Faculty Profile: James Haddow, M.D.

James Haddow, M.D.
Professor of Pathology & Laboratory Medicine (Research)
Pathology & Laboratory Medicine
Work: +1 401-453-7650
Dr. Haddow's interests focus on translating clinical research into practice, specifically in the areas of medical screening and public health. Beginning in 1974, his work led to the introduction of the first statewide screening program for detecting neural tube defects prenatally. This expanded to include detection of Down syndrome in 1985, along with several other serious medical disorders. In 1999, he reported a landmark study on maternal thyroid deficiency during pregnancy and its effects on the baby's brain. His recent interests include screening adults for serious medical problems, such as hereditary breast cancer and thyroid insufficiency.

Biography

Dr. Haddow earned a B.A. degree from Harvard in 1957 and an M.D. degree from Tufts University School of Medicine in 1961. He completed a rotating internship at Maine Medical Center in 1962 and a residency in Pediatrics at Boston City Hospital (BCH) in 1964. From 1964 to 1966, he served in the United States Army as a Pediatrician at Fort Campbell, Kentucky, and from 1966 to 1967 he had a fellowship in Pediatric Metabolism and Endocrinology at BCH. From 1967 to 1974, he was an Assistant Director of the Pediatric Clinical Center and Director of Pediatric Endocrinology at BCH. In 1974, he moved to Maine to take a position with the Rheumatic Disease Laboratory at the Maine Medical Center. In that position, he became interested in the discipline of medical screening, initially in the specific area of prenatal screening. In the following years, at the Foundation for Blood Research, he established an internationally recognized research program in prenatal screening and extended his interests to include other areas of medical screening, such as hemochromatosis, thyroid deficiency, and breast cancer. He is now the Co-Director of the Division of Medical Screening and Special Testing at Women & Infants Hospital of Rhode Island. He has written numerous chapters for medical texts and hundreds of scientific papers published in peer-reviewed journals. He is recognized as one of the world's experts in translating research into clinical practice in the area of medical screening.

Research Description

Dr. Haddow's research focuses in the general area of medical screening, with ongoing emphasis on prenatal screening for serious fetal and maternal disorders. This work, by definition, falls under the heading of "clinical" or "applied" research and relies on promising discoveries at the basic science level, which are ready to be taken into a translational phase and assessed for feasibility in everyday practice. This interest began in the mid-1970s, when the first biochemical marker (alpha-fetoprotein) for detecting a serious fetal disorder (open spina bifida) was discovered by David Brock, in Edinburgh. Initially, measurement of alpha-fetoprotein was limited to amniotic fluid and could only be justified when a woman had experienced a previous pregnancy with spina bifida, or a related neural tube defect, such as anencephaly. This seriously restricted the application of this important discovery, because fewer than 5% of spina bifida cases delivered in a given year were to women known to be at high risk. A second follow-up discovery by Brock, in collaboration with Nicholas Wald, demonstrated that alpha-fetoprotein levels were also elevated in maternal serum during the second trimester in the presence of fetal open spina bifida. These levels were not as clearly separated from those of unaffected pregnancies as in amniotic fluid, however, meaning that maternal serum might be suitable for screening, but not diagnostic, purposes. A 19-center collaborative study was then begun in the U.K. to test the feasibility of this new screening process, and several investigators in the U.S., including Dr. Haddow, began to explore how this type of screening process might be made to work in a decentralized health care system. This early work on both sides of the Atlantic led to initiating the era of prenatal screening, which now extends to include detection of a number of other serious fetal disorders (most notably, Down syndrome) and has substantially reduced the birth prevalence of these conditions.

As a first step, it was necessary for Dr. Haddow to develop reagents for measuring alpha-fetoprotein (AFP), because none were available at that time from commercial sources. This included isolating and purifying AFP from cord blood, producing antibodies to the isolate in an animal source, setting up a double-antibody assay using radioactive tracers, and establishing reference ranges. Once the assay was in place, it became possible to design a model system for introducing the testing process via primary care physician offices throughout the state of Maine. This was the first statewide pilot prenatal screening project in the U.S. and contained the prototype materials and protocols that are now a standard component of prenatal screening programs. A major feature of the project's design was the outreach connection between laboratory and clinician, in which the laboratory provided informational materials for both health professionals and patients, included both interpretations and recommended actions on the laboratory report, and served as a central resource to answer questions arising at the office level. The success of this design served as an example for others who considered introducing screening in the U.S. and demonstrated that prenatal screening could be successfully applied in a decentralized healthcare system. Three international conferences were organized by Dr. Haddow (1977, 1978, 1980) to bring together scientists, policy makers, reagents industry representatives, third party payers, patient advocates, and government agencies to examine the progress and potential of this rapidly emerging technology.

All of Dr. Haddow's subsequent research is built upon this background, and selected examples follow:

  1. Studies involving smoking in pregnancy—Dr. Haddow and colleagues became interested in the potential of using cotinine measurements to assess pregnant women's exposure to tobacco smoke. Once again, it was necessary to construct an assay for cotinine and then apply it to serum samples from a cohort of women in the second trimester. We confirmed the association between smoking and adverse outcomes, such as low birth weight, and then carried out a randomized intervention trial, using cotinine as the basis for persuading women to stop smoking. This study was superimposed on our statewide screening program for spina bifida.

  2. New biochemical markers to improve screening for Down syndrome—As collaborators with Jack Canick and Nicholas Wald, we reported the discovery of unconjugated estriol as a new screening marker for Down syndrome and demonstrated that it could be successfully combined with two other markers to substantially improve screening performance. A subsequent intervention trial by us in Maine and Rhode Island demonstrated its feasibility in practice.

