Consecutive Pregnancy Losses Research Articles

New insights into mechanisms behind miscarriage

Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition.

Effect of interpregnancy interval on outcomes of pregnancy after recurrent pregnancy loss

Objective: To examine the effect of interpregnancy interval (IPI) on outcomes of pregnancy after recurrent pregnancy loss (RPL).Methods: A retrospective cohort study including 325 patients treated at a RPL clinic, with two or more consecutive pregnancy losses followed by a subsequent (index) pregnancy, of whom 163 had IPI ≤ 6 months, and 212 had IPI > 6 months.Results: Pregnancy loss rate in the index pregnancy was positively associated with increased IPI (18.6% in women with IPI ≤ 6 months, and 29.7% in women with IPI > 6 months; p = 0.029). In a multivariable logistic analysis, excluding women with fertility problems, and adjusting for maternal age and ethnicity, the OR for pregnancy loss rate for IPI longer than 6 months compared to shorter IPI was 1.76 (95%CI: 0.96–3.22, p = 0.067).Conclusions: Our results suggest that IPI shorter than 6 months, in women with no fertility problems, is associated with lower rate of subsequent miscarriage. Further studies are needed to substantiate this finding.

Polymorphisms of the transforming growth factor-beta 1 gene in relation to idiopathic recurrent miscarriage (P6248)

Abstract Transforming growth factor, β1 (TGFB1) plays a significant role in the pregnancy outcome. We investigated the association of TGFB1 exon 1 (rs1800471, rs1800470) and promoter region (rs1800469, rs1800468) polymorphisms with recurrent pregnancy loss (RPL) in 675 Tunisian women: 304 women with a history of three consecutive pregnancy loss of unknown etiology with the same partner, and 371 age-matched multiparous control women. TGFB1 genotyping was done by TaqMan assays. Higher minor allele frequency (MAF) for rs1800471 (i.e. +915G/C or R25P) (P < 0.001), but not for rs1800470, rs1800469, or rs1800468 was found in cases compared to controls. Significant difference in the distribution of rs1800471 genotypes was seen between RPL cases and control women, irrespective of the genetic model used. Increased RPL risk was seen with rs1800471 allele C in both heterozygous and even more so in the homozygous state, thus establishing a dose-dependent effect. Haploview analysis revealed differential linkage disequilibrium between TGFB1 SNPs analyzed. TGFB1 haplotypes analysis identified 8 common haplotypes (rs1800471/rs1800470/rs1800469/rs1800468) with three (GTTG, Pc = 0.014; CCTG, Pc = 0.003, and CTCG, Pc = 0.01) being positively associated with RPL, while one (GCCG, Pc = 0.009) was negatively associated with RPL. This study provides the first evidence that TGFB1 genotype is possibly associated with RPL.

MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among north Indian women

The present study attempts to understand the role of methylenetetrahydrofolate reductase C677T (MTHFR C677T) in recurrent pregnancy losses in North Indian women because of hyperhomocysteinemia in light of serum folate and vitamin B₁₂. One hundred and seven women with three or more consecutive unexplained recurrent pregnancy losses and 343 women with two or more successful and uncomplicated pregnancies were recruited. Plasma homocysteine, serum folate and vitamin B₁₂ were analyzed using chemiluminescence. MTHFR C677T detection was completed in all subjects. MTHFR genotypic distribution among cases and controls showed no significant difference (P=0.409). However, MTHFR C677T polymorphism was found to be significantly associated with increased homocysteine in the case group (P=0.031). Hyperhomocysteinemia and vitamin B₁₂ deficiency were found to be significant risk factors for recurrent pregnancy loss (RPL) (OR=7.02 and 16.39, respectively). Folate deficiency was more common in controls (63.47%) as compared to the case group (2.56%). Low vitamin B₁₂ increases homocysteine, specifically among T allele carrying case mothers, suggesting T allele is detrimental with B₁₂ deficiency. The study emphasizes the importance of vitamin B₁₂ in the prevention of RPL in North Indian women.

