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The PregMed 5-Year Report

Name of Center:
PREGMED: The Indiana University Center for Pharmacogenetics and Therapeutics Research and Education in Maternal and Child Health

Director of Center:
David M. Haas, MD, MS

Year Signature Center designation was awarded: 2010

A. Short description of research center

Mission
The mission of PREGMED continues to be to improve pharmacotherapy for women and children using a personalized medicine approach that builds on the strength of Indiana University in the areas of pharmacogenomics, clinical obstetrics, and pediatrics. The center’s activities focus on the vision of developing new paradigms for the treatment of the multiple important conditions that affect pregnant women and children. This mission is unchanged with the exception of an expanded focus on education in this understudied area (as evidenced by the addition of “Education” to the Center title. The long-term goals of the center are to serve as a leader in the field of maternal-fetal pharmacology and to be a collaborative research leader in translating basic research into clinical studies that can drive a more personalized pharmacotherapy approach to maternal and child therapeutics.

Unique and Distinctive Features
PREGMED builds on the strengths of the IU School of Medicine in the areas of obstetrics, neonatology, and the cutting edge science of pharmacogenomics. A multi-disciplinary approach to the research includes faculty from the Center for Bioethics, School of Nursing, Department of Biostatistics, Psychiatry, Pediatric Endocrinology, and Bioinformatics. PREGMED at IUSM brings a diverse, unique, and collaborative set of skills and strengths to the study of maternal-fetal pharmacology. We have the expertise to conduct a wide array of collaborative projects across the translational spectrum.

B. Center infrastructure and budget

Addition/loss of core center members in the past 5 years

  • Key additions: Laura Haneline, MD (Neonatology) and Sara Quinney (OB/GYN, Clinical Pharmacology) have been elevated to become associate directors of the Center. We have successfully recruited Dr. Avinash Patil, one of the few dual trained Maternal-Fetal Medicine and Clinical Pharmacology fellowship trained researchers in the country to the group.
  • Key losses: Jim Lemons (neonatology- retired), Alan Golichowski (MFM- left university)
  • In addition we transitioned research coordinators but have had a stable research team for the last 2 years.

Changes in center leadership

  • As above- addition of key faculty to Director level leadership roles. No other changes in leadership.

Composition of advisory board (internal and/or external)

External Advisors were Craig Brater (Dean, IUSM) and Gideon Koren (SickKids Hospital, Toronto). We have expanded our External Advisory Board and also created an Internal Advisory Board. The organization of the key components of PREGMED as were recently submitted for Obstetric-Fetal Pharmacology Research Center funding are diagrammed below:

chart-pregmed-5-year-report.gif

Overview of annual operating budget for the past 5 years

PREGMED has been funded for the last 5 years primarily by the Obstetric-Fetal Pharmacology Research Units grant which supports some of the time for the Directors, the coordinators, some key faculty members involved in specimen analysis and statistical analyses, and research staff. This funding provided support for the conduct of 4 major OPRU studies:

  • Glyburide and Metformin for gestational diabetes RCT
  • Progestins for prevention of preterm birth observational cohort study
  • Pravastatin to prevent recurrent severe preeclampsia RCT
  • Understudied drugs in pregnancy, observational pharmacokinetic study

It also provided funding for several translational studies in Dr. Haneline’s lab and clinical projects involving Betamethasone pharmacogenetics to improve neonatal outcomes in preterm birth.

Remaining support for projects and for the OB-Clin Pharm fellowship came from joint funding from the Department of OB/GYN and the Division of Clinical Pharmacology. Continued funding is committed from these same sources in addition to the pending OPRC funding decision and the status of several R01 applications being prepared for submission by core faculty members for PREGMED work.

C. Summary of accomplishments in the past 5 years

Collaborative output

Grants and contracts

Funded

5 U10 HD063094-03 Flockhart, DA (PI) 02/01/2010 – 12/31/2015

NIH/NICHD Indiana PREGMED

The major goals of this project are to develop an Obstetric Pharmacology Research Unit which will bring together skills and technologies that have been key to the therapeutic revolution to the study of therapeutics in pregnancy. Center members involved: Flockhart, Haas, Haneline, Renbarger, Skaar, Li, Quinney, Jones

1R01GM088076 Skaar (PI)           09/30/09-02/28/18                                         

NIGMS                               Regulation of drug metabolizing enzymes by miRNAs.

