Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise

• ClinicalTrials.gov Identifier: NCT03775954
• Recruitment Status: Recruiting
• First Posted: December 14, 2018
• Last Update Posted: March 20, 2023
• Sponsor: Medical College of Wisconsin
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Wisconsin, Madison; Children's Hospital and Health System Foundation, Wisconsin; Shared Medical Technology, Inc.; Tristan Technologies, Inc
• Information provided by (Responsible Party): Janette F. Strasburger, Medical College of Wisconsin

Tracking Information

• First Submitted Date: October 24, 2018
• First Posted Date: December 14, 2018
• Last Update Posted Date: March 20, 2023
• Actual Study Start Date: July 1, 2018
• Estimated Primary Completion Date: April 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 23, 2021)

• Heart rate variability using fMCG [ Time Frame: Comparison of procedures at approximately 20-27 weeks gestation, at 30-37 weeks gestation, and at neonatal ECG at 0-4 weeks of age ]
  To measure and compare the fMCG heart rate variability in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses.
• Cardiac conduction [ Time Frame: Comparison of cardiac time intervals at approximately 20-27 weeks gestation, 30-37 weeks gestation and at neonatal ECG at 0-4 weeks of age ]
  To measure and compare the fMCG cardiac time intervals in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses and to neonatal ECGs at 0-4 weeks of age.
• Cardiac repolarization [ Time Frame: Comparison of cardiac repolarization at approximately 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-4 weeks of age. ]
  To measure and compare the fMCG cardiac repolarization patterns in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses, and to neonatal ECGs at 0-4 weeks of age.

Original Primary Outcome Measures (submitted: December 13, 2018)

• Heart rate variability using fMCG [ Time Frame: Comparison of procedures at 20-27 weeks gestation, and 30-37 weeks gestation ]
  To measure and compare the fMCG heart rate variability in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses.
• Cardiac conduction [ Time Frame: Comparison of cardiac time intervals at 20-27 weeks gestation, 30-37 weeks gestation and at neonatal ECG at 0-2 weeks of age ]
  To measure and compare the fMCG cardiac time intervals in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses and to neonatal ECG at 2 weeks of age.
• Cardiac repolarization [ Time Frame: Comparison of cardiac repolarization at 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-2 weeks of age. ]
  To measure and compare the fMCG cardiac repolarization patterns in five pregnancy conditions associated with fetal demise, to those of gestation matched normal fetuses, and to neonatal ECG at 2 weeks of age.

Current Secondary Outcome Measures (submitted: November 23, 2021)

• Unique "signature" electrophysiologic abnormalities [ Time Frame: Comparison of findings at approximately 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-4 weeks of age ]
  2a) To determine whether unique "signature" electrophysiologic abnormalities are present in any of these five maternal-fetal diseases, and 2b) to define at what trimester these develop. Understanding any unique findings could allow study of specific treatment strategies in the future. findings are first seen.
• Pregnancy outcomes [ Time Frame: Comparison of findings at approximately 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-4 weeks of age ]
  To correlate fMCG findings with 3a) outcomes of pregnancies (fetal demise, premature delivery, small for GA, 5 minute APGAR < 5, neonatal death) and 3b) fMCG cardiac time intervals with postnatal ECG intervals at 0-4 weeks of age.

Original Secondary Outcome Measures (submitted: December 13, 2018)

