"Therapeutic cloning" refers to the potential use of SCNT in regenerative medicine; this approach has been championed as an answer to the many issues concerning embryonic stem cells (ESCs) and the destruction of viable embryos for medical use, though questions remain on how homologous the two cell types truly are.
Introduction
Somatic
cell nuclear transfer is a technique for cloning in which the nucleus
of a somatic cell is transferred to the cytoplasm of an enucleated egg.
After the somatic cell transfers, the cytoplasmic factors affect the
nucleus to become a zygote. The blastocyst stage is developed by the egg
to help create embryonic stem cells from the inner cell mass of the
blastocyst. The first mammal to be developed by this technique was Dolly the sheep, in 1996.
Early 20th-Century
Although
Dolly is generally recognized as the first animal to be cloned using
this technique, earlier instances of SCNT exist as early as the 1950s.
In particular, the research of Sir John Gurdon in 1958 entailed the cloning of Xenopus laevis utilizing the principles of SCNT.
In short, the experiment consisted of inducing a female specimen to
ovulate, at which point her eggs were harvested. From here, the egg was
enucleated using ultra-violet irradiation to disable the egg's
pronucleus. At this point, the prepared egg cell and nucleus from the
donor cell were combined, and then incubation and eventual development
into a tadpole proceeded.
Gurdon's application of SCNT differs from more modern applications and
even applications used on other model systems of the time (i.e., Rana pipiens) due to his usage of UV irradiation to enucleate the egg instead of using a pipette to remove the nucleus from the egg.
Process
BTX ECM 2001 electrofusion generator used for SCNT and Cloning applications
The process of somatic cell nuclear transfer involves two different
cells. The first being a female gamete, known as the ovum (egg/oocyte).
In human SCNT experiments, these eggs are obtained through consenting
donors, utilizing ovarian stimulation. The second being a somatic cell,
referring to the cells of the human body. Skin cells, fat cells, and
liver cells are only a few examples. The genetic material of the donor
egg cell is removed and discarded, leaving it 'deprogrammed.' What is
left is a somatic cell and an enucleated egg cell. These are then fused
by inserting the somatic cell into the 'empty' ovum. After being inserted into the egg, the somatic cell nucleus is reprogrammed
by its host egg cell. The ovum, now containing the somatic cell's
nucleus, is stimulated with a shock and will begin to divide. The egg is
now viable and capable of producing an adult organism containing all
necessary genetic information from just one parent. Development will
ensue normally and after many mitotic divisions, the single cell forms a
blastocyst (an early stage embryo with about 100 cells) with an identical genome to the original organism (i.e. a clone).
Stem cells can then be obtained by the destruction of this clone embryo
for use in therapeutic cloning or in the case of reproductive cloning
the clone embryo is implanted into a host mother for further development
and brought to term.
Conventional SCNT requires the use of micromanipulators, which are expensive machines used to accurately manipulate cells. Using the micromanipulator, a scientist makes an opening in the zona pellucida
and sucks out the egg cell's original nucleus using a pipette. They
then make another opening to a different pipette to inject the donor
nucleus. Alternatively, electric energy can be applied to fuse the empty egg cell with a donor cell containing a nucleus.
An alternative technique called "handmade cloning" was described
by Indian scientists in 2001. This technique requires no use of a
micromanipulator and has been used for the cloning of several livestock
species.
Removal of the nucleus can be done chemically, by centrifuge, or with
the use of a blade. The empty egg is glued to the donor cell with phytohaemagglutinin,
then fused using electricity. (If a blade is used, two fusion steps
would be required: the first fusion is between the donor and an empty
half-egg, the second between the half-size "demi-embryo" and another
empty half-egg.)
Applications
Stem cell research
Somatic cell nuclear transplantation has become a focus of study in stem cell research. The aim of carrying out this procedure is to obtain pluripotent cells from a cloned embryo. These cells genetically
matched the donor organism from which they came. This gives them the
ability to create patient specific pluripotent cells, which could then
be used in therapies or disease research.
Embryonic stem cells
are undifferentiated cells of an embryo. These cells are deemed to have
a pluripotent potential because they have the ability to give rise to
all of the tissues found in an adult organism. This ability allows stem
cells to create any cell type, which could then be transplanted to
replace damaged or destroyed cells. Controversy
surrounds human ESC work due to the destruction of viable human
embryos, leading scientists to seek alternative methods of obtaining
pluripotent stem cells, SCNT is one such method.
A potential use of stem cells genetically matched to a patient
would be to create cell lines that have genes linked to a patient's
particular disease. By doing so, an in vitro model could be
created, would be useful for studying that particular disease,
potentially discovering its pathophysiology, and discovering therapies. For example, if a person with Parkinson's disease
donated their somatic cells, the stem cells resulting from SCNT would
have genes that contribute to Parkinson's disease. The disease specific
stem cell lines could then be studied in order to better understand the
condition.
Another application of SCNT stem cell research is using the
patient specific stem cell lines to generate tissues or even organs for
transplant into the specific patient. The resulting cells would be genetically identical to the somatic cell donor, thus avoiding any complications from immune system rejection.
Though there has been numerous successes with cloning animals,
questions remain concerning the mechanisms of reprogramming in the ovum.
Despite many attempts, success in creating human nuclear transfer
embryonic stem cells has been limited. There lies a problem in the human
cell's ability to form a blastocyst; the cells fail to progress past
the eight cell stage of development. This is thought to be a result from
the somatic cell nucleus being unable to turn on embryonic genes
crucial for proper development. These earlier experiments used
procedures developed in non-primate animals with little success.
A research group from the Oregon Health & Science University
demonstrated SCNT procedures developed for primates successfully using
skin cells. The key to their success was utilizing oocytes in metaphase
II (MII) of the cell cycle. Egg cells in MII contain special factors in
the cytoplasm that have a special ability in reprogramming implanted
somatic cell nuclei into cells with pluripotent states. When the ovum's
nucleus is removed, the cell loses its genetic information. This has
been blamed for why enucleated eggs are hampered in their reprogramming
ability. It is theorized the critical embryonic genes are physically
linked to oocyte chromosomes, enucleation negatively affects these
factors. Another possibility is removing the egg nucleus or inserting
the somatic nucleus causes damage to the cytoplast, affecting
reprogramming ability.
Taking this into account the research group applied their new
technique in an attempt to produce human SCNT stem cells. In May 2013,
the Oregon group reported the successful derivation of human embryonic
stem cell lines derived through SCNT, using fetal and infant donor
cells. Using MII oocytes from volunteers and their improved SCNT
procedure, human clone embryos were successfully produced. These embryos
were of poor quality, lacking a substantial inner cell mass and poorly
constructed trophectoderm.
The imperfect embryos prevented the acquisition of human ESC. The
addition of caffeine during the removal of the ovum's nucleus and fusion
of the somatic cell and the egg improved blastocyst formation and ESC
isolation. The ESC obtain were found to be capable of producing
teratomas, expressed pluripotent transcription factors, and expressed a
normal 46XX karyotype, indicating these SCNT were in fact ESC-like.
This was the first instance of successfully using SCNT to reprogram
human somatic cells. This study used fetal and infantile somatic cells
to produce their ESC.
In April 2014, an international research team expanded on this
break through. There remained the question of whether the same success
could be accomplished using adult somatic cells. Epigenetic and age
related changes were thought to possibly hinder an adult somatic cells
ability to be reprogrammed. Implementing the procedure pioneered by the
Oregon research group they indeed were able to grow stem cells generated
by SCNT using adult cells from two donors aged 35 and 75, indicating
that age does not impede a cell's ability to be reprogrammed.
Late April 2014, the New York Stem Cell Foundation was successful
in creating SCNT stem cells derived from adult somatic cells. One of
these lines of stem cells was derived from the donor cells of a type 1
diabetic. The group was then able to successfully culture these stem
cells and induce differentiation. When injected into mice, cells of all
three of the germ layers successfully formed. The most significant of
these cells, were those who expressed insulin and were capable of
secreting the hormone.
These insulin producing cells could be used for replacement therapy in
diabetics, demonstrating real SCNT stem cell therapeutic potential.
The impetus for SCNT-based stem cell research has been decreased
by the development and improvement of alternative methods of generating
stem cells. Methods to reprogram normal body cells into pluripotent stem cells
were developed in humans in 2007. The following year, this method
achieved a key goal of SCNT-based stem cell research: the derivation of
pluripotent stem cell lines that have all genes linked to various
diseases.
Some scientists working on SCNT-based stem cell research have recently
moved to the new methods of induced pluripotent stem cells. Though
recent studies have put in question how similar iPS cells are to
embryonic stem cells. Epigenetic memory in iPS affects the cell lineage
it can differentiate into. For instance, an iPS cell derived from a
blood cell using only the yamanaka factors will be more efficient at
differentiating into blood cells, while it will be less efficient at
creating a neuron.
Recent studies indicate however that changes to the epigenetic memory
of iPSCs using small molecules can reset them to an almost naive state
of pluripotency. Studies have even shown that via tetraploid complementation, an entire viable organism can be created solely from iPSCs.
SCNT stem cells have been found to have similar challenges. The cause
for low yields in bovine SCNT cloning has, in recent years, been
attributed to the previously hidden epigenetic memory of the somatic
cells that were being introduced into the oocyte.
This technique is currently the basis for cloning animals (such as the famous Dolly the sheep),
and has been proposed as a possible way to clone humans. Using SCNT in
reproductive cloning has proven difficult with limited success. High
fetal and neonatal death make the process very inefficient. Resulting
cloned offspring are also plagued with development and imprinting
disorders in non-human species. For these reasons, along with moral and
ethical objections, reproductive cloning in humans is proscribed in more
than 30 countries.
Most researchers believe that in the foreseeable future it will not be
possible to use the current cloning technique to produce a human clone
that will develop to term. It remains a possibility, though critical
adjustments will be required to overcome current limitations during
early embryonic development in human SCNT.
There is also the potential for treating diseases associated with
mutations in mitochondrial DNA. Recent studies show SCNT of the nucleus
of a body cell afflicted with one of these diseases into a healthy
oocyte prevents the inheritance of the mitochondrial disease. This
treatment does not involve cloning but would produce a child with three
genetic parents. A father providing a sperm cell, one mother providing
the egg nucleus, and another mother providing the enucleated egg cell.
