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• W2903601158 abstract "To assess the added value of chromosomal microarray analysis (CMA) over conventional karyotyping to assess the genetic causes in stillbirth. To identify relevant studies, published in English or Spanish and without publication time restrictions, we performed a systematic search of PubMed, SCOPUS and ISI Web of Science databases, The Cochrane Library and the PROSPERO register of systematic reviews, for case series of fetal loss ≥ 20 weeks of gestation, with normal or suspected normal karyotype, undergoing CMA and with at least five subjects analyzed. To investigate quality, two reviewers evaluated independently the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. For the meta-analysis, the incremental yield of CMA over karyotyping was assessed by single-proportion analysis using a random-effects model (weighting by inverse variance). We assessed heterogeneity between studies and performed a sensitivity analysis and a subgroup analysis of structurally abnormal (malformed or growth-restricted) and normal fetuses. Included in the meta-analysis were seven studies involving 903 stillborn fetuses which had normal karyotype. The test success rate achieved by conventional cytogenetic analysis was 75%, while that for CMA was 90%. The incremental yield of CMA over conventional karyotyping based on the random-effects model was 4% (95% CI, 3–5%) for pathogenic copy-number variants (pCNVs) and 8% (95% CI, 4–17%) for variants of unknown significance. Subgroup analysis showed a 6% (95% CI, 4–10%) incremental yield of CMA for pCNVs in structurally abnormal fetuses and 3% (95% CI, 1–5%) incremental yield for those in structurally normal fetuses. The pCNV found most commonly was del22q11.21. CMA, incorporated into the stillbirth work-up, improves both the test success rate and the detection of genetic anomalies compared with conventional karyotyping. To achieve a genetic diagnosis in stillbirth is particularly relevant for the purpose of counseling regarding future pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. Valor añadido del análisis de microarrays cromosómicos sobre el cariotipado convencional en el estudio de éxitus fetal: revisión sistemática y metaanálisis Evaluar el valor añadido del análisis de microarrays cromosómicos (AMC) sobre el cariotipado convencional para evaluar las causas genéticas en el éxitus fetal. Para identificar estudios relevantes, publicados en inglés o español y sin restricciones de tiempo de la publicación, se realizó una búsqueda sistemática en las bases de datos PubMed, SCOPUS e ISI Web of Science, The Cochrane Library y el registro de revisiones sistemáticas PROSPERO, para series de casos de pérdida fetal ≥ 20 semanas de gestación, con cariotipo normal o presuntamente normal, sometidos a AMC y con al menos cinco sujetos analizados. Para investigar la calidad, dos revisores evaluaron de forma independiente el riesgo de sesgo mediante la herramienta Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Para el metaanálisis, se evaluó el rendimiento incremental del AMC sobre el cariotipado mediante un análisis de proporción única que empleó un modelo de efectos aleatorios (ponderación por varianza inversa). Se evaluó la heterogeneidad entre los estudios y se realizó un análisis de sensibilidad y un análisis de subgrupos de fetos estructuralmente anómalos (con malformación o con restricción del crecimiento) y normales. En el metaanálisis se incluyó siete estudios que comprendían 903 casos de éxitus fetal con cariotipo normal. La tasa de éxito de la prueba alcanzada mediante el análisis citogenético convencional fue del 75%, mientras que la del AMC fue del 90%. El rendimiento incremental del AMC sobre el cariotipado convencional en el modelo de efectos aleatorios fue del 4% (IC 95%, 3–5%) para las variantes patógenas del número de copias (VNCp) y del 8% (IC 95%, 4–17%) para las variantes de significancia desconocida. El análisis de subgrupos mostró un rendimiento incremental del AMC del 6% (IC 95%, 4–10%) para los fetos estructuralmente anormales y del 3% (IC 95%, 1-5%) para los fetos estructuralmente normales. La VNCp encontrada más comúnmente fue del22q11.21. El AMC, incorporado en el estudio del éxitus fetal, mejora tanto la tasa de éxito de las pruebas como la detección de anomalías genéticas en comparación con el cariotipado convencional. El diagnóstico genético en el éxitus fetal es especialmente relevante para el asesoramiento en futuros embarazos. 染色体微阵列分析相对于传统核型分析在死胎检查中的附加价值:系统回顾与Meta分析 评价染色体微阵列分析(CMA)相对于传统核型分析在死胎遗传因素检查中的附加价值。 为了确定以英文或西班牙文出版的，且不受出版时间限制的相关研究资料，我们在PubMed、SCOPUS 和ISI科学网数据库，Cochrane图书馆和 PROSPERO系统回顾注册系统进行了系统搜索。