About Dr. Crombleholme
Timothy M. Crombleholme, MD, is a recognized leader in the field of fetal surgery and pediatric surgery.
A graduate of Tufts University School of Medicine, Boston (1984), Dr. Crombleholme was a surgical resident and chief resident at the University of California at San Francisco (1984 to 1991), and a chief resident in pediatric surgery at The Floating Hospital for Infants and Children at the now Tufts Medical Center in Boston, MA (1991 to 1993). He was a fetal surgery research fellow under Michael R. Harrison, MD, who is widely recognized as the founder of fetal surgery.
Prior to starting the Fetal Care Center at Cincinnati Children's Hospital Medical Center in 2004, he helped start the Center for Fetal Diagnosis and Treatment at Children's Hospital of Philadelphia (1996 to 2004). Previously, he was director of the Fetal Treatment Program at the New England Medical Center in Boston, MA (1993 to 1995).
In addition to his surgical expertise, Dr. Crombleholme is active in clinical and laboratory research. He established the Center for Molecular Fetal Therapy as the NIH-funded basic research laboratory component of the Fetal Care Center of Cincinnati.
Dr. Crombleholme's clinical investigations include the National Institutes of Health funded multicenter trial to determine the best treatment for twin-twin transfusion syndrome / TTTS and research on new techniques for open fetal surgery and fetoscopic surgery. His laboratory research includes NIH-funded studies of gene therapy in tissue repair, fetal gene therapy and the role of the fetal fibroblast in fetal wound healing.
Dr. Crombleholme's clinical expertise is in fetoscopic surgery, open fetal surgery and EXIT procedures to treat a broad spectrum of prenatally diagnosed conditions including congenital diaphragmatic hernia, twin-twin transfusion syndrome, congenital cystic adenomatoid malformation of the lung, bladder outlet obstruction, sacrococcygeal teratoma and TRAP sequence. His postnatal clinical interest is in the neonatal care and treatment of congenital diaphragmatic hernia, CCAM, SCT and abdominal wall defects. In 2011, he served as the President of the International Fetal and Surgery Society.
BA: University of Pennsylvania, College of Arts and Sciences, Philadelphia, PA, 1980.
MD: Tufts University School of Medicine, Boston, MA, 1984.
Certification: Diplomate of the National Board of Medical Examiners, 1984; Diplomate of the American Board of Surgery, 1992, Recertified in 2003; Special Qualification in Pediatric Surgery, 1994, Recertified in 2007.
Awards and Honors
- President, International Fetal and Surgery Society
- Best Doctors in America, 2001-2011
- Who's Who in Diabetes Treatment, Education and Research
- Who's Who in Medicine
- Who's Who in Science and Engineering
- Career Development Award, American Diabetes Foundation
- Ethel Brown Foerderer Fellow
- American College of Surgeons Faculty Research Scholarship
- Young Investigator Award, Surgical Section of the American Academy of Pediatrics
- Young Investigator Award, American Society of Clinical Oncology
- Alpha Omega Alpha Honor Medical Society
- Gene Therapy in Tissue Repair: The focus of this work is using adenoviral-mediated gene transfer to accelerate healing, prevent scar formation, or induce angiogenesis in diabetic mouse models.
- Gene therapy to correct placental insufficiency: Using gene transfer of Insulin-like Growth Factor 1 (IGF-1) and Insulin-like Growth Factor 2 (IGF-2) to correct placental insufficiency (PI) in mouse, rat and rabbit models where PI is created by ligating a mesenteric branch of the uterine artery. We have also shown, in these animal models, that gene transfer of IGF-1 in PI will prevent the development of hypertension and diabetes in adulthood.
- Endothelial Precursor Cell Recruitment in Neovascularization: The focus of this work is using adenoviral mediated gene transfer of angiogenic growth factors to recruit endothelial precursor cells (EPCs) to sites of neovascularization in models of diabetic impaired neovascularization of wounds and in response to ischemia.
- Role of Endothelial Precursor Cells (EPCs) in Compensatory Lung Growth following Pneumonectomy: The focus of this work is to demonstrate that bone marrow-derived EPCs are important in the process of compensatory lung growth after pneumonectomy.
Mentoring of Junior faculty Research in Collaboration
- Foong-Yen Lim, MD - Lung Development in Fetal Tracheal Occlusion for Diaphragmatic Hernia in mice: The focus of this work is on identification of novel molecular insights into mechanisms responsible for down regulation of type II pneumocyte differentiation and molecular pathways during lung development.