Interspecies
nuclear transfer (iSCNT) is a means of somatic cell nuclear transfer
being used to facilitate the rescue of endangered species, or even to
restore species after their extinction. The technique is similar to SCNT
cloning
which typically is between domestic animals and rodents, or where there
is a ready supply of oocytes and surrogate animals. However, the
cloning of highly endangered or extinct species requires the use of an
alternative method of cloning. Interspecies nuclear transfer utilizes a
host and a donor of two different organisms that are closely related
species and within the same genus. In 2000, Robert Lanza was able to produce a cloned fetus of a gaur, Bos gaurus, combining it successfully with a domestic cow, Bos taurus.
In 2017, the first cloned Bactrian camel was born through iSCNT, using oocytes of dromedary camel and skin fibroblast cells of an adult Bactrian camel as donor nuclei.
Limitations
Somatic cell nuclear transfer (SCNT) can be inefficient due to
stresses placed on both the egg cell and the introduced nucleus. This
can result in a low percentage of successfully reprogrammed cells. For
example, in 1996 Dolly the sheep was born after 277 eggs were used for
SCNT, which created 29 viable embryos, giving it a measly 0.3%
efficiency. Only three of these embryos survived until birth, and only one survived to adulthood. Millie, the offspring that survived, took 95 attempts to produce. Because the procedure was not automated and had to be performed manually under a microscope,
SCNT was very resource intensive. Another reason why there is such high
mortality rate with the cloned offspring is due to the fetus being
larger than even other large offspring, resulting in death soon after
birth. The biochemistry involved in reprogramming the differentiated
somatic cell nucleus and activating the recipient egg was also far from
understood. Another limitation is trying to use one-cell embryos during
the SCNT. When using just one-cell cloned embryos, the experiment has a
65% chance to fail in the process of making morula or blastocyst. The
biochemistry also has to be extremely precise, as most late term cloned
fetus deaths are the result of inadequate placentation. However, by 2014, researchers were reporting success rates of 70-80% with cloning pigs and in 2016 a Korean company, Sooam Biotech, was reported to be producing 500 cloned embryos a day.
In SCNT, not all of the donor cell's genetic information is transferred, as the donor cell's mitochondria that contain their own mitochondrial DNA
are left behind. The resulting hybrid cells retain those mitochondrial
structures which originally belonged to the egg. As a consequence,
clones such as Dolly that are born from SCNT are not perfect copies of
the donor of the nucleus. This fact may also hamper the potential
benefits of SCNT-derived tissues and organs for therapy, as there may be
an immuno-response to the non-self mtDNA after transplant.
Additionally, the genes found in the mitochondria’s genome need to
communicate with the cell’s genome and a failure of somatic cell nuclear
reprogramming can lead to non communication to the cell’s genome
causing SCNT to fail.
Epigenetic factors play an important role in the success or
failure of SCNT attempts. The varying gene expression of a previously
activated cell and its mRNAs may lead to overexpression,
underexpression, or in some cases non functional genes which will affect
the developing fetus.
One such example of epigenetic limitations to SCNT is regulating
histone methylation. Differing regulation of these histone methylation
genes can directly affect the transcription of the developing genome,
causing failure of the SCNT.
Another contributing factor to failure of SCNT includes the X
chromosome inactivation in early development of the embryo. A non coding
gene called XIST is responsible for inactivating one X chromosome
during development, however in SCNT this gene can have abnormal
regulation causing mortality to the developing fetus.
Nuclear transfer techniques present a different set of ethical
considerations than those associated with the use of other stem cells
like embryonic stem cells which are controversial
for their requirement to destroy an embryo. These different
considerations have led to some individuals and organizations who are not opposed to human embryonic stem cell research to be concerned about, or opposed to, SCNT research.
One concern is that blastula creation in SCNT-based human stem
cell research will lead to the reproductive cloning of humans. Both
processes use the same first step: the creation of a nuclear transferred
embryo, most likely via SCNT. Those who hold this concern often
advocate for strong regulation of SCNT to preclude implantation of any
derived products for the intention of human reproduction, or its prohibition.
A second important concern is the appropriate source of the eggs that are needed. SCNT requires human egg cells,
which can only be obtained from women. The most common source of these
eggs today are eggs that are produced and in excess of the clinical need
during IVF treatment. This is a minimally invasive procedure, but it
does carry some health risks, such as ovarian hyperstimulation syndrome.
One vision for successful stem cell therapies is to create custom
stem cell lines for patients. Each custom stem cell line would consist
of a collection of identical stem cells each carrying the patient's own
DNA, thus reducing or eliminating any problems with rejection when the
stem cells were transplanted for treatment. For example, to treat a man
with Parkinson's disease, a cell nucleus from one of his cells would be
transplanted by SCNT into an egg cell from an egg donor, creating a
unique lineage of stem cells almost identical to the patient's own
cells. (There would be differences. For example, the mitochondrial DNA
would be the same as that of the egg donor. In comparison, his own cells
would carry the mitochondrial DNA of his mother.)
Potentially millions of patients could benefit from stem cell
therapy, and each patient would require a large number of donated eggs
in order to successfully create a single custom therapeutic stem cell
line. Such large numbers of donated eggs would exceed the number of eggs
currently left over and available from couples trying to have children
through assisted reproductive technology.
Therefore, healthy young women would need to be induced to sell eggs to
be used in the creation of custom stem cell lines that could then be
purchased by the medical industry and sold to patients. It is so far
unclear where all these eggs would come from.
Stem cell experts consider it unlikely that such large numbers of
human egg donations would occur in a developed country because of the
unknown long-term public health effects of treating large numbers of
healthy young women with heavy doses of hormones in order to induce
hyper-ovulation (ovulating several eggs at once). Although such
treatments have been performed for several decades now, the long-term
effects have not been studied or declared safe to use on a large scale
on otherwise healthy women. Longer-term treatments with much lower doses
of hormones are known to increase the rate of cancer decades later.
Whether hormone treatments to induce hyper-ovulation could have similar
effects is unknown. There are also ethical questions surrounding paying
for eggs. In general, marketing body parts is considered unethical and
is banned in most countries. Human eggs have been a notable exception to this rule for some time.
To address the problem of creating a human egg market, some stem
cell researchers are investigating the possibility of creating
artificial eggs. If successful, human egg donations would not be needed
to create custom stem cell lines. However, this technology may be a long
way off.
In the United States, the practice remains legal, as it has not been addressed by federal law.
However, in 2002, a moratorium on United States federal funding for
SCNT prohibits funding the practice for the purposes of research. Thus,
though legal, SCNT cannot be federally funded.
American scholars have recently argued that because the product of SCNT
is a clone embryo, rather than a human embryo, these policies are
morally wrong and should be revised.
In 2003, the United Nations adopted a proposal submitted by Costa Rica,
calling on member states to "prohibit all forms of human cloning in as
much as they are incompatible with human dignity and the protection of
human life." This phrase may include SCNT, depending on interpretation.
The Council of Europe'sConvention on Human Rights and Biomedicine and its Additional
Protocol to the Convention for the Protection of Human Rights and
Dignity of the Human Being with regard to the Application of Biology and
Medicine, on the Prohibition of Cloning Human Being appear to ban SCNT of human beings. Of the Council's 45 member states, the Convention has been signed by 31 and ratified by 18. The Additional Protocol has been signed by 29 member nations and ratified by 14.
The stem cell controversy concerns the ethics of research involving the development and use of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves human embryos. For example, adult stem cells, amniotic stem cells, and induced pluripotent stem cells
do not involve creating, using, or destroying human embryos, and thus
are minimally, if at all, controversial. Many less controversial sources
of acquiring stem cells include using cells from the umbilical cord,
breast milk, and bone marrow, which are not pluripotent.
For many decades, stem cells have played an important role in medical research, beginning in 1868 when Ernst Haeckel
first used the phrase to describe the fertilized egg which eventually
gestates into an organism. The term was later used in 1886 by William Sedgwick to describe the parts of a plant that grow and regenerate. Further work by Alexander Maximow and Leroy Stevens introduced the concept that stem cells are pluripotent. This significant discovery led to the first human bone marrow transplant by E. Donnall Thomas
in 1956, which although successful in saving lives, has generated much
controversy since. This has included the many complications inherent in
stem cell transplantation (almost 200 allogeneic marrow transplants were
performed in humans, with no long-term successes before the first
successful treatment was made), through to more modern problems, such as
how many cells are sufficient for engraftment of various types of hematopoietic stem cell
transplants, whether older patients should undergo transplant therapy,
and the role of irradiation-based therapies in preparation for
transplantation.
The discovery of adult stem cells led scientists to develop an
interest in the role of embryonic stem cells, and in separate studies in
1981 Gail Martin and Martin Evans derived pluripotent stem cells from the embryos of mice for the first time. This paved the way for Mario Capecchi, Martin Evans, and Oliver Smithies to create the first knockout mouse,
ushering in a whole new era of research on human disease. In 1995 adult
stem cell research with human use was patented (US PTO with effect from
1995). In fact, human use was published in World J Surg 1991 & 1999
(B G Matapurkar). Salhan, Sudha (August 2011).
In 1998, James Thomson and Jeffrey Jones
derived the first human embryonic stem cells, with even greater
potential for drug discovery and therapeutic transplantation. However,
the use of the technique on human embryos led to more widespread
controversy as criticism of the technique now began from the wider
public who debated the moral ethics of questions concerning research
involving human embryonic cells.
Potential use in therapy
Since
pluripotent stem cells have the ability to differentiate into any type
of cell, they are used in the development of medical treatments for a
wide range of conditions.
Treatments that have been proposed include treatment for physical
trauma, degenerative conditions, and genetic diseases (in combination
with gene therapy).
Yet further treatments using stem cells could potentially be developed
due to their ability to repair extensive tissue damage.
Great levels of success and potential have been realized from
research using adult stem cells. In early 2009, the FDA approved the
first human clinical trials using embryonic stem cells. Only cells from
an embryo at the morula stage or earlier are truly totipotent,
meaning that they are able to form all cell types including placental
cells. Adult stem cells are generally limited to differentiating into
different cell types of their tissue of origin. However, some evidence
suggests that adult stem cell plasticity may exist, increasing the
number of cell types a given adult stem cell can become.