Preventing recurrent miscarriage of unknown aetiology

Key content One to three per cent of couples are affected by recurrent miscarriage (defined as more than three consecutive pregnancy losses). Current interventions are centred on known causes of aetiology. Recent research on miscarriage of unknown cause has investigated the requirements for successful embryo implantation. Treatment of immunological risk factors with immunotherapy does not have a strong evidence base. The overall evidence supporting the use of human chorionic gonadotrophin supplementation during pregnancy is inconclusive. The efficacy of progesterone as an intervention remains empirical, with further trials under way. Learning objectives To understand the aetiology of recurrent miscarriage and patient risk factors. To understand the theoretical pathophysiology underlying miscarriage of unknown aetiology. To be aware of the potential agents of intervention for recurrent miscarriage and their efficacy. Ethical issues Treating patients with recurrent miscarriage can be emotive; should women be treated with interventions that have limited evidence‐based clinical efficacy? How do we manage patients with the psychological impact of recurrent miscarriage?

PF.11 Abnormal Platelet Function is Seen in Women with Unexplained Recurrent Miscarriage During Pregnancy

ObjectiveTo evaluate platelet aggregation in patients with a history of recurrent miscarriage (RM) during a subsequent successful pregnancy and compare them to healthy pregnant controls.Study designA prospective longitudinal study was...

Correlation between thrombophilia and recurrent pregnancy loss in patients with polycystic ovary syndrome: A comparative study

BackgroundPatients with polycystic ovary syndrome (PCOS) have an increased prevalence of thrombophilia, leading to higher rates of pregnancy loss. The aim of this study was to determine the association between thrombophilia and recurrent pregnancy loss (RPL) in patients with and without PCOS. MethodsIn this comparative case–control study, we included 60 patients with RPL (≥3 consecutive pregnancy losses at <20 weeks of gestation) and PCOS (Group 1), 60 patients with PCOS and without RPL (Group 2), 60 patients with RPL and without PCOS (Group 3), and 60 healthy individuals (Group 4). These four study groups were compared regarding serum levels of testosterone, fasting insulin, homocysteine (Hcy), plasminogen activator inhibitor activity (PAI-Fx), protein C, protein S, antithrombin III, activated protein C ratio (APCR), factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase gene mutations. ResultsPatients in Group 1 had significantly higher levels of testosterone (p = 0.026), dehydroepiandrosterone sulfate (p = 0.035), fasting insulin (p = 0.015), Hcy (p = 0.036), and PAI-Fx (p = 0.008) compared to Group 3. They also had higher proportions of APCR (p = 0.009) and a higher prevalence of factor V Leiden mutations compared to Group 3 (p = 0.001). However, there was no significant difference in protein C (p = 0.088), protein S (p = 0.514), or antithrombin III (p = 0.627) between the four study groups. ConclusionHyperinsulinemia, hyperandrogenemia, hypofibrinolysis, and hyperhomocysteinemia as well as APCR and factor V Leiden mutations are associated with RPL in patients with PCOS.

Genetic variation in TGFB1 gene and risk of idiopathic recurrent pregnancy loss

Transforming growth factor β1 plays a significant role in pregnancy outcome. We investigated the association of TGFB1 exon 1 (rs1800471, rs1800470) and promoter region (rs1800469, rs1800468) polymorphisms with recurrent pregnancy loss (RPL) in 675 Tunisian women: 304 women with a history of three consecutive pregnancy losses of unknown etiology with the same partner and 371 age-matched multiparous control women. TGFB1 genotyping was done by TaqMan assays. Higher minor allele frequency for rs1800471 (P< 0.001), but not for rs1800470, rs1800469 or rs1800468 was found in RPL cases compared with controls. A significant difference in the distribution of rs1800471 genotypes was seen between the RPL cases and control women, irrespective of the genetic model used. Increased RPL risk was seen with rs1800471 allele C in the heterozygous state and to a greater degree in the homozygous state, thus establishing a dose-dependent effect. Haploview analysis revealed differential linkage disequilibrium between the TGFB1 single-nucleotide polymorphisms analyzed. TGFB1 haplotype analysis identified eight common haplotypes (rs1800471/rs1800470/rs1800469/rs1800468) with three (GTTG, Pc = 0.02; CCTG, Pc = 0.02 and CTCG, Pc = 0.02) positively associated with RPL and one (GCCG, Pc = 0.009) negatively associated with RPL. This study provides the first evidence that the TGFB1 genotype may influence RPL.

Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage

IntroductionRecurrent miscarriage (RM; ≥3 consecutive pregnancy losses) occurs in 1–3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified. We aimed to profile whole-genome differential gene expression in RM placental tissue, and to determine the protein levels of identified loci in maternal sera in early pregnancy. MethodsGeneChips (Affymetrix®) were used for discovery and Taqman RT-qPCR assays for replication of mRNA expression in placentas from RM cases (n = 13) compared to uncomplicated pregnancies matched for gestational age (n = 23). Concentrations of soluble TRAIL (sTRAIL) and calprotectin in maternal serum in normal first trimester (n = 35) and failed pregnancies (early miscarriage, n = 18, late miscarriage, n = 4; tubal pregnancy, n = 11) were determined using ELISA. ResultsIn RM placentas 30 differentially expressed (with nominal P-value < 0.05) transcripts were identified. Significantly increased placental mRNA expression of TNF-related apoptosis-inducing ligand (TRAIL; P = 1.4 × 10−3; fold-change 1.68) and S100A8 (P = 7.9 × 10−4; fold-change 2.56) encoding for inflammatory marker calprotectin (S100A8/A9) was confirmed by RT-qPCR. When compared to normal first trimester pregnancy (sTRAIL 16.1 ± 1.6 pg/ml), significantly higher maternal serum concentration of sTRAIL was detected at the RM event (33.6 ± 4.3 pg/ml, P = 0.00027), and in pregnant women, who developed an unpredicted miscarriage 2–50 days after prospective serum sampling (28.5 ± 4.4 pg/ml, P = 0.039). Women with tubal pregnancy also exhibited elevated sTRAIL (30.5 ± 3.9 pg/ml, P = 0.035). Maternal serum levels of calprotectin were neither diagnostic nor prognostic to early pregnancy failures (P > 0.05). ConclusionsThe study indicated of sTRAIL as a potential predictive biomarker in maternal serum for early pregnancy complications.

Soluble TRAIL is elevated in recurrent miscarriage and inhibits the in vitro adhesion and migration of HTR8 trophoblastic cells

What is the potential physiopathological role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in recurrent miscarriage (RM), characterized by at least three consecutive pregnancy losses. The levels of serum TRAIL immediately after miscarriage in RM patients are significantly elevated with respect to that in first-trimester normal pregnant women, and recombinant TRAIL inhibits the adhesion and migration of HTR8 trophoblastic cells in vitro. Both TRAIL and its trans-membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3and TRAIL-R4) have been documented in the placenta, but their physiopathological role is incompletely understood. The study populations consisted of RM patients (n = 80) and first-trimester normal pregnant women (n = 80). Blood samples were obtained within 24 h after abortion (RM) or at gestational 12-week (normal pregnant women). As additional controls, third-trimester normal pregnant women (n = 28) were examined before (within 72 h) and after (within 24 h) partum. The concentrations of TRAIL were analysed in serum samples by ELISA. In parallel, the effect of soluble recombinant TRAIL (0.1-1000 ng/ml) was analysed on the survival of primary extravillus trophoblasts (EVTs) and on the survival, proliferation, adhesion and migration of trophoblastic HTR8 cells. The circulating levels of TRAIL in RM women (median: 52.5 pg/ml; mean and SD: 55.5 ± 24.4 pg/ml) were significantly higher with respect to first-trimester normal pregnant women (median: 44.9 pg/ml; mean and SD: 47 ± 15.1 pg/ml) and third-trimester normal pregnant women, as assessed before (median: 45.1 pg/ml; mean and SD: 46 ± 12.4 pg/ml) and after partum (median: 35.4 pg/ml; mean and SD: 38 + 17.5 pg/ml). Both primary EVT and HTR8 cells expressed detectable levels of TRAIL death receptors, but exposure to soluble recombinant TRAIL did not induce cell death of trophoblastic cells. On the other hand, TRAIL dose-dependently inhibited the adhesion of HTR8 cells to decidual endothelial cells (DEC) as well as the migration of HTR8 in transwell assays using either fibronectin or DEC. Although this study suggests that TRAIL might have a pathogenic role in RM by inhibiting both the adhesion and migration capabilities of first trimester trophoblastic cells, there is a possibility that the elevated serum levels of TRAIL in RM are not cause but rather the result of RM. Our current findings together with data of other authors suggest that circulating TRAIL should be further analysed as a potential important biomarker in different physiopathological settings. This study was funded by FIRB projects (RBAP11Z4Z9_002 to Giorgio Zauli and RBAP10447J_002 to Paola Secchiero). The authors have no competing interests to declare.

