From Newborn Screening to Maternal Health

1. From Newborn Screening to Maternal Health Violanda Grigorescu, MD, MSPH Steven J. Korzeniewski, MA, MSc, Janice V. Bach, MS Division of Genomics, Perinatal Health and Chronic Disease Epidemiology 23rd Annual Michigan Healthy Mothers, Healthy Babies Conference, June 5th, 2008, Bay City, Michigan.

2. Objectives Describe the statewide Newborn screening and follow up (NBS) program (Korzeniewski) Understand the NBS program long term impact on strategies and standard of care as they relate to preconception care, maternal and perinatal health (Grigorescu) Describe the Michigan bio-storage project (Bach) Lead an interactive discussion of ways to improve maternal and child health via NBS follow-up and bio-storage in Michigan

3. Introduction to the Michigan Newborn Screening Follow-up Program Steven J. Korzeniewski Newborn Screening Epidemiologist, Division of Genomics, Perinatal Health and Chronic Disease Epidemiology

4. Making a difference - Newborn Screening (NBS) NBS Purpose: Early identification of health conditions followed by their subsequent timely treatment Potential Outcome of Screened Conditions: Brain/neurological damage, mental retardation, damage to the liver, eyes, spleen, stroke, death, and more if not detected early. NBS Program Components: Laboratory screening, follow-up, and medical management

5. Michigan Newborn Screening Overview 02/01/2009 PCP’s Medical Home Results Lookup EBC MCIR Positives early and unsats Endocrine Follow-up U of M 125,000 94 Hospitals MDCH NBS Laboratory Positives early and unsats MDCH NBS Follow-up Program POSITIVES Metabolic Follow-up CHM/Wayne State 600 58 Midwives Hemoglobinopathies Sickle Cell Association of Michigan/CHM negative reports Education/Training QA Reports Monitoring Cystic Fibrosis Follow-up U of M

6. Newborn Screening Follow up Follow up: Short-term follow up of all newborns with unsatisfactory/positive screening results Assures that diagnostic and medical management infrastructure is in place Documents long term follow up of diagnosed newborns Monitors the newborn screening process and provides quality assurance for all Michigan hospitals with newborn nursery Provides training and education for health care providers involved in the newborn screening process Engages parents in education and decision making Medical management: Assists laboratory in establishing analyte cut-offs Provides diagnostic algorithms and confirmatory diagnoses for all newborns with positive screening results Assures that all diagnosed newborns receive appropriate medical management services and long-term follow up

7. NBS Follow Up Program Follow-upof positive specimens Follow-up of unsat and early Education – Primarily Hospital staff Pediatrician and Family Practice Physicians Monitoring Hospitals and Midwives Assuring and Monitoring Medical Management contracts with University of Michigan, Children’s Hospital of Michigan and Sickle Cell Association of Michigan Medical Home in collaboration with other programs Other New Initiatives: Hospital Coordinators Network, Parents Network

8. Table 1: Disorders Included in the Newborn Screening Panel, Michigan, 2007 Table 1: Disorders Included in the Newborn Screening Panel, Michigan, 2007 *Hearing screening was added to the NBS panel in 2007; however, because hearing screening is conducted by the Early Hearing Detection and Intervention (EHDI) program, this report will not focus on hearing screening.

9. Michigan Newborn Screening Milestones • 1960s: Bacterial inhibition assay to diagnose phenlyketonuria (PKU) • 1965: NBS for PKU to Michigan • 1977: Congenital hypothyroidism (CH) was added to the NBS panel • 1985: Galactosemia screening was initiated. • 1987: Public Health Act 14 of 1987 mandated further expansion • biotinidase deficiency, maple syrup urine disease (MSUD), and hemoglobinopathies such as sickle cell disease were added, • State laboratory was designated as the sole testing site, mandated a fee to fund the program, and added comprehensive programs for follow-up, medical management, and quality assurance. • 1993: Congenital adrenal hyperplasia (CAH) was added to the screening panel • 2003: Tandem mass spectrometry (TMS) was introduced enabling screening for a large number of disorders detectable from a single blood spot. • 2004: NBS screening panel expanded to include three other amino acid disorders: homocystinuria (HCY), citrullinemia (CIT) and argininosuccinic aciduria (ASA). • 2005: Pilot project was initiated to expand the screening panel to 48 disorders by adding the additional TMS disorders recommended by the American College of Medical Genetics (ACMG) and the March of Dimes. • February 23, 2006, SB 794 was passed and amended Public Act 368 of 1978 by adding sections 5430 and 5432 creating a ten-member Newborn Screening Quality Assurance Advisory Committee • October 1, 2007: Screening for Cystic Fibrosis began, thus meeting another recommendation of the ACMG.