Points of controversy
Destruction
of a human embryo is required in order to research new embryonic cell
lines. Much of the debate surrounding human embryonic stem cells,
therefore, concern ethical and legal quandaries around the destruction
of an embryo. Ethical and legal questions such as "At what point does
one consider life to begin?" and "Is it just to destroy a human embryo
if it has the potential to cure countless numbers of patients and
further our understanding of disease?" are central to the controversy.
Political leaders debate how to regulate and fund research studies that
involve the techniques used to remove the embryo cells. No clear
consensus has emerged.
Much of the criticism has been a result of religious beliefs and, in the most high-profile case, US PresidentGeorge W Bush
signed an executive order banning the use of federal funding for any
stem cell lines other than those already in existence, stating at the
time, "My position on these issues is shaped by deeply held beliefs,"
and "I also believe human life is a sacred gift from our Creator." This ban was in part revoked by his successor Barack Obama,
who stated: "As a person of faith, I believe we are called to care for
each other and work to ease human suffering. I believe we have been
given the capacity and will to pursue this research and the humanity and
conscience to do so responsibly."
Alternatives to embryonic stem cells
Some
stem cell researchers are working to develop techniques of isolating
stem cells with similar potency as embryonic stem cells, but do not
require the destruction of a human embryo.
Induced pluripotent stem cells (iPSCs)
Foremost
among these was the discovery in August 2006 that human adult somatic
cells can be cultured in vitro with the four “Yamanaka factors” (Oct-4, SOX2, c-Myc, KLF4) which effectively returns a cell to the pluripotent state similar to that observed in embryonic stem cells. This major breakthrough won a Nobel Prize for the discoverers, Shinya Yamanaka and John Gurdon. Induced pluripotent stem cells are those derived from adult somatic cells and have the potential to provide an alternative for stem cell research that does not require the destruction of human embryos.
Some debate remains about the similarities of these cells to embryonic
stem cells as research has shown that the induced pluripotent cells may
have a different epigenetic
memory or modifications to the genome than embryonic stem cells
depending on the tissue of origin and donor the iPSCs come from.
While this may be the case, epigenetic manipulation of the cells is
possible using small molecules and more importantly, iPSCs from multiple
tissues of origin have been shown to give rise to a viable organism
similar to the way ESCs can.
This allows iPSCs to serve as a powerful tool for tissue generation,
drug screening, disease modeling, and personalized medicine that has far
fewer ethical considerations than embryonic stem cells that would
otherwise serve the same purpose.
Somatic cell nuclear transfer (SCNT)
In an alternative technique, researchers at Harvard University, led by Kevin Eggan and Savitri Marajh, have transferred the nucleus of a somatic cell into an existing embryonic stem cell, thus creating a new stem cell line. This technique known as somatic cell nuclear transfer (SCNT) creates pluripotent cells that are genetically identical to the donor. While the creation of stem cells via SCNT does not destroy an embryo, it requires an oocyte
from a donor which opens the door to a whole new set of ethical
considerations such as the debate as to whether or not it is appropriate
to offer financial incentives to female donors.
Single-Cell blastomere biopsy
Researchers at Advanced Cell Technology, led by Robert Lanza and Travis Wahl, reported the successful derivation of a stem cell line using a process similar to preimplantation genetic diagnosis, in which a single blastomere is extracted from a blastocyst. At the 2007 meeting of the International Society for Stem Cell Research (ISSCR), Lanza announced that his team had succeeded in producing three new stem cell lines without destroying the parent embryos. "These
are the first human embryonic cell lines in existence that didn't
result from the destruction of an embryo." Lanza is currently in
discussions with the National Institutes of Health to determine whether
the new technique sidesteps U.S. restrictions on federal funding for ES
cell research.
Amniotic fluid stem cells (AFSCs)
Anthony Atala of Wake Forest University says that the fluid surrounding the fetus has been found to contain stem cells
that, when used correctly, "can be differentiated towards cell types
such as fat, bone, muscle, blood vessel, nerve and liver cells." The
extraction of this fluid is not thought to harm the fetus in any way. He
hopes "that these cells will provide a valuable resource for tissue
repair and for engineered organs, as well."
AFSCs have been found to express both embryonic and adult stem cell
markers as well as having the ability to be maintained over 250
population doublings.
Umbilical cord blood (UCB)
Similarly, pro-life supporters claim that the use of adult stem cells from sources such as the cord blood has consistently produced more promising results than the use of embryonic stem cells.
Research has shown that umbilical cord blood (UCB) is in fact a viable
source for stem cells and their progenitors which occur in high
frequencies within the fluid. Furthermore, these cells may hold an
advantage over induced PSC as they can create large quantities of homogenous cells.
IPSCs and other embryonic stem cell alternatives must still be collected and maintained with the informed consent
of the donor as a donor's genetic information is still within the cells
and by the definition of pluripotency, each alternative cell type has
the potential to give rise to viable organisms. Generation of viable offspring using iPSCs has been shown in mouse models through tetraploid complementation.
This potential for the generation of viable organisms and the fact that
iPSC cells contain the DNA of donors require that they be handled along
the ethical guidelines laid out by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and International Society for Stem Cell Research (ISSCR).
Viewpoints
Stem cell debates have motivated and reinvigorated the anti-abortion
movement, whose members are concerned with the rights and status of the
human embryo as an early-aged human life. They believe that embryonic
stem cell research profits from and violates the sanctity of life and is tantamount to murder. The fundamental assertion of those who oppose embryonic stem cell research is the belief that human life is inviolable,
combined with the belief that human life begins when a sperm cell
fertilizes an egg cell to form a single cell. The view of those in
favor is that these embryos would otherwise be discarded, and if used as
stem cells, they can survive as a part of a living human person.
A portion of stem cell researchers use embryos that were created but not used in in vitro fertility
treatments to derive new stem cell lines. Most of these embryos are to
be destroyed, or stored for long periods of time, long past their viable
storage life. In the United States alone, an estimated at least 400,000
such embryos exist. This has led some opponents of abortion, such as Senator Orrin Hatch, to support human embryonic stem cell research. See also embryo donation.
Medical researchers widely report that stem cell research has the
potential to dramatically alter approaches to understanding and
treating diseases, and to alleviate suffering. In the future, most
medical researchers anticipate being able to use technologies derived
from stem cell research to treat a variety of diseases and impairments.
Spinal cord injuries and Parkinson's disease are two examples that have
been championed by high-profile media personalities (for instance, Christopher Reeve and Michael J. Fox,
who have lived with these conditions, respectively). The anticipated
medical benefits of stem cell research add urgency to the debates, which
has been appealed to by proponents of embryonic stem cell research.
In August 2000, The U.S. National Institutes of Health's Guidelines stated:
... research involving human pluripotent stem cells ...
promises new treatments and possible cures for many debilitating
diseases and injuries, including Parkinson's disease, diabetes, heart
disease, multiple sclerosis, burns and spinal cord injuries. The NIH
believes the potential medical benefits of human pluripotent stem cell
technology are compelling and worthy of pursuit in accordance with
appropriate ethical standards.
In 2006, researchers at Advanced Cell Technology of Worcester,
Massachusetts, succeeded in obtaining stem cells from mouse embryos
without destroying the embryos.
If this technique and its reliability are improved, it would alleviate
some of the ethical concerns related to embryonic stem cell research.
Another technique announced in 2007 may also defuse the
longstanding debate and controversy. Research teams in the United
States and Japan have developed a simple and cost-effective method of
reprogramming human skin cells to function much like embryonic stem
cells by introducing artificial viruses. While extracting and cloning
stem cells is complex and extremely expensive, the newly discovered
method of reprogramming cells is much cheaper. However, the technique
may disrupt the DNA in the new stem cells, resulting in damaged and
cancerous tissue. More research will be required before noncancerous
stem cells can be created.
Update of article to include 2009/2010 current stem cell usages in clinical trials:
The planned treatment trials will focus on the effects of oral lithium
on neurological function in people with chronic spinal cord injury and
those who have received umbilical cord blood mononuclear cell
transplants to the spinal cord. The interest in these two treatments
derives from recent reports indicating that umbilical cord blood stem
cells may be beneficial for spinal cord injury and that lithium may
promote regeneration and recovery of function after spinal cord injury.
Both lithium and umbilical cord blood are widely available therapies
that have long been used to treat diseases in humans.
Endorsement
Embryonic
stem cells have the ability to grow indefinitely in a laboratory
environment and can differentiate into almost all types of bodily
tissue. This makes embryonic stem cells a prospect for cellular therapies to treat a wide range of diseases.
Human potential and humanity
This argument often goes hand-in-hand with the utilitarian argument, and can be presented in several forms:
Embryos are not equivalent to human life while they are still
incapable of surviving outside the womb (i.e. they only have the
potential for life).
More than a third of zygotes do not implant after conception. Thus, far more embryos are lost due to chance than are proposed to be used for embryonic stem cell research or treatments.
Blastocysts are a cluster of human cells that have not
differentiated into distinct organ tissue, making cells of the inner
cell mass no more "human" than a skin cell.
Some parties contend that embryos are not human persons, believing that the life of Homo sapiens only begins when the heartbeat develops, which is during the fifth week of pregnancy, or when the brain begins developing activity, which has been detected at 54 days after conception.
Efficiency
In vitro fertilization (IVF) generates large numbers of unused embryos (e.g. 70,000 in Australia alone).
Many of these thousands of IVF embryos are slated for destruction.
Using them for scientific research uses a resource that would otherwise
be wasted.
While the destruction of human embryos is required to establish a
stem cell line, no new embryos have to be destroyed to work with
existing stem cell lines. It would be wasteful not to continue to make
use of these cell lines as a resource.
Superiority
This
is usually presented as a counter-argument to using adult stem cells,
as an alternative that does not involve embryonic destruction.
Embryonic stem cells make up a significant proportion of a
developing embryo, while adult stem cells exist as minor populations
within a mature individual (e.g. in every 1,000 cells of the bone
marrow, only one will be a usable stem cell). Thus, embryonic stem cells
are likely to be easier to isolate and grow ex vivo than adult stem cells.