Goals: 1)To determine the effect of altered miRNA expression on hepatocyte drug metabolism. 2) To identify functional genetic variants in predicted miRNA binding sites in genes involved in hepatic drug metabolism. 3) to determine the association of plasma miRNA patterns with the variable hepatic drug metabolism. This includes fetal and pediatric livers. Center members involved: Skaar, Flockhart, Renbarger

U54HD071598 Renbarger (PI) 09/26/11-06/30/16

NICHD Indiana University Center for Pediatric Pharmacology

The goal of this project is to promote collaborative translational pediatric pharmacology research among a nationwide network of sites with relevant expertise. Center members involved: Renbarger, Haneline, Flockhart, Skaar, Quinney, Li, Jones

1U01HG007762 Flockhart (co-PI) 09/05/14-06/30/18

NIH Embedding clinical pharmacogenomics in a large health care system for the underserved

The goals of this project are to implement pharmacogenetic testing into practice in a health care system. This includes pregnant women as one of the key recruitment populations. Center members involved: Flockhart, Haas, Skaar

Pediatric CTSI PDT Haneline (PI) 10/05/2013 – 09/30/2015

Maternal and neonatal methadone metabolism and associations with neonatal abstinence syndrome

The goal of this project is to better characterize the maternal and neonatal contributions to neonatal narcotic withdrawal syndrome using a translational pharmacokinetic and pharmacogenetic approach. Center members involved: Haneline, Haas, Quinney, Jones

T32 HD069047 Renbarger (PI) 07/01/2013 – 06/30/2015

NICHD Postdoctoral research training in pediatric clinical pharmacology

The goal of this program is to develop researchers with the expertise and skill to advance the field of pediatric pharmacology. Center members involved: Renbarger, Haneline, Flockhart, Skaar, Li, Quinney, Jones

Grant # PED-301 Haas, DM (Site PI) 08/06/2013 – 12/31/2015

Duchesnay Pharmaceutical, Inc.

Title: A Multicenter Trial Comparing the Efficacy and Safety of Diclegis® for Nausea and Vomiting of

Pregnancy in Pregnant Adolescents

The primary objective of this randomized, placebo-controlled trial is to demonstrate efficacy and safety of Diclegis in the treatment of NVP in adolescent women. Center members involved: Haas, Quinney

 

1R01 GM104483 Li, L (PI) 09/01/2014 – 05/31/2018

NIH/NIGMS

Title: A Translational Bioinformatics Approach in the Drug Interaction Research

The major goals of this project are do utilize novel data techniques to model drug and drug interaction adverse drug reactions in various populations. Center members involved: Li, Quinney

5 K23 HD071134-03 Quinney (PI) 07/01/2012 – 06/30/2017

NIH/NICHD

Individualization of nifedipine dosing for preterm labor

The major goal of this project is a five-year period of mentored training in patient-oriented clinical research aimed at incorporating in vitro data with in vivo clinical pharmacokinetic (PK) and pharmacodynamics (PD) knowledge to create a mechanistic PK/PD model of nifedipine in pregnancy. Center members involved: Quinney, Flockhart, Haas, Haneline, Li, Jones

 

Pending

1U54HD085579 Haas, Haneline (MPI) $3,466,595 07/01/15-06/30/20

NIH/NICHD

PREGMED: The Indiana University center for pharmacogenetics and therapeutics research and education in maternal and child health

The goals of this project are to continue on the research, education, and administration efforts of PREGMED at advancing individualized pharmacotherapy in maternal and child health. Center members involved: Haas, Haneline, Flockhart, Renbarger, Quinney, Patil, Li

1R01 GM117206-01 Quinney (PI) 09/01/2015 – 08/31/2018

NIH/NIGMS

Integrated bioinformatic and pharmacokinetic models of high-dimensional drug interactions

The long-term goal of our research is to develop an end-user oriented platform to detect potential HD-DDI’s from EMRs in real-time in order to provide feedback to a prescriber regarding risk/benefit of potential drug combinations in a patient. In this proposal, we seek to establish bioinformatic and statistical approaches to detect clinically relevant HD-DDIs from medical databases. The mechanism of these HD-DDIs will be evaluated in vitro to provide further supporting evidence. Center members involved: Quinney, Li.

