BY: JUDITH PRATT ROSSITER, MD
Dr. Rossiter is director, The Perinatal Center, St. Joseph
Medical Center, Towson, MD.
The Second Article in a Series about the Significance
of Genetic Science for Catholic Health Care
A Medical View
Historically, genetics was a discipline whose place in clinical medicine
was limited almost entirely to the field of pediatrics, including the diagnosis
and treatment of inherited syndromes and inborn errors of metabolism. Subsequently,
applications of genetics were expanded into the realm of obstetrics, as prenatal
diagnostic techniques and ultrasound offered windows through which one could
view the developing fetus. Over the past two decades, with vast improvements
in molecular genetics techniques and with the sequencing of the human genome,
the incorporation of genetics into every field of medicine has become commonplace.
Early Pediatric Genetics
Pediatric genetics began as a descriptive field. Many syndromes were named
by and for those physicians who first systematically described the syndromes'
clinical features. For example, in a manuscript published in 1866 entitled "Observations
on an Ethnic Classification of Idiots," J. L. H. Down, MD, characterized
the features of Down syndrome.1 Although descriptions of clinical
syndromes were carefully recorded, beginning in the mid 1800s, understanding
of their underlying mechanisms did not occur until many years later.
The first chromosome disorder identified was in 1959, when Jerome
Lejeune, MD, reported that Down syndrome resulted from the presence of an extra
copy of chromosome 21 (trisomy 21). In the 1940s, the accumulation of phenylketones
was recognized as the cause of severe mental retardation in the metabolic condition
phenylketonuria (PKU). Following this discovery, a screening test for PKU was
developed by Robert Guthrie, MD, ultimately resulting in the birth of newborn
screening in 1961. Currently, newborn screening is performed throughout the
United States and accounts for the vast majority of genetic testing.
The Technologies Advance
The introduction of genetics into obstetric practice in the United States
began with the availability of amniocentesis for prenatal diagnosis in the early
1960s. In this procedure, a small amount of amniotic fluid is obtained to test
for fetal chromosome abnormalities or inherited conditions. Widespread application
of genetic screening to obstetrics began in the mid-1980s with the introduction
of maternal serum screening to identify pregnancies at risk for fetal neural
tube defects or Down syndrome.
As technologies advance and as our understanding of inherited
conditions increases, genetic testing and screening during pregnancy continue
to grow. Carrier screening for recessive conditions is intended to identify
couples at risk for having children with inherited diseases that are either
debilitating or lethal. If both members of a couple carry a deleterious mutation
in the same gene, each of their children has a 25 percent risk of inheriting
the abnormal gene from both parents, thus being affected with the disease. The
carrier parents usually have no clinical manifestations of the disorder.
In October 2001, the American College of Obstetricians and Gynecologists
and the American College of Medical Genetics published a combined report outlining
guidelines for preconception and prenatal carrier screening for cystic fibrosis.
The authors recommended that "cystic fibrosis carrier screening be offered
to all couples in whom one or both partners are Caucasian and are planning a
pregnancy or seeking prenatal care."2 Outside of newborn screening,
these recommendations represent the largest application of genetic screening
in the United States to date.
Identifying Risk for Down Syndrome
With the movement of women into the workforce and the resultant delay in
childbearing, the increasing risk of fetal chromosome abnormalities with advancing
maternal age has become more apparent and—if the number of pages in medical
journals devoted to a subject is any indication—a topic of great interest.
The majority of these articles focus on the question: How can
we noninvasively identify those pregnancies at risk for Down syndrome (trisomy
21)? Initially, the only "screen" was a patient's age, with a gradual
increase in risk for a fetus with an abnormal number of chromosomes with each
subsequent year. For example, the risk of any chromosome abnormality in a live-born
child of a 20-year-old is approximately 1:1,500; the risk to a 35-year-old is
1:180; and the risk to a 45-year-old is approximately 1:18.3
Over the years, maternal serum screening for fetal chromosome
abnormalities has been expanded and refined. The screening was first introduced
in the mid-1980s, following the retrospective observation of a low maternal
serum concentration of alpha-fetoprotein (AFP, the primary fetal protein) in
a pregnancy from which a baby with trisomy 18 was delivered. Further investigation
revealed a consistent association between low maternal serum AFP concentration
and fetal chromosome abnormalities, specifically trisomy 21 and trisomy 18.4
This relationship proved to be significant, ultimately resulting in the incorporation
of maternal serum screening for Down syndrome into routine obstetrics practice.