Embryonic stem cells divide more rapidly than adult stem cells,
potentially making it easier to generate large numbers of cells for
therapeutic means. In contrast, adult stem cell might not divide fast
enough to offer immediate treatment.
Embryonic stem cells have greater plasticity, potentially allowing them to treat a wider range of diseases.
Adult stem cells from the patient's own body might not be effective in treatment of genetic disorders. Allogeneic embryonic stem cell transplantation (i.e. from a healthy donor) may be more practical in these cases than gene therapy of a patient's own cell.
DNA abnormalities found in adult stem cells that are caused by toxins and sunlight may make them poorly suited for treatment.
Embryonic stem cells have been shown to be effective in treating heart damage in mice.
Embryonic stem cells have the potential to cure chronic and
degenerative diseases which current medicine has been unable to
effectively treat.
Individuality
Before the primitive streak
is formed when the embryo attaches to the uterus around 14 days after
fertilization, two fertilized eggs can combine by fusing together and
develop into one person (a tetragametic chimera).
Since a fertilized egg has the potential to be two individuals or half
of one, some believe it can only be considered a 'potential' person,
not an actual one. Those who subscribe to this belief then hold that
destroying a blastocyst for embryonic stem cells is ethical.
Viability
Viability is another standard under which embryos and fetuses have been regarded as human lives. In the United States, the 1973 Supreme Court case of Roe v. Wade concluded that viability determined the permissibility of abortions
performed for reasons other than the protection of the woman's health,
defining viability as the point at which a fetus is "potentially able to
live outside the mother's womb, albeit with artificial aid."
The point of viability was 24 to 28 weeks when the case was decided and
has since moved to about 22 weeks due to advancement in medical
technology. Embryos used in medical research for stem cells are well
below development that would enable viability.
Further uses for stem cells
Adult
stem cells have provided many different therapies for illnesses such as
Parkinson's disease, leukemia, multiple sclerosis, lupus, sickle-cell
anemia, and heart damage (to date, embryonic stem cells have also been used in treatment).
Moreover, there have been many advances in adult stem cell research,
including a recent study where pluripotent adult stem cells were
manufactured from differentiated fibroblast by the addition of specific
transcription factors.
Newly created stem cells were developed into an embryo and were
integrated into newborn mouse tissues, analogous to the properties of
embryonic stem cells.
Austria, Denmark, France, Germany, Portugal and Ireland do not allow the production of embryonic stem cell lines, but the creation of embryonic stem cell lines is permitted in Finland, Greece, the Netherlands, Sweden, and the United Kingdom.
In 1973, Roe v. Wade legalized abortion in the United States. Five years later, the first successful human in vitro fertilization resulted in the birth of Louise Brown
in England. These developments prompted the federal government to
create regulations barring the use of federal funds for research that
experimented on human embryos. In 1995, the NIH Human Embryo Research
Panel advised the administration of President Bill Clinton to permit federal funding for research on embryos left over from in vitro
fertility treatments and also recommended federal funding of research
on embryos specifically created for experimentation. In response to the
panel's recommendations, the Clinton administration, citing moral and
ethical concerns, declined to fund research on embryos created solely
for research purposes, but did agree to fund research on leftover embryos created by in vitro fertility treatments. At this point, the Congress intervened and passed the 1995 Dickey–Wicker Amendment
(the final bill, which included the Dickey-Wicker Amendment, was signed
into law by Bill Clinton) which prohibited any federal funding for the
Department of Health and Human Services be used for research that
resulted in the destruction of an embryo regardless of the source of
that embryo.
In 1998, privately funded research led to the breakthrough discovery of human embryonic stem cells (hESC).
This prompted the Clinton administration to re-examine guidelines for
federal funding of embryonic research. In 1999, the president's National
Bioethics Advisory Commission recommended that hESC harvested from
embryos discarded after in vitro fertility treatments, but not
from embryos created expressly for experimentation, be eligible for
federal funding. Though embryo destruction had been inevitable in the
process of harvesting hESC in the past (this is no longer the case),
the Clinton administration had decided that it would be permissible
under the Dickey-Wicker Amendment to fund hESC research as long as such
research did not itself directly cause the destruction of an embryo.
Therefore, HHS issued its proposed regulation concerning hESC funding in
2001. Enactment of the new guidelines was delayed by the incoming George W. Bush administration which decided to reconsider the issue.
President Bush announced, on August 9, 2001, that federal funds,
for the first time, would be made available for hESC research on
currently existing embryonic stem cell lines. President Bush authorized
research on existing human embryonic stem cell lines, not on human
embryos under a specific, unrealistic timeline in which the stem cell
lines must have been developed. However, the Bush administration chose
not to permit taxpayer funding for research on hESC cell lines not
currently in existence, thus limiting federal funding to research in
which "the life-and-death decision has already been made."
The Bush administration's guidelines differ from the Clinton
administration guidelines which did not distinguish between currently
existing and not-yet-existing hESC. Both the Bush and Clinton guidelines
agree that the federal government should not fund hESC research that
directly destroys embryos.
Neither Congress nor any administration has ever prohibited
private funding of embryonic research. Public and private funding of
research on adult and cord blood stem cells is unrestricted.
U.S. congressional response
In April 2004, 206 members of Congress
signed a letter urging President Bush to expand federal funding of
embryonic stem cell research beyond what Bush had already supported.
In May 2005, the House of Representatives voted 238–194 to loosen
the limitations on federally funded embryonic stem-cell research – by
allowing government-funded research on surplus frozen embryos from in vitro fertilization clinics to be used for stem cell research with the permission of donors – despite Bush's promise to veto the bill if passed. On July 29, 2005, Senate Majority LeaderWilliam H. Frist (R-TN) announced that he too favored loosening restrictions on federal funding of embryonic stem cell research.
On July 18, 2006, the Senate passed three different bills concerning
stem cell research. The Senate passed the first bill (the Stem Cell Research Enhancement Act)
63–37, which would have made it legal for the federal government to
spend federal money on embryonic stem cell research that uses embryos
left over from in vitro fertilization procedures.
On July 19, 2006, President Bush vetoed this bill. The second bill
makes it illegal to create, grow, and abort fetuses for research
purposes. The third bill would encourage research that would isolate
pluripotent, i.e., embryonic-like, stem cells without the destruction of
human embryos.
In 2005 and 2007, Congressman Ron Paul introduced the Cures Can Be Found Act, with 10 cosponsors. With an income tax credit, the bill favors research upon non-embryonic stem cells obtained from placentas, umbilical cordblood, amniotic fluid,
humans after birth, or unborn human offspring who died of natural
causes; the bill was referred to committee. Paul argued that hESC
research is outside of federal jurisdiction either to ban or to
subsidize.
On March 9, 2009, President Obama removed the restriction on federal funding for newer stem cell lines. Two days after Obama removed the restriction, the president then signed the Omnibus Appropriations Act of 2009, which still contained the long-standing Dickey–Wicker Amendment
which bans federal funding of "research in which a human embryo or
embryos are destroyed, discarded, or knowingly subjected to risk of
injury or death;" the congressional provision effectively prevents federal funding being used to create new stem cell lines
by many of the known methods. So, while scientists might not be free to
create new lines with federal funding, President Obama's policy allows
the potential of applying for such funding into research involving the
hundreds of existing stem cell lines as well as any further lines created using private funds or state-level funding. The ability to apply for federal funding for stem cell lines
created in the private sector is a significant expansion of options
over the limits imposed by President Bush, who restricted funding to the
21 viable stem cell lines that were created before he announced his
decision in 2001.
The ethical concerns raised during Clinton's time in office continue to
restrict hESC research and dozens of stem cell lines have been excluded
from funding, now by judgment of an administrative office rather than
presidential or legislative discretion.
Funding
In 2005, the NIH funded $607 million worth of stem cell research, of which $39 million was specifically used for hESC. Sigrid Fry-Revere
has argued that private organizations, not the federal government,
should provide funding for stem-cell research, so that shifts in public
opinion and government policy would not bring valuable scientific
research to a grinding halt.
In 2005, the State of California took out $3 billion in bond loans to fund embryonic stem cell research in that state.
Asia
China
has one of the most permissive human embryonic stem cell policies in
the world. In the absence of a public controversy, human embryo stem
cell research is supported by policies that allow the use of human
embryos and therapeutic cloning.
Religious views
Generally
speaking, no group advocates for unrestricted stem cell research,
especially in the context of embryonic stem cell research.
Jewish view
According
to Rabbi Levi Yitzchak Halperin of the Institute for Science and Jewish
Law in Jerusalem, embryonic stem cell research is permitted so long as
it has not been implanted in the womb. Not only is it permitted, but
research is encouraged, rather than wasting it.
As long as it has not been
implanted in the womb and it is still a frozen fertilized egg, it does
not have the status of an embryo at all and there is no prohibition to
destroy it...
However in order to remove all doubt [as to the
permissibility of destroying it], it is preferable not to destroy the
pre-embryo unless it will otherwise not be implanted in the woman who
gave the eggs (either because there are many fertilized eggs, or because
one of the parties refuses to go on with the procedure – the husband or
wife – or for any other reason). Certainly it should not be implanted
into another woman.... The best and worthiest solution is to use it for
life-saving purposes, such as for the treatment of people that suffered
trauma to their nervous system, etc.
— Rabbi Levi Yitzchak Halperin, Ma'aseh Choshev vol. 3, 2:6
Similarly, the sole Jewish majority state, Israel, permits research on embryonic stem cells.
Catholicism
The Catholic Church
opposes human embryonic stem cell research calling it "an absolutely
unacceptable act." The Church supports research that involves stem cells
from adult tissues and the umbilical cord, as it "involves no harm to
human beings at any state of development."
This support has been expressed both politically and financially, with
different Catholic groups either raising money indirectly, offering
grants, or seeking to pass federal legislation, according to the United States Conference of Catholic Bishops.
Specific examples include a grant from the Catholic Archiocese of
Sydney which funded research demonstrating the capabilities of adult
stem cells, and the U.S. Conference of Catholic Bishops working to pass
federal legislation creating a nationwide public bank for umbilical cord
blood stem cells.