对妊娠≥20周的死胎，伴有正常或疑似正常核型，接受CMA检查的至少5例以上病例的研究进行了分析。为了观察质量，两位评论人员使用诊断性试验准确性质量评价工具(QuADAS-2)独立地评估了偏倚风险。在Meta分析中，采用随机效应模型(逆方差加权)，通过单比例分析评估CMA相对于核型分析的增量。我们评估了研究之间的异质性，并对结构异常的(畸形或生长受限)胎儿和正常的胎儿进行了敏感性分析和亚组分析。 Meta分析纳入涉及903例死胎的7项研究，这些死胎的核型正常。传统细胞遗传学检测成功率为75%，CMA检测成功率为90%。在随机效应模型下，与传统核型分析相比，致病拷贝数变异(pCNVs)的CMA增量为4%(95%CI，3-5%)，意义不明拷贝数变异的CMA增量为8%(95%CI，4-17%)。亚组分析显示，结构异常胎儿的CMA增量为6%(95%CI，4-10%)，结构正常胎儿的CMA增量为3%(95%CI，1-5%)。最常见的pCNV为del22q11.21。 与传统核型分析相比，CMA应用于死胎检测可提高检测成功率和遗传异常的检出率。死胎的遗传诊断对于将来妊娠的咨询尤其重要。 Stillbirth occurs in approximately three to six of every 1000 pregnancies in developed countries1-3. It is caused by fetal growth restriction/placental insufficiency in around 30% of cases, fetal structural/chromosomal abnormalities in 19%, fetal infections in 13%, placental abruption in 10%, umbilical cord complications in 7%4-7, pre-eclampsia in 4%, fetomaternal transfusion in 3%, twin-to-twin transfusion syndrome in 2%, cholestasis of pregnancy in 1%, diabetes mellitus in 1% and alloimmunization in 1%, while the reason remains unknown in 9%4-9. Regarding the genetic causes of stillbirth, it is well established that the frequency of chromosomal anomalies is highly dependent on the presence (50% of cases) or absence (5% of cases) of fetal structural anomalies4, 9. Although described several years ago, it is only now that the use of chromosomal microarray analysis (CMA) is being introduced effectively into clinical practice, allowing far better resolution (10–100 kb) than the 10 Mb that is achievable using conventional karyotyping. Another advantage is that CMA does not require cells to be in metaphase for analysis, resulting in a higher test success rate given that cell culture is unnecessary so culture failure is avoided and maternal cell and bacterial contamination minimized10. The aim of this systematic review and meta-analysis was to assess the added value of CMA above normal karyotyping in fetal loss after 20 weeks of gestation, particularly regarding both the test success rate and the diagnostic yield, with the main objective of assisting clinicians in the assessment of the recurrence risk of genetic abnormalities in couples with previous stillbirth. Before data extraction, the review was registered with PROSPERO (International Prospective Register of Systematic Reviews) (registration No: CRD42017079428). To identify relevant studies, published in English or Spanish and without publication time restrictions, we performed a systematic search of the literature (including PubMed, SCOPUS and ISI Web of Science databases, The Cochrane Library and the PROSPERO register of systematic reviews) for observational studies that included fetal loss ≥ 20 weeks of gestation (stillbirths), undergoing CMA, with a normal karyotype and with at least five subjects analyzed. Karyotype was defined as ‘normal’ both in cases with a normal result and in cases in which karyotyping had failed or was unknown and CMA did not reveal any chromosomal anomaly that would have been detected by karyotyping (genomic imbalance ≥ 10 Mb). Institutional review board approval is not required for systematic reviews in our hospital. References of relevant publications were searched manually for additional potentially relevant published studies. The first search was run on 20 May 2017 and a second search was carried out, to identify recent publications, on 20 August 2018. This review was carried out adhering to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines11 and the PRISMA guidelines for systematic reviews and meta-analyses12, 13. Abstracts identified as potentially relevant were assessed by two independent evaluators (R.J.M.-P. and A.H.-V.), both blinded to studies' authorship, authors' institutions and studies' results. If a study fitted the inclusion criteria, the full-text article was reviewed. A third and fourth investigator (A.B. and M.P.) resolved by discussion any lack of consensus between evaluators. In the case of a relevant study with missing information, the corresponding author was contacted by e-mail. Appendix S1 details the search strategy and query syntaxes. The following data were extracted into a datasheet based on the Cochrane Consumers and Communication Review Group's data extraction template14: author, year of publication, country in which the study was conducted, study period, original inclusion criteria, total number of cases included in the study, number of fetal losses ≥ 20 weeks of gestation (i.e. stillbirths), number of stillbirths with normal karyotype, number of stillbirths with normal karyotype and structural defects (fetal malformations or growth restriction), sample source and CMA type. Two reviewers (R.J.M.