Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center

(2022) 20:168 Cai et al. Journal of Translational Medicine https://doi.org/10.1186/s12967-022-03373-z Journal of Translational Medicine Open Access RESEARCH Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center Meiying Cai1†, Na Lin1†, Linjuan Su1, Xiaoqing Wu1, Xiaorui Xie1, Shiyi Xu2, Xianguo Fu3, Liangpu Xu1* and Hailong Huang1* Abstract Background: The etiology of fetal growth restriction (FGR) is complex and currently, there is a paucity of research about the genetic etiology of fetal growth restriction. We investigated the genetic associations and pregnancy outcomes in cases of fetal growth restriction. Methods: A retrospective analysis of 210 pregnant women with fetal growth restriction was performed using karyotype analysis and single nucleotide polymorphism arrays (SNP-array). The differences in pathogenic copy number variation (CNV) detected by the two methods were compared. At the same time, the fetuses were divided into three groups: isolated FGR (n = 117), FGR with ultrasonographic soft markers (n = 48), and FGR with ultrasonographic structural anomalies (n = 45). Further, the differences in pathogenic copy number variations were compared among the groups. Results: The total detection rate of pathogenic CNVs was 12.4% (26/210). Pathogenic copy number variation was detected in 14 cases (6.7%, 14/210) by karyotype analysis. Furthermore, 25 cases (11.9%, 25/210) with pathogenic CNVs were detected using the SNP-array evaluation method. The difference in the pathogenic CNV detection rate between the two methods was statistically significant. The result of the karyotype analysis and SNP-array evaluation was inconsistent for 13 cases with pathogenic CNV. The rate of detecting pathogenic CNVs in fetuses with isolated FGR, FGR combined with ultrasonographic soft markers, and FGR combined with ultrasonographic structural malformations was 6.0, 10.4, and 31.1%, respectively, with significant differences among the groups. During the follow-up, 35 pregnancies were terminated, two abortions occurred, and 13 cases were lost to follow-up. Of the 160 deliveries, nine fetuses had adverse pregnancy outcomes, and the remaining 151 had normal postnatal growth and developmental assessments. Conclusions: Early diagnosis and timely genomic testing for fetal growth restriction can aid in its perinatal prognosis and subsequent intervention. Keywords: Fetal growth restriction, SNP-array, Karyotype analysis, Copy number variation *Correspondence: ; † Meiying Cai and Na Lin are contributed equally to this work 1 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China Full list of author information is available at the end of the article Background Fetal growth restriction (FGR) refers to the condition of inadequate growth of a fetus due to a variety of factors. The American College of Obstetricians and Gynecologists defines FGR in terms of fetal birth mass that is below the 10th percentile of the average body mass for © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cai et al. Journal of Translational Medicine (2022) 20:168 a child of the same gestational age [1]. FGR is a common obstetric complication that is associated with premature delivery, fetal death in utero, neonatal death, and other adverse outcomes [2, 3]. Hence, preventing FGR is significant in improving the pediatric outcomes. However, the etiology of FGR is complex, and can be caused by maternal, fetal, placental, and umbilical cord factors [3]. These factors do not allow the fetus to receive adequate energy and nutrients for growth and development [4]. It is essential to identify the etiology of FGR for better diagnosis and providing possible treatments for this condition. Previous research focused on diagnosis, intrauterine monitoring, treatment, and prognosis of fetuses with FGR; however, currently there are only a few studies on the genetic etiology of FGR. Genetic factors that cause FGR have rarely been reported, and some studies that reported a genetic association were conducted with small sample sizes [5]. Single-nucleotide polymorphism array (SNP-array) can detect copy number variations (CNVs) at a genome-wide level, as well as chimeras (> 30%), loss of heterozygosity, and uniparental disomy (UPD) [6, 7]. SNP-array has been widely used in the diagnosis of fetal structural malformations, primary mental retardation, growth and developmental retardation, autism, and tumors [8, 9]. In this study, we utilized karyotyping and SNP-array for the genomic analysis of 210 fetuses who were prenatally diagnosed with FGR using ultrasound, and investigate the genetic etiology of FGR and evaluate the diagnostic value of SNP-array. The outcomes of these pregnancies were also monitored. Methods Patient data This study retrospectively enrolled 210 pregnant women, who received a prenatal diagnosis of FGR by fetal ultrasound at a tertiary care center between November 2016 and February 2021. The gestational age range was 16–35+6 weeks and the maternal age range was 17–48 years. Depending on the gestational age, amniotic fluid or cord blood samples were collected for karyotype analysis and SNP-array evaluation. The inclusion criteria were as follows: Gestational age determined based on the date of last menstruation, a detailed menstrual history, and ultrasound examination during the first trimester. Fetal abdominal circumference, head circumference, biparietal diameter, and femur length were measured by ultrasound, and the estimated fetal weight was calculated using the Hadlock formula. FGR was defined as a fetal mass below the 10th percentile of the average weight of a normal fetus of the same gestational age [10]. The exclusion criteria were as (...truncated)