Baptists
The Southern Baptist Convention
opposes human embryonic stem cell research on the grounds that the
"Bible teaches that human beings are made in the image and likeness of
God (Gen. 1:27; 9:6) and protectable human life begins at
fertilization." However, it supports adult stem cell research as it does "not require the destruction of embryos."
Methodism
The United Methodist Church opposes human embryonic stem cell research, saying, "a human embryo, even at its earliest stages, commands our reverence." However, it supports adult stem cell research, stating that there are "few moral questions" raised by this issue.
Pentecostalism
The Assemblies of God opposes human embryonic stem cell research, saying, it "perpetuates the evil of abortion and should be prohibited."
Islam
Islamic
scholars generally favor the stance that scientific research and
development of stem cells is allowed as long as it benefits society
while causing the least amount of harm to the subjects. "Stem cell
research is one of the most controversial topics of our time period and
has raised many religious and ethical questions regarding the research
being done. With there being no true guidelines set forth in the Qur'an
against the study of biomedical testing, Muslims have adopted any new
studies as long as the studies do not contradict another teaching in the
Qur'an. One of the teachings of the Qur'an states that 'Whosoever saves
the life of one, it shall be if he saves the life of humankind' (5:32),
it is this teaching that makes stem cell research acceptable in the
Muslim faith because of its promise of potential medical breakthrough."
This statement does not, however, make a distinction between adult,
embryonic, or stem-cells. In specific instances, different sources have
issued fatwas, or nonbinding but authoritative legal opinions according to Islamic faith, ruling on conduct in stem cell research. The Fatwa
of the Islamic Jurisprudence Council of the Islamic World League
(December 2003) addressed permissible stem cell sources, as did the FatwaKhamenei
(2002) in Iran. Several different governments in predominantly Muslim
countries have also supported stem cell research, notably Iran. but Saudi Arabia religious officials issued a decree that sanctions the use of embryos for therapeutic and research purposes.
The Church of Jesus Christ of Latter-day Saints
The First Presidency of the Church of Jesus Christ of Latter-day Saints
"has not taken a position regarding the use of embryonic stem cells for
research purposes. The absence of a position should not be interpreted
as support for or opposition to any other statement made by Church
members, whether they are for or against embryonic stem cell research.”
Varies based on severity with FAS having a life expectancy of 34 years old without interventions. Unconfirmed (other types)
Frequency
Unconfirmed; between 1 in 20 (~390 million) and 1 in 13 (~600 million) (all types) 0.2 and 9 per 1,000 (FAS)
Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed.
The several forms of the condition (in order of most severe to least severe) are: fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Other terms used are fetal alcohol effects (FAE), partial fetal alcohol effects (PFAE), alcohol-related birth defects (ARBD),and static encephalopathy, but these terms have fallen out of favor and are no longer considered part of the spectrum.
Not all infants exposed to alcohol in utero will have detectable
FASD or pregnancy complications. The risk of FASD increases with the
amount consumed, the frequency of consumption, and the longer duration
of alcohol consumption during pregnancy, particularly binge drinking.
The variance seen in outcomes of alcohol consumption during pregnancy
is poorly understood. Diagnosis is based on an assessment of growth,
facial features, central nervous system, and alcohol exposure by a
multidisciplinary team of professionals. The main criteria for diagnosis
of FASD are nervous system damage and alcohol exposure, with FAS
including congenital malformations of the lips and growth deficiency.
FASD is often misdiagnosed as or comorbid with ADHD.
Almost all experts recommend that the mother abstain from alcohol
use during pregnancy to prevent FASDs. As the woman may not become
aware that she has conceived until several weeks into the pregnancy, it
is also recommended to abstain while attempting to become pregnant.
Although the condition has no known cure, treatment can improve
outcomes. Treatment needs vary but include psychoactive medications,
behavioral interventions, tailored accommodations, case management, and
public resources.
Globally, one in 10 women drinks alcohol during pregnancy, and the
prevalence of having any FASD disorder is estimated to be at least 1 in
20. The rates of alcohol use, FAS, and FASD are likely to be
underestimated because of the difficulty in making the diagnosis and the
reluctance of clinicians to label children and mothers. Some have
argued that the FAS label stigmatizes alcohol use, while authorities
point out that the risk is real. The condition has appeared in several
works of fiction.
Signs and symptoms
Facial characteristics of a child with FAS
The key signs of fetal alcohol syndrome (FAS) required for diagnosis include:
Nervous system damage: Clinically significant structural neurological, or functional impairment
Popova et al. identified 428 ICD-10
conditions as co-occurring in individuals with FAS. Excluding
conditions used in FAS diagnosis, co-occurring conditions with 50%
prevalence or greater include:
Conduct disorder, behavioral problems, disruptive behavior, or impulsivity
Small eye openings (blepharophimosis), or an abnormally increased distance between the eyes, or both (hypertelorism)
Other FASD conditions are partial expressions of FAS, where the
central nervous system shows clinical deficits. In these other FASD
conditions, an individual may be at greater risk for adverse outcomes
because brain damage is present without associated visual cues of poor
growth or the "FAS face" that might ordinarily trigger an FASD
evaluation. Such individuals may be misdiagnosed with primary mental health disorders such as ADHD or oppositional defiance disorder
without appreciation that brain damage is the underlying cause of these
disorders, which requires a different treatment paradigm than typical
mental health disorders. While other FASD conditions may not yet be
included as an ICD or DSM-IV-TR diagnosis, they nonetheless pose significant impairment in functional behavior because of underlying brain damage.
Many indications of fetal alcohol spectrum disorders are developmental.
Therefore, although a child may appear 'normal' at birth, intellectual
disabilities caused by alcohol before birth may not appear until the
child begins school.
More broadly, alcohol use during pregnancy is also associated with:
Intellectual disability, both in overall IQ measurements and in many functional tests
Cleft lip with or without a cleft palate:
Alcohol is known to be a folic acid antagonist, and a baby's palate and
lip develop during the first trimester of the pregnancy (first 12
weeks). Heavy alcohol consumption and binge drinking during this time
have been linked to orofacial cleft.
Alcohol can also harm the fertility of women who are planning for
pregnancy. Adverse effects of alcohol can lead to malnutrition,
seizures, vomiting, and dehydration. The mother can suffer from anxiety
and depression, which can result in child abuse/neglect. It has also
been observed that when the pregnant mother withdraws from alcohol, its
effects are visible on the infant as well. The baby remains in an
irritated mood, cries frequently, does not sleep properly, weakening of
sucking ability and increased hunger.
In 2019, a study found that individuals with FASD have a higher risk of hypertension independent of race/ethnicity and obesity.
Causes
Fetal alcohol spectrum disorders are caused by alcohol exposure during gestational development. If an individual was not exposed to alcohol before birth, they will not have FASD. However, not all infants exposed to alcohol in utero will have detectable FAS, FASD, or pregnancy complications.
Exposure limit
No safe level of fetal alcohol exposure has been established. Because alcohol is a known teratogen,
it is considered unethical to do randomized controlled trials on
pregnant women to determine the precise toxicity effects of alcohol.
Among women who consume any quantity of alcohol during pregnancy, the
risk of giving birth to a child with FASD is about 15%, and to a child
with FAS about 1.5%. Drinking 2 standard drinks
a day, or 6 standard drinks in a short time, carries a 4.3% risk of a
FAS birth (i.e. one of every 23 heavy-drinking pregnant women will
deliver a child with FAS). Furthermore, alcohol-related congenital
abnormalities occur at an incidence of roughly one out of 67 women who
drink alcohol during pregnancy. Among those mothers who have an alcohol use disorder, an estimated one-third of their children have FAS. The variance seen in outcomes of alcohol consumption during pregnancy is poorly understood. Aggravating factors may include advanced maternal age, smoking, poor diet,genetics, and social risk factors.
The risk of FASD increases with the amount consumed, the
frequency of consumption, and a longer duration of alcohol consumption
during pregnancy. Blood alcohol concentration has been identified as a relevant factor. All forms of alcohol, such as beer, wine, and liquor, pose similar risk. Binge drinking
increases the chances and severity of FASD to such an extent that
Svetlana Popova has stated that "binge drinking is the direct cause of
FAS or FASD".
Small amounts of alcohol may not cause an abnormal appearance,
however, small amounts of alcohol consumption while pregnant may cause
behavioral problems and also increases the risk of miscarriage.
Quasi-experimental studies provide moderately strong evidence that
prenatal alcohol exposure causes detrimental cognitive outcomes, and
some evidence of reduced birthweight, although no study was fully rated
at low risk of bias and quantity of studies was limited.
The evidence is inconsistent and contradictory regarding the
effects of low-to-moderate drinking, for example, less than 12 grams of
ethanol per day.
Many studies find no significant effect, but some find beneficial
associations, and others find detrimental associations, even on the same
outcomes. Summarizing studies by country shows some similarity in
results, due to using the same data sources. The definition of low
alcohol consumption varies significantly among studies and often fails
to incorporate all aspects of timing, dose, and duration. Recall bias
and socioeconomic and psychosocial factors have been controlled for in
most studies, but it is likely that residual confounding due to missing
factors and variation in methods still exists and is larger than any
observed effects.
Paternal Alcohol Use
Fathers who consume alcohol before conception may contribute to FASD through long-term epigenetic modification of the father's sperm, but this has been challenged; evidence it can cause complete FAS is inconclusive.
Almost all experts recommend that the mother abstain from alcohol use during pregnancy to prevent FASDs.
A pregnant woman may not become aware that she has conceived until
several weeks into the pregnancy, so it is also recommended to abstain
from alcohol while attempting to become pregnant. The recommendations of abstaining from alcohol during pregnancy and while attempting to become have been made by the Surgeon General of the United States, the Centers for Disease Control, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the World Health Organization, the United Kingdom's National Institute for Health and Clinical Excellence, and many others.
In the United States, federal legislation has required that warning
labels be placed on all alcoholic beverage containers since 1988 under
the Alcoholic Beverage Labeling Act.
