Endocrinology and recurrent early pregnancy loss

Endocrine disorders have been frequently linked to recurrent pregnancy loss (RPL). Because embryo attachment and early implantation are exquisitely controlled by the local hormonal milieu, endocrine-related pregnancy failures are likely to occur early in gestation. Thyroid disorders, luteal phase defects, and polycystic ovary syndrome are the endocrine abnormalities most commonly associated with RPL. In this review we discuss new concepts in the pathophysiology and treatment of these diseases with the ultimate goal of improving pregnancy maintenance. We have also included our recommendations on testing and treatment of women with isolated and repeated pregnancy failure that is believed to be at least partially mediated by newly defined hypothyroidism, thyroid autoimmunity, luteal phase defects, obesity, and polycystic ovary syndrome.     

An analysis of the pattern of pregnancy loss in women with recurrent miscarriage

OBJECTIVE: To describe the pattern of pregnancy loss in women with a history of recurrent miscarriage (RM). DESIGN: Retrospective, observational study. SETTING: A tertiary referral center for RM. PATIENT(S): Five hundred thirty-eight subjects with RM. INTERVENTION(S): Women with antiphospholipid syndrome were treated with clexane and aspirin; some patients with uterine anomalies underwent corrective surgery, and some cases of retarded endometrium were treated with hMG. MAIN OUTCOME MEASURE(S): Pregnancy outcome, including the stage of pregnancy at which pregnancy loss occurred. RESULT(S): In women with a prothrombotic state, the miscarriage rate before the detection of fetal heart activity (early loss) in the untreated group (50%) was significantly higher than in the treatment group (17.5%). In women with a uterine anomaly, the early loss rate and the later loss rate (after detection of fetal heart activity) were both increased. Women with retarded endometrium, women with >/=6 losses, and older women (>/=41 years) are more likely to have a further early loss but not a later loss. CONCLUSION(S): An understanding of the patterns of pregnancy loss provides further insight into the mechanism of the reproductive failure, which has implications for treatment.     

Combined thrombophilic factors among women with late recurrent spontaneous abortions

The aim of this study was to assess the role of combined thrombophilic factors carrier status for development of late recurrent pregnancy loss (RPL). The polymorphism 4G/5G (PL 4G/5G) - genotype 4G/4G in plasminogen activator inhibitor type 1 (PAI-1), Factor V Leiden (FVL) and prothrombin (FII) gene mutation 20210 G>A in 52 women with recurrent pregnancy loss between 10 and 20 weeks of gestation and in 125 healthy women with at least one uncomplicated full-term pregnancy was investigated. Combined carrier status for thrombophilic factors was more pronounce among women with RPL (7.7%) compared to control subjects (3.2%), (OR=2.52, 95% CI (0.5- 12.62), p-ns). The most common association was between FVL and PL 4G/5G (5.8% compared to 0.8% in patients and controls, OR=7.59, 95% CI (0.68 - 191.04), p-ns). Because of relatively small size of the study, the difference in carrier status between women with RPL and control subjects did not rich statistical significance. A weak association between double carrier status for inherited thrombophilic factors and RPL was established. The strong determination in larger studies of the relation between combined inherited thrombophilic status and RPL development could better specify anticoagulant prophylaxis in further pregnancy     

NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss,implantation failures,preeclampsia, and pelvic endometriosis

The regulation of uterine and peripheral blood natural killer (NK) cells has been associated with problems related to reproductive immunology such as recurrent pregnancy loss (RPL), implantation failure or preeclampsia. NKp46, one of the natural cytotoxicity receptors (NCRs), is a unique marker that functions in NK cell cytotoxicity and cytokine production. Expression of NKp46 on NK cells is lower in women with recurrent pregnancy loss and pregnancy‐induced hypertension. Moreover, expression of NKp46 on peritoneal fluid NK cells is lower in women with pelvic endometriosis. Therefore, evaluation of NKp46 on peripheral blood NK cells may provide a means of screening for reproductive abnormalities. Recently, a new type of NK cell, the NK22 cell, has been reported. This cell may be a regulator not only of the mucosal barrier but also of reproduction. For women with RPL showing abnormal uterine and/or peripheral blood NK cells, both intravenous immunoglobulin treatment and intralipid treatment have been reported. The effects of these treatments are still controversial, and further studies are needed in order to clarify their true impact. The present review examines variations in the expression of NCRs on NK cells, the participation of NK22 cells in reproduction, and the possible use of intravenous immunoglobulin or intralipid treatment for women with recurrent pregnancy loss and NK cell abnormality.     

