Genetics of recurrent miscarriage and fetal loss.

Despite years of research, miscarriage, particularly when recurrent, continues to pose a medical challenge. An embryo chromosomal error is responsible for 50-60% of recurrent cases; however, up to 30-50% remains an enigma. Successful pregnancy involves different maternal physiologic changes and certain complex interactions between the fetus and the mother by cytokines, angiogenic mediators and hormones. To date, research lines have focused on genetic and epigenetic polymorphisms related mainly to immune response and inflammatory mediators, and have yielded a significant relationship between recurrent miscarriage and immune mechanisms. Thus, unknown causes of miscarriage could be due to an immune imbalance induced by T-helper Th1/Th2/Th17 cytokines and regulatory T cells. Furthermore, these genes and mediators have long been suspected of being blood markers for the clinical diagnosis and management of miscarriage; however, more evidence is required for them to be included in medical practice and obstetric guidelines.

Síndrome antifosfolipídico obstétrico / Obstetric antiphospholipid syndrome

El síndrome antifosfolipídico obstétrico es una alteración autoinmune adquirida que asocia diversas complicaciones obstétricas, en ausencia de historia trombótica previa, junto con la existencia de anticuerpos antifosfolipídicos dirigidos contra fosfolípidos, proteínas denominadas cofactores o contra complejos fosfolípidos-cofactor. Aunque las complicaciones obstétricas se han relacionado con sus propiedades procoagulantes, estudios anatomopatológicos en placentas humanas han demostrado su capacidad proinflamatoria vía sistema del complemento-citocinas proinflamatorias. No hay acuerdo general sobre cuál es el perfil de anticuerpos antifosfolipídicos (categoría de laboratorio) que confiere más riesgo obstétrico, aunque las denominadas categorías I y IIa son las mejores candidatas. El tratamiento combinado con dosis bajas de aspirina y heparina consigue buenos resultados obstétricos y maternos. Se revisan también las posibilidades terapéuticas en los casos refractarios. La evolución a otras enfermedades autoinmunes es baja. Se comenta brevemente el denominado síndrome antifosfolipídico obstétrico incompleto, también conocido como síndrome de morbilidad obstétrica asociada a anticuerpos antifosfolipídicos (AU)

Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and, in the absence of prior history of thrombosis, with the presence of antiphospholipid antibodies directed against other phospholipids, proteins called cofactors or PL-cofactor complexes. Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies, pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines. There is no general agreement on which antiphospholipid antibodies profile (laboratory) confers the greatest obstetric risk, but the best candidates are categories I and IIa. Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes. In this study, we also review the therapeutic possibilities in refractory cases, although the likelihood of progressing to other autoimmune diseases is low. We briefly comment on incomplete obstetric antiphospholipid syndrome, also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome (AU)

Do knowledge of uterine artery resistance in the second trimester and targeted surveillance improve maternal and perinatal outcome? UTOPIA study: a randomized controlled trial.

OBJECTIVES: To ascertain whether screening for pre-eclampsia (PE) and intrauterine growth restriction (IUGR) by uterine artery (UtA) Doppler in the second trimester of pregnancy and targeted surveillance improve maternal and perinatal outcomes in an unselected population. METHODS: This was a multicenter randomized open-label controlled trial. At the routine second-trimester anomaly scan, women were assigned randomly to UtA Doppler or non-Doppler groups. Women with abnormal UtA Doppler were offered intensive surveillance at high-risk clinics of the participating centers with visits every 4 weeks that included measurement of maternal blood pressure, dipstick proteinuria, fetal growth and Doppler examination. The primary outcome was a composite score for perinatal complications, defined as the presence of any of the following: PE, IUGR, spontaneous labor < 37 weeks' gestation, placental abruption, stillbirth, gestational hypertension, admission to neonatal intensive care unit and neonatal complications. Secondary outcomes were a composite score for maternal complications (disseminated intravascular coagulation, maternal mortality, postpartum hemorrhage, pulmonary edema, pulmonary embolism, sepsis), and medical interventions (for example, corticosteroid administration and induction of labor) in patients developing placenta-related complications. RESULTS: In total, 11 667 women were included in the study. Overall, PE occurred in 348 (3.0%) cases, early-onset PE in 48 (0.4%), IUGR in 722 (6.2%), early-onset IUGR in 93 (0.8%) and early-onset PE with IUGR in 32 (0.3%). UtA mean pulsatility index > 90(th) percentile was able to detect 59% of early-onset PE and 60% of early-onset IUGR with a false-positive rate of 11.1%. When perinatal and maternal data according to assigned group (UtA Doppler vs non-Doppler) were compared, no differences were found in perinatal or maternal complications. However, screened patients had more medical interventions, such as corticosteroid administration (relative risk (RR), 1.79 (95% CI, 1.4-2.3)) and induction of labor for IUGR (RR, 1.36 (95% CI, 1.07-1.72)). In women developing PE or IUGR, there was a trend towards fewer maternal complications (RR, 0.46 (95% CI, 0.19-1.11)). CONCLUSIONS: Routine second-trimester UtA Doppler ultrasound in an unselected population identifies approximately 60% of women at risk for placental complications; however, application of this screening test failed to improve short-term maternal and neonatal morbidity and mortality. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Obstetric antiphospholipid syndrome.

Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and, in the absence of prior history of thrombosis, with the presence of antiphospholipid antibodies directed against other phospholipids, proteins called cofactors or PL-cofactor complexes. Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies, pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines. There is no general agreement on which antiphospholipid antibodies profile (laboratory) confers the greatest obstetric risk, but the best candidates are categories I and IIa. Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes. In this study, we also review the therapeutic possibilities in refractory cases, although the likelihood of progressing to other autoimmune diseases is low. We briefly comment on incomplete obstetric antiphospholipid syndrome, also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome.

Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria.

In 1964, Miyoshi reported a series of patients with diverse symptoms after receiving treatment with silicone or paraffin fillers. Miyoshi named this condition 'human adjuvant disease'. Since then, the literature has been flooded with case reports and case series of granulomatous and systemic autoimmune disorders related to vaccines, infection or other adjuvants such as silicone and other biomaterials. A new term -autoimmune/inflammatory syndrome induced by adjuvants--has recently been coined for a process that includes several clinical features previously described by Miyoshi plus other clinical and laboratory parameters related to exposure to diverse external stimuli. Disorders such as siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, sick building syndrome and post-vaccination syndrome have been included in autoimmune/inflammatory syndrome induced by adjuvants. Disorders such as Spanish toxic oil syndrome and Ardystil syndrome could also be included. Furthermore, biomaterials other than silicone should also be considered as triggering factors for these adjuvant-related syndromes. New diagnostic criteria in this field have been proposed. Nevertheless, many of these criteria are too subjective, leading to some patients being diagnosed with chronic fatigue syndrome or other 'central sensitization syndromes'. Diagnostic criteria based only on objective clinical and laboratory data to be further discussed and validated are proposed herein.

Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells.

The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal-fetal interface prevented fetal allo-rejection by creating a "tolerant" microenvironment characterised by the expression of IL-10, TGF-ß and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-ß, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal-fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.

Expectant management in pregnant women with early and severe preeclampsia and concomitant risk factors.

AIM: The aim of this study was to demonstrate that women with severe early-onset preeclampsia and concomitant risk factors benefit from expectant management. METHODS: This retrospective study was conducted between January 2009 and December 2010. Stable women with severe preeclampsia between 23+6 and 33+6weeks of gestation were admitted to the IOCU for conservative management. They were classified into two groups: those with concomitant risk factors, i.e. associated medical conditions, HELLP syndrome, severe oligohydramnios, fetal growth restriction and multiple pregnancies (group A) and those without (group B). P values lesser than 0.05 were considered statistically significant. RESULTS: No significant differences were found in maternal and perinatal outcomes between groups. Neither were differences observed in pregnancy prolongation (mean: 8.42days (SD±7.462) in group A and 10.5days (SD±8.235) in group B (p=0.391)). At the start of expectant management, 31.8% of fetuses had an abnormal middle cerebral artery Doppler; prior to delivery, this percentage was 77.4%. CONCLUSION: Pregnant women with severe early-onset preeclampsia and associated risk factors benefited from expectant management. During expectant management using a continuous magnesium sulfate regimen, the majority of fetuses showed cerebral vasodilatation. The exact clinical value of this finding should be clarified in further studies.

Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management.