Stigma
The
most current advocacy perspectives encourage people and systems to
approach FASD with interventions and support for individuals already
living with FASD. Focusing on prevention often only further stigmatizes
individuals with FASD and their birth parents. Advocates say, if a
person is supporting people currently living with FASD, then that person
is spreading the awareness needed for successful prevention efforts;
"Intervention is Prevention". Many social determinants of health impact the effects of PAE:
Genetics
Poverty/Access to nutritious food
Malnutrition
Poor social support networks
Lack of personal autonomy
Access to healthcare
Generational and sociocultural traumas
Access to mental health care and treatment
Medication
Women
can experience serious symptoms that accompany alcohol withdrawal
during pregnancy. According to the World Health Organization, these
symptoms can be treated during pregnancy with brief use of benzodiazepinetranquilizers. Currently, the FDA has approved three medications—naltrexone, acamprosate, and disulfiram—for the treatment of alcohol use disorder (AUD). However, there is insufficient data regarding the safety of these medications for pregnant women.
Naltrexone is a nonselective opioid antagonist that is used to treat AUD and opioid use disorder. The long-term effects of naltrexone on the fetus are currently unknown.
Animal studies show that naltrexone administered during pregnancy
increases the incidence of early fetal loss; however, there are
insufficient data available to identify the extent to which this is a
risk in pregnant women.
Acamprosate functions as both an antagonist of NMDA and glutamate and an agonist at GABAA
receptors, although its molecular mechanism is not completely
understood. Acamprosate is effective at preventing alcohol relapse
during abstinence. Animal data, however, suggest that acamprosate can have possible teratogenic effects on fetuses.
Disulfiram prevents relapse by blocking the metabolism of acetaldehyde after consumption of alcohol, which leads to headache, nausea, and vomiting.
Some evidence suggests that disulfiram use during the first trimester
is associated with an increased risk of congenital malformations such as
reduction defects and cleft palate.
Additionally, the effects of disulfiram can involve hypertension, which
can be harmful to both the pregnant woman and the fetus.
American Psychiatric Association
guidelines recommend that medications not be used to treat alcohol use
disorder in pregnant women except in cases of acute alcohol withdrawals
or other co-existing conditions.
Instead, behavioral interventions are usually preferred as treatments
for pregnant women with AUD. Medications should only be used for
pregnant women after carefully considering the potential risks and harms
of the medications versus the benefits of alcohol cessation.
Mechanism
After
a pregnant woman consumes alcohol, the alcohol crosses through the
placenta and umbilical cord to the developing fetus. Alcohol metabolizes
slowly in the fetus and remains for a long time when compared to an
adult. A human fetus appears to be at triple risk from maternal alcohol consumption:
The placenta allows free entry of ethanol and toxic metabolites like acetaldehyde into the fetal compartment. The so-called placental barrier is practically absent concerning ethanol.
The developing fetal nervous system appears particularly sensitive
to ethanol toxicity. The latter interferes with proliferation,
differentiation, neuronal migration, axonal outgrowth, integration, and
fine-tuning of the synaptic network. In short, all major processes in
the developing central nervous system appear compromised.
Fetal tissues are quite different from adult tissues in function and
purpose. For example, the main detoxifying organ in adults is the liver,
whereas the fetal liver is incapable of detoxifying ethanol, as the ADH
and ALDH enzymes have not yet been brought to expression at this early
stage. Up to term, fetal tissues do not have significant capacity for
the detoxification of ethanol, and the fetus
remains exposed to ethanol in the amniotic fluid for periods far longer
than the decay time of ethanol in the maternal circulation. The lack of
significant quantities of ADH and ALDH means that fetal tissues have
much lower quantities of antioxidant enzymes, like SOD, glutathione transferases, and glutathione peroxidases, resulting in antioxidant protection being much less effective.
Although alcohol is known to be a teratogen
(causing birth defects), the exact biological mechanisms for the
development of FAS or FASD are unknown. However, clinical and animal
studies have identified a broad spectrum of pathways through which
maternal alcohol can negatively affect the outcome of a pregnancy. Clear
conclusions with universal validity are difficult to draw, since
different ethnic groups show considerable genetic polymorphism for the hepatic enzymes responsible for ethanol detoxification.
Genetic examinations have revealed a continuum of long-lasting
molecular effects that are not only timing specific but are also dosage
specific; with even moderate amounts being able to cause alterations. Additionally, ethanol may alter fetal development by interfering with retinoic acid signaling as acetaldehyde can compete with retinaldehyde and prevents its oxidation to retinoic acid.
Developmental stages
Different
body systems in the infant grow, mature, and develop at specific times
during gestation. The effect of consumption of alcohol differs during
each of these developmental stages:
From conception to the third week, the most susceptible systems
and organs are the brain, spinal cord, and heart. The effects of alcohol
consumption early in the pregnancy can result in defects in these
systems and organs.
During the third week, alcohol can also damage the central nervous system of the fetus.
During the fourth week of gestation, the limbs are being formed, and
it is at this point that alcohol can affect the development of arms,
legs, fingers, and toes. The eyes and ears also form during the fourth
week and are more susceptible to the effects of alcohol.
By the sixth week of gestation, the teeth and palate are forming,
and alcohol consumption at this time will affect these structures.
Alcohol use in this window is responsible for many of the facial
characteristics of fetal alcohol syndrome.
During the twelfth week, frequent alcohol exposure can negatively
impact brain development, which affects cognitive, learning, and
behavioral skills before birth.
By the 20th week of gestation, the formation of organs and organ
systems is well-developed. The infant is still susceptible to the
damaging effects of alcohol.
Ethanol exposure in the second trimester reduces nutrition levels
and can affect the functioning of the endocrine system in both fetus and
mother. This is because blood flow via the umbilical artery to the
fetal brain is reduced.
Diagnosis
Fetal alcohol spectrum disorders encompass a range of physical and neurodevelopmental
problems which can result from prenatal alcohol exposure. Diagnosis is
based on the signs and symptoms in the person and evidence of alcohol
use. These diagnoses of fetal alcohol spectrum disorders are currently recognized:
Fetal alcohol syndrome (FAS)
Partial fetal alcohol syndrome (pFAS) refers to individuals with a
known, or highly suspected, history of prenatal alcohol exposure who
have alcohol-related physical and neurodevelopmental deficits that do
not meet the full criteria for FAS.
Presently, four FASD diagnostic systems that diagnose FAS and other FASD conditions have been developed in North America:
The Institute of Medicine's guidelines for FAS, the first system to standardize diagnoses of individuals with prenatal alcohol exposure;
The University of Washington's "The 4-Digit Diagnostic Code", which ranks the four key features of FASD on a Likert scale
of one to four and yields 256 descriptive codes that can be categorized
into 22 distinct clinical categories, ranging from FAS to no findings;
The Centers for Disease Control's
"Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis", which
established consensus on the diagnosis FAS in the U.S. but deferred
addressing other FASD conditions; and
Canadian guidelines for FASD diagnoses, which established criteria
for diagnosing FASD in Canada and harmonized most differences between
the IOM and the University of Washington's systems.
Each diagnostic system requires an assessment of four key features:
growth, facial features, central nervous system, and alcohol exposure.
To determine any FASD condition, a multi-disciplinary evaluation is necessary to assess each of the four key features for assessment. Generally, a trained physician
will determine growth deficiency and FAS facial features. While a
qualified physician may also assess central nervous system structural
abnormalities or neurological problems, usually central nervous system
damage is determined through psychological, speech-language, and occupational therapy assessments to ascertain clinically significant impairments in three or more of the Ten Brain Domains. Prenatal alcohol exposure risk may be assessed by a qualified physician, psychologist, social worker,
or chemical health counselor. These professionals work together as a
team to assess and interpret data of each key feature for assessment and
develop an integrative, multi-disciplinary report to diagnose FAS (or
other FASD conditions) in an individual.
A positive finding on all four features is required for a
diagnosis of FAS, and the four diagnostic systems essentially agree on
criteria for fetal alcohol syndrome (FAS). However, there are
differences among systems when full criteria for FAS are not met.
Prenatal alcohol exposure and central nervous system damage are the
critical elements of the spectrum of FASD, and a positive finding in
these two features is sufficient for an FASD diagnosis in all FASD
systems.
But different researchers and systems may use a wide variety of
terminology to describe an individual's FASD condition, as the
nomenclature is still evolving. Most individuals with deficits resulting
from prenatal alcohol exposure do not express all features of FAS and
fall into other FASD conditions.
The Canadian guidelines recommend the assessment and descriptive
approach of the "4-Digit Diagnostic Code" for each key feature of FASD
and the terminology of the IOM in diagnostic categories, excepting ARBD.
Fetal alcohol syndrome
The most severe condition is called Fetal Alcohol Syndrome (FAS),
which refers to individuals who have a specific set of birth defects
and neurodevelopmental disorders characteristic of the diagnosis. The following criteria must be fully met for an FAS diagnosis:
Prenatal or postnatal height or weight (or both) at or below the 10th percentile
All three FAS facial features present
Clinically significant structural, neurological, or functional impairment of the central nervous system
Confirmed or Unknown prenatal alcohol exposure
FAS is the only expression of FASD that has garnered consensus among experts to become an official ICD-9 and ICD-10 diagnosis.
Partial FAS
Partial
FAS (pFAS) was previously known as atypical FAS in the 1997 edition of
the "4-Digit Diagnostic Code". People with pFAS have a confirmed history
of prenatal alcohol exposure, but may lack growth deficiency or the
complete facial stigmata. Central nervous system damage is present at
the same level as FAS. These individuals have the same functional
disabilities but "look" less like FAS.
The following criteria must be fully met for a diagnosis of Partial FAS:
Two or three FAS facial features present
Clinically significant structural, neurological, or functional impairment in three or more of the Ten Brain Domains
Confirmed prenatal alcohol exposure
Growth or height may range from normal to deficient.
Alcohol-related neurodevelopmental disorder
Alcohol-related
neurodevelopmental disorder (ARND) is the specific diagnosis of the
non-dysmorphic type of FASD, where a majority of the symptoms are
witnessed.
The diagnosis was initially suggested by the Institute of Medicine to
replace the terms FAE (fetal alcohol effects). It focuses on central
nervous system damage, rather than growth deficiency or FAS facial
features. The Canadian guidelines also use this diagnosis and the same
criteria. While the "4-Digit Diagnostic Code" includes these criteria
for three of its diagnostic categories, it refers to this condition as static encephalopathy.
The behavioral effects of ARND are not necessarily unique to alcohol
however, so use of the term must be within the context of confirmed
prenatal alcohol exposure.
ARND may be gaining acceptance over the terms FAE and ARBD to describe
FASD conditions with central nervous system abnormalities or behavioral
or cognitive abnormalities or both due to prenatal alcohol exposure
without regard to growth deficiency or FAS facial features.
The following criteria must be fully met for a diagnosis of ARND or static encephalopathy:
Minimal or no FAS facial features present
Clinically significant structural, neurological, or functional impairment in three or more of the Ten Brain Domains
Confirmed prenatal alcohol exposure
Growth or height may range from normal to minimally deficient.
Neurobehavioral disorder associated with prenatal alcohol exposure
Neurobehavioral
disorder associated with prenatal alcohol exposure (ND-PAE) is the
spectrum-wide term for the psychiatric, behavioral, and neurological
symptoms of all FASDs. It was introduced into the DSM-V as a "condition
for further study" and as a specified condition under, "other specified
neurodevelopmental disorders" as a way to better study the behavioral
aspects of all FASD disorders.
Specific criteria
Growth
In terms of FASD, growth deficiency is defined as significantly below average height, weight or both due to prenatal alcohol exposure and can be assessed at any point in the lifespan. Growth measurements must be adjusted for parental height, gestational age (for a premature infant), and other postnatal insults (e.g., poor nutrition), although birth height and weight are the preferred measurements.
Deficiencies are documented when height or weight falls at or below the
10th percentile of standardized growth charts appropriate to the
population. Prenatal or postnatal presentation of growth deficits can occur, but are most often postnatal.
Criteria for FASD are least specific in the Institute of Medicine
(IOM) diagnostic system ("low birth weight..., decelerating weight not
due to nutrition..., [or] disproportional low weight to height" p. 4 of
executive summary), while the CDC use the 10th percentile as a cut-off to determine growth deficiency.
The "4-Digit Diagnostic Code" allows for mid-range gradations in growth
deficiency (between the 3rd and 10th percentiles) and severe growth
deficiency at or below the 3rd percentile.
Growth deficiency (at severe, moderate, or mild levels) contributes to
diagnoses of FAS and pFAS, but not ARND or static encephalopathy.
The "4-Digit Diagnostic Code" from 2004 ranks growth deficiency as follows:
Severe: Height and weight at or below the 3rd percentile.
Moderate: Either height or weight at or below the 3rd percentile, but not both.
Mild: Either height or weight or both between the 3rd and 10th percentiles.
None: Height and weight both above the 10th percentile.
In the initial studies that described FAS, growth deficiency was a
requirement for inclusion in the studies; thus, all the original people
with FAS had growth deficiency as an artifact of sampling characteristics used to establish criteria for the syndrome.
That is, growth deficiency is a key feature of FASD because growth
deficiency was a criterion for inclusion in the study that defined FAS.
Growth deficiency may be less critical for understanding the
disabilities of FASD than the neurobehavioral sequelae to the brain
damage. Canadian guidelines updated in 2016 deleted growth as a diagnostic criterion.
Facial features
Smooth philtrum seen on a six-month-old baby with FAS
Several characteristic craniofacial abnormalities are often visible in individuals with FAS. The presence of FAS facial features indicates brain damage,
although brain damage may also exist in their absence. FAS facial
features (and most other visible, but non-diagnostic, deformities) are
believed to be caused mainly during the 10th to 20th week of gestation.
Refinements in diagnostic criteria since 1975 have yielded three
distinctive and diagnostically significant facial features which
distinguish FAS from other disorders with partially overlapping
characteristics. The three FAS facial features are:
A smooth philtrum: The divot or groove between the nose and upper lip flattens with increased prenatal alcohol exposure.
Thin vermilion: The upper lip thins with increased prenatal alcohol exposure.
Small palpebral fissures: Eye width decreases with increased prenatal alcohol exposure.
Measurement of FAS facial features uses criteria developed by the University of Washington. The lip and philtrum are measured by a trained physician with the Lip-Philtrum Guide, a five-point Likert scale
with representative photographs of lip and philtrum combinations
ranging from normal (ranked 1) to severe (ranked 5). Palpebral fissure
length (PFL) is measured in millimeters with either calipers or a clear ruler and then compared to a PFL growth chart, also developed by the University of Washington.
Ranking FAS facial features is complicated because the three
separate facial features can be affected independently by prenatal
alcohol. A summary of the criteria follows:
Severe: All three facial features ranked independently as severe
(lip ranked at 4 or 5, philtrum ranked at 4 or 5, and PFL two or more
standard deviations below average).
Moderate: Two facial features ranked as severe and one feature ranked as moderate (lip or philtrum ranked at 3, or PFL between one and two standard deviations below average).
Mild: A mild ranking of FAS facial features covers a broad range of facial feature combinations:
Two facial features ranked severe, and one ranked within normal limits,
One facial feature ranked sever,e and two ranked moderate, or
One facial feature ranked severe, one ranked moderate, and one ranked within normal limits.
None: All three facial features ranked within normal limits.
Central nervous system
Central nervous system (CNS) damage is the primary feature of any FASD diagnosis. Prenatal alcohol exposure, which is classified as a teratogen,
can damage the brain across a continuum of gross to subtle impairments,
depending on the amount, timing, and frequency of the exposure as well
as genetic predispositions of the fetus and mother.
While functional abnormalities are the behavioral and cognitive
expressions of the FASD disability, CNS damage can be assessed in three
areas: structural, neurological, and functional impairments.
All four diagnostic systems allow for assessment of CNS damage in
these areas, but the criteria vary. The IOM system requires structural
or neurological impairment for a diagnosis of FAS, but also allows a
"complex pattern" of functional anomalies for diagnosing PFAS and ARND.
The "4-Digit Diagnostic Code" and CDC guidelines allow for a positive
CNS finding in any of the three areas for any FASD diagnosis, but
functional anomalies must measure at two standard deviations or worse in
three or more functional domains for a diagnosis of FAS, PFAS, and
ARND.
The "4-Digit Diagnostic Code" also allows for an FASD diagnosis when
only two functional domains are measured at two standard deviations or
worse. The "4-Digit Diagnostic Code" further elaborates the degree of CNS damage according to four ranks:
Definite: Structural impairments or neurological impairments for FAS or static encephalopathy.
Probable: Significant dysfunction of two standard deviations or worse in three or more functional domains.
Possible: Mild to moderate dysfunction of two standard deviations or worse in one or two functional domains or by judgment of the clinical evaluation team that CNS damage cannot be dismissed.
Unlikely: No evidence of CNS damage.
Structural
Structural
abnormalities of the brain are observable, and physical damage to the
brain or brain structures caused by prenatal alcohol exposure.
Structural impairments may include microcephaly (small head size) of two or more standard deviations below the average, or other abnormalities in brain structure (e.g., agenesis of the corpus callosum, cerebellar hypoplasia).
Microcephaly is determined by comparing head circumference (often
called occipitofrontal circumference, or OFC) to appropriate OFC growth
charts. Other structural impairments must be observed through medical imaging
techniques by a trained physician. Because imaging procedures are
expensive and relatively inaccessible to most people, diagnosis of FAS
is not frequently made via structural impairments, except for
microcephaly.
Evidence of a CNS structural impairment due to prenatal alcohol
exposure will result in a diagnosis of FAS, and neurological and
functional impairments are highly likely.
During the first trimester of pregnancy, alcohol interferes with the migration and organization of brain cells, which can create structural deformities or deficits within the brain. During the third trimester, damage can be caused to the hippocampus,
which plays a role in memory, learning, emotion, and encoding visual
and auditory information, all of which can create neurological and
functional CNS impairments as well.
As of 2002, there were 25 reports of autopsies on infants known to have FAS. The first was in 1973, on an infant who died shortly after birth. The examination revealed extensive brain damage, including microcephaly, migration anomalies, corpus callosum dysgenesis, and a massive neuroglial, leptomeningealheterotopia covering the left hemisphere.
In 1977, Clarren described a second infant whose mother was a
binge drinker. The infant died ten days after birth. The autopsy showed
severe hydrocephalus, abnormal neuronal migration, and a small corpus callosum. FAS has also been linked to brainstem and cerebellar changes, agenesis of the corpus callosum and anterior commissure, neuronal migration errors, absent olfactory bulbs, meningomyelocele, and porencephaly.
All four diagnostic systems show virtual agreement on their
criteria for CNS damage at the neurological level, and evidence of a CNS
neurological impairment due to prenatal alcohol exposure will result in
a diagnosis of FAS or pFAS, and functional impairments are highly
likely.
Neurological problems are expressed as either hard signs, or diagnosable disorders, such as epilepsy or other seizure disorders, or soft signs. Soft signs are broader, nonspecific neurological impairments, or symptoms, such as impaired fine motor skills, neurosensoryhearing loss, poor gait, clumsiness, and poor eye–hand coordination. Many soft signs have norm-referenced criteria,
while others are determined through clinical judgment. "Clinical
judgment" is only as good as the clinician, and soft signs should be
assessed by either a pediatric neurologist, a pediatric
neuropsychologist, or both.
Functional
When
structural or neurological impairments are not observed, all four
diagnostic systems allow CNS damage due to prenatal alcohol exposure to
be assessed in terms of functional impairments. Functional impairments are deficits, problems, delays, or abnormalities
due to prenatal alcohol exposure (rather than hereditary causes or
postnatal insults) in observable and measurable domains related to daily
functioning, often referred to as developmental disabilities. There is no consensus on a specific pattern of functional impairments due to prenatal alcohol exposure and only CDC guidelines label developmental delays as such, so criteria (and FASD diagnoses) vary somewhat across diagnostic systems.
