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
PCPs 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
POSITIVES
MDCH NBS Follow-up Program
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-up of 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, Childrens
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
Phenylketonuria (PKU) Maple syrup disease (MSUD) Short-chain acyl-CoA dehydrogenase deficiency (SCAD) Isovaleric acidemia (IVA)
Benign hyperphenylalaninemia (H-PHE) Homocystinuria (HCY) Glutaric acidemia type II (GA II) 2-Methyl butyryrl-CoA dehydrogenase deficiency (2MBG)
Biopterin cofactor biosynthesis (BIOPT (BS)) Hypermethioninemia (MET) Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)
Defects of biopterin cofactor regeneration (BIOPT(Reg)) Citrullinemia (CIT) Long-chain L-3-OH acyl-CoA dehydrogenase deficiency (LCHAD) 3-OH 3-CH3 glutaric aciduria (HMG)
Carnitineacylcarnitine translocase deficiency (CACT) Citrullinemia Type II (CIT II) Trifunctional protein deficiency (LCHAD/TFP) 3-Methylglutaconic aciduria (3MGA)
Carnitine palmitoyltransferase II deficiency (CPT II) Argininosuccinic acidemia (ASA) Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) Beta-ketothiolase deficiency (BKT)
Carnitine uptake defect (CUD) Tyrosinemia Type I (TYR I) Medium-chain ketoacyl-CoA thiolase deficiency (MCKAT) Glutaric acidemia type I (GA I)
Carnitine palmitoyltransferase IA deficiency (liver) (CPT 1A) Argininemia (ARG) Congenital adrenal hyperplasia (CAH) Hb S/C Disease (Hb S/C)
Propionic acidemia (PA) Malonic acidemia (MAL) Congenital hypothyroidism (CH) Hb S/Beta-thalassemia (Hb S/Beta-Th)
Methylmalonic acidemia (mutase deficiency) (MUT) Isobutyryl-CoA dehydrogenase deficiency (IBG) Galactosemia (GALT) Sickle cell anemia (Hb SS)
Methylmalonic acidemia (Cbl A,B) M Methylmalonic acidemia (Cbl C,D) MA Multiple carboxylase deficiency (MCD) Biotinidase deficiency (BIOT)
2-Methyl 3 hydroxy butyric aciduria (2M3HBA) 2-Methyl 3 hydroxy butyric aciduria (2M3HBA) Hearing Hearing
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
Type of Disorder Classification (Year Screening Began) Cases in 2006 (N) Cases Through 2006 (N) Cumulative Detection Rate
Galactosemia (1985) 11 116 1 24,850
Biotinidase Deficiencies (1987) 20 148 1 16,928
Amino Acid Disorders (1965) 16 590 1 9,901
Organic Acid Disorders (2005) 8 10 1 12,752
Fatty Acid Oxidation Disorders (2003) 11 39 1 9,951
Congenital Hypothyroidism (1987) 59 1,394 1 1,870
Congenital Adrenal Hyperplasias (1993) 3 103 1 16,819
Hemoglobinopathies (1987) 63 1,336 1 1,951
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 womens 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 babys 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 Governors 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 childs 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 childs DBS
sample used for research?

• Parents may request that their childs 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 publics 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

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