From newborn screening to preconception care:

1
From newborn screening to preconception care
PKU mothers and their offspring
Violanda Grigorescu, MD, MSPH, William Young,
PhD, Karen Andruszewski, MA, Steve Korzeniewski,
MS, MA Michigan Department of Community Health,
Division of Genomics, Perinatal Health and
Chronic Disease Epidemiology
Table 1 Disorders Included in the Newborn
Screening Panel
Michigan, 2006
Results There were 350 PKU cases diagnosed in
Michigan between 1965 and 1992, 169 (48) were
women. Information was found on 54 women that had
91 pregnancies. Table 2 Distribution by type of
PKU Pregnancy outcomes Less than one third
(28 30.8) of the pregnancies ended in abortions
(12 therapeutic and 16 spontaneous) and 63
(69.2) in live births. Table 3 Live births
outcomes by type of PKU In total, nearly
one-fourth of the newborns suffered microcephaly
among mothers with classic PKU the proportion of
newborns with microcephaly was much greater
(57.1). However, the proportion of newborns
identified with microcephaly is likely
under-reported in our study given that no
information on pregnancy outcome could be found
for 30 of the PKU mothers.

Lesson learned
The Starfish Story
Once
upon a time, there was a wise man who used to go
to the
ocean to do his writing. He had a habit of
walking on the beach
before he began his work. One
day, as he was walking along the
shore, he looked
down the beach and saw a human figure moving
like a
dancer. He smiled to himself at the thought of
someone
who would dance to the day, and so, he
walked faster to catch up. As he got closer, he
noticed that the figure was that of a young man,
and that what he was doing was not dancing at
all. The young man was reaching down to the
shore, picking up small objects, and throwing
them into the ocean. He came closer still and
called out "Good morning! May I ask what it is
that you are doing?" The young man paused, looked
up, and replied "Throwing starfish into the
ocean." "I must ask, then, why are you throwing
starfish into the ocean?" asked the somewhat
startled wise man. To this, the young man
replied, "The sun is up and the tide is going
out. If I don't throw them in, they'll
die. Upon hearing this, the wise man commented,
"But, young man, do you not realize that there
are miles and miles of beach and there are
starfish all along every mile? You can't possibly
make a difference! At this, the young man bent
down, picked up yet another starfish, and threw
it into the ocean. As it met the water, he said,
"It made a difference for that one." Adapted
from The Star Thrower by Loren Eiseley (1907
1977) Michigans Newborn Screening Update,
Winter 2007