10. Disorders Identified via Newborn Screening, Michigan Residents, 1965-2006 *Note: Denominators, the number of live births eligible to have een screened, are calculated from the year screening began onward; thus, if screening commenced other than at the start of the year the denominator will be slightly larger than the true denominator. Galactosemia includes both classical cases and Duarte varients (DG) since 2004. Biotinidase Deficiency includes both partial and profound biotinidase deficiency.

11. Newborn Screening and Maternal & Perinatal Health Violanda Grigorescu, MD, MSPH, State MCH Epidemiologist, Director, Division of Genomics, Perinatal Health and Chronic Disease Epidemiology

12. Maternal morbidity May relates to a pre-existing medical condition that affects or is exacerbated by pregnancy, or a pregnancy-related medical condition An emerging issue that needs to be further explored Is not very well understood, less frequently measured and more difficult to track at the population level than maternal mortality

13. Why it matters? Women comprise over half of the US population They live longer than men but have high rates of morbidity and thus the need for health services is much greater Women are the major health care decision-makers in their families The Life span concept of women’s health

14. Phenylketonuria (PKU) • A genetic disorder characterized by an inability of the body to utilize the essential amino acid, phenylalanine • Most common- Classic PKU: the enzyme that breaks down phenylalanine phenylalanine hydroxylase, is completely or nearly completely deficient. This enzyme normally converts phenylalanine to another amino acid, tyrosine. Without this enzyme, phenylalanine and its' breakdown chemicals from other enzyme routes, accumulate in the blood and body tissues. • The term 'hyperphenylalaninemia' strictly means elevated blood phenylalanine, but used to describe a group of disorders other than classic PKU caused by a partial deficiency of the phenylalanine breakdown enzyme or the lack of another enzyme important to the processing of this amino acid. • A normal blood phenylalanine level is about 1 mg/dl. In classic PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. • Chronically high levels of phenylalanine and some of its breakdown products can cause significant brain damage.

15. PKU-Cause and symptoms • PKU and the other causes of hyperphenylalaninemia are inherited in a recessive fashion: an affected person inherited two traits for the disorder (e.s., one from each parent). • A person with one trait for the disorder, is called a 'carrier' for PKU. Carriers do not have symptoms of the disorder. • Infants with PKU appear normal at birth. Many have blue eyes and fairer hair and skin than other family members. • Currently, most symptoms of untreated PKU are avoided by newborn screening, early identification, and management.

16. PKU-Treatment • The goal of PKU treatment is to maintain the blood level of phenylalanine between 2 and 10 mg/dl. • Some phenylalanine is needed for normal growth so the diet that has some phenylalanine but in much lower amounts than normal. • Maintaining phenylalanine blood levels in the recommended range maximizes the ability of individuals with PKU to reach their potential for normal development and lifespan. • Women with PKU who are of child bearing age, must closely adhere to the low- phenylalanine diet and monitor phenylalanine levels before conception and throughout pregnancy. • The risk of spontaneous abortion, mental retardation, microcephaly, and/or congenital heart disease in the child is high if mother's blood phenylalanine is poorly controlled.

17. Maternal PKU (MPKU) syndrome • Occurs when females with PKU do not adhere to strict dietary treatment • The teratogenic effects of elevated maternal blood phenylalanine on the developing fetus could result in cognitive and physical problems (i.e., congenital heart defects, microcephaly, dysmorphic facial features, mental retardation)

18. Emerging needs for prevention efforts targeted to women with PKU: 1/ adherence to dietary treatment; 2/ continued education about the risks for offspring; 3/ continued and careful health status assessment prior to conception, during pregnancy and after delivery

19. Our retrospective study Data source • Clinical database of PKU patients born between 1965 and 1992 and treated at the Metabolic Medical Management Center was used for this study. Study design • The incomplete information on Phe levels limited our ability to compare pregnancy outcomes in diet-controlled PKU versus non-controlled by using the retrospective cohort design. • Univariate and bivariate analyses were conducted instead, as permitted by the data available.

20. Results • There were 350 PKU cases diagnosed in Michigan between 1965 and 1992; 169 (48%) were women • Information was found on 54 (31.9%) women that had 91 pregnancies. Distribution by type of PKU

21. Pregnancy outcomes • Less than one third (28; 30.8%) of pregnancies ended in abortions (12 therapeutic and 16 spontaneous) and 63 (69.2%) in live births. Live births outcomes by type of PKU

22. Conclusion • The expansion of Newborn Screening panel was not mirrored by the development of corresponding long term follow up strategies and standards of care • This was due in part to the limited number of professionals with corresponding training and understanding of the specifics of each hereditary condition identified through Newborn Screening

23. Further steps As those diagnosed through this program become adults, we are challenged to: 1/ include preconception and interconception health assessment within Newborn Screening long-term follow up strategies and standards of care 2/ continue to educate providers about the life time health challenges/needs of those diagnosed through Newborn Screening

