Original Research Obstetrics|Articles in Press

Copy number variants and fetal growth in stillbirths

Published:November 07, 2022DOI:


      Fetal growth abnormalities are associated with a higher incidence of stillbirth, with small and large for gestational age infants incurring a 3 to 4- and 2 to 3-fold increased risk, respectively. Although clinical risk factors such as diabetes, hypertension, and placental insufficiency have been associated with fetal growth aberrations and stillbirth, the role of underlying genetic etiologies remains uncertain.


      This study aimed to assess the relationship between abnormal copy number variants and fetal growth abnormalities in stillbirths using chromosomal microarray.

      Study Design

      A secondary analysis utilizing a cohort study design of stillbirths from the Stillbirth Collaborative Research Network was performed. Exposure was defined as abnormal copy number variants including aneuploidies, pathogenic copy number variants, and variants of unknown clinical significance. The outcomes were small for gestational age and large for gestational age stillbirths, defined as a birthweight <10th percentile and greater than the 90th percentile for gestational age, respectively.


      Among 393 stillbirths with chromosomal microarray and birthweight data, 16% had abnormal copy number variants. The small for gestational age outcome was more common among those with abnormal copy number variants than those with a normal microarray (29.5% vs 16.5%; P=.038). This finding was consistent after adjusting for clinically important variables. In the final model, only abnormal copy number variants and maternal age remained significantly associated with small for gestational age stillbirths, with an adjusted odds ratio of 2.22 (95% confidence interval, 1.12–4.18). Although large for gestational age stillbirths were more likely to have an abnormal microarray: 6.2% vs 3.3% (P=.275), with an odds ratio of 2.35 (95% confidence interval, 0.70–7.90), this finding did not reach statistical significance.