OBJECTIVE: To date, there are no reliable data regarding the actual treatment received by women with refractory obstetric antiphospholipid syndrome (OAPS). The aim of this study was to assess current clinical evidence and new trends in the treatment of refractory OAPS. METHODS: A non-systematic but comprehensive literature search using relevant keywords was made to identify relevant articles published in English from different computerized databases: PubMed (Medline), Google Scholar electronic database search and The Cochrane Library, from January 2000 to March 2012. Studies on the treatment of poor obstetric outcomes in women with OAPS were included. Prospective randomized clinical trials, cohort studies, reviews, systematic reviews and meta-analysis were retrieved. RESULTS: A total of 130 articles were finally selected for this review, including 17 randomized clinical trials and four meta-analyses. The majority of articles were non-randomized original papers and basic and clinical reviews. CONCLUSION: Up to 20% of women with OAPS do not receive the currently recommended therapeutic regimen. Unfortunately, well-designed studies regarding the usefulness of new drugs in refractory OAPS are scarce. Hydroxychloroquine and low-dose prednisolone appear to be useful when added to standard therapy. Current data do not support the use of intravenous immunoglobulins in this field. The role played by double anti-aggregant therapy, fondaparinux, vitamin D, pentoxifylline and TNF-targeted therapies should be tested in well-designed studies.

Autoimmune/inflammatory syndrome (ASIA) induced by biomaterials injection other than silicone medical grade.

BACKGROUND: Systemic autoimmune/granulomatous adverse reactions related to biomaterials other than silicone have rarely been reported. AIM: The aim of this paper is to communicate the cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in a study of Spanish patients suffering from inflammatory disorders related to biomaterial injections other than silicone, principally hyaluronic acid, acrylamides or methacrylate compounds. METHODS: The authors performed a retrospective analysis of the clinical, laboratory, histopathology and follow-up of a cohort of 250 cases of patients suffering from inflammatory/autoimmune disorders related to bioimplant injections. RESULTS: Of these 250 cases, patients with adverse reactions related to silicone injections (n = 65) were excluded. Of the remaining 185, 15 cases (8%) had systemic or distant and multiple complaints that could be categorized as ASIA. In all but four patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Eleven cases (73.3%) with inflammatory localized nodules and panniculitis evolved into a variety of disorders, namely, primary biliary cirrhosis, Sjögren's syndrome, sarcoidosis, human adjuvant disease and inflammatory polyradiculopathy. Four cases presented primarily with systemic autoimmune disorders. CONCLUSIONS: Infrequently, biomaterials other than silicone can provoke local inflammatory adverse reactions that may evolve into systemic autoimmune and/or granulomatous disorders. Whether or not these biomaterials act as an adjuvant, they could be included in the ASIA category.

Pregnancy in women with portal vein thrombosis: results of a multicentric European study on maternal and fetal management and outcome.

BACKGROUND & AIMS: Women of childbearing age account for approximately 25% of patients with non-cirrhotic portal vein thrombosis (PVT). We aimed at assessing maternal and fetal outcome in pregnant women with known PVT. METHODS: We performed a retrospective analysis of the files of women with chronic PVT in three European referral centers between 1986 and 2010. RESULTS: Forty-five pregnancies, 28 (62%) treated with low molecular weight heparin, occurred in 24 women. Nine (20%) were lost before gestation week 20. Preterm birth occurred in 38% of deliveries: there were 3 births at week 24-25, 7 at week 32-36, and 26 after week 37. A term birth with a healthy infant occurred in 58% of pregnancies. Cesarean section was used in 53% of deliveries. Two women developed HELLP syndrome. A favorable outcome happened in 64% of pregnancies. Pregnancies with an unfavorable outcome were associated with a higher platelet count at diagnosis. Bleeding from esophageal varices occurred in 3 patients during pregnancy, all without adequate primary prophylaxis. Genital or parietal bleeding occurred postpartum in 4 patients, only one being on anticoagulation therapy. Thrombotic events occurred in 2 patients, none related to lower limbs or mesenteric veins. There were no maternal deaths. CONCLUSIONS: In pregnant PVT patients treated with anticoagulation on an individual basis, the rate of miscarriage and preterm birth appears to be increased. However, fetal and maternal outcomes are favorable for most pregnancies reaching gestation week 20. High platelet counts appear to increase the risk for unfavorable outcome. Pregnancy should not be contraindicated in stable PVT patients.