Completed during last 5 years

K23HD055305 Haas, DM (PI) 08/11/2008 – 07/31/2013

NIH/NICHD

Title: Pharmacogenetics of antenatal corticosteroids to improve neonatal outcomes

The overall goal of the grant is to provide mentorship, training, and research funds to develop independent clinical researchers. The objective of this study is to evaluate potential pharmacogenetic implications for antenatal corticosteroid therapy to improve neonatal outcomes in preterm delivery. Center members involved: Haas, Flockhart, Quinney, Li

1RC1CA14688 Renbarger (PI) 9/30/09-8/31/10

NCI

Title: Developing a prediction model for vincristine-induced peripheral neuropathy

The overall goal of this grant was to develop a predictive model to help with individualizing chemotherapy for childhood cancer to reduce toxicity. Center members involved: Renbarger, Quinney, Li

Submitted but not funded

Impacts of maternal phenotype on breast milk metabolome (Haas Co-PI)

NIH 07/01/15-06/30/17

Protective innate immune response in preeclampsia (Haas Co-I)

1R01HD083284-A1 NIH/NICHD 11/01/15-10/31/20

Assessment of Novel Markers of Spontaneous Preterm Birth Using Maternal Serum Derived Circulating Microparticles in the Early Gestational Period (SBIR) (Haas Co-PI- collaborative with industry)

1R43HD084026 NIH/NICHD 04/01/15-09/30/15

Pharmacogenetics of antenatal corticosteroids- building optimal therapy models (R01) (Haas, Quinney)- resubmission not funded NIH/NICHD 04/01/12-03/31/17

Pravastatin for Preeclampsia Prevention (Haas, Haneline Co-I)

UTMB/FDA 11/01/12-10/31/15

Perinatal angiogenic factors and bronchopulmonary dysplasia (Haas, Haneline Co-I), resubmission not funded either NHLBI 4/1/14-3/31/19

Anti-angiogenic preeclamptic milieu impairs infant lung and vascular development (Haas, Haneline Co-I)

1R01HL122215 NHLBI 09/01/14-8/31/19

Pharmacogenetics of vincristine toxicity (Quinney, Renbarger)

St. Baldrick’s Fdtn 7/1/10-6/30/11

Indiana University PREGMED Research Training Program in Obstetric-Fetal Clinical Pharmacology (Haas PI, Flockhart, Haneline, Quinney)

NICHD T32 program 7/1/14-6/30/19

Indiana University PREGMED Research Training Program in Obstetric-Fetal Clinical Pharmacology (Haas PI, Flockhart, Haneline, Quinney)

NICHD T32 program 7/1/13-6/30/18

A pilot study of CYP2D6 screening for adverse drug reactions to hydrocodone in breast milk (Quinney PI, Haas)

Showalter Trust 7/1/12-6/30/13

A pilot study of CYP2D6 screening for adverse drug reactions to hydrocodone in breast milk (Quinney PI, Haas)

IUSM BRG 11/1/11-10/31/12

Publications (since 2010, related to PREGMED activities, Center members underlined)