  3. Impact of maternal thyroid deficiency on fetal brain development—Using sera stored in the freezer from a cohort of screened pregnancies, we retrospectively identified women with thyroid deficiency during pregnancy and tested their offspring at age eight years, documenting that untreated maternal thyroid deficiency was associated with lower I.Q.

  4. A new methodology for evaluating genetic tests—As an extension of our ongoing interest in new test application, we designed a new assessment tool for DNA tests, called ACCE (Analytic Validity, Clinical Validity, Clinical Utility, and ELSI). This tool has now been applied to several candidate screening tests outside of the prenatal screening area.

Grants and Awards

Visiting Scientist, 1985
Department of Environmental and Preventive Medicine
Medical College of St. Bartholomew's Hospital
London, England

Libra Distinguished Professor, 1997-1998
In Applied Immunology,
University of Southern Maine

Honorary Research Fellow, 2004-present
Wolfson Institute of Preventive Medicine
London, England

Affiliations

1974-present Society for Pediatric Research
1974–1980 Maine Chapter, American Academy of Pediatrics
1978-1997 New England Regional Genetics Group, Member
Steering Committee, Member, 1979-1997
1978 Maine Association for Human Genetics—Vice President
1979 Maine Association for Human Genetics—President
1991-1995 New England Pediatric Society
1997-present American College of Medical Genetics
2001-present Medical Screening Society; founding co-director

Funded Research

Project Title: "Reducing Mercury Toxicity with Spironolactone"
Funding Agency: Hood Foundation
Funding Amount: $25,000
Dates: 1970-1971
PI: James E. Haddow, M.D.

Project Title: "Counseling and Testing for Neural Tube Defects"
Funding Agency: Developmental Disabilities Council, State of Maine
Funding Amount: $36,000
Dates: 10/1976-9/1980
PI: James E. Haddow, M.D.

Project Title: "Intervention to Reduce Smoking during Pregnancy"
Funding Agency: National Institute of Child Health and Human Development, NIH
Funding Amount: $333,833
Dates: 2/1/1984–1/31/1988
PI: James E. Haddow, M.D.

Project Title: "Prenatal Screening to Reduce Amniocentesis over Age 35"
Funding Agency: Maternal/Child Health Bureau, U.S. Department of Health and Human Services
Funding Amount: $904,473
Dates: 6/1/1990-5/31/1992
PI: James E. Haddow, M.D.

Project Title: "First Trimester Prenatal Screening for Down Syndrome"
Funding Agency: National Institute of Child Health and Human Development, NIH
Funding Amount: $1,010,525
Dates: 12/1/1993-11/30/1996
PI: James E. Haddow, M.D.

Project Title: "DNA and Biochemical Markers of Hemochromatosis"
Funding Agency: Davis Family Foundation
Funding Amount: $12,500
Dates: 1997
PI: James Haddow, M.D.

Project Title: "Development of Guidelines for Validation of Genetic Tests"
Funding Agency: Massachusetts Health Research Institute (MHRI)
Funding Amount: $17,194
Dates: 10/1/1996-9/30/1997
PI: James Haddow, M.D.

Project Title: "Is Maternal Hypothyroidism Associated with Low IQ in Offspring?"
Funding Agency: Thrasher Research Fund
Funding Amount: $100,835
Dates: 10/1/1995–9/30/1997
PI: James E. Haddow, M.D.

Project Title: "Is Maternal Hypothyroidism Associated with Low IQ in Offspring?"
Funding Agency: Knoll Pharmaceutical Company
Funding Amount: $100,000
Dates: 10/1/1995-9/30/1997
PI: James E. Haddow, M.D.

Project Title: "Is Maternal Hypothyroidism Associated with Low IQ in Offspring?"
Funding Agency: Knoll Pharmaceutical Company
Funding Amount: $12,650
Dates: 1997
PI: James E. Haddow, M.D.

Project Title: "Delivery of Genetic Services in Maine—Enhancing the Role of PCP"
Funding Agency: Maternal/Child Health Bureau, U.S. Department of Health and Human Services
Funding Amount: $392,000
Dates: 10/1/1994-9/30/1997
PI: James E. Haddow, M.D.

Project Title: "Epidemiologic Approach to EHS in High School Biology"
Funding Agency: National Center for Research Resources, NIH
Funding Amount: $328,672
Dates: 10/1/1997-9/30/2000
PI: James E. Haddow, M.D.

Project Title: "Developing Processes for Evaluating DNA Tests"
Funding Agency: Centers for Disease Control and Prevention
Funding Amount: $766,134
Dates: 9/30/2000-9/29/2004
PI: James E. Haddow, M.D.

Project Title: "Hepatocellular Carcinoma and Hemochromatosis"
Funding Agency: Centers for Disease Control and Prevention
Funding Amount: $63,500
Dates: 2003
PI: James E. Haddow

Project Title: "Are IQs Low in Offspring of Euthyroid Women with Low T4?"
Funding Agency: National Institute of Child Health and Human Development, NIH
Funding Amount: $1,194,750
Dates: 2/1/2004-1/31/2009
PI: James E. Haddow, M.D.

Project Title: "Feasibility of Prenatal Screening for SLO Syndrome"
Funding Agency: National Institute of Child Health and Human Development, NIH
Funding Amount: $4,392,769
Dates: 4/1/2000-3/31/2005
PI: James E. Haddow, M.D.