Primary vs. secondary recurrent pregnancy loss – epidemiological characteristics, etiology, and next pregnancy outcome

To compare epidemiological and obstetric characteristics, etiology and next pregnancy outcomes of women with primary vs. secondary recurrent pregnancy loss (RPL). A retrospective cohort study, including 420 patients with two or more consecutive pregnancy losses followed by a subsequent (index) pregnancy, of whom 162 were primary RPL women and 258 were secondary RPL women. All patients were evaluated and treated in the RPL clinic at the Soroka University Medical Center. Live birth rate in the index pregnancy was not statistically different between primary and secondary RPL women (75.9 and 70.9%, respectively). The only significant difference in the etiology evaluation was in abnormal prolactin levels (14.1% of the primary and 1.4% of the secondary RPL group). Women with primary RPL had, at the index pregnancy, significantly higher rates of preterm delivery, fetal growth restriction, and gestational diabetes mellitus. In a multivariable logistic regression analysis, primary RPL adjusted for maternal age and gravidity, was an independent risk factor for preterm delivery compared with secondary RPL [adjusted OR 2.62, CI (95%) 1.30-5.26]. The prognosis of the two groups was similar regarding live birth rate at the index pregnancy; however, women with primary RPL were more prone to adverse obstetric and neonatal outcomes.

Pregnancy in a woman with Wilson's disease treated with zinc: A case report

Wilson’s disease is a rare hereditary disorder of copper metabolism affecting 30 per million populations. Copper get deposited in liver, brain and kidney due to decreased hepato-cellular excretion and leading to diverse clinical manifestations. Patient may remain apparently asymptomatic or may present with fulminant liver disease or neuropsychiatric illness. Reproductive outcome in untreated Wilson’s disease is poor. Women remaining untreated either suffer from infertility or experience recurrent pregnancy losses. Invention of copper chelating agents and their usage in these women resulted in successful pregnancy outcome. Penicillamine or zinc salts can be used as copper chelator in pregnancy with Wilson’s disease with equal effectiveness in respect to pregnancy outcome. We report a case of previously undiagnosed Wilson’s disease with three consecutive pregnancy losses who achieved a live birth after successfully treated with zinc salts. The several points regarding antenatal care, drug therapy and optimum time and mode of delivery for the woman with Wilson’s disease are discussed here.

Association study of microRNA polymorphisms with risk of idiopathic recurrent spontaneous abortion in Korean women

AimThe aim of this study was to investigate the association of microRNA polymorphisms (miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G) in Korean patients with recurrent spontaneous abortion (RSA). MethodsWe conducted a case–control study of 564 Korean women: 330 patients with at least two unexplained consecutive pregnancy losses and 234 healthy controls with at least one live birth and no history of pregnancy loss. ResultsRSA patients exhibited significantly different frequencies of the miR-196a2CC (TT+TC vs. CC; adjusted odds ratio [AOR], 1.587; 95% confidence interval [CI], 1.042–2.417) and miR-499AG+GG genotypes (AOR, 1.671; 95% CI, 1.054–2.651) compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645–7.624). ConclusionmiR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women.

What a difference an egg makes

In October, 2007, a 29-year-old white woman presented to our clinic with a history of four consecutive pregnancy losses, comprising a miscarriage in 2002, and three molar pregnancies in 2005, 2006, and 2007. She had no other relevant personal or family history. Histopathological review confirmed that the three recent pregnancies were all complete hydatidiform moles (figure A). Fluorescent microsatellite genotyping showed that all three hydatidiform moles were diploid and biparental in origin. We then screened our patient for mutations in NLRP7; she was found to be a compound heterozygote for two mutations, p.E13GfsX7 and p.R693P 1 Wang CM Dixon PH Decordova S et al. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine rich region. J Med Genet. 2009; 46: 569-575 Crossref PubMed Scopus (121) Google Scholar (figure B).

