Antiphospholipid Antibodies in Mental Disorders.

Thrombotic events striking the central nervous system are clinical criteria for the antiphospholipid syndrome (APS). Besides these, neuropsychiatric non-APS criteria manifestations are increasingly described in patients with persistently positive antiphospholipid antibodies (aPL). Among these are psychiatric manifestations. Animal models mainly describe hyperactive behavior and anxiety associated with hippocampal abnormalities. Cases of associations with psychosis, mood disorders, bipolarity, anxiety, obsessive-compulsive behavior, and depression have been reported but are still rare. Systematic human clinical association studies are concordant with a risk of psychosis, depression (simple to major), and anxiety disorders, but these are limited and of inconstant methodological quality. Brain imaging in patients, also insufficiently investigated, shows early signs of hypoperfusion and of subtle diffuse white matter changes compatible with an alteration of the axonal structure and changes in the myelin sheath. Direct interactions of aPL with the brain cells, both on cell lines and on animal and human brain biopsies, targeting both glial cells, astrocytes, and neurons, can be demonstrated. These clusters of arguments make the association between psychiatric diseases and aPL increasingly plausible. However, a considerable amount of clinical research must still be performed in accordance with the highest standards of methodological quality. The therapeutic management of this association, in terms of both prevention and cure, currently remains unresolved.

NEUT-RI, a surrogate marker of NETosis is lower in patients with strong IgM antiphospholipid antibodies.

BACKGROUND: Antiphospholipid antibody syndrome (APS) is an acquired autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or pregnancy complications. Recently, thrombotic APS was linked to increased neutrophil extracellular traps (NET) formation, suggesting an association between NETs and the severity of APS-related thrombosis. METHODS: We performed a retrospective study on patients tested for presence of antiphospholipid antibodies (990 negative and 374 positive) to evaluate the association between the neutrophil activation state, estimated by the neutrophil reactive index (NEU-RI), a parameter routinely available from some haematology analysers, and antiphospholipid antibodies. RESULTS: We do not observe a difference in NEU-RI values between positive and negative patients globally. However, interestingly, we highlight an association between high titers of IgM and low NEU-RI values indicating a lower neutrophil activation. CONCLUSION: Our data are in line with the recent questioning about the putative clinical consistency of positive solid-phase aPL IgM.

Catastrophic Antiphospholipid Syndrome.

Unlike classic APS, CAPS causes multiple microthrombosis due to an increased inflammatory response, known as a "thrombotic storm". CAPS typically develops after infection, trauma, or surgery and begins with the following symptoms: fever, thrombocytopenia, muscle weakness, visual and cognitive disturbances, abdominal pain, renal failure, and disseminated intravascular coagulation. Although the presence of antiphospholipid antibodies in the blood is one of the diagnostic criteria, the level of these antibodies can fluctuate significantly, which complicates the diagnostic process and can lead to erroneous interpretation of rapidly developing symptoms. Triple therapy is often used to treat CAPS, which includes the use of anticoagulants, plasmapheresis, and high doses of glucocorticosteroids and, in some cases, additional intravenous immunoglobulins. The use of LMWH is recommended as the drug of choice due to its anti-inflammatory and anticoagulant properties. CAPS is a multifactorial disease that requires not only an interdisciplinary approach but also highly qualified medical care, adequate and timely diagnosis, and appropriate prevention in the context of relapse or occurrence of the disease. Improved new clinical protocols and education of medical personnel regarding CAPS can significantly improve the therapeutic approach and reduce mortality rates.

Assessment-based management of placenta-mediated pregnancy complications: Pragmatism until a precision medicine approach evolves.