-P. and A.H.-V.) assessed independently the quality of the selected studies. Quality assessment of the studies was carried out using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) scale15-17. The following characteristics were evaluated: (1) patient selection (Could the selection of patients have introduced bias? Are there concerns that the included patients and setting do not match the review question?); (2) index test (Could the conduct or interpretation of the index test have introduced bias? Are there concerns that the index test, its conduct, or its interpretation differ from the review question?); (3) reference standard (Could the reference standard, its conduct, or its interpretation have introduced bias? Are there concerns that the index test, its conduct, or its interpretation differ from the review question?); and (4) flow and timing (Could the patient flow have introduced bias?). Results from these questions were plotted and assessed using Review Manager (RevMan) version 5.318. Extracted results were pooled in a meta-analysis. The test success rate, or rate of informative results, was compared between karyotyping and CMA. The incremental yield of CMA over karyotyping (proportion of additional cases diagnosed by CMA that were undetected by karyotyping) was assessed for pathogenic copy-number variants (pCNVs) and for variants of unknown significance (VOUS). The incremental yield was assessed as the pooled effect size by single proportion analysis19 using random-effects modeling (weighting by inverse variance), along with the Clopper–Pearson ‘exact’ method for calculation of confidence intervals20. For estimating between-study variance, a fixed-effects model was preferred over a random-effects model due to the poor precision of the random-effects model when there is a small number of studies21. Between-study heterogeneity/variability was assessed using the tau2, χ2 (Cochran's Q) and I2 statistics. Results were assessed using forest plots and are presented as proportions. Publication bias could not be quantified or assessed by funnel plots due to the small number of included studies22. Heterogeneity among the pooled estimates was investigated by a sensitivity analysis of studies with low risk of bias. Furthermore, a subgroup analysis was conducted to assess the incremental yield of CMA over karyotyping in structurally abnormal (presenting with malformations or growth restriction) and structurally normal stillborn fetuses with a normal karyotype. Statistical analysis was conducted using Stata software for Mac v15 (module ‘meta’23) (Stata Corp., College Station, TX, USA) and R studio v1.0.136 (package ‘meta v4.2’) (The R Foundation for Statistical Computing24). In total, 490 studies were identified by the database search, including three additional series25-27 that were identified through other articles and systematic reviews. Of these, 22 articles were eligible for full-text review. After review, 15 studies were excluded26, 28-41, leaving a total of seven series for inclusion in this systematic review10, 25, 27, 42-45. For two of the studies42, 45 we contacted the authors and they provided their original data for analysis. The PRISMA flow diagram12, 13 for selection of studies is given in Figure 1 and the characteristics of the included series are described in Table 1. 1 Mb BAC DNA microarrays (2632 BACS) from PerkinElmer (PerkinElmer, Waltham, MA, USA) GenomeWide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA, USA) 2008–2012 180K oligonucleotide whole-genome coverage array (Oxford Gene Technology, Begbroke, Oxfordshire, UK) Among the seven included studies, we judged: one to be at high risk of bias in patient selection45 and another one to have unclear risk25; one study to have unclear risk of bias in the reference standard25; one study to have high risk of bias in flow and timing42; and, finally, all studies to have low risk for applicability concerns. Figures S1 and S2 summarize the risk of bias of the observational studies included in this meta-analysis according to the QUADAS-2 scale15-17. The seven studies selected for this systematic review and meta-analysis included 1443 fetal losses ≥ 20 weeks of gestation, of which 63% (n = 903) were stillbirths with a normal karyotype. Of these, 7.5% (n = 68) were ‘virtual’ normal karyotypes, defined by absence of genomic imbalance ≥ 10 Mb on CMA. Two studies10, 44 provided information on the total number of cases with normal CMA in which karyotyping yielded a positive result: the karyotype was abnormal in eight of 670 cases in which CMA was negative, corresponding to a 1.2% (8/670) false-negative rate for CMA. The mean gestational age at stillbirth was 29 + 6 weeks, as provided by three of the studies10, 44, 45. Only two studies10, 45 reported on infectious disease (n = 23) and on fetal growth restriction (n = 35) as a possible cause for fetal demise. Data on fetal structural anomalies as a possible cause of stillbirth were provided in all seven studies; there were structural anomalies in 36% (323/903) of the cases with normal karyotype10, 25, 27, 42-45. Among the five series for which data were provided10, 25, 42, 43, 45, a total of 1057 karyotyping and 701 CMA tests were performed. The test success rate, or rate of informative results, was 75% (791/1057) for conventional karyotyping and 90% (632/701) for CMA. In three of the selected studies, accounting for 31% of the total sample of fetal losses ≥ 20 weeks of gestation (445/1443)10, 25, 43, karyotyping and CMA were performed concurrently in all cases. In another series, different subsets of cases underwent either karyotyping (11%; 13/116) or CMA (41%; 47/116), with some overlap between the two subsets42. In the remaining three series, one of the two genetic tests was performed for all the samples, either karyotyping45 or CMA27, 44, but in only two studies44, 45 was a second technique performed in a subset of the cases (66%; 198/30044 and 19%; 91/48145). The pCNVs reported in the studies are listed in Table S1. The most frequent pCNV detected on CMA was del22q11.21 (DiGeorge syndrome), which was observed in three cases. In two of these cases, congenital heart disease was detected, while in the third, no structural anomalies were reported10, 44. All seven studies10, 25, 27, 42-45 (including 903 stillbirths with normal or failed karyotyping which underwent CMA) gave information on the incremental yield of CMA over karyotyping for pCNVs (Figure 2). The weighted proportion under a random-effects model was 4% (95% CI, 3–5%). The Q-index of 5.68, with six degrees of freedom, indicates that the variability among studies was due to sample error (P = 0.46). There was no heterogeneity between studies (I2 = 0%). The sensitivity analysis of studies with low risk of bias based on the random-effects model showed 37% variability among studies, but this variability was due to sample error rather than a true effect (Q = 4.77; P = 0.19 (Figure S3)). All seven studies10, 25, 27, 42-45 also gave information on the incremental yield of CMA over karyotyping for VOUS, which was 8% (95% CI, 4–17%). The forest plot for individual and pooled results is shown in Figure 3. There was considerable variability among studies (Q = 40.74; P < 0.01). The heterogeneity between studies was high (I2 = 85%). The sensitivity analysis of studies with low risk of bias fully explained the heterogeneity in this group, from 85% to 48% (Figure S4). Six studies10, 25, 27, 42, 44, 45 provided information on the number of pCNVs detected by CMA among structurally abnormal stillborn fetuses (malformed and/or growth restricted) and five studies10, 42-45 provided information on structurally normal fetuses. With respect to pCNVs, the incremental yield of CMA over karyotyping among the structurally normal stillborn fetuses was 3% (95% CI, 1–5%) compared with 6% (95% CI, 4–10%) in fetuses with a structural anomaly (Figure 4), but this difference was not statistically significant (P = 0.064). There was little or no heterogeneity (I2 = 21% and 0%, respectively). With respect to VOUS, pooled results showed an incremental yield of CMA over karyotyping of 10% (95% CI, 5–19%) in structurally normal fetuses and 8% (95% CI, 2–23%) in fetuses with a structural anomaly (Figure 5), but this difference was not statistically significant (P = 0.739). Heterogeneity was high for this group (I2 = 78% and 81%, respectively). There are three main findings of this systematic review and meta-analysis of data on stillborn fetuses (fetal demise ≥ 20 weeks) undergoing CMA. Firstly, CMA provided informative results in an extra 15% of cases of stillbirth as compared with karyotyping, with an increase in test success rate from 75% to 90%. Secondly, regarding detection of pCNVs, CMA provided a 3% incremental yield over karyotyping in structurally normal fetuses, while in structurally abnormal fetuses there was a greater incremental yield, of 6%. Finally, regarding detection of VOUS, CMA provided a 10% increased yield over karyotyping in structurally normal fetuses, compared with 8% in structurally abnormal fetuses. Genetic testing by means of karyotyping has been standard practice in stillbirth, being included in the work-up for decades. Although CMA has been recommended in stillborn fetuses, due to its higher diagnostic utility related to the lower capability of cytogenetic analysis to provide a