Over time, additional markers have been added, to the extent that
patients are now offered a "quadruple screen," including AFP, human
chorionic gonadotropin (hCG), unconjugated estriol (uE3), and dimeric inhibin-A
(inhibin). With this screen, which is performed between 15 and 20 weeks of gestation
(three-and-a-half to four-and-a-half months), the detection rate of pregnancies
at risk for Down syndrome is 75 percent, with 5 percent (1 in 20) of all pregnancies
being identified as "screen positive," that is, having a risk equal
to or greater than that of a 35-year-old, 1:270.5
In the past decade, tremendous energy has been invested into moving
screening for chromosome abnormalities into the first trimester (first 14 weeks
or three months) of pregnancy. This can be accomplished by combining sonographic
measurement of the space below the skin at the back of the fetal neck (nuchal
translucency) with measurement of two maternal serum markers, pregnancy-associated
plasma protein A (PAPP-A) and free beta hCG. This screening, performed between
eleven-and-a-half and thirteen-and-six-sevenths weeks, can detect up to 85 percent
of Down syndrome pregnancies.6 Screening this early in pregnancy
does, in fact, allow patients the greatest variety of reproductive options;
the screening (some of which is contrary to Catholic moral teaching) has been
enthusiastically accepted into clinical practice throughout the United Kingdom
and in some parts of the United States.
Speaking personally, since we incorporated first-trimester screening
into our center's practice, I have noted that patients increasingly opt
for screening in an effort to avoid diagnostic testing and the attendant risk
of pregnancy loss.
Current Diagnostic Procedures
When, through any screening method, a patient is identified as having an
increased risk for a fetal chromosome abnormality, she is offered a diagnostic
procedure that will provide a definitive answer. The current available techniques
include placental biopsy or chorionic villus sampling (CVS); amniocentesis;
and fetal blood sampling.
CVS is usually performed between 10 and 13 weeks (two to three
months), preferably by a highly trained physician (usually a maternal-fetal
medicine specialist or an obstetrician geneticist) and has a risk of miscarriage
of 1:200, even when done by an experienced practitioner. Amniocentesis involves
withdrawal of a small aliquot of fluid from the amniotic cavity, is most frequently
done between 15 and 20 weeks (three and a half to four and a half months), but
can be performed through term, and carries a 1:300 risk of miscarriage. Fetal
blood sampling is limited to high-risk circumstances, particularly when there
is urgency in the timing of results. This technique, usually performed after
18 weeks (four months), entails obtaining blood from the umbilical cord under
ultrasound guidance, and thus requires extensive training. The technique has
a 1:100 (one percent) risk of pregnancy loss, even when performed by experienced
hands. Patients who are appropriately counseled before a diagnostic procedure
understand the technique, the alternatives, the information that may be gained,
and the risks of the procedure.
Counseling Is Essential
Information obtained from prenatal diagnosis is often assumed to be solely
for the purpose of determining whether to continue a pregnancy. My experience,
based on directing prenatal diagnostic services at a Catholic hospital for eight
years, is quite the contrary. Many patients are not interested in termination.
Rather, they desire information that can help them either alleviate anxiety
or to help prepare for the birth of a child with special needs.
Prenatal diagnosis allows for selection of an appropriate site
for delivery, particularly should the baby require intervention in the newborn
period, such as cardiac surgery. During the pregnancy, parents can meet with
health care providers likely to be involved with their newborn's care,
at a time when the immediate needs of the infant are not yet a concern. Often,
the parents become educated about the baby's diagnosis, network with families
of children with similar conditions, and select a pediatrician with familiarity
with (or a willingness to learn about) the disease the baby is known to have.
Counseling of patients who receive an abnormal result from prenatal diagnosis
is essential so that they understand all of their options, are aware of the
available resources, and feel supported, regardless of the decision they ultimately
Molecular Genetics and the Future of Prenatal Diagnosis
Recent advances in molecular genetics techniques allow information to be
drawn from minuscule amounts of genetic material—as little as one cell.
Two methods that have made this possible are polymerase chain reaction (PCR)
and florescence in situ hybridization (FISH).
With PCR, specific segments of DNA can be copied from one or a
few cells to make hundreds or thousands of copies of the gene segment(s) of
interest. The copies can then be used to determine the genetic makeup of the
original cell(s) with reference to a particular gene of interest, such as the
cystic fibrosis gene for a family that has a 25 percent risk for having an affected
FISH technology involves attaching a fluorescent tag to a piece
of DNA that is unique to a particular chromosome or chromosome segment. This
"probe" (tagged DNA) is then used to identify that region, and by
counting fluorescent signals in a cell, the number of copies of that chromosome
or chromosome segment can be determined. For example, with a chromosome 21 probe,
a normal cell would have two signals, whereas a cell from an individual with
Down syndrome would have three.
In combination with in vitro fertilization, PCR and FISH can be
used for preimplantation genetic diagnosis. One or two cells are removed from
each early embryo after in vitro fertilization. Depending on the condition for
which the pregnancy is at risk, either PCR (for an inherited disease) or FISH
(for chromosome abnormalities) is done. Only those embryos determined to be
without the disorder are then "transferred," or placed into the uterus.
And, though I am not proposing this, it is the case that some couples find this
process to be preferable to prenatal diagnosis during pregnancy, particularly
if they would like to avoid both pregnancy termination and a child with an inherited
The future may bring dramatic changes in prenatal diagnosis. During
pregnancy, a small number of intact fetal cells cross into the maternal circulation.
