Long QT Syndrome Screening in Newborns

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, University of California, Irvine

The purpose of this project is to test a new, very compact, 12-lead ECG device as a way to detect long QT syndrome (LQTS) in infants. The device -- called QTScreen -- was developed in Phase I of this project. In Phase II, the goals are to test the capacity of the device for LQTS screening in newborns and to obtain prevalence data on LQTS in California. The 4 main objectives are: To validate the capacity of QTScreen for LQTS screening in newborns. To determine the extent to which parents are able to use QTScreen on their babies at home. To survey end-user experience and opinions. To estimate the LQTS prevalence in California.

Long QT syndrome (LQTS) is a genetic disorder characterized by a prolonged QT interval on the ECG and occurrence of syncope, ventricular arrhythmias, and sudden death. LQTS is a major cause of sudden death in infants, children, and young adults. Treatment by β-blockers and/or placement of an implantable cardioverter defibrillator (ICD) are effective in preventing sudden death, if the diagnosis of LQTS is made early. The efficacy of ECG screening of newborns for LQTS has been demonstrated in Italy. Furthermore, within the national healthcare system in Italy, universal ECG screening in newborns (<30 days old) is cost-effective. The U.S. debate for universal LQTS screening started in the mid-2000's. In a 2007survey completed by North American pediatric cardiologists, 27% favored optional ECG screening of newborns, whereas 11% supported mandatory screening (363 responses, 35% response rate). There may be stronger support for universal screening, now that more data are available. Obtaining a good standard 12-lead EKG on a neonate in the clinic is difficult and time consuming. If an ECG device for newborn screening were readily available, reliable, easy to use, and cost-effective, then universal screening of all 4 million newborns in the U.S. each year would identify 2,000 infants with LQTS who are at risk for sudden death, assuming the prevalence is the same as in Italy. Perhaps more than 300 deaths per year from SIDS could be prevented, as well as many more sudden deaths in children, adolescents, and young adults. During Phase I of this project, a new device was developed to meet this clinical need (called QTScreen). In Phase II, the aim is to test the capacity of QTScreen for LQTS screening in newborns and the feasibility of home screening by parents in an ethnically diverse population of Northern and Southern California. The results of this clinical trial may validate the device as a screening tool for LQTS, and also provide important scientific data for supporting newborn screening for LQTS in the U.S. The 4 main objectives are: To validate the capacity of QTScreen for LQTS screening in newborns. This will be a clinical trial on 4,000 newborns, conducted at the Los Angeles Biomedical Research Institute (LABioMed). To determine the extent to which parents are able to use QTScreen on their babies at home. To survey end-user experience and opinions. The target users of QTScreen are parents. Participating parents will be asked to complete a survey, to obtain data for further development of the device. To estimate the LQTS prevalence in California. To date, the only population-based estimate of LQTS prevalence is 1 in 2,000 in Italy. In a recent study in Japan, 4,285 1-month-old infants had ECG screening. The LQTS prevalence was not reported, because only 10% of subjects with QTc values >450 msec had gene testing. There has been no population-based study of LQTS in the US. In a study of 707 children with hearing loss in California, 2 subjects had potassium voltage-gated channel KQT-like subfamily member 1 (KCNQ1 potassium channel) mutations, truncation or splicing. This trial will provide data on the LQTS prevalence in California. Study Sites: Study procedures will be conducted at subjects' homes. Subjects will be recruited from LA BioMed at Harbor-UCLA Medical Center, Providence Little Company of Mary Medical Center-Torrance, Santa Clara Valley Medical Center, and St. Francis Medical Center. Approval from each of the recruitment sites will be obtained prior to commencing recruitment. Consent: Consent will be sought from one parent only. Parents will be given the opportunity to thoroughly read the consent form and to ask questions. Risk/Benefit: ECG is a routine test performed on infants, children and adults every day in the hospital for many years with no problems or adverse events. The QTScreen system used in this study is a simplified way of performing an ECG test on infants. Some subjects may undergo genetic testing as part of this research and there are some risks associated with genetic testing, such as emotional and confidentiality. There is a very small risk of infection or rash related to the procedure involved in ECG testing. The subject may feel some discomfort from the sticky patches placed on and removed from his/her chest. Discomfort will be minimized by using an adhesive remover wipe which is commercially available and used by hospitals. Although infection is very unlikely to occur, rules and procedures of the nursery and clinic will be followed. This includes cleaning the ECG equipment and sanitizing it using a disinfecting wipe before and after each use to prevent infection. The effects of drawing blood are usually pain, bleeding and/or a bruise where the needle is inserted. Occasionally the area around the vein may swell. Serious complications such as a blood clot or infection may occur but these are rare. Some people feel faint when having blood drawn. Necessary precautions, such as gloves and proper sterilization, will be taken to minimize pain and infection. A small amount of local anesthetic cream may be placed on the child's forearm. Appropriate precautions will be used to minimize the risks associated with this project and feel that in general the risks associated with this project are low. The information gained from this study will help to find ways to possibly simplify the ECG test. This research study may also lead to a better understanding of LQTS which can provide important insight for future treatments and research. Therefore the general feeling is that the benefits of this project outweigh the risks.