24. Michigan Neonatal Bio-Trust Project Janice V. Bach, MS, Genomics Unit Manager, Division of Genomics, Perinatal Health and Chronic Disease Epidemiology

25. What is a dried blood spot (DBS)? • The newborn screening samples on the filter paper card are often referred to as “dried blood spots”

26. Are blood spots ever left over after testing? • Most babies have normal results, so one or two spots often remain unused • Five spots are collected to be sure there is enough blood to test for all the different disorders • In case of a positive test, the lab can double check the result with the extra spots • In case one spot is damaged or cannot be used, all the tests can still be done without needing to draw baby’s blood again

27. What happens to the dried blood spots after screening is finished? • The filter paper cards are stored by the state public health laboratory • Good laboratory practice requires that samples be kept for a period of time after testing is done • Michigan Attorney General opinion to keep at least 21 ½ years • 1999 Governor’s task force recommended retaining indefinitely • Over 3 million samples dating back to 1984 are currently stored

28. Are blood spots used for anything else after NBS? State laboratory may use anonymous samples Develop new NBS tests Check that screening equipment works properly Investigate infectious disease outbreaks or epidemics Parents may request their own child’s sample Diagnose a disease after the child has died Participate in a research study Assist in missing child investigation State law allows use of leftover samples for medical research Identifiable information is removed so there is no way to know which DBS have been used

29. Is there oversight of how dried blood spots are used for research? Research requests reviewed by Newborn Screening Laboratory Director Approved by Bureau of Laboratories Director Reviewed and approved by MDCH Institutional Review Board (IRB) to assure human subjects protection before any DBS are released

30. Why use dried blood spots for health-related research? May lead to new screening tests May provide clues about factors that impact health or cause diseases not only in Michigan but worldwide Contain genetic information and other biological markers May contain evidence of exposure to environmental agents such as infections, toxins or chemicals Can study large numbers of people without collecting new samples DBS samples no longer needed

31. What kind of research has been done? To date, only a few research studies have used dried blood spots from Michigan babies Examples: Laboratory improvement: Investigation of additional screening methods (sickle cell diseases) Public health research: Incidence of gene variants for an inherited condition that leads to iron overload (hereditary hemochromatosis) Medical research: Search for new markers to predict disease (childhood leukemia)

32. What if a parent does not want a child’s DBS sample used for research? Parents may request that their child’s sample be destroyed after newborn screening is completed Sample is incinerated by lab personnel in presence of lab manager as a witness Call the Newborn Screening Program for more information at 1-866-673-9939

33. What is the Michigan Neonatal BioTrust project? Make the DBS more useful for medical and public health research Store under conditions that better preserve samples Let researchers know samples are available

34. Why now? Advances in technology make DBS samples more useful than in the past Increasing national and international interest in research using DBS and other stored biological samples

35. Who will be in charge? Michigan Department of Community Health would continue to manage the stored DBS samples, holding them “in trust” for future research Scientific and ethical review boards appointed to oversee operations and review research requests Members from major state universities, research institutions, disease organizations, community groups and general public All proposals reviewed and approved by MDCH, IRB to assure human subjects protection before DBS are released

36. What kind of research will be allowed? Guiding principle is to promote research that benefits the public’s health Not possible to anticipate precisely what studies will be possible as technology advances Medical Public health

37. Why use DBS? *Hypothetical, for illustration purposes only The state health agency is concerned about a high rate of cancer that is affecting young people in a certain region of the state. Citizens think it may be caused by a chemical in the drinking water. DBS from babies whose mothers lived in the region are checked for the chemical to determine how many people were exposed, and over what period of time.

38. Why use DBS? The levels of the chemical are studied in DBS from young people with certain kinds of cancer reported to the state cancer registry. The DBS are then compared with control groups to determine whether early exposure to the chemical may be a factor in the cancer cluster occurring in the region. *Hypothetical, for illustration purposes only

39. Why use DBS?*Hypothetical, for illustration purposes only Prematurity is a major public health problem. A researcher thinks certain genes may make a baby more likely to be born too soon. The researcher requests several thousand blood spots from two groups: Babies with low birth weight that were born prematurely Babies of normal weight that were born at term The researcher compares the DNA from these two groups of babies.

40. Why use DBS? The researcher finds a change in a gene (shown in red) that is much more common in premature babies than full-term babies. Five years later, after additional studies confirm these results, a screening test to detect the gene variant in pregnant mothers is developed. Mothers who carry the gene receive special monitoring during pregnancy. Fewer premature babies are born. *Hypothetical, for illustration purposes only Full-term babies Premature babies

41. What are the next steps? Obtain input from Michigan citizens Incorporate results from community feedback into operations plan and guiding principles for acceptable research uses

42. Acknowledgments William Young, PhD - Newborn Screening Follow Up Program Manager Karen Andruszewski - Departmental Specialist, Newborn Screening Follow Up Program