Factor V Leiden G1691A and factor II G20210A point mutations and pregnancy in North-West of Iran

The roles of several hereditary predispositions for venous thromboembolism have been evaluated in women with habitual abortion. We studied the prevalence of FV Leiden G1691A and FII G20210A mutations in women with habitual abortion and healthy controls. 60 unrelated fertile females, as controls, and 70 unrelated women with at least three consecutive pregnancy losses entered at the present study. MAS-PCR was carried out for detection of FV Leiden G1691A and FII G20210A mutations. FV Leiden G1691A mutation was not found in the studied cases and controls, that is, all of the cases and the controls had normal FV Leiden 1691GG genotype. FII 20210AA genotype was not found in any of patients or controls. 2.5% of alleles (3 out of 120 chromosomes) in controls and 15.714% of alleles (22 out of 140 chromosomes) in cases had FII 20210A mutation. The FII G20210A allele frequency was 0.157 in cases and 0.025 in controls. Regarding FII G20210A mutation, the distribution of GG, GA and AA genotypes were 48 (68.57%), 22 (31.43%) and 0 (0%) in the cases and 95 (95%), 5 (5%) and 0 (0%) in the controls, respectively. Significant differences in both FII G20210A alleles and FII G20210A genotypes frequencies were observed in the cases versus the controls. FII G20210A mutation is significantly associated with habitual abortion.

Haplotype-based association of ACE I/D, AT1R 1166A>C, and AGT M235T polymorphisms in renin–angiotensin–aldosterone system genes in Korean women with idiopathic recurrent spontaneous abortions

Objectives The objective of this study was to determine whether or not the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin II type 1 receptor (AT1R), and angiotensinogen (AGT) gene polymorphisms are associated with idiopathic recurrent spontaneous abortions (RSAs) in Korean women. Study design A total of 251 patients with unexplained consecutive pregnancy losses, and 126 healthy controls with at least one live birth and no history of pregnancy loss. Result The odds ratios (ORs) of the ACE ID (OR = 2.423; 95% confidence interval (CI) = 1.417–4.142; p = 0.001) and the ACE II (OR = 2.050; 95% CI = 1.143–3.675; p = 0.018) for the ACE DD genotype were significantly different between patients with idiopathic RSA and controls; however, there were no significant differences between patients and controls with respect to the AT1R 1166A>C and AGT M235 T polymorphisms. In a haplotype-based analysis of I-A ( p = 0.010), D-A ( p = 0.004), I-A-T ( p = 0.033), D-A-T ( p = 0.0005), and D-C-T ( p = 0.013) polymorphism pairs with synergistic effects derived by the MDR method in patients and in controls showed significant results. Conclusion This study suggests that ACE, AT1R and AGT polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women.

Post-abortion hysteroscopy: a method for early diagnosis of congenital and acquired intrauterine causes of abortions

Objective Recurrent pregnancy loss is often defined as three or more consecutive pregnancy losses but there are no strict criteria for initiation of investigations after a miscarriage. We compared the frequency of uterine anomalies diagnosed by hysteroscopy following one, two and three or more miscarriages. Study design In our study 151 patients underwent diagnostic hysteroscopy following a missed or an incomplete abortion. Uterine septum, subseptum, arcuate uterus, and uterine hypoplasia are classified as congenital uterine anomalies and polyps, synechia, and submucous myomas are classified as acquired uterine abnormalities. Results 151 Patients were enrolled in the study. The pregnancy numbers of the patients varied between 1 and 12. Sixty nine (46%) of the patients had one miscarriage, 42 (28%) had two miscarriages and 40 (26%) had three or more miscarriages. Diagnostic hysteroscopy revealed normal uterine cavity in 61.1% of the patients, congenital uterine anomalies in 20.4% and acquired uterine pathologies in 18.5%. Among the congenital anomalies, 14 (9.3%) were uterine septum, 10 (6.6%) were subseptate uterus, 4 (2.6%) were arcuate uterus and 3 (1.9%) were uterine hypoplasia. Among acquired abnormalities 14 (9.3%) were uterine synechia, 12 (7.9%) were endometrial polyps, and 2 (1.3%) were submucous myoma. Among patients who had one miscarriage 64.1% had a normal uterine cavity, 18.2% had congenital abnormalities and 17.7% had acquired uterine pathologies. Of patients with two miscarriages, 52% had a normal uterine cavity, 21.9% had congenital anomalies and 26.1% had acquired uterine pathology. In the three or more miscarriage group, 58.4% had normal uterine cavity, 25.3% had congenital anomalies, and 16.3% had acquired uterine pathology. We did not find any statistically significant difference between the number of miscarriages and pathologic diagnostic hysteroscopy findings. Conclusions Post-abortion office hysteroscopy is a simple and efficient tool in the early diagnosis of congenital and acquired uterine pathologies. Diagnostic hysteroscopy can be performed after the first miscarriage in order to determine congenital and acquired uterine pathologies, with regard to the patient's age and anxiety level.