  1. Pierson RC, Malone AM, Haas DM. Increasing influenza vaccination rates in a busy urban clinic. J Nat Sci 2015;1(3):e57.
  2. Combs CA, Garite TJ, Lapidus JA, Lapointe JP, Gravett M, Rael J, Amon E, Baxter JK, Brady K, Clewell W, Eddleman K, Fortunato S, Franco A, Haas DM, Heyborne K, Hickok DE, How HY, Luthy D, Miller H, Nageotte M, Pereira L, Porreco R, Robilio PA, Simhan H, Sullivan SA, Trofatter K, Westover T. Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. Am J Obstet Gynecol 2015;212:482.e1-12.
  3. Fu M, Zhang L, Ahmed A, Plaut K, Haas DM, Szucs K, Casey TM. Does circadian disruption play a role in metabolic-hormonal link to delayed lactogenesis II? Frontiers in Nutr 2015;2:1-13.
  4. Mantel CR, O’Leary HA, Chitteti BR, Huang X, Cooper S, Hangoc G, Brustovetsky N, Srour EF, Lee M, Messina-Graham, S, Haas DM, Falah N, Kapur R, Pelus LM, Bardeesy N, Fitamant J, Ivan M, Kim K, Broxmeyer HE. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 2015, in press.
  5. Crews KR, Caudle KE, Dunnenberger HM, Sadhasivam S, Skaar TC. Considerations for the Utility of the CPIC Guideline for CYP2D6 Genotype and Codeine Therapy. Clin Chem. 2015 Mar 13.
  6. Levy KD, Pratt VM, Skaar TC, Vance GH, Flockhart DA. FDA's draft guidance on laboratory-developed tests increases clinical and economic risk to adoption of pharmacogenetic testing. J Clin Pharmacol. 2015 Jul;55(7):725-7.
  7. Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 May 13.
  8. Blue EK, Sheehan BM, Nuss ZV, Boyle FA, Hocutt CM, McClintick JN, Haneline LS.  Epigenetic regulation of PLAC8 contributes to altered function of endothelial colony forming cells exposed to intrauterine gestational diabetes mellitus.  Diabetes.  2015 Feb 26, in press.
  9. Bolduan AJ, Haas DM. A systematic review of the use of bupropion for hypoactive sexual desire disorder in premenopausal women. J Wom Reprod Health 2015;in press.
  10. Pierson RC, Gordon SS, Haas DM. A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes. Obstet Gynecol 2014;124:515-9.
  11. Haas DM. Pharmacogenetics and individualizing drug treatment during pregnancy. Pharmacogenomics, 2014;15:69-78.
  12. Blue EK, DiGiuseppe R, Derr-Yellin E, Acosta JC, Mund JA, Case J, Haneline LS. Gestational Diabetes Induces Alterations in the Function of Neonatal Endothelial Colony Forming Cells. Pediatr Res. 2014, Feb;75(2):266-72.
  13. Blue EK, Ballman K, Boyle F, Oh E, Kono T, Quinney S.K., Thurmond DC, Evans-Molina C, Haneline LS. Fetal hyperglycemia and a high fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats. Pediatr Res. 2014 Nov 20. doi: 10.1038/pr.2014.185. [Epub ahead of print] PubMed PMID: 25412163
  14. Ren Z, Haneline LS, Introduction to Common Drugs Used in Pregnancy:an update from the Obstetric-Fetal Pharmacology Research Unit Network. Semin Perinatol.2014 Dec; 38(8):473-4.
  15. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD007892. DOI: 10.1002/14651858.CD007892.pub4
  16. Haas DM, Benjamin T, Sawyer R, Quinney SK. Short-term tocolytics for preterm delivery- current perspectives. Int J Women’s Health 2014;6:343-348.
  17. Falah N, Haas DM. Antenatal corticosteroid therapy: current strategies and identifying mediators and markers for response. Sem Perinat 2014;38:528-533.
  18. Levy KD, Decker BS, Carpenter JS, Flockhart DA, Dexter PR, Desta Z, Skaar TC. Prerequisites to Implementing a Pharmacogenomics Program in a Large Health-Care System. Clin Pharmacol Ther. 96:307-9, 2014.
