New approach for estimating risk of miscarriage after chorionic villus sampling.

OBJECTIVE: To estimate the risk of miscarriage associated with chorionic villus sampling (CVS). METHODS: This was a retrospective cohort study of women attending for routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation at one of eight fetal-medicine units in Spain, Belgium and Bulgaria, between July 2007 and June 2018. Two populations were included: (1) all singleton pregnancies undergoing first-trimester assessment at Hospital Clínico Universitario Virgen de la Arrixaca in Murcia, Spain, that did not have CVS (non-CVS group); and (2) all singleton pregnancies that underwent CVS following first-trimester assessment at one of the eight participating centers (CVS group). We excluded pregnancies diagnosed with genetic anomalies or major fetal defects before or after birth, those that resulted in termination and those that underwent amniocentesis later in pregnancy. We used propensity score (PS) matching analysis to estimate the association between CVS and miscarriage. We compared the risk of miscarriage of the CVS and non-CVS groups after PS matching (1:1 ratio). This procedure creates two comparable groups balancing the maternal and pregnancy characteristics that are associated with CVS, in a similar way to that in which randomization operates in a randomized clinical trial. RESULTS: The study population consisted of 22 250 pregnancies in the non-CVS group and 3613 in the CVS group. The incidence of miscarriage in the CVS group (2.1%; 77/3613) was significantly higher than that in the non-CVS group (0.9% (207/22 250); P < 0.0001). The PS algorithm matched 2122 CVS with 2122 non-CVS cases, of which 40 (1.9%) and 55 (2.6%) pregnancies in the CVS and non-CVS groups, respectively, resulted in a miscarriage (odds ratio (OR), 0.72 (95% CI, 0.48-1.10); P = 0.146). We found a significant interaction between the risk of miscarriage following CVS and the risk of aneuploidy, suggesting that the effect of CVS on the risk of miscarriage differs depending on background characteristics. Specifically, when the risk of aneuploidy is low, the risk of miscarriage after CVS increases (OR, 2.87 (95% CI, 1.13-7.30)) and when the aneuploidy risk is high, the risk of miscarriage after CVS is paradoxically reduced (OR, 0.47 (95% CI, 0.28-0.76)), presumably owing to prenatal diagnosis and termination of pregnancies with major aneuploidies that would otherwise have resulted in spontaneous miscarriage. For example, in a patient in whom the risk of aneuploidy is 1 in 1000 (0.1%), the risk of miscarriage after CVS will increase to 0.3% (0.2 percentage points higher). CONCLUSIONS: The risk of miscarriage in women undergoing CVS is about 1% higher than that in women who do not have CVS, although this excess risk is not solely attributed to the invasive procedure but, to some extent, to the demographic and pregnancy characteristics of the patients. After accounting for these risk factors and confining the analysis to low-risk pregnancies, CVS seems to increase the risk of miscarriage by about three times above the patient's background risk. Although this is a substantial increase in relative terms, in pregnancies without risk factors for miscarriage, the risk of miscarriage after CVS remains low and similar to, or slightly higher than, that in the general population. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Nuevo enfoque para estimar el riesgo de aborto después de una biopsia de vellosidades coriónicas OBJETIVO: Estimar el riesgo de aborto asociado con la biopsia de vellosidades coriónicas (BVC). MÉTODOS: Se trata de un estudio retrospectivo de cohorte de mujeres que acudieron a un examen ecográfico de rutina entre las 11+0 y las 13+6 semanas de gestación a una de entre un total de ocho centros de medicina fetal en España, Bélgica y Bulgaria, entre julio de 2007 y junio de 2018. En el estudio se incluyeron dos poblaciones: 1) todos los embarazos con feto único sometidos a evaluación del primer trimestre en el Hospital Clínico Universitario Virgen de la Arrixaca de Murcia (España), a las que no se les hizo una BVC (grupo no BVC); y 2) todos los embarazos con feto único sometidos a BVC tras la evaluación del primer trimestre en uno de los ocho centros participantes (grupo BVC). Se excluyeron los embarazos diagnosticados con anomalías genéticas o defectos fetales importantes antes o después del nacimiento, los que resultaron en una interrupción y los que más tarde se sometieron a amniocentesis durante el embarazo. Para estimar la relación entre la BVC y el aborto espontáneo se utilizó el pareamiento por puntaje de propensión (PPP). Se comparó el riesgo de aborto de los grupos BVC y no BVC después del pareamiento PPP (razón 1:1). Este procedimiento creó dos grupos comparables en los que las características de la madre y el embarazo que se asocian con la BVC estaban equilibradas, de manera similar a cómo funciona la aleatorización en un ensayo clínico aleatorizado. RESULTADOS: La población de estudio consistió en 22.250 embarazos en el grupo no BVC y 3.613 en el grupo BVC. La incidencia de abortos en el grupo BVC (2,1%; 77/3.613) fue significativamente mayor que en el grupo no BVC (0,9% (207/22.250); P<0,0001). El algoritmo del PPP emparejó 2.122 BVC con 2.122 casos no BVC, de los cuales 40 (1,9%) y 55 (2,6%) embarazos en los grupos BVC y no BVC, respectivamente, resultaron en un aborto espontáneo (razón de momios (RM), 0,72 (IC 95%, 0,48-1,10); P=0,146). Se encontró una interacción significativa entre el riesgo de aborto espontáneo después de una BVC y el riesgo de aneuploidía, lo que sugiere que el efecto de la BVC en el riesgo de aborto espontáneo difiere según las características del contexto. Concretamente, cuando el riesgo de aneuploidía es bajo, el riesgo de aborto después de una BVC aumenta (RM, 2,87 (IC 95%, 1,13-7,30)) y cuando el riesgo de aneuploidía es alto, paradójicamente el riesgo de aborto después de una BVC se reduce (RM, 0,47 (IC 95%, 0,28-0,76)), presumiblemente debido al diagnóstico prenatal y a la interrupción de embarazos con aneuploidías importantes que, de otro modo, hubieran provocado un aborto espontáneo. Por ejemplo, en una paciente para quien el riesgo de aneuploidía es de 1 entre 1000 (0,1%), el riesgo de aborto después de la BVC aumenta al 0,3% (0,2 puntos porcentuales más alto). CONCLUSIONES: El riesgo de aborto espontáneo en las mujeres que se someten a una BVC es aproximadamente un 1% mayor que el de las mujeres a las que no se les hace, aunque este exceso de riesgo no se atribuye únicamente al procedimiento agresivo sino, en cierta medida, a las características demográficas y del embarazo de cada paciente. Después de tener en cuenta estos factores de riesgo y limitar el análisis a los embarazos de bajo riesgo, la BVC parece triplicar aproximadamente el riesgo de aborto en comparación con el riesgo de fondo de la paciente. Aunque se trata de un aumento sustancial en términos relativos, en los embarazos sin factores de riesgo de aborto, después de una BVC el riesgo de aborto sigue siendo bajo y similar, o ligeramente superior, al de la población en general. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

