Advertisement

Evaluating perinatal and neonatal outcomes among children with vascular Ehlers–Danlos syndrome

  • Sara B. Stephens
    Affiliations
    Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX

    Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX
    Search for articles by this author
  • Melissa Russo
    Affiliations
    Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School at Brown University, Providence, RI
    Search for articles by this author
  • Sherene Shalhub
    Affiliations
    Division of Vascular Surgery, Department of Surgery, University of Washington, Seattle, WA
    Search for articles by this author
  • Taylor Beecroft
    Affiliations
    Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX
    Search for articles by this author
  • Justin Weigand
    Affiliations
    Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX
    Search for articles by this author
  • Dianna M. Milewicz
    Affiliations
    Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX
    Search for articles by this author
  • Shaine A. Morris
    Correspondence
    Correspondence and requests for materials should be addressed to Shaine A. Morris, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, 6651 Main Street E1920, Houston, TX 77030
    Affiliations
    Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX
    Search for articles by this author
Published:August 19, 2022DOI:https://doi.org/10.1016/j.gim.2022.07.010

      Abstract

      Purpose

      Birth outcomes data for patients with vascular Ehlers–Danlos syndrome (VEDS) are limited.

      Methods

      Patients with a pathogenic or likely pathogenic COL3A1 variant were included. Outcomes included gestational age (GA), birthweight (BW), and maternal complications. Birth outcomes were first compared with that of US population data, then compared by sex, maternal affected status, and COL3A1 genotype.

      Results

      A total of 41 children were included (70.7% male), including 32 with high-risk (missense and splice site) variants. Preterm birth (<37 weeks) was more common in patients with VEDS than in the US population (48.8% vs 12.2%, P < .0001). Low BW (<2.5 kg) was also more common in patients with VEDS than in the US population (P < .0001), although, it was appropriate after GA adjustment (median GA-adjusted z-score 0.01 vs z-score 0.0, P = .26). No differences in GA or BW were observed by sex or maternal affected status. Those with high-risk variants were more likely to be born preterm than those with haploinsufficient variants, although this did not meet significance criteria (53% vs 33%, P = .35). Of the 6 affected mothers, 5 had perinatal complications.

      Conclusion

      Preterm birth is more common in children with VEDS than in the general population. Maternal affected status is not associated with preterm birth, suggesting that risk is conferred by the fetal VEDS diagnosis alone.

      Keywords

      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'

      ACMG Member Login

      Are you an ACMG Member? Sign in for online access.

      Subscribe:

      Subscribe to Genetics in Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342(10):673-680. Published correction appears in N Engl J Med. 2001;344(5):392. https://doi.org/10.1056/NEJM200003093421001

        • Shalhub S.
        • Byers P.H.
        • Hicks K.L.
        • et al.
        A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.
        J Vasc Surg. 2020; 71: 149-157https://doi.org/10.1016/j.jvs.2019.04.487
        • El Masri H.
        • Loong T.H.
        • Meurette G.
        • Podevin J.
        • Zinzindohoue F.
        • Lehur P.A.
        Bowel perforation in type IV vascular Ehlers-Danlos syndrome. A systematic review.
        Tech Coloproctol. 2018; 22: 333-341https://doi.org/10.1007/s10151-018-1783-4
        • Oderich G.S.
        • Panneton J.M.
        • Bower T.C.
        • et al.
        The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience.
        J Vasc Surg. 2005; 42: 98-106https://doi.org/10.1016/j.jvs.2005.03.053
        • Baderkhan H.
        • Wanhainen A.
        • Stenborg A.
        • Stattin E.L.
        • Björck M.
        Celiprolol treatment in patients with vascular Ehlers-Danlos syndrome.
        Eur J Vasc Endovasc Surg. 2021; 61: 326-331https://doi.org/10.1016/j.ejvs.2020.10.020
      2. Byers PH. Vascular Ehlers-Danlos syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews [Internet]. University of Washington; 1993-2022. Published September 2, 1999. Updated February 21, 2019. Accessed February 16, 2022. https://www.ncbi.nlm.nih.gov/books/NBK1494/.

        • Leistritz D.F.
        • Pepin M.G.
        • Schwarze U.
        • Byers P.H.
        COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy.
        Genet Med. 2011; 13: 717-722https://doi.org/10.1097/GIM.0b013e3182180c89
        • Schwarze U.
        • Schievink W.I.
        • Petty E.
        • et al.
        Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.
        Am J Hum Genet. 2001; 69: 989-1001https://doi.org/10.1086/324123
        • Byers P.H.
        • Belmont J.
        • Black J.
        • et al.
        Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome.
        Am J Med Genet C Semin Med Genet. 2017; 175: 40-47https://doi.org/10.1002/ajmg.c.31553
        • Frank M.
        • Albuisson J.
        • Ranque B.
        • et al.
        The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.
        Eur J Hum Genet. 2015; 23: 1657-1664https://doi.org/10.1038/ejhg.2015.32
        • Shalhub S.
        • Black III, J.H.
        • Cecchi A.C.
        • et al.
        Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes.
        J Vasc Surg. 2014; 60: 160-169https://doi.org/10.1016/j.jvs.2014.01.070
        • Rudd N.L.
        • Nimrod C.
        • Holbrook K.A.
        • Byers P.H.
        Pregnancy complications in type iv Ehlers-Danlos syndrome.
        Lancet. 1983; 1: 50-53https://doi.org/10.1016/s0140-6736(83)91577-5
        • Murray M.L.
        • Pepin M.
        • Peterson S.
        • Byers P.H.
        Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome.
        Genet Med. 2014; 16: 874-880https://doi.org/10.1038/gim.2014.53
        • Lurie S.
        • Manor M.
        • Hagay Z.J.
        The threat of type IV Ehlers-Danlos syndrome on maternal well-being during pregnancy: early delivery may make the difference.
        J Obstet Gynaecol. 1998; 18: 245-248https://doi.org/10.1080/01443619867416
        • Baas A.F.
        • Spiering W.
        • Moll F.L.
        • et al.
        Six uneventful pregnancy outcomes in an extended vascular Ehlers-Danlos syndrome family.
        Am J Med Genet A. 2017; 173: 519-523https://doi.org/10.1002/ajmg.a.38033
        • Palmquist M.
        • Pappas J.G.
        • Petrikovsky B.
        • Blakemore K.
        • Roshan D.
        Successful pregnancy outcome in Ehlers-Danlos syndrome, vascular type.
        J Matern Fetal Neonatal Med. 2009; 22: 924-927https://doi.org/10.1080/14767050902874071
        • Nicolaides K.H.
        • Wright D.
        • Syngelaki A.
        • Wright A.
        • Akolekar R.
        Fetal Medicine Foundation fetal and neonatal population weight charts.
        Ultrasound Obstet Gynecol. 2018; 52: 44-51https://doi.org/10.1002/uog.19073
        • Orioli I.M.
        • Ribeiro M.G.
        • Castilla E.E.
        Clinical and epidemiological studies of amniotic deformity, adhesion, and mutilation (ADAM) sequence in a South American (ECLAMC) population.
        Am J Med Genet A. 2003; 118A: 135-145https://doi.org/10.1002/ajmg.a.10194
        • Oliver J.M.
        • González A.
        • Gallego P.
        • Sánchez-Recalde A.
        • Benito F.
        • Mesa J.M.
        Discrete subaortic stenosis in adults: increased prevalence and slow rate of progression of the obstruction and aortic regurgitation.
        J Am Coll Cardiol. 2001; 38: 835-842https://doi.org/10.1016/s0735-1097(01)01464-4
        • Atta C.A.M.
        • Fiest K.M.
        • Frolkis A.D.
        • et al.
        Global birth prevalence of spina bifida by folic acid fortification status: a systematic review and meta-analysis.
        Am J Public Health. 2016; 106: e24-e34https://doi.org/10.2105/AJPH.2015.302902
        • Sillesen A.S.
        • Vøgg O.
        • Pihl C.
        • et al.
        Prevalence of bicuspid aortic valve and associated aortopathy in newborns in Copenhagen, Denmark.
        JAMA. 2021; 325: 561-567https://doi.org/10.1001/jama.2020.27205
        • Konen E.
        • Goitein O.
        • Sternik L.
        • Eshet Y.
        • Shemesh J.
        • Di Segni E.
        The prevalence and anatomical patterns of intramuscular coronary arteries: a coronary computed tomography angiographic study.
        J Am Coll Cardiol. 2007; 49: 587-593https://doi.org/10.1016/j.jacc.2006.09.039
        • Möhlenkamp S.
        • Hort W.
        • Ge J.
        • Erbel R.
        Update on myocardial bridging.
        Circulation. 2002; 106: 2616-2622https://doi.org/10.1161/01.cir.0000038420.14867.7a
      3. Texas health data- birth defects. Texas Birth Defects by Mother’s Race/Ethnicity. Accessed February 15, 2022. https://healthdata.dshs.texas.gov/dashboard/births-and-deaths/birth-defects.