  19. Pratt VM, Beyer BN, Koller DL, Skaar TC, Flockhart DA, Levy KD, Vance GH. Report of New Haplotype for ABCC2 Gene: rs17222723 and rs8187718 in cis. J Mol Diagn. 2014 Dec 29. [Epub ahead of print]
  20. Quinney S.K., Patil AS, Flockhart DA. Is personalized medicine achievable in obstetrics? Semin Perinatol. 2014 Oct 1. pii: S0146-0005(14)00105-0. doi: 10.1053/j.semperi.2014.08.017. [Epub ahead of print] Review. PubMed PMID: 25282474
  21. Starrick E, Bath N, Haas DM. Investigating the balance of reporting maternal and infant outcomes in pregnancy and childbirth Cochrane Reviews. Am J Perinat, 2014;31:689-694.
  22. Lehmann AS, Renbarger JL, McCormick CL, Topletz AR, Rouse C, Haas DM. Pharmacogenetic predictors of nausea and vomiting of pregnancy severity and response to antiemetic therapy: a pilot study. BMC Preg Childbirth 2013;13:132.
  23. Haas DM, Dantzer J, Lehmann AS, Philips S, Skaar TC, McCormick CL, Hebbring SJ, Jung J, Li L. The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration. Am J Obstet Gynecol, 2013;208:215.e1-6.
  24. Haas DM. Obstetric therapeutics- how pharmacogenetics may inform drug therapy for pregnant women in the future. OBGYN Surv, 2013;68:650-54.
  25. Costantine MM, Cleary K; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-53 (Corporate authorship for PREGMED faculty members: Haneline, Flockhart)
  26. Haas DM, Quinney SK, Clay JM, Renbarger JL, Hebert MF, Clark S, Umans JG, Caritis SN. Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic. Am J Perinat 2013;30:275-283.
  27. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev, 2013;1:CD007892.
  28. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: a systematic review and network meta-analysis. BMJ, 2012;344:e6226.
  29. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003511. DOI: 10.1002/14651858.CD003511.pub3.
  30. Wu HY, Karnik S, Subhadarshini A, Wang Z, Philips S, Han X, Chiang C, Liu L, Boustani M, Rocha LM, Quinney S.K., Flockhart D, Li L. An integrated pharmacokinetics ontology and corpus for text mining. BMC Bioinformatics. 2013 Feb 1;14:35. doi: 10.1186/1471-2105-14-35. PubMed PMID: 23374886; PubMed Central PMCID: PMC3571923
  31. Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod, VL, Skaar TC, Müller DJ, Gaedigk A, and Stingl JC. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clin Pharm Therap 93(5):402-8, 2013.
  32. Quinney SK, Mohamed AN, Hebert MF, Haas DM, Clark S, Umans JG, Caritis SN, Li L. A semi-mechanistic metabolism model of CYP3A substrates in pregnancy: predicting changes in midazolam and nifedipine pharmacokinetics. CPT: Pharmacomet System Pharm, 2012;1:e2 (epub ahead of print 9/26/2012)
  33. Haas DM, Lehmann AS, Skaar T, Philips S, McCormick CL, Beagle K, Hebbring SJ, Dantzer J, Li L, Jung J. The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use. Am J Obstet Gynecol, 2012;206:447.e17-24.
  34. Haas DM, D’Alton M. Pharmacogenetics and other reasons why drugs can fail in pregnancy: higher dose or different drug? Obstet Gynecol, 2012:120(5):1176-1179.
  35. Haas DM, Quinney SK, McCormick CL, Jones DR, Renbarger JL. A pilot study of the impact of genotype on nifedipine pharmacokinetics when used as a tocolytic. J Matern Fetal Neonatal Med 2012;25:419-23.
  36. McIntosh JJ, McHugh K, Haas DM. Difficulties in establishing routine amniocentesis for preterm labor evaluation. J Matern Fetal Neonatal Med 2012;25:313-314.