[CLINICAL IMPLEMENTATION OF CELL-FREE DNA ANALYSIS IN MATERNAL BLOOD IN SCREENING FOR ANEUPLOIDIES IN SINGLETON PREGNANCIES].

OBJECTIVE: Clinical implementation of cell free(cf) DNA testing in maternal blood for aneuploidies in singleton pregnancies. METHODS: This is a retrospective study conducted in two centers for fetal medicine in Sofia, Bulgaria, between October 2013 and August 2015. We examined the clinical implementation of cf DNA testing in the routine practice for trisomies 21, 18 and13 after the performance of the first trimester combined test, second trimester biochemical test and/or the combination between first and second trimester integrated test. RESULTS: Cell-free DNA testing was performed in 170 singleton pregnancies with a median maternal age of 35 (range 22-46) years. The primary risk assessment for aneuploidies was derived from 95 cases after the first trimester combined screening test, 39 cases after the second trimester biochemical screening test, 16 cases after the integrated screening test and 20 cases there were no screening test performed. The results from the first line screening test were : 8 pregnancies with risk for trisomy 21 > 1: 100; 23 pregnancies with risk for trisomy 21 from 1:100 to 1: 300; 43 pregnancies with risk for trisomy 21 from 1:300 to 1:1000 and 76 pregnancies with risk for trisomy 21 < 1: 1000. No pregnancies with high risk for T13/T18 were identified. The analysis of cf DNA in the maternal blood reported 3 cases with T21 and no cases with T18 or T13. There was only one case of T21 in the group with risk >1:100 identified by the cf DNA analysis which was also identified by the first trimester combined screening test. The positive results were confirmed with invasive testing: CVS in the first trimester (one case) and Amniocentesis in the second trimester (two cases). CONCLUSION: Clinical implementation of cell-free DNA analysis in the contingent policy for screening could improve the detection rate for T21 and could reduce the rate of invasive procedures.

[FETAL THERAPY: INTRAUTERINE THORACO-AMNIOTIC SHUNTING IN MACROCYSTIC TYPE CYSTIC ADENOMATOID MALFORMATION OF THE LUNG: REVIEW OF THE LITERATURE AND CASE REPORT].

ABSTRACT OBJECTIVE: To present a case of macrocystic type cystic adenomatoid malformation of the lung (CCAM) treated with thoraco-amniotic shunt and to review the published data to evaluate the efficiency of thoraco-amniotic shunts for drainage of (CCAM). MATERIALS AND METHODS: This wass case reported of a fetus with a large thoracic cyst, major mediastinal shift and polyhidramnion treated with thoraco-amniotic shunting. We identified 8 cases diagnosed with CCAM and only one case met the criteria for fetal surgery. Thoracoamniotic shunting was successfully performed under local anesthesia and ultrasound control with operating time of 35 minutes. Medline was searched to identify cases of CCAM treated by thoraco-amniotic shunting. RESULTS: Fetal therapy forlung lesion was successfully performed at 30 weeks of gestation with CCAM volume ratio > 1.6 January, 2015 and amniodrenage after the procedure was carried out. The pregnancy has progressed uneventfully and planned Cesarean section was performed at 38 weeks of gestation. The optimal management of such case was performed for the first time in Bulgaria, which required an experienced interdisciplinary team. The newborn underwent resection of the lesion with no growth or neurodevelopment delay. The literature search identified cases with CCAM treated with thoraco-amniotic shunting between 1987 and 2016 and the the survival rate of non-hydropic fetuses that underwent treatment was 88%. CONCLUSIONS: Thoraco-amniotic shunting for macrocystic type CCAM is associated reduced risk of fetal intrauterine death and is also likely to be beneficial for the following major postnatal surgery

[Ultrasound Examination and Management of Twin Pregnancy.]

Twin pregnancies are found in about 3 % of all pregnancies and 2/3 are dizygotic and 1/3 are monozygotic. In the last 30 years after the introduction of assisted conception and increasing maternal age the rate of twin pregnancies dramatically increased. Compared to singletons, twins have more complications such as intrauterine demise, intrauterine selective fetal growth reStriction, congenital anomalies, miscarriage and preterm labour. Monochorionic twins are at high risk for unique complications because of blood exchange through vascular communications in the shared placenta. Twin pregnancies should be considered as a high risk pregnancies and the well-being of the two fetuses should be taken into account with a strict protocol for follow up and management options. CONCLUSION: Ultrasound examination olavs a maior role in fetal surveillance.

[Intrauterine Fetal Growth Restriction- Screening Model. Literature Review.]