        • Martin J.A.
        • Hamilton B.E.
        • Ventura S.J.
        • et al.
        Births: final data for 2009.
        Natl Vital Stat Rep. 2011; 60: 1-70
        • Wonder C.D.C.
        Centers for Disease Control and Prevention.
        http://wonder.cdc.gov/
        Date accessed: February 16, 2022
        • Roubelakis M.G.
        • Trohatou O.
        • Anagnou N.P.
        Amniotic fluid and amniotic membrane stem cells: marker discovery.
        Stem Cells Int. 2012; 2012107836https://doi.org/10.1155/2012/107836
        • Moore R.M.
        • Mansour J.M.
        • Redline R.W.
        • Mercer B.M.
        • Moore J.J.
        The physiology of fetal membrane rupture: insight gained from the determination of physical properties.
        Placenta. 2006; 27: 1037-1051https://doi.org/10.1016/j.placenta.2006.01.002
        • Liu X.
        • Wu H.
        • Byrne M.
        • Krane S.
        • Jaenisch R.
        Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development.
        Proc Natl Acad Sci U S A. 1997; 94: 1852-1856https://doi.org/10.1073/pnas.94.5.1852
        • Kuivaniemi H.
        • Tromp G.
        Type III collagen (COL3A1): gene and protein structure, tissue distribution, and associated diseases.
        Gene. 2019; 707: 151-171https://doi.org/10.1016/j.gene.2019.05.003
        • Beighton P.H.
        • Murdoch J.L.
        • Votteler T.
        Gastrointestinal complications of the Ehlers-Danlos syndrome.
        Gut. 1969; 10: 1004-1008https://doi.org/10.1136/gut.10.12.1004
        • Hiratzka L.F.
        • Bakris G.L.
        • Beckman J.A.
        • et al.
        2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
        Circulation. 2010; 121 (Published correction appears in Circulation. 2010;122(4):e410): e266-e369
        • Koitabashi N.
        • Yamaguchi T.
        • Fukui D.
        • et al.
        Peripartum iliac arterial aneurysm and rupture in a patient with vascular Ehlers-Danlos syndrome diagnosed by next-generation sequencing.
        Int Heart J. 2018; 59: 1180-1185https://doi.org/10.1536/ihj.17-451
        • Roman M.J.
        • Pugh N.L.
        • Hendershot T.P.
        • et al.
        Aortic complications associated with pregnancy in Marfan syndrome: the NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC).
        J Am Heart Assoc. 2016; 5e004052https://doi.org/10.1161/JAHA.116.004052
        • Narula N.
        • Devereux R.B.
        • Malonga G.P.
        • Hriljac I.
        • Roman M.J.
        Pregnancy-related aortic complications in women with Marfan syndrome.
        J Am Coll Cardiol. 2021; 78: 870-879https://doi.org/10.1016/j.jacc.2021.06.034