      Genetic abnormalities are more common in the setting of small for gestational age stillborn fetuses. Abnormal copy number variants not detectable by traditional karyotype make up approximately 50% of the genetic abnormalities in this population.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hoyert D.L.
        • Gregory E.C.W.
        Cause-of-death data from the fetal death file, 2015-2017.
        Natl Vital Stat Rep. 2020; 69: 1-20
        • Dongarwar D.
        • Aggarwal A.
        • Barning K.
        • Salihu H.M.
        Trends in stillbirths and stillbirth phenotypes in the United States: an analysis of 131.5 million births.
        Int J MCH AIDS. 2020; 9: 146-148
        • Bukowski R.
        • Hansen N.I.
        • Willinger M.
        • et al.
        Fetal growth and risk of stillbirth: a population-based case-control study.
        PLoS Med. 2014; 11e1001633
        • Page J.M.
        • Blue N.R.
        • Silver R.M.
        Fetal growth and stillbirth.
        Obstet Gynecol Clin North Am. 2021; 48: 297-310
        • Albu A.R.
        • Anca A.F.
        • Horhoianu V.V.
        • Horhoianu I.A.
        Predictive factors for intrauterine growth restriction.
        J Med Life. 2014; 7: 165-171
        • Maulik D.
        Fetal growth restriction: the etiology.
        Clin Obstet Gynecol. 2006; 49: 228-235
        • Bukowski R.
        Stillbirth and fetal growth restriction.
        Clin Obstet Gynecol. 2010; 53: 673-680
        • Burton G.J.
        • Jauniaux E.
        Pathophysiology of placental-derived fetal growth restriction.
        Am J Obstet Gynecol. 2018; 218: S745-S761
        • Society for Maternal-Fetal Medicine (SMFM)
        Electronic address: [email protected], Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012).
        Am J Obstet Gynecol. 2020; 223: B2-B17
        • American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics and the Society forMaternal-FetalMedicin
        ACOG Practice Bulletin No. 204: fetal growth restriction.
        Obstet Gynecol. 2019; 133: e97-e109
        • Caradeux J.
        • Martinez-Portilla R.J.
        • Basuki T.R.
        • Kiserud T.
        • Figueras F.
        Risk of fetal death in growth-restricted fetuses with umbilical and/or ductus venosus absent or reversed end-diastolic velocities before 34 weeks of gestation: a systematic review and meta-analysis.
        Am J Obstet Gynecol. 2018; 218: S774-S782.e21
        • Unterscheider J.
        • O’Donoghue K.
        • Daly S.
        • et al.
        Fetal growth restriction and the risk of perinatal mortality-case studies from the multicentre PORTO study.
        BMC Pregnancy Childbirth. 2014; 14: 63
        • Reddy U.M.
        • Page G.P.
        • Saade G.R.
        • et al.
        Karyotype versus microarray testing for genetic abnormalities after stillbirth.
        N Engl J Med. 2012; 367: 2185-2193
        • Page J.M.
        • Christiansen-Lindquist L.
        • Thorsten V.
        • et al.
        Diagnostic tests for evaluation of stillbirth: results from the stillbirth collaborative research network.
        Obstet Gynecol. 2017; 129: 699-706
        • Wapner R.J.
        • Lewis D.
        Genetics and metabolic causes of stillbirth.
        Semin Perinatol. 2002; 26: 70-74
        • Meler E.
        • Sisterna S.
        • Borrell A.
        Genetic syndromes associated with isolated fetal growth restriction.
        Prenat Diagn. 2020; 40: 432-446
        • Yao R.
        • Contag S.A.
        • Goetzinger K.R.
        • et al.
        The role of fetal growth restriction in the association between Down syndrome and perinatal mortality.
        J Matern Fetal Neonatal Med. 2020; 33: 952-960
        • Stanley K.E.
        • Giordano J.
        • Thorsten V.
        • et al.
        Causal genetic variants in stillbirth.
        N Engl J Med. 2020; 383: 1107-1116
        • Martinez-Portilla R.J.
        • Pauta M.
        • Hawkins-Villarreal A.
        • et al.
        Added value of chromosomal microarray analysis over conventional karyotyping in stillbirth work-up: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2019; 53: 590-597
        • Korteweg F.J.
        • Bouman K.
        • Erwich J.J.H.M.
        • et al.
        Cytogenetic analysis after evaluation of 750 fetal deaths: proposal for diagnostic workup.
        Obstet Gynecol. 2008; 111: 865-874
        • Reddy U.M.
        • Page G.P.
        • Saade G.R.
        The role of DNA microarrays in the evaluation of fetal death.
        Prenat Diagn. 2012; 32: 371-375
        • Zhu H.
        • Lin S.
        • Huang L.
        • et al.
        Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction.
        Prenat Diagn. 2016; 36: 686-692
        • Borrell A.
        • Grande M.
        • Meler E.
        • et al.
        Genomic microarray in fetuses with early growth restriction: a multicenter study.
        Fetal Diagn Ther. 2017; 42: 174-180
        • Dar P.
        • Gross S.J.
        Macrosomia: a genetic perspective.
        Clin Obstet Gynecol. 2000; 43: 298-308
        • Society of Maternal Fetal Medicine
        Obstetric Care Consensus: management of stillbirth delivery.
        Obstet Gynecol. 2020; 135: E110-E132
        • Parker C.B.
        • Hogue C.J.R.
        • Koch M.A.
        • et al.
        Stillbirth Collaborative Research Network: design, methods and recruitment experience.
        Paediatr Perinat Epidemiol. 2011; 25: 425-435
        • Kearney H.M.
        • Thorland E.C.
        • Brown K.K.
        • Quintero-Rivera F.
        • South S.T.
        Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants.
        Genet Med. 2011; 13: 680-685
        • Gurbich T.A.
        • Ilinsky V.V.
        ClassifyCNV: a tool for clinical annotation of copy-number variants.
        Sci Rep. 2020; 10: 20375
        • Riggs E.R.
        • Andersen E.F.
        • Cherry A.M.
        • et al.
        Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).
        Genet Med. 2020; 22: 245-257
        • Stillbirth Collaborative Research Network Writing Group
        Causes of death among stillbirths.
        JAMA. 2011; 306: 2459-2468
        • Alexander G.R.
        • Himes J.H.
        • Kaufman R.B.
        • Mor J.
