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based on DSMB recommendation at interim analysis
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| Name | Class |
|---|---|
| Mallinckrodt | INDUSTRY |
| Thrasher Research Fund | OTHER |
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Inhaled nitric oxide (iNO) is an effective treatment for pulmonary hypertension (PH) in term and near-term infants. Preterm infants are at risk for early PH that is associated with high risk for bronchopulmonary dysplasia or death. In multiple clinical trials, iNO treatment was not effective for BPD prevention. However, infants were not screened for PH and iNO treatment was not targeted for PH. iNO treatment for PH in preterm infants is controversial due to lack of evidence. The study team hypothesizes that early diagnosis of PH (72-96 hours of life) and iNO treatment will decrease the incidence of death and bronchopulmonary dysplasia and improve oxygenation in extremely preterm infants.
This is a single center, blinded, randomized control clinical trial to evaluate the effects of inhaled nitric oxide on the outcome of survival and incidence of bronchopulmonary dysplasia. This trial has a planned enrollment of 138 infants with 68 infants with delayed pulmonary transition assigned to either the treatment or placebo group. There is no enrollment restriction based on gender, ethnicity, or race. Enrollment is expected to take 36 months with an additional 12 months for data analysis.Infants with early pulmonary hypertension will be randomized to the treatment or placebo group. Treatment will continue until resolution of pulmonary hypertension or through Day 14, whichever comes first. Serial echocardiograms will be performed every 48 hours +/-12 hours until Day 14. Oxygen saturation levels will be averaged every 24 hour period following enrollment. This study will provide evidence for the beneficial effects of early diagnosis and treatment of pulmonary hypertension in preterm infants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment group - active | Active Comparator | inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. |
|
| Treatment group - placebo | Placebo Comparator | Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. |
|
| Control group | No Intervention | Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| inhaled nitric oxide | Drug | inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
|
| Measure | Description | Time Frame |
|---|---|---|
| Death | Incidence of death | 36 weeks post menstrual age |
| Bronchopulmonary (BPD) Dysplasia (Yes/no) | Incidence of bronchopulmonary dysplasia as determined by need for positive pressure ventilation or supplemental oxygen after room air challenge test | 36 weeks post menstrual age |
| Measure | Description | Time Frame |
|---|---|---|
| Pulmonary Hypertension | Pulmonary arterial pressure will be evaluated every 24-48 hours after enrollment. | Duration of treatment or up to Day 14 |
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Inclusion Criteria:
Step 1:
Step 2:
Exclusion Criteria:
Step 1:
Step 2:
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| Name | Affiliation | Role |
|---|---|---|
| Hussnain Mirza, MD | AdventHealth | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AdventHealth | Orlando | Florida | 32803 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21471086 | Background | Laughon MM, Langer JC, Bose CL, Smith PB, Ambalavanan N, Kennedy KA, Stoll BJ, Buchter S, Laptook AR, Ehrenkranz RA, Cotten CM, Wilson-Costello DE, Shankaran S, Van Meurs KP, Davis AS, Gantz MG, Finer NN, Yoder BA, Faix RG, Carlo WA, Schibler KR, Newman NS, Rich W, Das A, Higgins RD, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1715-22. doi: 10.1164/rccm.201101-0055OC. Epub 2011 Mar 4. | |
| 26500107 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Group - Active | inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. inhaled nitric oxide: inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
| FG001 | Treatment Group - Placebo | Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. Placebo: placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
| FG002 | Control Group | Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Treatment Group - Active | inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. inhaled nitric oxide: inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Death | Incidence of death | Posted | Count of Participants | Participants | 36 weeks post menstrual age |
|
Until 36 weeks post-menstrual age
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment Group - Active | inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. inhaled nitric oxide: inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| IVH | Nervous system disorders | Systematic Assessment | Intraventricular Hemorrhage |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| MetHb% >2 | Blood and lymphatic system disorders | Systematic Assessment | Methemoglobinemia |
Majority of preterm infants with hypoxic respiratory failure or severe pulmonary hypertension were excluded due to the clinical treatment with inhaled nitric oxide prior to our study echocardiogram
