Molecular and Cytogenetic Analysis in Stillbirth: Results from 481 Consecutive Cases

Abstract

Introduction: The underlying causes of stillbirth are heterogeneous and in many cases unexplained. Our aim was to conclude clinical results from karyotype and quantitative fluorescence-polymerase chain reaction (QF-PCR) analysis of all stillbirths occurring in Stockholm County between 2008 and 2012. By screening a subset of cases, we aimed to study the possible benefits of chromosomal microarray (CMA) in the analysis of the etiology of stillbirth. Methods: During 2008-2012, 481 stillbirths in Stockholm County were investigated according to a clinical protocol including karyotype or QF-PCR analysis. CMA screening was performed on a subset of 90 cases, corresponding to all stillbirths from 2010 without a genetic diagnosis. Results: Chromosomal aberrations were detected by karyotype or QF-PCR analysis in 7.5% of the stillbirths. CMA analysis additionally identified two known syndromes, one aberration disrupting a known disease gene, and 26 variants of unknown significance. Furthermore, CMA had a significantly higher success rate than karyotyping (100 vs. 80%, p < 0.001). Discussion: In the analysis of stillbirth, conventional karyotyping is prone to failure, and QF-PCR is a useful complement. We show that CMA has a higher success rate and aberration detection frequency than these methods, and conclude that CMA is a valuable tool for identification of chromosomal aberrations in stillbirth.

The prediction of fetal death with a simple maternal blood test at 24-28 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio)

“…The pathologic processes implicated in fetal death include: infection 65–84 , placental abruption, 5, 37, 70, 85–92 vascular lesions of the placenta, 28, 35, 93–100 preeclampsia, 41, 101–105 fetal growth restriction 9, 106–114 , maternal anti-fetal rejection, 35, 115–120 metabolic disorders, 121–133 genetic disorders, 80, 131, 134–137 umbilical cord accident, 97, 138–145 trauma 146–148 , and placental senescence 22 ; however, most of the 47,000 stillbirths reported from developed countries in 2015 149 were classified as unknown etiology. It is currently believed that the causes of fetal loss change with gestational age: chromosomal abnormalities 150–153 and infection 75 are the most common causes during the first half of pregnancy, placental causes (abruption or vascular abnormalities) 154–156 , and maternal anti-fetal rejection 118 become the most common causes after 26 weeks until term 14 , after which the etiology of in most cases, especially after 40 weeks, is unknown 14 .…”

Added value of chromosomal microarray analysis over conventional karyotyping in stillbirth work‐up: systematic review and meta‐analysis

“…Two studies 10,44 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 studies 10,44,45 . Only two studies 10,45 reported on infectious disease (n = 23) and on fetal growth restriction (n = 35) as a possible cause for fetal demise.…”

“…Only two studies 10,45 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 karyotype 10,25,27,[42][43][44][45] .…”

“…After review, 15 studies were excluded 26,[28][29][30][31][32][33][34][35][36][37][38][39][40][41] , leaving a total of seven series for inclusion in this systematic review 10,25,27,[42][43][44][45] . For two of the studies 42,45 we contacted the authors and they provided their original data for analysis. The PRISMA flow diagram 12,13 for selection of studies is given in Figure 1 and the characteristics of the included series are described in Table 1.…”

“…Among the five series for which data were provided 10,25,42,43,45 , 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.…”