Secondary recurrent miscarriage is associated with previous male birth

Secondary recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses after delivery of a viable infant. Previous reports suggest that a firstborn male child is associated with less favourable subsequent reproductive potential, possibly due to maternal immunisation against male-specific minor histocompatibility antigens. In a retrospective cohort study of 85 cases of secondary RM we aimed to determine if secondary RM was associated with (i) gender of previous child, maternal age, or duration of miscarriage history, and (ii) increased risk of pregnancy complications. Fifty-three women (62.0%; 53/85) gave birth to a male child prior to RM compared to 32 (38.0%; 32/85) who gave birth to a female child (p=0.002). The majority (91.7%; 78/85) had uncomplicated, term deliveries and normal birth weight neonates, with one quarter of the women previously delivered by Caesarean section. All had routine RM investigations and 19.0% (16/85) had an abnormal result. Fifty-seven women conceived again and 33.3% (19/57) miscarried, but there was no significant difference in failure rates between those with a previous male or female child (13/32 vs. 6/25, p=0.2). When patients with abnormal results were excluded, or when women with only one previous child were considered, there was still no difference in these rates. A previous male birth may be associated with an increased risk of secondary RM but numbers preclude concluding whether this increases recurrence risk. The suggested association with previous male birth provides a basis for further investigations at a molecular level.

Hereditary thrombophilia and recurrent pregnancy loss: a retrospective cohort study of pregnancy outcome and obstetric complications

The association among hereditary thrombophilia, recurrent pregnancy loss (RPL) and obstetric complications is yet uncertain. The objective of the study was to assess the prognostic value of the factor V Leiden (FVL) and prothrombin (PT) mutations for the subsequent chance of live birth for women with RPL. Pregnancy outcome was recorded in a retrospective cohort of 363 women with a minimum of three consecutive pregnancy losses (early miscarriage, late miscarriage or stillbirth/neonatal death) who were not treated with anticoagulation therapy. Of the 363 women, 29 were FVL-mutation carriers and 6 were PT-mutation carriers. The unadjusted live birth rate was 45.7% in FVL/PT carriers versus 63.4% in FVL/PT non-carriers, P = 0.04. The adjusted odds ratio for live birth in FVL/PT carriers was 0.48 (95% CI = 0.23-1.01), P = 0.05. Among the obstetric complications, only excessive bleeding was found to be associated with FVL/PT mutations. In the unadjusted analysis, FVL and PT mutations have a negative prognostic impact on the live birth rate in women with RPL; however, when adjusting for significant covariates, the results no longer reach statistical significance. Strong conclusions on the association between obstetric complications and hereditary thrombophilia cannot be drawn from this study. Whether anticoagulation therapy would improve the prognosis in women with RPL and FVL/PT mutations remains to be documented in large randomized controlled trials.

Pathogenesis, diagnosis, and treatment of recurrent spontaneous abortion with immune type

Recurrent spontaneous abortion (RSA), defined as three or more consecutive pregnancy losses before 20 weeks of gestation, is difficult to treat in the clinical setting. It affects 1%-5% of women of reproductive age. In the investigations of immunopathogenesis, diagnosis, and treatment of RSA since the late 1980s, it was found that RSA was associated with abnormal maternal local or systemic immune response. The pathogenesis of autoimmune RSA was mainly associated with antiphospholipid antibody (APA), while that of alloimmune RSA was due to the disturbance of maternofetal immunological tolerance. Systemic etiological screening process and diagnosis systems of RSA with immune type were developed, and anticardiolipin (ACL or ACA) + anti-β2-GP1 antibody combining multiple assays for effective diagnosis of RSA with autoimmune type was first established. According to the dynamic monitoring of clinical parameters before and during gestation, low-dose, short-course, and individual immunosuppressive therapy and lymphocyte immunotherapy for RSA with immune type were carried out. The outcomes of the offsprings of patients with RSA were followed up, and the safety and validity of the therapies were confirmed. The research achievement leads to great progress in the diagnosis and treatment of RSA in China.