result in fetal loss28, its incremental yield with respect to the detection of submicroscopic anomalies was unclear. With 903 cases from the seven included observational studies, to our knowledge, this is the first meta-analysis that assesses the incremental yield of CMA above conventional karyotyping in stillbirth30, 31. The two largest series included were multicenter North American studies and these demonstrated a 2% (Reddy et al.10) and 5% (Rosenfeld et al.44) incremental yield of CMA over karyotyping for cases with pCNVs. Identification of genetic causes of stillbirth provides multiple clinical benefits. Firstly, the risk of recurrence can be established if parents carry an inheritable anomaly or an autosomal trisomy46. Secondly, finding an explanation for fetal demise has been shown to confer a psychological benefit to women and may reduce stigma and marginalization47-49. Furthermore, parents benefit from this knowledge in terms of a reduced risk of post-traumatic stress disorder50, 51. Our group recently reported an analogous systematic review and meta-analysis on the added value of CMA over karyotyping in gestational loss < 20 weeks of gestation52. While only a few studies have reported the added value of CMA over conventional karyotyping in stillbirth, there have been many reported series in miscarriage. That review52 included 5507 early gestational losses from 23 studies, and demonstrated a 27% increase in test success rate of CMA over karyotyping (68% to 95%), a value greater than the increased success rate observed in the current meta-analysis (75% to 90%). Although a statistical comparison is not possible, the fact that the observed rate of informative results of CMA in stillbirth was slightly higher compared with that in miscarriage (95% vs 90%), while the reverse was true for karyotyping (68% vs 75%), appears to be of limited clinical relevance. In miscarriage, the products of conception would be expected to favor successful karyotyping or CMA, since more tissue is usually available for analysis, although maternal cell contamination may account for a marked reduction (down to about 60%) in the fetal karyotyping success rate. In stillbirth, the cell source is highly variable, and can include fetal skin, antenatal and postnatal placental biopsy, umbilical cord blood, amniotic fluid and liver biopsy; it may therefore be misleading to calculate a single success rate. Our study has several strengths. Firstly, the systematic review was carried out by two investigators, who were blinded to the studies' authorship, the hospitals' name and the results, thus limiting the chance of bias. Secondly, there was no time restriction for the extensive literature search, using the most well-known databases in order to ensure the collection of all existing literature. Thirdly, we were able to collect a large number of fetal losses ≥ 20 weeks of gestation (n = 1443), and efforts were made to contact corresponding authors of studies for which further information was needed for data extraction38-41. Finally, we performed a sensitivity analysis of studies with low risk of bias, and a subgroup analysis of structurally abnormal stillborn fetuses, in order to assess formally the cause of heterogeneity in pCNV and VOUS results. A limitation is the small number of studies meeting the inclusion criteria. This meant that there was reduced capability or insufficient power for assessment of publication bias by funnel plots, or to quantify it by other methods22. In an attempt to assess whether other fetal conditions could have influenced CMA results, we performed a subanalysis of the group of fetuses with structural anomalies and those without. However, potential coexisting reasons for stillbirth, such as fetal infection, could not be evaluated further by subgroup analysis due to the limited number of cases. Compared with karyotyping, CMA yields a higher test success rate (75% vs 90%), and has a 3% incremental yield for pCNVs in structurally normal stillborn fetuses. This information may be helpful in counseling couples with a structurally normal stillborn fetus with normal karyotype. Further research is needed to assess the added value of CMA over karyotyping, not only in stillbirth but also in other conditions that may benefit from a more exhaustive genetic analysis. Our sincere thanks go to Dr A. J. Kooper and Dr E. Sahlin for sharing with us data from their studies. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2903601158 title "Added value of chromosomal microarray analysis over conventional karyotyping in stillbirth work‐up: systematic review and meta‐analysis" @default.
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