Background Newborn screening (NBS) is a process
of early identification of health conditions
followed by their subsequent timely treatment
before the onset of disease processes thereby
minimizing the risk of long-term sequelae.
Depending on the condition, potential outcomes of
disorders included in the NBS panel include but
are not limited to brain/neurological damage,
mental retardation, damage to the liver, eyes,
spleen, stroke, or death if not detected early.
To prevent such outcomes from occurring, NBS
programs test blood spots collected from infants
during the first few days of life for signs of
treatable disorders. Michigan Newborn Screening
Milestones - 1960s Dr. Robert Gutherie
developed the bacterial inhibition assay to
diagnose phenlyketonuria (PKU) by determining the
level of the amino acid phenylalanine in a drop
of a babys blood placed on a strip of filter
paper. - 1965 Dr. Stanley Read at the Michigan
Department of Public Health and Dr. Richard Allen
at the University of Michigan introduced NBS for
PKU to Michigan - 1977 a test for congenital
hypothyroidism (CH) was added to the NBS panel
- 1985 screening for galactosemia was
initiated. - 1987 The Public Act 14 of 1987
mandated further expansion of screening with the
addition of three disorders, biotinidase
deficiency, maple syrup urine disease (MSUD), and
hemoglobinopathies such as sickle cell disease.
The act also designated the state laboratory 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 and thus enabled the state
laboratory to efficiently screen for a large
number of disorders detectable from a single
blood spot. The first was medium chain acyl CoA
dehydrogenase deficiency (MCAD), a disorder of
fatty acid oxidation that can result in sudden
death during periods of fasting. - 2004
Further expansion of the NBS screening panel to
include three other amino acid disorders
homocystinuria (HCY), citrullinemia (CIT) and
argininosuccinic aciduria (ASA). - 2005 a
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. - October 1, 2007
Screening for Cystic Fibrosis began, thus meeting
another recommendation of the ACMG. ( Detailed
information about the disorders in the screening
panel, confirmation of diagnoses, and follow-up
of positive tests including algorithms can be
found in the NBS Procedure Manual available at
www.michigan.gov/newbornscreening
) Phenylketonuria (PKU) is known as a genetic
disorder that results in severe mental
retardation if not identified and treated quickly
with a diet low in phenylalanine (Phe)
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 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.
Phenylketonuria (PKU) Isovaleric acidemia (IVA)
Benign hyperphenylalaninemia (H-PHE) 2-Methyl butyryrl-CoA dehydrogenase deficiency (2MBG)
Biopterin cofactor biosynthesis (BIOPT (BS)) 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)
Defects of biopterin cofactor regeneration (BIOPT(Reg)) 3-OH 3-CH3 glutaric aciduria (HMG)
Maple syrup disease (MSUD) 3-Methylglutaconic aciduria (3MGA)
Homocystinuria (HCY) Beta-ketothiolase deficiency (BKT)
Hypermethioninemia (MET) Glutaric acidemia type I (GA I)
Citrullinemia (CIT) Propionic acidemia (PA)
Citrullinemia Type II (CIT II) Methylmalonic acidemia (mutase deficiency) (MUT)
Argininosuccinic acidemia (ASA) Methylmalonic acidemia (Cbl A,B) MA
Tyrosinemia Type I (TYR I) Methylmalonic acidemia (Cbl C,D) MA
Argininemia (ARG) Multiple carboxylase deficiency (MCD)
Carnitineacylcarnitine translocase deficiency (CACT) 2-Methyl 3 hydroxy butyric aciduria (2M3HBA)
Carnitine palmitoyltransferase II deficiency (CPT II) Malonic acidemia (MAL)
Carnitine uptake defect (CUD) Isobutyryl-CoA dehydrogenase deficiency (IBG)
Carnitine palmitoyltransferase IA deficiency (liver) (CPT 1A) Congenital adrenal hyperplasia (CAH)
Short-chain acyl-CoA dehydrogenase deficiency (SCAD) Congenital hypothyroidism (CH)
Glutaric acidemia type II (GA II) Galactosemia (GALT)
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) Biotinidase deficiency (BIOT)
Long-chain L-3-OH acyl-CoA dehydrogenase deficiency (LCHAD) Sickle cell anemia (Hb SS)
Trifunctional protein deficiency (LCHAD/TFP) Hb S/C Disease (Hb S/C)
Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) Hb S/Beta-thalassemia (Hb S/Beta-Th)
Medium-chain ketoacyl-CoA thiolase deficiency (MCKAT)
Classic PKU Mild PKU Hyperphe Total
Women 25 46.3 13 24.1 16 29.6 54
Pregnancies 34 37.4 27 29.7 30 33.0 91
Classic PKU Mild PKU Hyperphe Total
Normal 5 17.9 9 32.1 14 50.0 28
Microcephaly 8 57.1 4 28.6 2 14.3 14
No info. found 7 36.8 5 26.3 7 36.8 19
PKU affected 0 0 0 0 2 100.0 2
Abstract Background Phenylketonuria (PKU) is
known as a genetic disorder that results in
severe mental retardation if not identified and
treated quickly with a diet low in phenylalanine
(Phe). Michigan as well as most other states,
initiated PKU screening in the 1960's. About
twenty years later, some of the children born to
females with PKU, in the U.S. and other
countries, presented with a myriad of cognitive
and physical problems (i.e., congenital heart
defects, microcephaly, dysmorphic facial
features, mental retardation) due to the
teratogenic effects of elevated maternal blood
phenylalanine on the developing fetus. This is
known as the Maternal PKU (MPKU) syndrome that
occurs when females with PKU do not adhere to
strict dietary treatment. Assessing the health
status of women with PKU is needed prior to
conception. Objective To understand the long
term implications of NBS program and the impact
on strategies and standard of care as they relate
to preconceptional health. Methods The clinical
database of PKU patients born between 1965 and
1992 and treated at the Metabolic Medical
Management Center was used for this study. 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 available data. Results There
were 350 PKU cases diagnosed in Michigan between
1965 and 1992, 169 (48) were women . Information
was found on 54 women that had 91 pregnancies. Of
91 pregnancies, 37 (34) were to 25 women (46.3
of 54) having classic PKU, 29.7 (27) to women
with a mild form (13 women 24.1 of 54) and 33
(30) to those having Hyperphe (16 women 29.6 of
54). Less than one third (28 30.8) ended in
abortions (12 therapeutic and 16 spontaneous) and
63 (69.2) in live births. Twenty-eight offspring
were reported as normal at birth (44.4) and
nearly one in four (22.2) as having
microcephaly. No information was found on more
than half. Public Health Implications As those
diagnosed through this program become adults,
public health professionals are challenged to
include preconception assessment within NBS
long-term follow up strategies and standards of
care.
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. Public
Health Implications As those diagnosed through
this program become adults, public health
professionals are challenged to 1/include
preconception and interconception health
assessment within Newborn Screening long-term
follow up strategies and standards of care
2/educate other providers about the health
challenges/needs of those diagnosed through
Newborn Screening.
Data source A clinical database including
information on 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 a diet-controlled PKU
versus non-controlled fashion by using the
retrospective cohort design. Accordingly, we
conducted a descriptive study utilizing
univariate and bivariate analyses as permitted by
the available data.
Success isnt measured by the position you reach
in life Its measured by the obstacles you
overcome. Booker T. Washington Michigans
Newborn Screening Update, Winter 2007