The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary first year report.

BACKGROUND: Obstetric morbidity (OM) is a common feature of antiphospholipid syndrome (OAPS). Women having OAPS-only and women with OM related to antiphospholipid antibodies (aPL) but not fulfilling APS classification criteria (OMAPS), may show similar patterns. AIM: The aim of this research was to collect records of OAPS and OMAPS cases in order to have valuable information about their clinical features, laboratory, treatment, pregnancy outcomes and long-term follow-up. METHODS: EUROAPS/EUROMAPS is a registry in the frame of the European Forum on Antiphospholipid Antibody projects. Its own website has been available since June 2010: www.euroaps.org. RESULTS: This registry comprises 211 women including 304 pre-enrolment pregnancies, and 226 prospective cases, 194 of OAPS and 32 of OMAPS. OM was more frequent in OAPS than in OMAPS, independent of treatment. In the prospective cohort, standard aPL data was available in 202 cases and treatment data in all 226 cases. Good fetal outcomes were obtained when low dose aspirin plus low molecular weight heparin were administered. Prevalence of thrombotic events and/or cases evolving into full-blown systemic lupus erythematosus (SLE) was low. CONCLUSIONS: OAPS could be a different form of APS. OMAPS/OMAPS fetal outcomes were better when treated. The prevalence of thrombosis and progression to SLE were lower than in 'classical' APS.

First trimester serum angiogenic/anti-angiogenic status in twin pregnancies: relationship with assisted reproduction technology.

BACKGROUND: The risk of pre-eclampsia (PE) increases in twin pregnancies, especially when assisted reproduction technologies (ART) are used. The aim of this study was to assess angiogenic/anti-angiogenic factors in maternal serum in the first trimester of twin pregnancies and establish if the mode of conception influences angiogenic status. METHODS: This prospective study enrolled women with twin (n = 61) and singleton (n = 50) pregnancies. Dichorionic twin pregnancies were divided into two groups according to their mode of conception. Singleton pregnancies were used as the control group. Soluble fms-like tyrosine kinase (sFlt-1), free placental growth factor (PlGF) and soluble endoglin (sEng) concentrations were measured in the first trimester maternal serum. RESULTS: In the first trimester, women with twin pregnancies had higher serum concentrations of the anti-angiogenic factor sFlt-1 than that with singleton pregnancies (3924 ± 250 versus 2426 ± 162 pg/ml, respectively; P < 0.001). Maternal serum PlGF concentrations were lower in singleton pregnancies than those in twin pregnancies (37 ± 3.7 versus 59 ± 5.6, respectively; P < 0.001). Serum concentrations of sFlt-1 were higher in twin pregnancies conceived by ART than those in spontaneous twin pregnancies (4313 ± 389 versus 3522 ± 300 pg/ml, respectively; P < 0.05). No differences between groups were observed for sEng. CONCLUSIONS: In the first trimester, twin pregnancies conceived using ART showed a heightened anti-angiogenic status that could explain the increased risk of PE in these cases.

Prevalence and clinical usefulness of antiphospholipid and anticofactor antibodies in different Spanish preeclampsia subsets.