Parent Performing ECG (PPE) Group--When the baby is 2 weeks old, research staff will contact interested parents to schedule a home visit. During the visit, a research assistant will provide the parents with a kit that includes the QTScreen system and instructions. The parents will perform an ECG on their child using the QTScreen and instructions. If after attempting the ECG on their own parents encounter problems, parents can ask the research assistant for assistance.

Staff Performing ECG (SPE) Group--When the baby is 2-4 weeks of age, research staff will contact the family to schedule a home visit. The QTScreen test will be done by a research assistant.

Subjects will be randomly assigned to the: Parents Performing ECG (PPE) group or Staff Performing ECG (SPE) group. This will assess whether parents are able to use QTScreen on babies at home.

A standard 12-lead ECG will be printed from the QTScreen recording. Investigators will manually measure a corrected QT interval (QTc) from lead II, and examine any clinical ECG abnormalities. Subjects with a positive history, or subjects with a median QTc ≥450 ms on the first QTScreen will be categorized as Intermediate Risk and undergo a repeat QTScreen in 2-4 weeks (before 2 months of age).

Participants in the PPE group will be provided with the QTScreen recording device along with instructions for conducting an ECG on their baby. While conducting the ECG, a research assistant will access the parents' ability in properly conducting the ECG via a questionnaire.

A research assistant will conduct a follow-up of each subject when the subject turns 1 year of age. For subjects <1 year of age when the project ends, the family will be contacted at the end of the project period and when the subject turns 1 year. Parents will be inquired about: any diagnosis of LQTS, heart disease, fainting, seizures, or sudden death (SIDS) after the screening. If a subject had fainting or seizures but no subsequent cardiac evaluation, he/she will be scheduled for a repeat QTScreen. If a subject died of sudden unexplained death or SIDS, the parents will be offered ECG and genetic testing for LQTS. After the follow-up questions, parents will be surveyed on their experience with QTScreen.

The large sample size and use of genetic conformation in this study provides a unique opportunity to evaluate the LQTS prevalence, as well as differences in certain ethnic groups, such as Latinos and White. The number of subjects with confirmed LQTS includes true positives, identified by positive QTScreen testing followed by gene testing, and false negatives identified by telephone follow up and subsequent confirmation. Prevalence data will be reported as the proportion of subjects with confirmed LQTS (and binomial exact 95% CI).

Inclusion Criteria: Born at ≥36 weeks of gestation. Birth weight 2.5-4.5 kg Exclusion Criteria: Babies that have been born with a heart disease. Babies who have a skin condition, allergies, or chest deformities making ECG on the chest difficult or impossible.

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