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Hussnain Mirza MD | AdventHealth | 9736263952 | Hussnain.Mirza.MD@adventhealth.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 10, 2020 | Sep 11, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D001997 | Bronchopulmonary Dysplasia |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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Masked randomized controlled trial
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|
| Placebo | Drug | placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
|
| Background |
| Ballard RA, Keller RL, Black DM, Ballard PL, Merrill JD, Eichenwald EC, Truog WE, Mammel MC, Steinhorn RH, Rogers EE, Ryan RM, Durand DJ, Asselin JM, Bendel CM, Bendel-Stenzel EM, Courtney SE, Dhanireddy R, Hudak ML, Koch FR, Mayock DE, McKay VJ, O'Shea TM, Porta NF, Wadhawan R, Palermo L; TOLSURF Study Group. Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide. J Pediatr. 2016 Jan;168:23-29.e4. doi: 10.1016/j.jpeds.2015.09.031. Epub 2015 Oct 21. |
| 18055675 | Background | Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007 Dec;120(6):1260-9. doi: 10.1542/peds.2007-0971. |
| 7768245 | Background | West JB, Mathieu-Costello O. Stress failure of pulmonary capillaries as a limiting factor for maximal exercise. Eur J Appl Physiol Occup Physiol. 1995;70(2):99-108. doi: 10.1007/BF00361536. |
| 25189821 | Background | Mirza H, Ziegler J, Ford S, Padbury J, Tucker R, Laptook A. Pulmonary hypertension in preterm infants: prevalence and association with bronchopulmonary dysplasia. J Pediatr. 2014 Nov;165(5):909-14.e1. doi: 10.1016/j.jpeds.2014.07.040. Epub 2014 Sep 1. |
| 22311993 | Background | Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics. 2012 Mar;129(3):e682-9. doi: 10.1542/peds.2011-1827. Epub 2012 Feb 6. |
| 25389562 | Background | Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, Poindexter BB, Ingram DA, Abman SH. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015 Jan 1;191(1):87-95. doi: 10.1164/rccm.201409-1594OC. |
| 24616323 | Background | Ambalavanan N, Mourani P. Pulmonary hypertension in bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014 Mar;100(3):240-6. doi: 10.1002/bdra.23241. Epub 2014 Mar 10. |
| 25755239 | Background | Finer NN, Evans N. Inhaled nitric oxide for the preterm infant: evidence versus practice. Pediatrics. 2015 Apr;135(4):754-6. doi: 10.1542/peds.2015-0144. Epub 2015 Mar 9. No abstract available. |
| 26703869 | Background | Kinsella JP, Steinhorn RH, Krishnan US, Feinstein JA, Adatia I, Austin ED, Rosenzweig EB, Everett AD, Fineman JR, Hanna BD, Hopper RK, Humpl T, Ivy DD, Keller RL, Mullen MP, Raj JU, Wessel DL, Abman SH. Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. J Pediatr. 2016 Mar;170:312-4. doi: 10.1016/j.jpeds.2015.11.050. Epub 2015 Dec 15. No abstract available. |
| 8414836 | Background | Abman SH, Kinsella JP, Schaffer MS, Wilkening RB. Inhaled nitric oxide in the management of a premature newborn with severe respiratory distress and pulmonary hypertension. Pediatrics. 1993 Oct;92(4):606-9. No abstract available. |
| 27225961 | Background | Ambalavanan N, Aschner JL. Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants. J Perinatol. 2016 Jun;36 Suppl 2:S20-7. doi: 10.1038/jp.2016.45. |
| 21930540 | Background | Askie LM, Ballard RA, Cutter GR, Dani C, Elbourne D, Field D, Hascoet JM, Hibbs AM, Kinsella JP, Mercier JC, Rich W, Schreiber MD, Wongsiridej PS, Subhedar NV, Van Meurs KP, Voysey M, Barrington K, Ehrenkranz RA, Finer NN; Meta-analysis of Preterm Patients on Inhaled Nitric Oxide Collaboration. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics. 2011 Oct;128(4):729-39. doi: 10.1542/peds.2010-2725. Epub 2011 Sep 19. |
| 17403837 | Background | Truog WE, Ballard PL, Norberg M, Golombek S, Savani RC, Merrill JD, Parton LA, Cnaan A, Luan X, Ballard RA; Nitric Oxide (to Prevent) Chronic Lung Disease Study Investigators. Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics. 2007 Apr;119(4):670-8. doi: 10.1542/peds.2006-2683. |
| 19812581 | Background | Posencheg MA, Gow AJ, Truog WE, Ballard RA, Cnaan A, Golombek SG, Ballard PL; NO CLD Investigators. Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. J Perinatol. 2010 Apr;30(4):275-80. doi: 10.1038/jp.2009.155. Epub 2009 Oct 8. |
| 26593082 | Background | Mourani PM, Abman SH. Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia. Clin Perinatol. 2015 Dec;42(4):839-55. doi: 10.1016/j.clp.2015.08.010. Epub 2015 Sep 26. |
| 24379225 | Background | Kumar P; Committee on Fetus and Newborn; American Academy of Pediatrics. Use of inhaled nitric oxide in preterm infants. Pediatrics. 2014 Jan;133(1):164-70. doi: 10.1542/peds.2013-3444. Epub 2013 Dec 30. |
| 21042341 | Background | Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV, Kramer M, Mitchell C, Neu J, Pursley DM, Robinson W, Rowitch DH. NIH consensus development conference: Inhaled nitric oxide therapy for premature infants. NIH Consens State Sci Statements. 2010 Oct 29;27(5):1-34. |