Significant efforts have been focused on methods to identify and isolate these
cells to allow for prenatal diagnosis without requiring an invasive procedure
(CVS or amniocentesis). Though great strides have been made, this technology
is far from ready for general practice. In contrast, many companies are actively
developing microchips. These are tiny (e.g., two millimeters by two millimeters
by one-tenth of a millimeter) chips coated with numerous small DNA segments
(oligonucleotides) that can be used to test for dozens of different gene mutations
at once, with an assay that can be run in a matter of minutes. This technology
may soon be applied to carrier screening of pregnant women for a multitude of
conditions, and perhaps even to fetal genome screening following CVS or amniocentesis.
Toward a National Agenda
Newborn screening is mandated by law throughout the United States, although
each state legislature determines the extent of testing to be done in that state.
As a result, the number of conditions for which screening is performed ranges
from three to 36. All states screen for three conditions: phenylketonuria (PKU),
hypothyroidism, and galactosemia. The rationale for newborn screening is to
identify potentially treatable diseases prior to accumulation of metabolites
(toxic substances) or intercurrent illness, which result in irreversible damage
with most of the inborn errors of metabolism identified by newborn screening.
After a baby has been identified as having a disease, physicians
immediately begin therapy and parental education in an effort to alter the long-term
course of the disease. For some diseases, such as PKU, the impact of newborn
screening and therapy has been dramatic. Untreated individuals with PKU develop
severe mental deficiency, whereas those treated with dietary intervention can
have normal IQs, hold regular jobs, and have families of their own. Although
the promise of early intervention has not been universally realized, newborn
screening is intended to improve the lives of children with inherited diseases.
Currently, the National Institutes of Health is working with a
number of concerned parties, including the American Academy of Pediatrics, the
Centers for Disease Control, the March of Dimes, and the Genetic Alliance to
develop a national agenda for uniform newborn screening throughout the United
This agenda would involve nondiscriminatory screening, regardless
of geographic location; centralized data collection; high-quality management;
and resources for patient and family education. The participating organizations
favor screening that uses tandem mass spectrometry (MS), a technique that allows
identification of more than 20 inborn errors of metabolism. MS is somewhat controversial
because many of the disorders it can identify have at present no available treatment
of proven benefit.
Hope for the future of pediatric genetics extends beyond expanded
newborn screening. Gene therapy has been successfully used to treat several
inherited conditions, including severe combined immune deficiency and some lysosomal
Among the mechanisms by which gene therapy cures disease are:
- Introducing a functional gene
- Decreasing expression of an abnormal gene
- Enhancing expression of a normal gene
Over the years, numerous problems with gene therapy have been
encountered. One involves targeting the gene to the specific cells or tissue
in which gene expression must be altered. Another is identifying a suitable
"vector," or vehicle, for introducing the genetic material into cells
without compromising the patient as a whole. This has been a particular problem,
as modified viruses have been used as vectors with varying success. Nevertheless,
with continued investigation, gene therapy is likely to play a major role in
treating some of the most devastating inherited conditions.
Difficult Decisions Ahead
As our understanding of the human genome increases, decisions will have
to be made regarding testing and screening children for predisposition to adult-onset
disease (such as diabetes and heart disease) and carrier status for recessive
conditions. Currently, the American Academy of Pediatrics (AAP) recommends that
such testing be deferred until adulthood, or at least adolescence, when the
patient will have developed mature decision-making capability.
In addition, the AAP does not support carrier screening except
in relation to a pregnancy. However, practitioners may soon be confronted by
anxious parents who want genetic testing of their children for a variety of
conditions, hoping that early identification may improve outcome, despite an
absence of supportive data. The risks in running the test include possible inaccurate
interpretation of the results, an absence of proven beneficial intervention,
and stigmatization. Genetic testing of children should be approached with great
- J. L. H. Down, "Observations on an Ethnic Classification of Idiots,"
Clinical Lecture Reports, London Hospital, 1866. The text can be found
- American College of Obstetricians and Gynecologists and American College
of Medical Genetics, Preconception and Prenatal Screening for Cystic
Fibrosis: Clinical and Laboratory Guidelines, American College of Obstetricians
and Gynecologists, Washington, DC, 2001.
- E. B. Hook, "Rates of Chromosome Abnormalities at Different Maternal
Ages," Obstetrics and Gynecology, vol. 58, no. 3, 1981, pp.
- R. Merkatz, et al., "An Association between Low Maternal Serum Alpha-Fetoprotein
and Fetal Chromosome Abnormalities," American Journal of Obstetrical
Gynecology, vol.148, no. 7, 1984, pp. 886-894.
- N. J. Wald, W. J. Huttly, and A. K. Hackshaw, "Antenatal Screening
for Down's Syndrome with the Quadruple Test," Lancet, vol.
361, no. 9,360, 2003, pp. 794-795.
- N. J. Wald, H. C. Watt, and A. K. Hackshaw, "Integrated Screening
for Down's Syndrome Based on Tests Performed during the First and Second
Trimesters, " New England Journal of Medicine, vol. 341, no.
7, 1999, pp. 461-467.
Copyright © 2005 by the Catholic Health Association of the United States
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