        • Kogan M.
        A united states national reference for fetal growth.
        Obstet Gynecol. 1996; 87: 163-168
        • Dudley D.J.
        • Goldenberg R.
        • Conway D.
        • et al.
        A new system for determining the causes of stillbirth.
        Obstet Gynecol. 2010; 116: 254-260
        • Pinar H.
        • Koch M.A.
        • Hawkins H.
        • et al.
        The stillbirth collaborative research network (SCRN) placental and umbilical cord examination protocol.
        Am J Perinatol. 2011; 28: 781-792
        • Pinar H.
        • Koch M.A.
        • Hawkins H.
        • et al.
        The stillbirth collaborative research network postmortem examination protocol.
        Am J Perinatol. 2012; 29: 187-202
        • Kaufman P.D.
        • Kobayashi R.
        • Kessler N.
        • Stillman B.
        The p150 and p60 subunits of chromatin assembly factor I: a molecular link between newly synthesized histories and DNA replication.
        Cell. 1995; 81: 1105-1114
        • Narang M.A.
        • Dumas R.
        • Ayer L.M.
        • Gravel R.A.
        Reduced histone biotinylation in multiple carboxylase deficiency patients: a nuclear role for holocarboxylase synthetase.
        Hum Mol Genet. 2004; 13: 15-23
        • Rodova M.
        • Kelly K.F.
        • VanSaun M.
        • Daniel J.M.
        • Werle M.J.
        Regulation of the rapsyn promoter by Kaiso and δ-catenin.
        Mol Cell Biol. 2004; 24: 7188-7196
        • Guo D.C.
        • Pannu H.
        • Tran-Fadulu V.
        • et al.
        Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.
        Nat Genet. 2007; 39: 1488-1493
        • Mountz J.D.
        • Talal N.
        Retroviruses, apoptosis and autogenes.
        Immunol Today. 1993; 14: 532-536
        • Katibah G.E.
        • Lee H.J.
        • Huizar J.P.
        • Vogan J.M.
        • Alber T.
        • Collins K.
        tRNA binding, Structure, and localization of the human interferon-induced protein IFIT5.
        Mol Cell. 2013; 49: 743-750
        • Liu S.Y.
        • Aliyari R.
        • Chikere K.
        • et al.
        Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.
        Immunity. 2013; 38: 92-105
        • Keller K.
        Chromosome 10, Distal trisomy 10q.
        (Available at:)
        • Chang P.L.
        • Sauer M.V.
        • Brown S.
        Y chromosome microdeletion in a father and his four infertile sons.
        Hum Reprod. 1999; 14: 2689-2694
        • Hui P.
        • Wang H.L.
        • Chu P.
        • et al.
        Absence of Y chromosome in human placental site trophoblastic tumor.
        Mod Pathol. 2007; 20: 1055-1060
        • Lou X.
        • Kang B.
        • Zhang J.
        • et al.
        MFAP3L activation promotes colorectal cancer cell invasion and metastasis.
        Biochim Biophys Acta. 2014; 1842: 1423-1432
        • Gibbs-Seymour I.
        • Fontana P.
        • Rack J.G.M.
        • Ahel I.
        HPF1/C4orf27 is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity.
        Mol Cell. 2016; 62: 432-442
        • Ronan A.
        • Fagan K.
        • Christie L.
        • Conroy J.
        • Nowak N.J.
        • Turner G.
        Familial 4.3-Mb duplication of 21q22 sheds new light on the Down syndrome critical region.
        J Med Genet. 2007; 44: 448-451
        • Pelleri M.C.
        • Cicchini E.
        • Locatelli C.
        • et al.
        Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype.
        Hum Mol Genet. 2016; 25: 2525-2538
        • Dobin S.
        Chromosome 5, trisomy 5p.
        (Available at:)
        Date: 2016
        Date accessed: December 13, 2021
        • Xu W.
        • Ahmad A.
        • Dagenais S.
        • Iyer R.K.
        • Innis J.W.
        Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-q34.3.
        Am J Med Genet A. 2012; 158A: 635-640
        • Allach El Khattabi L.A.
        • Heide S.
        • Caberg J.H.
        • et al.
        16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations.
        J Med Genet. 2020; 57: 301-307
        • Ramalingam A.
        • Zhou X.G.
        • Fiedler S.D.
        • et al.
        16P13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders.
        J Hum Genet. 2011; 56: 541-544
        • Monk D.
        • Wakeling E.L.
        • Proud V.
        • et al.
        Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome.
        Am J Hum Genet. 2000; 66: 36-46
        • Burnside R.D.
        22q11.21 deletion syndromes: a review of proximal, central, and distal deletions and their associated features.
        Cytogenet Genome Res. 2015; 146: 89-99
        • Chen Y.
        • Chen P.L.
        • Chen C.F.
        • Jiang X.
        • Riley D.J.
        Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control.
        Cell Cycle. 2008; 7: 3194-3201
        • Thiel C.
        • Kessler K.
        • Giessl A.
        • et al.
        NEK1 mutations cause short-rib polydactyly syndrome type Majewski.
        Am J Hum Genet. 2011; 88: 106-114
        • Pappano W.N.
        • Steiglitz B.M.
        • Scott I.C.
        • Keene D.R.
        • Greenspan D.S.
        Use of BMP1 / Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases.
        Mol Cell Biol. 2003; 23: 4428-4438
        • Bakircioglu M.
        • Carvalho O.P.
        • Khurshid M.
        • et al.
        The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
        Am J Hum Genet. 2011; 88: 523-535
        • Feng Y.
        • Walsh C.A.
        Mitotic spindle regulation by Nde1 controls cerebral cortical size.
        Neuron. 2004; 44: 279-293
        • Pawlisz A.S.
        • Mutch C.
        • Wynshaw-Boris A.
        • Chenn A.
        • Walsh C.A.
        • Feng Y.
        Lis1-Nde1-dependent neuronal fate control determines cerebral cortical size and lamination.
        Hum Mol Genet. 2008; 17: 2441-2455
        • Armour C.M.
        • Dougan S.D.
        • Brock J.A.
        • et al.
        Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.
        J Med Genet. 2018; 55: 215-221
        • Stillbirth Collaborative Research Network Writing Group
        Association between stillbirth and risk factors known at pregnancy confirmation.
        JAMA. 2011; 306: 2469-2479