  37. Endicott S, Haas DM. The current state of therapeutic drug trials in pregnancy. Clin Pharmacol Ther 2012; 92(2):149-150.
  38. Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharm Therap 91:321-6, 2012. PMC3289963
  39. Philips S, Rae JM, Oesterreich S, Hayes DF, Stearns V, Henry NL, Storniolo AM, Flockhart DA, Skaar TC. Whole genome amplification of DNA for genotyping pharmacogenetics candidate genes. Frontiers in Pharmacogenetics and Pharmacogenomics.;3:54, 2012 PMC3315790
  40. Haas DM, Kirkpatrick P, McIntosh JJ, Caldwell DM. Assessing the quality of evidence for preterm labor tocolytic trials. J Matern Fetal Neonatal Med 2012;25(9)1646-52.
  41. Haas DM. From no to yes: the history and ethics of including pregnant women in clinical trials. Clin Inv 2011 1(10):1349-1351.
  42. Haas DM, Daum M, Skaar T, Philips S, Miracle D, Renbarger JL. Human breast milk as a source of deoxyribonucleic acid for amplification. J Clin Pharmacol, 2011;51:616-619 (epub ahead of print date 5/26/2010).
  43. Haas DM. Opioid exposure and birth defects. Am J Obstet Gynecol 2011;205:e8-e10.
  44. Egbelakin A, Ferguson MJ, Macgill EA, Lehmann AS, Topletz AR, Quinney S.K., Li L, McCammack KC, Hall SD, Renbarger JL. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011 Mar; 56(3):361-7. PMID 21072834
  45. Haas DM, Gallauresi B, Shields K, Zeitlin D, Clark SM, Hebert MF, Ren A, Nallani SC, Meslin EM, Feibus KB, Koren G, Goebel WS, Easterling T, Denne AC, Flockhart DA, Renbarger JL. Pharmacotherapy and pregnancy: highlights from the Third International Conference for Individualized Pharmacotherapy in Pregnancy. Clin Transl Sci 2011;4:204-209.
  46. Haas DM, Sischy AC, McCullough W, Simsiman AJ. Maternal ethnicity influences on neonatal respiratory outcomes after antenatal corticosteroid use for anticipated preterm delivery. J Matern Fetal Neonatal Med 2011;24:516-520.
  47. Acosta JC, Haas DM, Saha CK, Dimeglio LA, Ingram DA, Haneline LS. Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets. Am J Obstet Gynecol 2011;204:254.e8-e15.
  48. Lehmann, AS, Haas DM, McCormick CL, Skaar TC, Renbarger JL. Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs. Am J Obstet Gynecol 2011;204;362.e1-6.
  49. Haas DM. Preterm Birth. Clin Evid 2011:1404.
  50. Matthews A, Dowswell T, Haas DM, Doyle M, O'Mathuna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database of Systematic Reviews 2010, Issue 9.
  51. Haas DM, Weida J, Smith R, Abernathy MP. A comparison of depression symptoms and histories in pregnant women. J Reprod Med 2010;56:39-43.
  52. Haas DM, Pazouki F, Smith RR, Fry AM, Podzielinski I, Al-Darei SM, Golichowski AM. Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidities: a randomized controlled trial. Am J Obstet Gynecol 2010;202:310.e1-6.
  53. Haas DM, Al Darei SM, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for prevention of postoperative infections. Cochrane Database of Systematic Reviews, 2010, Issue 3.
  54. Kochhar K, Saywell RM, Zollinger TW, Mandzuk CA, Haas DM, Howell LK, Sevilla Martir JF, Reger MK. Herbal remedy use among Hispanic women and Hispanic women with a history of pregnancy or breast feeding: are physicians informed? Hisp Health Care Int 2010;8:93-106.
  55. Haas DM. Preterm birth. BMJ Clin Evid 2010;01:1404 (PCMID-19450293)
  56. Haas DM, Wunder K, Wolf JG, Denne SC. Women’s healthcare providers’ attitudes towards research in pregnancy. J Reprod Med 2010;55:108-144.