• Unique "signature" electrophysiologic abnormalities [ Time Frame: Comparison of findings at 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-2 weeks of age ]
  2a) To determine whether unique "signature" electrophysiologic abnormalities are present in any of these five maternal-fetal diseases, and 2b) to define at what trimester these develop. Understanding any unique findings could allow study of specific treatment strategies in the future. findings are first seen.
• Pregnancy outcomes [ Time Frame: Comparison of findings at 20-27 weeks gestation, 30-37 weeks gestation and neonatal ECG at 0-2 weeks of age ]
  To correlate fMCG findings with 3a) outcomes of pregnancies (fetal demise, premature delivery, small for GA, 5 minute APGAR < 5, neonatal death) and 3b) fMCG cardiac time intervals with postnatal ECG intervals at 0-2 weeks of age.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise
• Official Title: Fetal Electrophysiologic Abnormalities in High-risk Pregnancies Associated With Fetal Demise
• Brief Summary: Each year world-wide, 2.5 million fetuses die unexpectedly in the last half of pregnancy, 25,000 in the United States, making fetal demise ten-times more common than Sudden Infant Death Syndrome. This study will apply a novel type of non-invasive monitoring, called fetal magnetocardiography (fMCG) used thus far to successfully evaluate fetal arrhythmias, in order to discover potential hidden electrophysiologic abnormalities that could lead to fetal demise in five high-risk pregnancy conditions associated with fetal demise.
• Detailed Description: Fetal demise occurs in over 25,000 pregnancies annually in the US and over 2.5 million in pregnancies worldwide. Certain maternal-fetal-placental abnormalities can have a high risk of fetal demise. Despite advances in fetal surveillance with ultrasound and cardiotocography, the reduction in fetal mortality lags behind that of the neonate and has shown little decline in the past decade. This suggests that the type of fetal monitoring used may not be assessing the correct indicators of mortality. In all other age groups, electrocardiographic (ECG) and continuous heart rate (HR) monitoring are used in every intensive care unit or emergency setting; however, for the fetus, the ECG signal is nearly completely insulated and inaccessible. As the result, indirect assessment of cardiac rhythm is obtained using echocardiography/Doppler, but echo/Doppler does not have the precision to assess beat-to-beat HR variability and cannot assess cardiac repolarization at all. In this study, the investigators will evaluate five high risk conditions (major congenital heart disease in the fetus, fetal hydrops (immune and non-immune), monochorionic twin pregnancy, prior pregnancy ending in fetal demise, and gastroschisis) using Fetal Magnetocardiography (fMCG)which detects the natural magnetic signals accompanying the cardiac electrical signal. It is a new, safe, and non-invasive recording technique that has been performed for several decades, and has recently gained FDA approval for recording cardiac signals at all ages, including in the fetus. Normative data has been obtained at the University of Wisconsin - Madison Biomagnetism Laboratory in 257 healthy fetuses by co-investigator Ronald T. Wakai, PhD. Over 550 serious fetal arrhythmias have been evaluated to date. Fetal MCG has proven invaluable in fetal Long QT Syndrome in identifying markers for risk of sudden death such as Torsades de Pointes Ventricular Tachycardia (VT), T wave alternans, 2nd degree AV block, and QTc>590 ms. To date, fMCG has not been systematically applied to diseases that are not associated with recognizable arrhythmias because the impact of silent conduction and repolarization defects has been underappreciated. In this grant, the investigators hypothesize that beat-to-beat fetal heart rate variability abnormalities and electrophysiologic abnormalities, are present in five high risk maternal-fetal-placental conditions associated with fetal demise. The study will determine which electrophysiologic abnormalities precede fetal demise or adverse pregnancy outcome. Preliminary findings in healthy normal subjects in RO1HL063174 (Wakai) show repolarization abnormalities in up to 5%, and some of these are modifiable once recognized. Two hundred pregnant subjects will be studied over a 5 year period both at referral (~20-27 weeks GA) and later in pregnancy at 30-37 weeks GA. fMCG results will be compared to neonatal ECG (nECG) obtained at 0-4 weeks of life. This will determine whether specific abnormal heart rate, rhythm and conduction patterns emerge that characterize the condition, which will then allow the high risk obstetrician to better predict risk of fetal demise in the future.
• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Current pregnancy complicated by one of the five diagnostic categories (fetal major congenital heart disease, prior unexplained Stillbirth at/after 20 weeks gestation, fetal hydrops, fetal gastroschesis, or monochorionic twin pregnancy.