The management of pregnant women with thrombophilia and a history of gestational vascular complications remains debatable. Treatment of the latter is often based on clinical outcome rather than disease mechanism. While the use of venous thromboembolism prophylaxis in pregnancy is recommended for those at increased risk, the ability of anticoagulant and/or antiplatelet agents to lower the risk of placenta-mediated complications in this clinical setting remains controversial. The available guidelines are inconsistent in some situations, which reflects the limited evidence base. This review critically discusses risk assessment models (RAMs) and management strategies of women with thrombophilia and pregnancy complications, using clinical vignettes. RAMs, taking into account obstetric and thrombotic history as well as thrombophilia status, could drive a precision medicine approach, based on disease mechanism, and guide individual therapeutic interventions in high-risk clinical settings.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Antiphospholipid Antibodies in Pregnancy: Maternal and Neonatal Implications.

Antiphospholipid antibodies (aPL Abs) have long been associated with the occurrence of certain specific pregnancy morbidities, affecting both mother and fetus. Antithrombotic-based prophylactic regimens are the standard of care. Their intensity is modulated by the thrombotic history and has greatly improved the prognosis related to spontaneous morbidity. Observational studies show that this treatment is still associated with the persistence of excess of late-pregnancy placental diseases, calling for new or complementary developments, yet to be validated. Rigorous prospective multicentric validation of clinical and laboratory parameters capable of identifying those women and fetuses at a risk of pejorative evolution, thus early prognosis, is a priority issue. These will make it possible to develop customized treatments and test them. Furthermore, there are still concerns, particularly neurodevelopmental ones, about children born to aPL Ab-positive mothers, and clarification based on regular, more systematic evaluations is required. Even after pregnancy, women with a pure obstetrical antiphospholipid syndrome are at a greater risk of venous and arterial thrombosis over time, and prevention needs to be improved. These women also appear to develop more psychiatric and mood disorders. Central nervous system imaging using high-resolution techniques has shown subtle impairments in the white matter, associated with the most pathogenic aPL Abs and the clinical significance of this is under investigation. These mothers also seem to develop an excess of cancers. The systemic impact of aPL Abs is gradually being suspected, although this requires further evidence, and prevention should be envisaged.

Clonal haematopoiesis of indeterminate potential in patients with venous thromboembolism.

Over the last decade, the concept of Clonal haematopoiesis of undetermined potential (CHIP) has emerged. Low frequency somatic mutations in hematopoietic cells can occur with age and might allow formation of clones in individuals with no characterized haematological pathology. These CHIP mutations are associated with an increased risk of cancer or atherothrombosis, and their prevalence are more and more studied in pathologies with an inflammatory component. In our study, we analysed, by next generation sequencing, the prevalence of CHIP mutation in 94 patients with deep venous thrombosis (DVT), distinguishing two clinical phenotypes: provoked distal and non-provoked proximal DVTs. We show that there is no difference in CHIP prevalence between these two groups, nor with a matched-aged control group. The number of mutation per patients and the affected genes remain also the same between the three groups. Consequently and despite the relative small number of patients in each cohort, it seems that CHIP is not a strong concern in venous thromboembolism.

Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort.

Malignancies can be associated with positive antiphospholipid antibodies but the incidence of cancer among women with the purely obstetric form of antiphospholipid syndrome (APS) is currently unknown. Our aim was to investigate the comparative incidence of cancers in women with a history of obstetric APS within a referral university hospital-based cohort (NOH-APS cohort). We performed a 17-year observational study of 1,592 non-thrombotic women with three consecutive spontaneous abortions before the 10th week of gestation or one fetal death at or beyond the 10th week of gestation. We compared the incidence of cancer diagnosis during follow-up among the cohort of women positive for antiphospholipid antibodies (n=517), the cohort of women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n=279) and a cohort of women with negative thrombophilia screening results (n=796). The annualized rate of cancer was 0.300% (0.20%-0.44%) for women with obstetric APS and their cancer risk was substantially higher than that of women with negative thrombophilia screening [adjusted hazard ratio (aHR) 2.483; 95% confidence interval (CI) 1.27-4.85]. The computed standardized incidence ratio for women with obstetric APS was 2.89; 95% CI: 1.89-4.23. Among antiphospholipid antibodies, lupus anticoagulant was associated with incident cancers (aHR 2.608; 95% CI: 1.091-6.236). Our cohort study shows that the risk of cancer is substantially higher in women with a history of obstetric APS than in the general population, and in women with a similar initial clinical history but negative for antiphospholipid antibodies.