- Daria Narmenova, PHD - The use of in situ tissue engineering with an angio-genic peptide scaffold to enhance diabetic wound healing in murine models.
- Mounira A. Habli, MD - The use of intraplacental gene transfer to correct placental insufficiency in murine modal.
- Helen N. Jones, PHD - Effect of placental insufficiency and intraplacental gene transfer on glucose and amino acid transport mechanisms.
- Sundeep Kesawani, MD - Cellular and molecular mechanisms of regenerative fetal wound healing.
- Prospective study of the acure effects on recipient survival and echocardiographic signs of Twin-Twin Transfusion Syndrome cardiomyopathy.
- The role of inhaled prostacyclin (Flolan) in the management of severe pulmonary hypertension in congenital diaphragmatic hernia.
- Open fetal surgery for complete bladder outlet obstruction due to posterior urethral valves associated oligohydramnios.
- Molecular genetic analysis of congenital diaphragmatic hernia is a study we are collaborating with Wendy Chung, PHD and Marc Arkovitz of Columbia University to define diaphragmatic-specific mutations in CDH.
- Proteomic analysis of amniotic fluid samples in Twin-Twin Transfusion Syndrome. The goal of this project is identify candidate proteins for study as etiologic factors in TTTS and define a severity-specific profile
- Twin-Twin Transfusion Syndrome: We currently have active IRB protocols for the study of different aspect of TTTS including: acute survival complications of fetoscopic surgery, role of cerclage in short cervix, role of brain atrial natriuretic peptide in cardiomyopathy, triplets and higher order multiples, MRI and echocardiographic assessment.
Publications, Most Recent
View PubMed Publications
Papanna, R, Habli M, Baschat A, Bebbington M, Mann LM, Johnson A, Ryan G, Walker M, Lewis D, Harman C, Crombleholme TM, Moise KJ Jr. Cerclage for cervical shortening at fetoscopic laser photocooqulation in twin-twin transfusion syndrome. Am J Obstet Gynecol in press 2012,
Tan X, Cnota J, Divanovic A, Statile C, Crombleholme TM, Michelfelder E. Right Ventricular Outflow Tract Abnormalities in Twin-Twin Transfusion Syndrome: Prevalence, Spectrum and Outcome [In Press 2012]
Balaji S, Vaikunth SS, Lang SA, Sheikh AQ, Lim FY, Crombleholme TM, Narmoneva DA. Tissue-engineered provisional matrix as a novel approach to enhance diabetic wound healing. Wound Repair Regen. 2011 Dec 8. doi: 10.1111/j.1524-475X.2011.00750.x. [Epub ahead of print]
Prada CE, Sellars EA, Spaeth CG, Kline-Fath BM, Crombleholme TM, Hopkin RJ. Severe cervical scoliosis in the fetus. Prenat Diagn. 2011 Dec;31(12):1198-202. doi: 10.1002/pd.2898. Epub 2011 Oct 26.
Habli M, Michelfelder E, Cnota J, Wall D, Polzin W, Lewis D, Lim FY, Crombleholme TM. Prevalence and progression of recipient-twin cardiomyopathy in early-stage twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2012 Jan;39(1):63-8. doi: 10.1002/uog.10117.
Cho H, Balaji S, Sheikh AQ, Hurley JR, Tian YF, Collier JH, Crombleholme TM, Narmoneva DA. Regulation of endothelial cell activation and angiogenesis by injectable peptide nanofibers. Acta Biomater. 2012 Jan;8(1):154-64. Epub 2011 Sep 6.
Le LD, Alam S, Lim FY, Keswani SG, Crombleholme TM. Prenatal and postnatal urologic complications of sacrococcygeal teratomas. J Pediatr Surg. 2011 Jun;46(6):1186-90.
Lee TC, Lim FY, Keswani SG, Frischer JS, Haberman B, Kingma PS, Habli M, Jaekle RK, Sharp G, Kline-Fath B, Rubio EI, Calvo M, Guimaraes C, Crombleholme TM. Late gestation fetal magnetic resonance imaging-derived total lung volume predicts postnatal survival and need for extracorporeal membrane oxygenation support in isolated congenital diaphragmatic hernia. J Pediatr Surg. 2011 Jun;46(6):1165-71.