OBJECTIVE: To study the prevalence and clinical usefulness of antiphospholipid antibodies in different preeclampsia subsets. DESIGN: Observational cross-sectional study. SETTING: Tertiary teaching hospital. PATIENTS: Ninety-nine women with preeclampsia versus 83 healthy pregnant women as controls. INTERVENTIONS: We analysed anticardiolipin IgG/IgM, anti-ß(2)glycoprotein IgG/IgM, antiphosphatidylserine IgG/IgM, antiAnnexin-A5 IgG/IgM, and lupus anticoagulant. MAIN OUTCOME MEASURE: Comparison of antiphospholipid antibody positivity between groups. RESULTS: Antiphospholipid antibody prevalence was 14.14% in the study group vs. 7.23% in controls. Excluding antiAnnexin-A5-positive women, overall antiphospholipid prevalence was 13.19% vs. 3.61% (p = 0.034). Only IgM-anticardiolipin positivity showed significant differences between preeclampsia group and controls (8.1% vs. 1.20%, p = 0.041). Comparing a severe preeclampsia subset vs. controls, we obtained these significant results: for two or more positive antiphospholipid tests: 9.09% vs. 1.20 (p = 0.037); IgM-anticardiolipin 10.91% vs. 1.20% (p = 0.016); IgG/IgM-anti-ß(2)glycoprotein-I 10.91% vs. 1.90% (p = 0.016), IgM-anti-ß(2)glycoprotein-I 9.09% vs.1.20 (p = 0.037). When comparing early-onset preeclampsia vs. controls we found IgM-anticardiolipin 11.11% vs. 1.20% (p = 0.029). CONCLUSIONS: Prevalence of antiphospholipid antibodies in preeclampsia patients is twice that in healthy pregnant women. Multipositive aPL test, IgM-anticardiolipin and IgM-anti-ß(2)glycoprotein-I isotypes showed an association with severe and early-onset preeclampsia. Larger studies are needed to establish the usefulness of antiphospholipid tests as risk markers for severe and early onset preeclampsia.

Angiogenic and antiangiogenic factors before and after resolution of maternal mirror syndrome.

Mirror syndrome is a rare condition that involves fetal hydrops, placentomegaly and severe maternal edema. The pathogenesis of this syndrome mimics endothelial dysfunction observed in pre-eclampsia. We report a case of maternal mirror syndrome caused by bilateral fetal hydrothorax that resolved after intrauterine pleuroamniotic shunt placement. At the time of the clinical manifestation there was an antiangiogenic state similar to that seen in pre-eclampsia, which resolved after fetal treatment. Our findings suggest that mirror syndrome is a manifestation of a broad spectrum of pathological conditions that induces an antiangiogenic state.

Hipocomplementemia en el síndrome antifosfolípido obstétrico / No disponible

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Delayed immune-mediated adverse effects related to hyaluronic acid and acrylic hydrogel dermal fillers: clinical findings, long-term follow-up and review of the literature.

INTRODUCTION: Implantation of dermal filler for cosmetic purposes is becoming increasingly common worldwide. It is thought that hyaluronic acid (HA) alone or combined with acrylic hydrogels (HA-AH) does not have severe nor persistent side-effects. However, recent evidence may show that major, local and/or systemic, immediate or delayed adverse effects may appear in relation with its use. OBJECTIVE: To evaluate the clinical complaints, laboratory data, treatment and follow-up of patients with delayed adverse effects related to HA and HA-AH implant fillers. DESIGN: Prospective, case-series study of patients filled with HA and HA-AH compounds. SETTING: The study has been done in a tertiary, teaching university hospital. PATIENTS: We report on a series of 25 patients, 15 of them in prospective manner, with severe, delayed side-effects related to HA-AH. Inclusion criteria have been drawn up. Patients with immediate side-effects were excluded. Patients were submitted to a clinical follow-up, battery of blood tests and thorax X-ray films. Besides, a review of the literature was made. We undertook a computed-assisted (MEDLINE), National Library of Medicine, Bethesda, MD, USA, search of the literature from 1996 up to December 2005. MAIN OUTCOME: Clinical evaluation of granulomas, skin manifestations and other local and systemic immune-mediated disorders possibly related to HA and HA-AH fillers or their cumulative interaction with previously administered fillers. RESULTS: Of 25 cases, 16 were filled with HA alone and 9 with a HA-AH compounds. Of 15 cases analysed and with long-term follow-up, 10 were filled with HA alone, and the remaining five were filled with a HA-AH. Time latency average up to beginning of symptoms was 13.7 months. Three of these 15 cases had been filled before with silicone and another one with Artecoll. Tender nodules were seen in 14 patients. Systemic manifestations appeared in three cases. Laboratory abnormalities were noted in all studied cases. After 16-month average follow-up, seven patients seem to be cured, and six have recurrent bouts. Two cases were lost during follow-up. CONCLUSION: Although in some cases, these clinical complications might have been associated with previous fillers or with other unknown foreign bodies, we feel that, although infrequently, delayed and recurrent chronic inflammatory and granulomatous reactions may complicate HA and HA-AH implant fillers.

Manifestaciones hemorrágicas y anticuerpos antifosfolípido / Bleeding manifestations and antiphospholipid antibodies

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