Note: There have been over 100 scientific presentations at meetings in the last 5 years as a Signature Center designee. The number of published abstracts from meeting presentations is too numerous to place in this report.

Current research focus areas

We continue to have a very active research portfolio, much of which is focused on pharmacotherapy in pregnancy and biomarker discovery and evaluation, potentially leading to novel therapeutic targets.

  • Preterm labor and preterm birth treatment and prevention
  • Antenatal corticosteroids
  • Nausea and vomiting in pregnancy
  • Pharmacotherapy of depression in pregnancy
  • Treatment of diabetes in pregnancy
  • Preeclampsia prevention
  • Pregnancy biobanking and subsequent biomarker and genetic evaluation
  • Environmental toxins and the impact on pregnancy and infant outcomes

Major activities

We completed the write-up of the Third International Conference for Individualized Pharmacotherapy in Pregnancy. Dr. Haneline was invited to guest edit a special edition of the journal Seminars in Perinatology on pregnancy pharmacology. Several of our PREGMED faculty members were authors of articles in this special edition of the journal. We have given multiple grand rounds and other invited talks and research presentations on the topic of maternal-fetal pharmacology. A few given by Dr. Haas, Center Director, are listed below:

Individualized pharmacotherapy in Pregnancy: science or science fiction St. Louis University School of Medicine Invited Grand Rounds 04/17/15
From bench to bedside: processes and pitfalls translating research findings into practice paradigms NIH Workshop: Placental Origins of adverse outcomes March 2015
Preterm labor- why we hand you babies too soon and what (if anything) we can do about it Pediatric Academic Society, 34th Midwest Conference on Perinatal Research 09/04/10
Preterm birth- why babies are born too soon and how we can stop it Decatur County Memorial Hospital
Invited Grand Rounds
Greensburg, IN
10/22/13
Betamethasone pharmacogenetics: Is individualized antenatal corticosteroid therapy on the horizon Neonatal Research Symposium, Indianapolis, IN 5/11/12
Exosomes in pregnancy: potential early windows for adverse pregnancy IUSM Division of Clinical Pharmacology Personalized Therapeutics Series Outcomes 8/5/14
Can statins be used in pregnancy to prevent recurrent preeclampsia IUSM Division of Clinical Pharmacology Personalized Therapeutics Series 11/27/12

Dr. Quinney has also presented the following:

Leveraging Literature and Clinical Data to Construct Pharmacokinetic Models of CYP3A Substrates:  Focus on Drug

Interactions and Effects of Pregnancy

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine

April 22, 2013

 

Exploring the Known and Unknown of Drug Metabolism in Pregnancy: The Utility of Pharmacokinetic Modeling

 

Butler University College of Pharmacy

 

November 12, 2012

 

Global analysis of CYP3A4 and CYP3A5 genotype on in vivo clearance of CYP3A substrates

 

American Society for Clinical Pharmacology and Therapeutics Annual Meeting

 

March 16, 2012

Another major accomplishment was the establishment of an OB/Clin Pharm Fellowship postdoctoral training program. Jointly funded by the OBGYN Department and the Division of Clinical Pharmacology, a fellowship program was started in 2012 specifically to train physicians and researchers in maternal-fetal pharmacology. Our 2nd fellow is currently in training. Our first fellow, Nadia Falah, graduated and went on for further training in a prominent Genetics Fellowship at University of Miami, FL. Our current fellow, Rebecca Pierson, is an OBGYN physician who is performing research in the pharmacogenetics of ovulation induction agents. Both have benefitted from the joint mentorship of several PREGMED faculty members, all of whom are intimately involved in the specific training of these fellows.

Of note, many of the publications listed above have co-authorship with residents, medical students, post-docs, and fellows, indicating the deep commitment of the PREGMED faculty members to train and mentor talented individuals at all levels in the field of individualized pharmacotherapy in pregnancy and maternal-fetal pharmacology research.

New external partnerships since designation was awarded

As part of the OPRU we have established new partnerships with Columbia University in New York (Pravastatin protocol), University of Utah and University of Alabama-Birmingham (GDM protocol). Our PREGMED activities have led to collaborative projects with researchers at Purdue (Dr. Casey- sleep disorders and lactogenesis; Drs. Kassab and Labarrere- placental inflammation and preeclampsia) and with industry innovators (NX Pharmagen, Louisville, KY- placental exosomes as predictors of preterm birth and adverse pregnancy outcomes; Analytical Biological Services, Inc- placental procurement for studies). We have been consulted by the FDA for potential with helping collaboratively build PBPK models for oseltamivir in pregnancy. We have initiated collaborative projects with the Asthma Pharmacogenetics researchers at Harvard (Boston) regarding betamethasone and fetal lung maturation therapy. We began collaboration with Dr. McEvoy at Oregon on an NIH-funded RCT of using vitamin C in smoking pregnant women to prevent newborn lung development abnormalities. We have also established key collaborations through our Building Blocks Pregnancy Biobank with pregnancy Biobank researchers at Washington University (St. Louis), Baylor University (Houston), Mt. Sinai (New York), and several other institutions as we lead the development of a comprehensive review and cataloging of pregnancy Biobank specimen availability for translational research internationally.

Key local partnerships since designation was awarded include:

  • Dr. Dukka & Prakasam (School of Dentistry)- placental microenvironment and adverse pregnancy outcomes
  • Dr. Buechler (Neonatology)- placental expression of TLR4 pathway in preterm infants
  • Dr. Parvez (Dept. of Environmental Health)- environmental toxicants in pregnancy and adverse outcomes
  • Dr. Winchester (Neonatology)- pesticides and adverse pregnancy outcomes
  • Dr. Reiter (OB/GYN)- placental epigenetics and the impact of smoking
  • Dr. Macy (School of Public Health)- smoking cessation strategies in pregnancy
  • Dr. Dexter (Regenstrief)- INGENIOUS study- embedding pharmacogenetics into clinical care
  • Dr. Tepper (Pediatric Pulmonology)- pregnancy interventions to promote fetal lung development in preeclamptic women
  • Dr. Kays (Cardiology)- carvedilol metabolism in pregnancy
  • Dr. Fadda (Butler University)- nifedipine absorption models

Impact of PREGMED

In recent years, there has been a groundswell of activity in the understudied area of maternal-fetal pharmacology. Much of this is driven by the activities and success of the OPRU and PREGMED’s role within it. At the 2015 Society for Maternal-Fetal Medicine Annual Meeting, there was an entire 2 day workshop co-sponsored by the NIH, FDA, and SMFM about medication therapy in pregnancy. Many OPRU members were invited speakers. In addition, an NIH RFA was released in 2013 directly related to development of therapeutic targets in pregnancy (PAR-13-389). To help support training in maternal-fetal pharmacology, the NIH released an RFA for specific T32 training programs in the field but with 3 years of applications, they only funded one center one time. However, due to the increased knowledge and critical mass that PREGMED has developed along with the other OPRU and research sites, this topic is being pushed to more of a national conversation within obstetrics and the high-risk community. The impact in the local research community is found within all of the collaborations that have grown from our research activities. We receive emails from investigators inside and outside of IUPUI seeking collaborations. Candidates for OBGYN residency and fellowship positions, as well as potential faculty recruits, frequently note the activities of PREGMED as being draws for their talent. Mentoring learners from high school students, college students, and graduate students, all the way to residents, post-docs, and others, has allowed PREGMED to truly sow seeds that will have a lasting impact in developing the knowledge of learners about this important field. Additionally, PREGMED faculty members have been key members in the CPIC guideline development for implementation of pharmacogenetics into clinical practice. Many of these drugs are used in pregnancy and these factors are incorporated into relevant guidelines. Pharmacometrics, as a distinct discipline from biostatistics/bioinformatics, has flourished on a broad scale as it has become woven into PREGMED activities. Dr. Bies has led the integration of pharmacometrics into pediatric therapeutics through the collaboration with Dr. Renbarger’s PREGMED work and Dr. Quinney has brought innovative pharmacokinetic modeling to the forefront in obstetrics. The activities since designation have continued to build critical mass and knowledge to bring the field forward and stimulate many collaborative research opportunities.

Other accomplishment not covered above

In development of our Building Blocks Pregnancy Biobank, we worked through the IUSM offices and developed a business model to assist with specimen distribution for research and for sustainability of the Biobank efforts. This has been key to several new collaborations listed above.

The IUPUI Signature Center PREGMED: The Indiana University Center for Pharmacogenetics and Therapeutics Research and Education in Maternal and Child Health continues to advance the fields of maternal-fetal and pediatric pharmacotherapy through innovative and productive collaborative research.

Indiana University School of Medicine
Department of Obstetrics and Gynecology
550 University Blvd
Indianapolis, IN 46202


obgyniu@iupui.edu

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