Stanek J, Sheridan RM, Le LD, Crombleholme TM. Placental fetal thrombotic vasculopathy in severe congenital anomalies prompting EXIT procedure. Placenta. 2011 May;32(5):373-9. doi: 10.1016/j.placenta.2011.02.002. Epub 2011 Mar 23.
Calvo-Garcia MA, Kline-Fath BM, Levitt MA, Lim FY, Linam LE, Patel MN, Kraus S, Crombleholme TM, Peña A. Fetal MRI clues to diagnose cloacal malformations. Pediatr Radiol. 2011 Sep;41(9):1117-28. Epub 2011 Mar 16.
Keswani SG, Le LD, Morris LM, Lim FY, Katz AB, Ghobril N, Habli M, Frischer JS, Crombleholme TM. Submucosal gland development in the human fetal trachea xenograft model: implications for fetal gene therapy. J Pediatr Surg. 2011 Jan;46(1):33-8.
Crombleholme TM, Lim FY, Habli M, Polzin W, Jaekle R, Michelfelder E, Cnota J, Liu C, Kim MO. Improved recipient survival with maternal nifedipine in twin-twin transfusion syndrome complicated by TTTS cardiomyopathy undergoing selective fetoscopic laser photocoagulation. Am J Obstet Gynecol. 2010 Oct;203(4):397.e1-9.
Habli M, Cnota J, Michelfelder E, Salisbury S, Schnell B, Polzin W, Lim FY, Crombleholme TM. The relationship between amniotic fluid levels of brain-type natriuretic peptide and recipient cardiomyopathy in twin-twin transfusion syndrome. Am J Obstet Gynecol. 2010 Oct;203(4):404.e1-7.
Eghtesady P, Michelfelder EC, Knilans TK, Witte DP, Manning PB, Crombleholme TM. Fetal surgical management of congenital heart block in a hydropic fetus: Lessons learned from a clinical experience. J Thorac Cardiovasc Surg. 2010 Jul 30.
Boat A, Mahmoud M, Michelfelder EC, Lin E, Ngamprasertwong P, Schnell B, Kurth CD, Crombleholme TM, Sadhasivam S. Supplementing desflurane with intravenous anesthesia reduces fetal cardiac dysfunction during open fetal surgery. Paediatr Anaesth. 2010 Aug;20(8):748-56.
Maldonado AR, Klanke C, Jegga AG, Aronow BJ, Mahller YY, Cripe TP, Crombleholme TM. Molecular engineering and validation of an oncolytic herpes simplex virus type 1 transcriptionally targeted to midkine-positive tumors. J Gene Med. 2010 Jul;12(7):613-23.
Linam LE, Yu X, Calvo-Garcia MA, Rubio EI, Crombleholme TM, Bove K, Kline-Fath BM. Contribution of magnetic resonance imaging to prenatal differential diagnosis of renal tumors: report of two cases and review of the literature. Fetal Diagn Ther. 2010;28(2):100-8. Epub 2010 Jun 30. Review.
Morris LM, Klanke CA, Lang SA, Pokall S, Maldonado AR, Vuletin JF, Alaee D, Keswani SG, Lim FY, Crombleholme TM. Characterization of endothelial progenitor cells mobilization following cutaneous wounding. Wound Repair Regen. 2010 Jul;18(4):383-90
Vuletin JF, Lim FY, Cnota J, Kline-Fath B, Salisbury S, Haberman B, Kingma P, Frischer J, Crombleholme TM. Prenatal pulmonary hypertension index: novel prenatal predictor of severe postnatal pulmonary artery hypertension in antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg. 2010 Apr;45(4):703-8.
Morris LM, Klanke CA, Lang SA, Lim FY, Crombleholme TM. TdTomato and EGFP identification in histological sections: insight and alternatives. Biotech Histochem. 2010 Dec;85(6):379-87.
Books, Most Recent:
Bianchi DW, Crombleholme TM, D'Alton ME, Malone, FD, Fetology: Diagnosis and Management of the Fetal Patient. 2nd Ed. McGraw Hill: New York, NY, 2010.
Open fetal surgery for the treatment of structural anomalies; fetoscopic surgery for twin-twin transfusion syndrome; EXIT procedures; neonatal surgery; diaphragmatic hernia; congenital cystic adenomatoid malformation of the lung