Placental dysfunction is involved in a spectrum of obs.tetric conditions including preeclampsia, placental abrution and intrauterine fetal growth restriction. Their timely and accurate recognition is often a chalange since diagnostic criteria are dill based on nonspecific signs and symptomes. Fetal growth restriction (FGR) refers to a fetus that has failed to achieve its genetically determined growth potential and affects up to 5-10% of pregnancies. FRR is associated with an increase in perinatal mortality and morbidity. The diagnoslic challenge is in distinguishing SGA pregnancies from FGR pregnancies because the majority of SGA pregnancies are associated with a good prognosis compared to FGR pregnancies. Multifetal gegations have a high incidence of FGR. About 20-30% of dichorionic twins will suffer from FGR, as will 40% of monochorionic twins. Ultrasound is the benchmark for accurate pregnancy dating and diagnosis of FGR. However, there is room for error and FGR is undetected in about 30% of routinely scanned cases and incorrectly detected in 50% of cases. In recent years, the main priority of the leading obstetric clinics in Europe and the USA is drafting a universal screening model for selecting patients at high risk of developing placental dysfunction. Now, this model is part of the standard screening for chromosomal aneuploidies in the firs and second trimester of pregnancy and prolonged screening in the second and third trimester in patients at high risk.

[PRENATAL DIAGNOSIS OF FOETAL TRISOMY 3Q WITH PATERNAL ORIGIN].

Balanced chromosomal translocations do not generally have phenotypic manifestation, but lead to increased risk of miscarriage and live-birth of chromosomally unbalanced offspring in carriers. Frequently prenatal diagnosis of an unbalanced translocation may incidentally detect a balanced translocation in the family. Here, we report a unique case of trisomy 3q (karyotype 46,XYder(3)t(3;21)(q11;p11)), detected prenatally due to abnormal findings of the fetus ascertained through ultrasound assessment like growth retardation, vermal agenesis, micrognathia, cystic hygroma of the neck, dextra position of arcus aortae, shorter for the gestational week long bones In order to determine the paternity of this chromosomal aberration, the cytogenetic analyses of the parents was performed. A balanced paternal translocation 46,XY,t(3;21)(q11;p11) wase identified. During the next pregnancy the same balanced translocation of paternal origin wase also identified. This case demonstrate the significance of prenatal ultrasound screening of the fetus; the necessity of cytogenetic analysis of a fetus with prenatal ultrasound abnormalities; genetic counseling of such families with aim of prenatal care and prevention during next pregnancies.

[Prenatal diagnosis and fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia. Case report].

We present a case of severe isolated congenital diaphragmatic hernia (CDH) diagnosed at 19 weeks of gestation and treated at 28 weeks with Fetal Endoscopic Tracheal Occlusion (FETO). The CDH was left-sided with part of the liver in the thorax and lung area to head circumference ratio (LHR) of 0.9. The FETO was successfully performed under spinal anesthesia. The pregnancy is progressing uneventfully and ultrasound examination 10 days after the FETO demonstrated an increased LHR to 1.1. Treatment with FETO for severe CDH has been performed for the first time in Bulgaria and this procedure addressed several questions for optimal management by an experienced interdisciplinary team.

[New screening method for aneuploidies based on analysis of cell-free DNA in the maternal blood].

UNLABELLED: The national program of screening for aneuploidies in Bulgaria is based on first trimester combined test, second trimester biochemical test and/or the combination between first and second trimester integrated test. OBJECTIVE: To review the literature for studies analyzing cell-free (cf) DNA in the maternal blood and to report the clinical implementation and validation of the method in the clinical practice. Literature search and study selection extracted studies since 2011 when the first article was published. The data source included searches from PubMed and Medline. The reported results for detection rates (DR) and false positive rates (FPR) in singleton pregnancies were about 99.0% and 0.08% respectively, for trisomy 21, 96.8% and 0.15% for trisomy 18, 92.1% and 0.20% for trisomy 13, 88.6% and 0.12% for monosomy X. For twin pregnancies, the DR was 94.4% and FPR was 0% for trisomy 21. CONCLUSION: Analysis of cell-free DNA in the maternal blood is an effective method of screening for aneuploidies.

[MODELS OF CLINICAL IMPLEMENTATION OF CELL FREE FETAL DNA IN THE MATERNAL SERUM SCREENING TEST-ANALYSIS].

UNLABELLED: Prenatal screening by definition is a way of identifying pregnancies, with a high enough risk to specific fetal damage as to justify the subsequent invasive diagnosis among the seemingly normal pregnancies. [1] The aim of the prenatal screening test is to reach the high diagnostic frequency (DR > 95%), with low false-positive rate (FPR < 1%). Several non-invasive prenatal tests (NIPT) are widely adopted and use in clinical practice: 1st Trimester Combined screening (First trimester Combined Screening) and 2nd trimester biochemical screening (Second trimester biochemical screening) and in the last few years through screening Fetal DNA in Maternal serum (cfDNA screening). Since the introduction of the sfDNA test were examined and discussed the results of several ways of application: (1) as a primary screening method without preceding the result of 1st trimester combined screening for chromosomal abnormalities, (2) as a contingent test after 1st trimester combined screening in high risk pregnancies (> 1:100) (3) as a contingent test after 1st trimester combined screening, when the calculated risk is between ( 1:10 to 1:2500). The purpose of the study: to compare the results of different ways of application screening through cfDNA: detection rate (DR) for Tri21, Tri18 and Tri13, procentage of invasive diagnostics and cost-effectiveness ratio of cfDNA test in comparison with the 1st trimester combined screening. To establish the most suitable algorithm for application of cfDNA test. METHODS AND MATERIALS: Analyzed were the results of several randomized multi-center clinical studies whose data are processed through a meta-analysis. RESULTS: cfDNA-test has a higher DR for Tri21 for lower FPR, compared to the combined screening in 1st trimester (cfDNA-DR 99%, 1st trimester screening-DR 96% and 0.4%FPR, respectively FPR 5%), but although it is with better results and reduces the incidence of invasive tests, does not justify the significant difference in price-performance ratio. On the other hand cfDNA-test is with a lower detection rate for Tri 18 or 13 (93-95%), which makes it worse for a primary screening test instead of combined screening in the 1st trimester. CONCLUSIONS: The performance of cfDNA-test in terms of the three most common Trisomies: 21,18 and 13 is highest when used after (contingent to) 1st trimester screening and only for patients with an intermediate risk from 1-st trimester screening (risk > 1:10 and 1:2500, around 27% of all pregnancies), as it increases the diagnostic rate of combined screening for Down syndrome (from 90% to 98%), and significantly reduces the percentage of invasive diagnostics (from 3% to 0.7-1%) and that way we are able to achieve optimal result in price-performance result.

[INTRODUCTION OF ENDOSCOPIC LASER THERAPY FOR COMPLICATED MONOCHORIONIC TWINS IN BULGARIA].

OBJECTIVE: The aim of this study is to describe our initial experience of endoscopic laser coagulation of inter-twin placental vessels in the treatment for severe twin-to-twin transfusion syndrome (TTTS) and selective fetal growth restriction (sFGR) at SABBAL "Dr Shterev Hospiat". METHODS: Endoscopic laser surgery was carried out in eight cases of TTTS and two cases of sFGR at a median gestational age of 21.4 (range 16.4-23.1) weeks. In the group of TTTS there was one, three and four cases of Quintero stage 2, 3 and 4, respectively. Both cases of sFGR were Gratacos type 2. RESULTS: In the eight cases of TTTS, there was survival of both twins in four cases (one, two and one of Quintero stages 2, 3 and 4, respectively), survival of one twin in one case (Quintero stage 3) and death of both twins in three cases (all Quintero stage 4). In the sFGR group, both twins survived in one case and one survived in one case. The three cases of TTTS with death of both twins were in the first four cases of the series and the death occurred during or within 24 hours of the procedure where in 2 cases there was SROM with cervical length 7 and 12 mm respectively. In the seven cases with survivors, the median gestational age at delivery was 32.3 (range 28.1-37.0) weeks. CONCLUSIONS: Our results from endoscopic surgery in TTTS and sFGR are encouraging and are likely to improve with increasing experience. There was at least one survivor in two of the first four cases and in all six subsequent cases.