Condition

• High Risk Pregnancy
• Congenital Heart Disease
• Fetal Hydrops
• Twin Monochorionic Monoamniotic Placenta
• Gastroschisis
• Fetal Demise
• Stillbirth
• Fetal Arrhythmia
• Long QT Syndrome
• Intrauterine Fetal Death
• Sudden Infant Death
• Pregnancy Loss
• Twin Twin Transfusion Syndrome
• Birth Defect
• Fetal Cardiac Anomaly
• Fetal Cardiac Disorder
• Fetal Death
• Brugada Syndrome

Intervention

Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram

Fetal Magnetocardiography (fMCG) is a new non-invasive diagnostic procedure that records tiny fetal cardiac signals similar to an Electrocardiogram or Holter monitor. The magnetometer has FDA clearance, and does not emit magnetic, electric or other energies. This is not an MRI. Examples of fetal MCG's can be found in the Links. The American Heart Association Scientific Statement on Fetal Diagnosis and Treatment (Circulation, 2014) has declared fMCG to be Class IIa for fetal heart rhythm abnormalities, meaning that benefit far exceeds risk. As part of this study, a neonatal electrocardiogram (nECG) will be obtained for comparison after the baby is born.

Study Groups/Cohorts

• 1) Fetal Congenital Heart Disease
  Pregnancy with major fetal congenital heart disease, after 20 weeks gestation, and as neonate following delivery. Two fetal magnetocardiograms (fMCG) and 1 neonatal electrocardiogram (nECG) will be obtained and heart rate, rhythm, and conduction patterns will be compared.
  Intervention: Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram
• 2) History of fetal demise (Stillbirth)
  Pregnancy with a history of an unexplained fetal demise (stillbirth at 20 -40 weeks gestation) during any prior pregnancy. Two fetal magnetocardiograms (fMCG) and 1 neonatal electrocardiogram (nECG) will be obtained and heart rate, rhythm, and conduction patterns will be compared.
  Intervention: Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram
• 3) Fetal hydrops, immune or non-immune
  Pregnancy with fetal hydrops, immune or non-immune, at or after 20 weeks gestation. Two fetal magnetocardiograms (fMCG) and 1 neonatal electrocardiogram (nECG) will be obtained and heart rate, rhythm, and conduction patterns will be compared.
  Intervention: Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram
• 4) Fetal gastroschisis
  Pregnancy with fetal gastroschisis, at or after 20 weeks gestation. Two fetal magnetocardiograms (fMCG) and 1 neonatal electrocardiogram (nECG) will be obtained and heart rate, rhythm, and conduction patterns will be compared.
  Intervention: Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram
• 5) Twin pregnancy, monochorionic
  Twin pregnancy, monochorionic, with or without twin-twin transfusion syndrome, at or after 20 weeks gestation. Two fetal magnetocardiograms (fMCG) and 1 neonatal electrocardiogram (fMCG) will be obtained and heart rate, rhythm, and conduction patterns will be compared.
  Intervention: Diagnostic Test: Fetal Magnetocardiogram and Neonatal Electrocardiogram

Publications *

• Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A, Cuneo BF, Huhta JC, Jonas RA, Krishnan A, Lacey S, Lee W, Michelfelder EC Sr, Rempel GR, Silverman NH, Spray TL, Strasburger JF, Tworetzky W, Rychik J; American Heart Association Adults With Congenital Heart Disease Joint Committee of the Council on Cardiovascular Disease in the Young and Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Council on Cardiovascular and Stroke Nursing. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation. 2014 May 27;129(21):2183-242. doi: 10.1161/01.cir.0000437597.44550.5d. Epub 2014 Apr 24. Erratum In: Circulation. 2014 May 27;129(21):e512.
• Strasburger JF, Wakai RT. Fetal cardiac arrhythmia detection and in utero therapy. Nat Rev Cardiol. 2010 May;7(5):277-90. doi: 10.1038/nrcardio.2010.32.
• Cuneo BF, Strasburger JF, Yu S, Horigome H, Hosono T, Kandori A, Wakai RT. In utero diagnosis of long QT syndrome by magnetocardiography. Circulation. 2013 Nov 12;128(20):2183-91. doi: 10.1161/CIRCULATIONAHA.113.004840.
• Batie M, Bitant S, Strasburger JF, Shah V, Alem O, Wakai RT. Detection of Fetal Arrhythmia Using Optically-Pumped Magnetometers. JACC Clin Electrophysiol. 2018 Feb;4(2):284-287. doi: 10.1016/j.jacep.2017.08.009. No abstract available.
• Strand S, Strasburger JF, Cuneo BF, Wakai RT. Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome. Circ Arrhythm Electrophysiol. 2020 May;13(5):e008082. doi: 10.1161/CIRCEP.119.008082. Epub 2020 May 18.
• Strand S, Lutter W, Strasburger JF, Shah V, Baffa O, Wakai RT. Low-Cost Fetal Magnetocardiography: A Comparison of Superconducting Quantum Interference Device and Optically Pumped Magnetometers. J Am Heart Assoc. 2019 Aug 20;8(16):e013436. doi: 10.1161/JAHA.119.013436. Epub 2019 Aug 9.
• Wacker-Gussmann A, Strasburger JF, Wakai RT. Fetal Magnetocardiography Alters Diagnosis and Management in Fetal Congenital Heart Disease and Cardiomyopathy. JACC Clin Electrophysiol. 2022 Sep;8(9):1159-1161. doi: 10.1016/j.jacep.2022.04.012. Epub 2022 Jun 29. No abstract available.
• Wacker-Gussmann A, Strasburger JF, Wakai RT. Contribution of Fetal Magnetocardiography to Diagnosis, Risk Assessment, and Treatment of Fetal Arrhythmia. J Am Heart Assoc. 2022 Aug 2;11(15):e025224. doi: 10.1161/JAHA.121.025224. Epub 2022 Jul 29.
• Strasburger JF, Eckstein G, Butler M, Noffke P, Wacker-Gussmann A. Fetal Arrhythmia Diagnosis and Pharmacologic Management. J Clin Pharmacol. 2022 Sep;62 Suppl 1(Suppl 1):S53-S66. doi: 10.1002/jcph.2129.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 13, 2018): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 30, 2023
• Estimated Primary Completion Date: April 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Current pregnancy complicated by one of the five diagnostic categories

