title: Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial.
abstract: OBJECTIVE
  The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.
  
  
  METHODS
  A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.
  
  
  RESULTS
  Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.
  
  
  CONCLUSIONS
  This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.
authors.affiliation: New York Medical College, Valhalla, NY, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Friedman
authors.forename: Carolina
authors.initials: C
authors.lastname: Llanos
authors.forename: Peter M
authors.initials: PM
authors.lastname: Izmirly
authors.forename: Brigit
authors.initials: B
authors.lastname: Brock
authors.forename: John
authors.initials: J
authors.lastname: Byron
authors.forename: Joshua
authors.initials: J
authors.lastname: Copel
authors.forename: Karen
authors.initials: K
authors.lastname: Cummiskey
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Dooley
authors.forename: Jill
authors.initials: J
authors.lastname: Foley
authors.forename: Cornelia
authors.initials: C
authors.lastname: Graves
authors.forename: Colleen
authors.initials: C
authors.lastname: Hendershott
authors.forename: Richard
authors.initials: R
authors.lastname: Kates
authors.forename: Elena V
authors.initials: EV
authors.lastname: Komissarova
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Paré
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.forename: Tracy
authors.initials: T
authors.lastname: Prosen
authors.forename: Dale
authors.initials: D
authors.lastname: Reisner
authors.forename: Eric
authors.initials: E
authors.lastname: Ruderman
authors.forename: Philip
authors.initials: P
authors.lastname: Samuels
authors.forename: Jerry K
authors.initials: JK
authors.lastname: Yu
authors.forename: Mimi Y
authors.initials: MY
authors.lastname: Kim
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
mesh_terms: D004452:Echocardiography; D005006:Ethnicity; D005260:Female; D005313:Fetal Death / Q000453:epidemiology; D005323:Fetal Monitoring; D006327:Heart Block / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000276:immunology / Q000517:prevention & control*; D008180:Lupus Erythematosus, Systemic / Q000000981:diagnostic imaging / Q000276:immunology; D011247:Pregnancy; D044469:Racial Groups
chemical_list: D016756:Immunoglobulins, Intravenous
references.citation: Arthritis Rheum. 2004 Jan;50(1):337-8; author reply 338
references.pmid: 14730639
references.citation: J Immunol. 2000 Nov 1;165(9):5345-51
references.pmid: 11046070
references.citation: J Immunol. 2002 Aug 15;169(4):2156-63
references.pmid: 12165545
references.citation: Circulation. 2008 Jan 29;117(4):485-93
references.pmid: 18195175
references.citation: J Immunol. 1996 Oct 15;157(8):3317-22
references.pmid: 8871627
references.citation: J Clin Invest. 2005 Dec;115(12):3440-50
references.pmid: 16284651
references.citation: Nat Clin Pract Rheumatol. 2009 Mar;5(3):139-48
references.pmid: 19252519
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19571-8
references.pmid: 19036920
references.citation: J Am Coll Cardiol. 2002 Aug 21;40(4):796-802
references.pmid: 12204513
references.citation: Arthritis Rheum. 2009 Oct;60(10):3091-7
references.pmid: 19790064
references.citation: Blood. 2002 Sep 15;100(6):2087-93
references.pmid: 12200371
references.citation: J Am Coll Cardiol. 1998 Jun;31(7):1658-66
references.pmid: 9626848
references.citation: Am J Cardiol. 2009 Apr 15;103(8):1102-6
references.pmid: 19361597
references.citation: N Engl J Med. 1999 Jan 21;340(3):227-8
references.pmid: 9895405
references.citation: Obstet Gynecol. 2007 Aug;110(2 Pt 1):249-55
references.pmid: 17666597
references.citation: Control Clin Trials. 1989 Mar;10(1):1-10
references.pmid: 2702835
references.citation: Ann Intern Med. 1994 Apr 1;120(7):544-51
references.pmid: 8116991
references.citation: Blood. 2006 Apr 1;107(7):2976-83
references.pmid: 16317099
references.citation: Am J Cardiol. 2000 Jul 15;86(2):236-9
references.pmid: 10913494
references.citation: Am J Obstet Gynecol. 2000 Jan;182(1 Pt 1):122-7
references.pmid: 10649166
references.citation: Arthritis Rheum. 2001 Aug;44(8):1832-5
references.pmid: 11508435
references.citation: Arthritis Rheum. 2001 Feb;44(2):487-8
references.pmid: 11229483
references.citation: Arthritis Rheum. 2003 Jan;48(1):280-1; author reply 281-2
references.pmid: 12528144
references.citation: Annu Rev Immunol. 2008;26:513-33
references.pmid: 18370923
references.citation: Arthritis Rheum. 1982 Nov;25(11):1271-7
references.pmid: 7138600
references.citation: Science. 2001 Jan 19;291(5503):484-6
references.pmid: 11161202
references.citation: Thromb Haemost. 2002 Dec;88(6):898-9
references.pmid: 12529736
references.citation: J Rheumatol. 1996 May;23(5):925-32
references.pmid: 8724310
references.citation: Ann Rheum Dis. 2002 Jun;61(6):554-8
references.pmid: 12006334
references.citation: J Am Coll Cardiol. 2001 Jan;37(1):238-42
references.pmid: 11153745
references.citation: Best Pract Res Clin Haematol. 2006;19(1):3-25
references.pmid: 16377538
references.citation: Arthritis Rheum. 2004 Jan;50(1):173-82
references.pmid: 14730614
references.citation: J Clin Invest. 2006 Sep;116(9):2413-22
references.pmid: 16906225