Plasminogen activator inhibitor type 1 activity in women with unexplained very early recurrent pregnancy loss

The aim of the study was to assess the independent role of polymorphism 4G/5G (PL 4G/5G)--genotype 4G/4G in plasminogen activator inhibitor type 1 (PAI-1) in the development of very early recurrent pregnancy loss (RPL)--before 10 weeks of gestation of pregnancy. The polymorphism 4G/5G as well as Factor V Leiden (FVL), prothrombin (FII) gene mutation 20210 G > A and polymorphism 677 C > T in methylentetrahydrofolat reductase (MTHFR) gene was investigated in 110 women with recurrent pregnancy loss before 10 weeks of gestation and in 97 healthy women with at least one uncomplicated full-term pregnancy. A significant prevalence of PL 4G/5G in women with RPL was found in comparison to prevalence of the polymorphism in controls (41.8% versus 26.8% respectively in patients and controls, OR: 1.96, 95% CI: 1.05 3.69, p = 0.034). The difference in prevalence of the polymorphism remains still significant after exclusion of patients and control carriers of FVL, FII 202010 G > A and 677 C > T in MTHFR (the prevalence of PL 4G/5G alone was 44.1% and 24% respectively in patients and controls, OR: 2,5, 95% CI: 1,15 5, 45, p = 0.018). The found association of PL 4G/5G in PAI-1 with early recurrent pregnancy loss encourage an extension of the list of inherited thrombophilic factors with this one. This result also could have had an implication for adjustment of further prophylactic low-molecular weight heparin implication in further pregnancy to prevent a poor foetal outcome.     

Prevalence of uterine defects in habitual abortion patients attended on at a University Health Service in Brazil

Objectives Assessment of the prevalence and types of uterine defects in patients with recurrent pregnancy loss (RPL) through hysteroscopy (HTC).Patients and methods Sixty non pregnant patients with history of three or more consecutive spontaneous abortions were evaluated through HTC. The findings were separated into three groups: synechias, polypoids lesions (endometrial polyps and submucous myomas), and alterations of the cavity shape (mullerian anomalies). The findings were gathered and tabulated according to the presence of each defect.Results Uterine anomalies were observed in 23 (38.3%) patients, with 16 (26.7%) synechias, 3 (5.0%) polypoids lesions and 8 (13.3%) shape alterations.Conclusions The results obtained here suggest that the uterine factor has high prevalence in patients with a RPL history, and for this reason it should be systematically assessed in patients with a RPL history.     

Clinical factors associated with pregnancy outcome in women with recurrent pregnancy loss

Abstract

The aim of this prospective cohort study was to evaluate clinical factors associated with pregnancy outcomes in women with recurrent pregnancy loss (RPL). Women with a history of two or more pregnancy losses underwent workups for clinical factors of RPL and their pregnancies were followed-up with informed consent. Two hundred eleven (81.5%) of 259 women with RPL became pregnant. The multivariable analyses demonstrated that age (p?<?.01, OR 0.9, 95%CI 0.97–0.83), uterine abnormality (p?<?.05, OR 0.3, 95%CI 0.11–0.8), and protein C (PC) deficiency (p?<?.01, OR 0.14, 95%CI 0.03–0.6) were independent factors for becoming pregnancy in women with RPL. The number of previous pregnancy loss (p?<?.01, OR 0.57, 95%CI 0.43–0.75) and natural killer (NK) cell activity ≥33% (p?<?.01, OR 0.31, 95%CI 0.13–0.73) were independent factors for live birth in the subsequent pregnancy. Advanced age, the presence of uterine abnormality, and PC deficiency were risk factors for reduced pregnancy rate in women with RPL. Increased number of previous pregnancy loss and high NK cell activity were risk factors for miscarriage in the subsequent pregnancy. These results involve important information and are helpful for clinical practitioners.     

Anatomic factors associated with recurrent pregnancy loss

Anatomic uterine defects appear to predispose women to reproductive difficulties, including first- and second-trimester pregnancy losses, higher rates of preterm labor and birth, and abnormal fetal presentation. These anatomic abnormalities can be classified as congenital, including müllerian and diethylstilbestrol-related abnormalities, or acquired, such as intrauterine adhesions or leiomyomata. In women with three or more consecutive spontaneous abortions who underwent hysterosalpingography or hysteroscopic examination of their uteri, mullerian anomalies have been found in 8 to 10%. Women with mullerian anomalies may be predisposed to recurrent pregnancy loss because of inadequate vascularity to the developing embryo and placenta, reduced intraluminal volume, or cervical incompetence. The reproductive history of most women with a müllerian anomaly is poor, especially for women with a uterine septum, the most common mullerian anomaly. Recurrent pregnancy losses resulting from a uterine septum, bicornuate uterus, intrauterine adhesions, and fibroids are amenable to surgical correction. Women with müllerian anomaly and a history of second-trimester pregnancy losses may benefit from a prophylactic cervical cerclage.     

Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Purpose

Researchers have hypothesized that an imbalance of immune cells in the uterine decidua and a dysfunction in cytokines they produce may contribute to recurrent pregnancy loss (RPL). The objective of this study was to determine if IL-22, IL-23 and IL-17 are expressed abnormally in the decidua of patients with RPL compared to those women with a normal pregnancy. We also sought to confirm that uterine natural killer (uNK) cells are lower in the decidua of patients with RPL, as well as identify IL-22 expression by uNK cells.

Methods

After meeting strict inclusion criteria, maternal decidua of nine patients with unexplained RPL and a confirmed euploid fetal loss, and 11 gestational age-matched patients undergoing elective pregnancy termination were included in our analysis. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to quantify RNA expression, Western blot was performed to quantify protein expression and immunohistochemistry (IHC) was performed to identify IL-22 and uNK cells.

Results

We found that women with unexplained RPL and a euploid fetal loss had significantly less gene and protein expression of IL-22 in the decidua. Additionally, we found that IL-22 is primarily expressed by uNK cells in the decidua.

Conclusions

In conclusion, our results suggest that lower levels of IL-22 in the uterine decidua in patients with unexplained RPL may contribute to a disruption of decidual homeostasis and ultimately lead to early pregnancy loss.     

Current Immunological Treatment of Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) is a prevalent health problem, affecting up to five percent of couples trying to establish a family. Endocrine, anatomical, infectious, and male factors were classically investigated in couples with a history of recurrent pregnancy loss, with abnormalities being identified in 56 percent of the couples. Research over the past decade has revealed increasing evidence that immunological factors are important in the evaluation of couples with a history of recurrent pregnancy loss. As we begin to understand the normal and abnormal immunological response to pregnancy, we will be able to develop more specific treatment protocols for couples with a history of unexplained recurrent pregnancy loss.     

Comparison of the accuracy of hysteroscopy and hysterosalpingography in evaluation of the uterine cavity in patients with recurrent pregnancy loss

The aim of this study was to compare the accuracy of hysteroscopy and hysterosalpingography (HSG) in evaluating the uterine cavity in patients with recurrent pregnancy loss (RPL). One hundred and twenty consecutive patients with a history of RPL were enrolled into this prospective-observational study in the reproductive endocrinology and infertility clinic of a tertiary referral center. Diagnostic office hysteroscopy without anesthesia or sedation, HSG, and diagnostic laparoscopy when indicated were performed in each case. Eighty-five of 120 (70.83%) hysteroscopic studies performed for RPL demonstrated an acquired (55 cases: 64.7%) or congenital (30 cases: 35.3%) intrauterine lesion. Furthermore, several other etiologic factors were also identified in RPL patients with intrauterine lesions. HSG accurately diagnosed an intrauterine defect in only 56 of 85 (65.88%) cases, based on hysteroscopic confirmation. Fifty percent of the cases with incomplete uterine septum were overlooked during HSG. The sensitivity, specificity, positive predictive value, and negative predictive value of HSG were 74.6%, 79.5%, 90.4%, and 54.7%, respectively. There was a single complication (0.83%) due to hysteroscopy. Hysteroscopy is more accurate than HSG in evaluating the uterine cavity in patients with RPL. We recommend it as a routine procedure instead of HSG.     

Reproductive performance of women with müllerian anomalies

PURPOSE OF REVIEW: This review discusses current diagnostic techniques for müllerian anomalies, reproductive outcome data, and management options in reproductive-age women. RECENT FINDINGS: Multiple retrospective studies have investigated reproductive outcomes with müllerian anomalies, but few current prospective studies exist. Uterine anomalies are associated with normal and adverse reproductive outcomes such as recurrent pregnancy loss and preterm delivery, but not infertility. Furthermore, unicornuate, didelphic, bicornuate, septate, arcuate, and diethylstilbestrol-exposed uteri have their own reproductive implications and associated abnormalities. Common presentations of müllerian anomalies and current diagnostic techniques are reviewed. Surgical intervention for müllerian anomalies is indicated in women with pelvic pain, endometriosis, obstructive anomalies, recurrent pregnancy loss, and preterm delivery. Although surgery for most uterine anomalies is a major intervention, the uterine septum is preferentially managed with a hysteroscopic procedure. Several recent studies and review articles discuss management of the septate uterus in asymptomatic women, infertile women, and women with a history of poor reproductive outcomes. Current assessment of reproductive outcomes with uterine anomalies and management techniques is warranted. SUMMARY: Müllerian anomalies, especially uterine anomalies, are associated with both normal and adverse reproductive outcomes, and management in infertile women remains controversial.     