| 26534956 | Background | Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99. doi: 10.1161/CIR.0000000000000329. Epub 2015 Nov 3. |
| 28783986 | Background | Seth SA, Soraisham AS, Harabor A. Risk factors and outcomes of early pulmonary hypertension in preterm infants. J Matern Fetal Neonatal Med. 2018 Dec;31(23):3147-3152. doi: 10.1080/14767058.2017.1365129. Epub 2017 Aug 21. |
| 27442155 | Background | Jiang Q, Gao X, Liu C, Chen D, Lin X, Xia S, Zhuang D, Yang C, Zhu W, Liu L, Chen C, Sun B. Early inhaled nitric oxide in preterm infants <34 weeks with evolving bronchopulmonary dysplasia. J Perinatol. 2016 Oct;36(10):883-9. doi: 10.1038/jp.2016.112. Epub 2016 Jul 21. |
| 20655106 | Background | Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Baldassarre J; EUNO Study Group. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 Jul 31;376(9738):346-54. doi: 10.1016/S0140-6736(10)60664-2. Epub 2010 Jul 23. |
| 25063725 | Background | Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, Abman SH. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr. 2014 Dec;165(6):1104-1108.e1. doi: 10.1016/j.jpeds.2014.06.018. Epub 2014 Jul 22. |
| 26751417 | Background | Evans N. Towards rational use of inhaled Nitric Oxide in preterm babies. Acta Paediatr. 2016 Feb;105(2):121-2. doi: 10.1111/apa.13273. No abstract available. |
| 19161864 | Background | Arul N, Konduri GG. Inhaled nitric oxide for preterm neonates. Clin Perinatol. 2009 Mar;36(1):43-61. doi: 10.1016/j.clp.2008.09.002. |
| 28820870 | Background | Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ. Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr Res. 2017 Dec;82(6):901-914. doi: 10.1038/pr.2017.200. Epub 2017 Oct 4. |
| 29625730 | Background | Mirza H, Garcia JA, Crawford E, Pepe J, Zussman M, Wadhawan R, Oh W. Natural History of Postnatal Cardiopulmonary Adaptation in Infants Born Extremely Preterm and Risk for Death or Bronchopulmonary Dysplasia. J Pediatr. 2018 Jul;198:187-193.e1. doi: 10.1016/j.jpeds.2018.02.034. Epub 2018 Apr 3. |
| 25859313 | Background | Bilan N, Dastranji A, Ghalehgolab Behbahani A. Comparison of the spo2/fio2 ratio and the pao2/fio2 ratio in patients with acute lung injury or acute respiratory distress syndrome. J Cardiovasc Thorac Res. 2015;7(1):28-31. doi: 10.15171/jcvtr.2014.06. Epub 2015 Mar 29. |
| 19242333 | Background | Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, Ware LB, Bernard GR, Ely EW. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med. 2009 Apr;37(4):1317-21. doi: 10.1097/CCM.0b013e31819cefa9. |
| 23372402 | Background | Peliowski A; Canadian Paediatric Society, Fetus and Newborn Committee. Inhaled nitric oxide use in newborns. Paediatr Child Health. 2012 Feb;17(2):95-100. doi: 10.1093/pch/17.2.95. |
| 39643111 | Derived | Mirza H, Garcia J, Zussman M, Wadhawan R, Pepe J, Oh W. Inhaled Nitric Oxide Treatment of Early Pulmonary Hypertension to Reduce the Risk of Death or Bronchopulmonary Dysplasia in Infants Born Extremely Preterm: A Masked Randomized Controlled Trial. J Pediatr. 2025 Mar;278:114427. doi: 10.1016/j.jpeds.2024.114427. Epub 2024 Dec 4. |
| BG001 |
| Treatment Group - Placebo |
Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. Placebo: placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension |
| BG002 | Control Group | Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | days |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
|
| Primary | Bronchopulmonary (BPD) Dysplasia (Yes/no) | Incidence of bronchopulmonary dysplasia as determined by need for positive pressure ventilation or supplemental oxygen after room air challenge test | Posted | Count of Participants | Participants | 36 weeks post menstrual age |
|
|
|
| Secondary | Pulmonary Hypertension | Pulmonary arterial pressure will be evaluated every 24-48 hours after enrollment. | Posted | Count of Participants | Participants | Duration of treatment or up to Day 14 |
|
|
|
| 1 |
| 16 |
| 2 |
| 16 |
| 14 |
| 16 |
| EG001 | Treatment Group - Placebo | Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. Placebo: placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension | 1 | 16 | 5 | 16 | 14 | 16 |
| NEC | Gastrointestinal disorders | Systematic Assessment | Necrotizing Enterocolitis |
|
| Culture positive sepsis | Infections and infestations | Systematic Assessment | Culture proven sepsis treated with antibiotics |
|
| PDA requiring treatment | Cardiac disorders | Systematic Assessment | Patent ductus arteriosus requiring medical or surgical treatment |
|
| Left Ventricular Dysfunction | Cardiac disorders | Systematic Assessment | Left ventricular dysfunction or EF less than 40% |
|
| Hyperbilirubinemia | Hepatobiliary disorders | Systematic Assessment | Neonatal Jaundice treated by Phototherapy |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Platelets less than 100,000 |
|
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| D002318 |
| Cardiovascular Diseases |
| D055397 | Ventilator-Induced Lung Injury |
| D055370 | Lung Injury |
| D007235 | Infant, Premature, Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |