

Dokras

. Diagnosis and treatment of unexplained infertility. Rev. Obstet. Gynecol. 1(2), 69–76 (2008).

88.

Coulam

Jeyendran

. Thrombophilic gene polymorphisms are risk factors for unexplained infertility. Fertil. Steril. 91(4 Suppl.), 1516–1517 (2009).

89.

Bianca

Barrano

Cutuli

. Unexplained infertility and inherited thrombophilia. Fertil. Steril. 92(1), e4; author reply e5 (2009).

90.

Rosenquist

Ratashak

Selhub

. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc. Natl Acad. Sci. USA 93(26), 15227–15232 (1996).

91.

Hecht

Pavlik

Lohse

Noss

Friese

Thaler

. Common 677C→T mutation of the 5,10-methyl-enetetrahydrofolate reductase gene affects follicular estradiol synthesis. Fertil. Steril. 91(1), 56–61 (2009).

92.

Casadei

Puca

Privitera

Zamaro

Emidi

. Inherited thrombophilia in infertile women: implication in unexplained infertility. Fertil. Steril. 94(2), 755–757 (2010).

93.

Cohn

Repping

Buller

Meijers

Middeldorp

. Increased sperm count may account for high population frequency of factor V Leiden. J. Thromb. Haemost. 8(3), 513–516 (2010).

94.

Chan

Dixon

. The ‘ART’ of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thromb. Res. 121(6), 713–726 (2008).

95.

Stewart

Hamilton

Murdoch

. Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum. Reprod. 12(10), 2167–2173 (1997).

96.

Bauersachs

Manolopoulos

Hoppe

Arin

Schleussner

. More on: the ‘ART’ behind the clot: solving the mystery. J. Thromb. Haemost. 5(2), 438–439 (2007).

97.

Baumann

Diedrich

. Thromboembolic complications associated with reproductive endocrinologic procedures. Hematol. Oncol. Clin. North Am. 14(2), 431–443 (2000).

98.

Arya

Shehata

Patel

. Internal jugular vein thrombosis after assisted conception therapy. Br. J. Haematol. 115(1), 153–155 (2001).

99.

Schafer

Levine

Konkle

Kearon

. Thrombotic disorders: diagnosis and treatment. Hematology Am. Soc. Hematol. Educ. Program 2003, 520–539 (2003).

100.

Machac

Lubusky

Prochazka

Streda

. Prevalence of inherited thrombophilia in patients with severe ovarian hyperstimulation syndrome. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 150(2), 289–292 (2006).

101.

Society for Reproductive Technology. Clinic summary report www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0

Fertility,Infertility and Thrombophilia

Abstract

Keywords

Recurrent fetal loss

IVF implantation failure

Unexplained infertility

Thrombotic risk & assisted reproductive treatment

Future perspective

Footnotes

References