  • prior unexplained Stillbirth at/after 20 weeks gestation
  • fetal major congenital heart defect
  • fetal hydrops
  • fetal gastroschisis
  • monochorionic twin pregnancy
• Subject must be 18 years of age or older
• Subject must be English speaking and must be able to read and sign the consent form in English
• Subject must be able to recline comfortably for 1-3 hours
• Subject must be willing to complete all three procedures (fMCG, fMCG, nECG) as per protocol, unless medically unable
• Subject must be willing to allow us to review her and her infants prenatal, deliver, and post-natal records to verify diagnosis, and clinical findings.

Exclusion Criteria:

• Severe claustrophobia not reduced by taking breaks, or by having the light on, or by having someone in the room with them.
• Active labor
• Acute illness
• Unable to recline comfortably with a pillow for more than 1-3 hours (assuming some breaks are provided)
• Weight over 450 lbs

• An electric stimulation device (TENS unit, pacemaker, or nerve stimulator) that could produce electric or magnetic noise.

  • Note that the Tristan 624 Magnetometer does not pose a risk to the subject's device, (since fMCG does not produce any energy or magnetism), but stimulators themselves can cause interference for our recordings. Some devices may still qualify, and discussion with study nurse may be useful if subject has a pacemaker or similar device.

The subject will have a single 2-3 hour fetal magnetocardiogram at approximately 20 and 27 weeks GA, and again, if medical condition allows, between 30 and 37 weeks GA, then her infant will have an ECG between 0 and 4 weeks of age. Subjects will be paid a nominal fee for their participation each time, as well as transportation reimbursement if >25 miles. For subjects traveling a long distance, the ECG may be performed locally or at home.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: This study involves pregnant women and subsequently-born neonate(s) of either gender.

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Mara C Koffarnus, MD; 414-266-4758; mkoffarn@mcw.edu

Contact: Gretchen Eckstein; 414-266-3539; geckstein@chw.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03775954
• Other Study ID Numbers: PRO00031598; R01HL143485 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Only de-identified data can be released

• Current Responsible Party: Janette F. Strasburger, Medical College of Wisconsin
• Original Responsible Party: Same as current
• Current Study Sponsor: Medical College of Wisconsin
• Original Study Sponsor: Same as current

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• University of Wisconsin, Madison
• Children's Hospital and Health System Foundation, Wisconsin
• Shared Medical Technology, Inc.
• Tristan Technologies, Inc

Investigators

• Principal Investigator: Janette F Strasburger, MD; Medical College of Wisconsin

• PRS Account: Medical College of Wisconsin
• Verification Date: March 2023