The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study.

BACKGROUND: To determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction). METHODS: The AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor. RESULTS: There were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35-1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17-0.84; p = 0.01). CONCLUSIONS: The risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.

Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study.

An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D-dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non-surviving patients, area under the receiver-operator characteristic curve (AUCROC ): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non-survivors using each of the three FGMs. A dose-effect relationship was observed between ISTH DIC scores and non-survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non-survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUCROC values testing the ability of the ISTH DIC score to predict non-survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially-available automated assays, automated FM is the FGM best related with late prognosis.

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. METHODS: We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. FINDINGS: We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. INTERPRETATION: Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. FUNDING: Canadian Institutes of Health Research.

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes.

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10-2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047).

THBD sequence variants potentially related to recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a frequently occurring disease, which is classified as idiopathic in more than 50% of cases. THBD, the endothelial cell receptor for thrombin, has been associated with distinct biological processes and considered a coherent RPL-related candidate gene. In the present study, we have sequenced the complete coding region of THBD in 262 patients affected by RPL. Bioinformatics analysis and screening of controls strongly suggested that the THBD-p.Trp153Gly mutation might be related to RPL aetiology. It could be used, after its validation by functional assays, as a molecular marker for diagnostic/prognostic purposes.

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study.

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study.

The incidence of pregnancy outcomes for women with the purely obstetric form of antiphospholipid syndrome (APS) treated with prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) has not been documented. We observed women without a history of thrombosis who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week. We compared the frequencies of complications during new pregnancies between treated women with APS (n = 513; LMWH + LDA) and women negative for antiphospholipid antibodies as controls (n = 791; no treatment). Among APS women, prior fetal loss was a risk factor for fetal loss, preeclampsia (PE), premature birth, and the occurrence of any placenta-mediated complication. Being positive for anticardiolipin immunoglobulin M antibodies was a risk factor for any placenta-mediated complication. Among women with a history of recurrent abortion, APS women were at a higher risk than other women of PE, placenta-mediated complications, and neonatal mortality. Among women with prior fetal loss, LMWH + LDA-treated APS women had lower pregnancy loss rates but higher PE rates than other women. Improved therapies, in particular better prophylaxis of late pregnancy complications, are urgently needed for obstetric APS and should be evaluated according to the type of pregnancy loss.

Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications.

A 35-year-old woman with recurrent severe placenta-mediated pregnancy complications in her 2 pregnancies asks: Will low-molecular-weight heparin help prevent recurrent placenta-mediated pregnancy complications in my next pregnancy? We performed a meta-analysis of randomized controlled trials (RCTs) comparing low-molecular-weight heparin (LMWH) vs no LMWH for the prevention of recurrent placenta-mediated pregnancy complications. We identified six RCTs that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications. The primary outcome was a composite of pre-eclampsia (PE), birth of a small-for-gestational-age (SGA) newborn (<10th percentile), placental abruption, or pregnancy loss >20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; 95% CI, 0.32 to 0.86; P = .01; I(2), 69%, indicating moderate heterogeneity). We identified similar relative risk reductions with LMWH for individual outcomes, including any PE, severe PE, SGA <10th percentile, SGA <5th percentile, preterm delivery <37 weeks, and preterm delivery <34 weeks with minimal heterogeneity. LMWH may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.

Placental growth factor and vascular endothelial growth factor serum levels in Tunisian Arab women with suspected preeclampsia.

The angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) play a central role in the process of angiogenesis. We evaluated the association of free PIGF and free VEGF levels and the risk of preeclampsia (PE) among Tunisian Arab women, and established the range of VEGF and PIGF in normal healthy pregnancies, between 24 and 42weeks of gestation. This retrospective case-control study included 345 women with PE, and 289 women with uncomplicated pregnancies. PIGF and VEGF plasma levels were quantitated by commercially-available ELISA. Compared to control women, plasma PIGF concentrations were lower in women with PE at all gestation age intervals (P<0.0001), compared to VEGF levels which were significantly lower in women with PE but only during early gestation age intervals ([29-32[ and [32-35[). High odds for developing PE, and correspondingly higher associations, were associated with low PIGF values (less than the 5(th) percentile), at all gestation age intervals. The only exception was recorded for the [29-32 [interval, which was not statistically significant. PIGF testing, recorded at 29-37weeks of gestation, had a higher specificity (93-100%) than sensitivity, and the positive predictive values ranged from 90% to 100% for 24-37weeks of gestation. This indicates that it mainly detects non-PE healthy women as well, and thus may be useful as a screening test, though currently unreliable for diagnostic purposes. Reduced PIGF levels during different gestation age intervals, and reduced VEGF levels during early gestation age intervals are also associated with subsequent development of PE in our population; the gestational age interval adjusted-5(th) percentiles of PIGF provide reference ranges for this marker in normal pregnancy.

Diffusion tensor imaging in patients with obstetric antiphospholipid syndrome without neuropsychiatric symptoms.

OBJECTIVES: To evaluate white matter (WM) integrity in neurologically asymptomatic antiphospholipid syndrome (APS) using diffusion tensor imaging (DTI) in women with no thrombotic history but with pregnancy loss. METHODS: Imaging was performed with a 3 T scanner using structural MRI (T1-weighted, fluid attenuation inversion recovery [FLAIR]) and DTI sequences in 66 women with APS and a control group of 17 women. Women with APS were further categorized as positive for lupus anticoagulant (LA) and/or aß2GPI-G antibodies (LA/aß2GPI-G-positive, N = 29) or negative (LA/aß2GPI-G-negative, N = 37) for both. Tract-based spatial statistics of standard DTI-based indices were compared among groups. RESULTS: Women with APS had significantly lower fractional anisotropy (p < 0.05) associated with higher mean diffusivity and radial diffusivity compared to the control group. There was a stronger association of abnormal DTI features among women positive for LA and/or aß2GPI-IgG antibodies than those who were negative. CONCLUSIONS: DTI appears sensitive to subtle WM changes in women with APS with no thrombotic history but with pregnancy loss, compatible with alterations in axonal structure and in the myelin sheath. The preferential association of abnormal DTI features with the two most pathogenic aPLAbs reinforces the pathophysiological relevance of our findings. KEY POINTS: • APS women exhibited lower FA and higher MD and RD than controls. • WM impairments are more severe in patients with positive LA or aß2GPI-IgG. • An association exists between abnormal DTI features and LA or aß2GPI-IgG positivity. • Diffusion tensor imaging detects microstructural white matter abnormalities in APS women.

Polymorphisms of human placental alkaline phosphatase are associated with in vitro fertilization success and recurrent pregnancy loss.

Fertility is a quantitative, complex character governed by a considerable number of genes. Despite clinical and scientific advances, several cases of human infertility remain unexplained. In the present study, using a positional cloning approach in a mouse model of interspecific recombinant lines, a candidate gene, ALPP, encoding the placental alkaline phosphatase, was identified as being potentially involved in recurrent spontaneous abortion. We then analyzed patients for detecting putative associations between ALPP polymorphisms, in vitro fertilization failures, and miscarriages. ALPP was sequenced in 100 controls and 100 patients affected by recurrent spontaneous abortion, from the same ethnic background. The frequency of several alleles and allelic combinations were different between recurrent spontaneous abortion and control women. One polymorphism induced a coding substitution (Ile89Leu) that was associated with a decreased risk of abortion and in vitro fertilization failure. Thereafter, the population was increased by the analysis of 92 additional controls and 612 additional patients for the coding polymorphism Ile89Leu. We finally show, by functional analysis, that the 89Leu placental alkaline phosphatase has an enhanced alkaline phosphatase activity. This study suggests that ALPP genotyping could be a strong predictor of implantation success.