Uterine factor in recurrent pregnancy loss

ObjectiveTo review the current understanding of the role the uterus plays in recurrent pregnancy loss.FindingsCongenital and acquired uterine abnormalities are associated with recurrent pregnancy loss in the first and second trimester. Relevant congenital Mullerian tract anomalies include unicornuate, didelphys, bicornuate and septate uteri. Pregnancy loss has also been associated with acquired uterine abnormalities that distort the uterine cavity such as intrauterine adhesions and submucosal myomas. Initial evaluation of women with recurrent pregnancy loss should include a uterine assessment such as a pelvic ultrasound or sonohysterography. Uterine abnormalities such as uterine septum, intrauterine adhesions and submucosal myomas may be managed surgically with operative hysteroscopy.ConclusionUterine abnormalities, both congenital and acquired, can be responsible for recurrent pregnancy loss.     

Increased plasma adrenomedullin in women with recurrent pregnancy loss

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

Factor seven activating protease activity levels in women with recurrent pregnancy loss

This study was designed to analyze the changes in circulating factor seven activating protease (FSAP) levels in association with the thrombophilic state of 40 women with recurrent pregnancy loss (RPL). All women were trying to conceive and were prospectively followed up until the achievement of spontaneous pregnancy. The results obtained showed that plasma FSAP activity levels were higher in RPL than in fertile women (P < .001) and represented an adverse predictor of pregnancy at multivariate analysis (P = .002). In 7 consenting RPL women, FSAP activity levels increased continuously during pregnancy until the third trimester, remained elevated immediately after delivery, and declined 6-week postpartum, although at levels that were still above the range of control women. These results suggest that FSAP activity levels might provide useful information during pregnancy progression in at-risk women, possibly acting as a predictive factor for adverse pregnancy outcome in RPL even in the absence of other well recognized thrombophilic conditions.     

Lack of association of TNFalpha gene polymorphisms and recurrent pregnancy loss in Caucasian women

The tumor necrosis factor alpha (TNFalpha) gene plays an important role in immunology and inflammation. Variant alleles of TNFalpha are associated with altered RNA and serum protein levels in humans. Conflicting results have been obtained regarding the role of TNFalpha during pregnancy and recurrent pregnancy loss (RPL). This study investigated the relationship between RPL and two polymorphisms in the promoter of the TNFalpha gene (TNFalpha -308 and -863). Genotyping was performed in 168 RPL women and 212 ethnically matched healthy individuals. In addition, we performed analysis of TNFalpha serum protein levels. We demonstrate that neither the polymorphism -308 nor the polymorphism -863 of the TNFalpha gene is associated with RPL in Caucasian women. In addition, we did not find any association between TNFalpha serum levels and the occurrence of RPL in a subset of 36 RPL women and 36 healthy individuals. We conclude that TNFalpha polymorphisms and resting blood TNFalpha levels do not correlate with the propensity to recurrent pregnancy loss in Caucasian women.     

Endometrial LGR7 expression and implantation failure

Implantation failure is considered as a major cause of infertility in women with recurrent pregnancy loss (RPL) and in otherwise healthy women with unexplained infertility. Preliminary data in primates suggested that relaxin (RLX) is involved in endometrial preparation for implantation. In a prospective observational study, the endometrial RLX receptor (LGR7) expression was assessed in three groups of patients with regular ovulatory cycle and normal uterine cavity: 23 with RPL (Group A), 23 with unexplained infertility undergone at least three cycles of failed in vitro fertilization (IVF) reporting good oocyte and embryo quality (Group B), 23 with proven fertility (Group C). Assessment of LGR7 expression was performed with both polymerase chain reaction (PCR) analysis and immunohistochemistry on endometrial samples obtained with hysteroscopic biopsy performed in the secretory phase of the menstrual cycle. Endometrial LGR7 was less expressed in group A and B versus C, both by PCR analysis (p?=?0.024) and immunohistochemistry. The decreased expression of the endometrial RLX receptor in women with implantation failures, both in vitro fertilization failure and recurrent pregnancy loss, suggests that RLX may play a crucial role in the structural and functional changes of the endometrium during the window of implantation.     

代谢综合征与复发性流产

代谢综合征患者发生复发性流产的概率升高,可能与血栓前状态、子宫内膜蜕膜化不良、卵子质量差、母胎界面免疫紊乱等机制有关,通过生活方法干预、减重、控制血糖、加强黄体支持以及抗凝可望改善再次妊娠结局。     

Anatomic factors in recurrent pregnancy loss

Anatomic uterine defects are present in 15% of women evaluated for three or more consecutive spontaneous abortions. These anatomic abnormalities can be classified as congenital or acquired. In addition to pregnancy loss, uterine malformations appear to predispose women to other reproductive difficulties including infertility, preterm labor, and abnormal presentation. These poor reproductive outcomes resulting from uterine septum, intrauterine adhesions, polyps, and fibroids are amenable to surgical correction. Therefore, it is essential to make an accurate diagnosis to offer an adequate treatment. In this article, we review the common congenital and acquired uterine anomalies associated with recurrent pregnancy losses, and discuss contemporary diagnosis and treatment options.