The four diagnostic systems list various CNS domains that can
qualify for functional impairment, which can determine an FASD
diagnosis:
Evidence of a complex pattern of behavior or cognitive
abnormalities inconsistent with developmental level in the following CNS
domains – Sufficient for a pFAS or ARND diagnosis using IOM guidelines
General cognitive deficits (e.g., IQ) at or below the 3rd percentile on standardized testing – Sufficient for an FAS diagnosis using CDC guidelines
Performance at or below the 16th percentile on standardized testing in three or more of the following CNS domains – Sufficient for an FAS diagnosis using CDC guidelines
Performance at two or more standard deviations on standardized
testing in three or more of the following CNS domains – Sufficient for
an FAS diagnosis using Canadian guidelines
Cognition, communication, academic achievement, memory,
executive functioning, adaptive behavior, motor skills, social skills,
social communication
Ten brain domains
A recent
effort to standardize assessment of functional CNS damage has been
suggested by an experienced FASD diagnostic team in Minnesota. The
proposed framework attempts to harmonize IOM, 4-Digit Diagnostic Code,
CDC, and Canadian guidelines for measuring CNS damage vis-à-vis FASD
evaluations and diagnosis. The standardized approach is referred to as
the Ten Brain Domains and encompasses aspects of all four diagnostic
systems' recommendations for assessing CNS damage due to prenatal
alcohol exposure. The framework provides clear definitions of brain
dysfunction, specifies empirical data needed for accurate diagnosis, and
defines intervention considerations that address the complex nature of
FASD with the intention to avoid common secondary disabilities.
The Fetal Alcohol Diagnostic Program (FADP) uses unpublished Minnesota state criteria of performance at 1.5 or more standard deviations on standardized testing
in three or more of the Ten Brain Domains to determine CNS damage.
However, the Ten Brain Domains are easily incorporated into any of the
four diagnostic systems' CNS damage criteria, as the framework only
proposes the domains, rather than the cut-off criteria for FASD.
Alcohol exposure
Prenatal
alcohol exposure is determined by interview of the biological mother or
other family members knowledgeable of the mother's alcohol use during
the pregnancy (if available), prenatal health records (if available),
and review of available birth records, court records (if applicable), chemical dependency treatment records (if applicable), chemical biomarkers, or other reliable sources.
Exposure level is assessed as confirmed exposure, unknown exposure, and confirmed absence of exposure by the IOM, CDC, and Canadian diagnostic systems. The "4-Digit Diagnostic Code" further distinguishes confirmed exposure as High Risk and Some Risk:
Confirmed exposure: The CDC guidelines are silent on using
information on the amount, frequency, and timing of prenatal alcohol use
for diagnostic purposes. The IOM and Canadian guidelines explore this
further, acknowledging the importance of significant alcohol exposure
from regular or heavy episodic alcohol consumption in determining, but
offer no standard for diagnosis. Canadian guidelines discuss this lack
of clarity and parenthetically point out that "heavy alcohol use" is
defined by the National Institute on Alcohol Abuse and Alcoholism as five or more drinks per episode on five or more days during 30 days. "The 4-Digit Diagnostic Code" ranking system distinguishes between levels of prenatal alcohol exposure as high risk and some risk. It operationalizes high risk exposure as a blood alcohol concentration
(BAC) greater than 100 mg/dL delivered at least weekly in early
pregnancy. This BAC level is typically reached by a 55 kg female
drinking six to eight beers in one sitting.
High Risk: Confirmed use of alcohol during pregnancy known to be at high blood alcohol levels (100 mg/dL or greater) delivered at least weekly in early pregnancy.
Some Risk: Confirmed use of alcohol during pregnancy with use less than High Risk or unknown usage patterns.
Unknown Risk: Unknown use of alcohol during pregnancy. For many
adopted adults and children in foster care, records or other reliable
sources may not be available for review. Reporting alcohol use during
pregnancy can also be stigmatizing to birth mothers, especially if
alcohol use is ongoing. Many are reluctant to admit to drinking or to
provide an accurate report of the quantity they drank.
In these cases, all diagnostic systems use an unknown prenatal alcohol
exposure designation. A diagnosis of FAS is still possible with an
unknown exposure level if other key features of FASD are present at
clinical levels.
No Risk: Confirmed absence of prenatal alcohol exposure. Confirmed
absence of exposure would apply to planned pregnancies in which no
alcohol was used or pregnancies of women who do not use alcohol or
report no use during the pregnancy. This designation is relatively rare,
as most people presenting for an FASD evaluation are at least suspected to have had a prenatal alcohol exposure due to the presence of other key features of FASD.
Biomarkers
Evidence is insufficient for the use of chemical biomarkers to detect prenatal alcohol exposure.
Biomarkers being studied include fatty acid ethyl esters (FAEE)
detected in the meconium (first feces of an infant) and hair. FAEE may
be present if chronic alcohol exposure occurs during the second and
third trimesters since this is when the meconium begins to form.
Concentrations of FAEE can be influenced by medication use, diet, and
individual genetic variations in FAEE metabolism, however.
Differential diagnosis
The CDC reviewed nine syndromes
that have overlapping features with FAS; however, none of these
syndromes include all three FAS facial features, and none are the result
of prenatal alcohol exposure:
Most people with FASD have most often been misdiagnosed with ADHD due to the large overlap between their behavioral deficits.
Treatment
Although the condition has no available cure, treatment can improve outcomes.
Because CNS damage, symptoms, secondary disabilities, and needs vary
widely by individual, there is no one treatment type that works for
everyone.
Between 2017 and 2019 researchers made a breakthrough when they
discovered a possible cure using neural stem cells (NSCs); they propose
that if applied to a newborn, the damage can be reversed and prevent any
lasting effects in the future.
Medications
Psychoactive drugs are frequently tried as many FASD symptoms are mistaken for or overlap with other disorders, most notably ADHD.
Medications are used to specifically treat symptoms of FASDs and not
FAS entirely. Some of the medications used are antidepressants,
stimulants, neuroleptics, and anti-anxiety drugs.
Children with FAS benefit from behavioral and functional
training, social skill training, and tutoring. Support groups and talk
therapy not only help the children suffering from FAS, but also help the
parents and siblings of these children.
Developmental framework
Many books and handouts on FAS recommend a developmental approach, based on developmental psychology,
even though most do not specify it as such and provide little
theoretical background. Optimal human development generally occurs in
identifiable stages (e.g., Jean Piaget's theory of cognitive development, Erik Erikson's stages of psychosocial development, John Bowlby's attachment framework, and other developmental stage theories). FAS interferes with normal development,
which may cause stages to be delayed, skipped, or immaturely developed.
Over time, an unaffected child can negotiate the increasing demands of
life by progressing through stages of development normally, but not so
for a child with FAS.
By knowing what developmental stages and tasks children follow,
treatment and interventions for FAS can be tailored to helping a person
meet developmental tasks and demands successfully. If a person is delayed in the adaptive behavior
domain, for instance, then interventions would be recommended to target
specific delays through additional education and practice (e.g.,
practiced instruction on tying shoelaces), giving reminders, or making
accommodations (e.g., using slip-on shoes) to support the desired
functioning level. This approach is an advance over behavioral
interventions, because it takes the person's developmental context into
account while developing interventions.
Advocacy model
The advocacy model takes the point of view that someone is needed to actively mediate between the environment and the person with FAS. Advocacy activities are conducted by an advocate (for example, a family member, friend, or case manager)
and fall into three basic categories. An advocate for FAS: (1)
interprets FAS and the disabilities that arise from it and explains it
to the environment in which the person operates, (2) engenders change or
accommodation on behalf of the person, and (3) assists the person in
developing and reaching attainable goals.
The advocacy model is often recommended, for example, when developing an individualized education program (IEP) for the person's progress at school.
An understanding of the developmental framework would presumably
inform and enhance the advocacy model, but advocacy also implies
interventions at a systems level as well, such as educating schools,
social workers, and so forth on best practices for FAS. However, several
organizations devoted to FAS also use the advocacy model at a community practice level as well.
Treating FAS at the public health and public policy level promotes FAS prevention and diversion of public resources to assist those with FAS.
It is related to the advocacy model but promoted at a systems level
(rather than with the individual or family), such as developing
community education and supports, state or province level prevention
efforts (e.g., screening for maternal alcohol use during OB/GYN
or prenatal medical care visits), or national awareness programs.
Several organizations and state agencies in the U.S. are dedicated to
this type of intervention.
Prognosis
The prognosis of FASD is variable depending on the type, severity, and whether treatment is issued. Prognostic disabilities are divided into primary and secondary disabilities.
Primary disabilities
The
primary disabilities of FAS are the functional difficulties with which
the child is born as a result of CNS damage due to prenatal alcohol
exposure.
Often, primary disabilities are mistaken as behavior problems, but the underlying CNS damage is the originating source of a functional difficulty,
rather than a mental health condition, which is considered a secondary
disability. The exact mechanisms for functional problems of primary
disabilities are not always fully understood, but animal studies
have begun to shed light on some correlates between functional problems
and brain structures damaged by prenatal alcohol exposure. Representative examples include:
Functional difficulties may result from CNS damage in more than one
domain, but common functional difficulties by domain include: Note that this is not an exhaustive list of difficulties.
Social communication: Intrude into conversations, inability to read nonverbal or social cues, "chatty" but without substance
Secondary disabilities
The
secondary disabilities of FAS are those that arise later in life,
secondary to CNS damage. These disabilities often emerge over time due
to a mismatch between the primary disabilities and environmental
expectations; secondary disabilities can be ameliorated with early
interventions and appropriate supportive services.
Six main secondary disabilities were identified in a University
of Washington research study of 473 subjects diagnosed with FAS, PFAS
(partial fetal alcohol syndrome), and ARND (alcohol-related
neurodevelopmental disorder):
Disrupted school experience: Suspended or expelled from school or
dropped out of school, experienced by 60% of the subjects (age 12 and
older)
Trouble with the law: Charged with or convicted of a crime, experienced by 60% of the subjects (age 12 and older)
Confinement: For inpatient psychiatric care, inpatient chemical
dependency care, or incarceration for a crime, experienced by about 50%
of the subjects (age 12 and older)
Inappropriate sexual behavior: Sexual advances, sexual touching, or
promiscuity, experienced by about 50% of the subjects (age 12 and older)
Alcohol and drug problems: Abuse or dependency, experienced by 35% of the subjects (age 12 and older)
Two additional secondary disabilities exist for adults:
Dependent living: Group home, living with family or friends, or
some sort of assisted living, experienced by 80% of the subjects (age 21
and older)
Problems with employment: Required ongoing job training or coaching,
could not keep a job, unemployed, experienced by 80% of the subjects
(age 21 and older)
Protective factors and strengths
Eight
factors were identified in the same study as universal protective
factors that reduced the incidence rate of the secondary disabilities:
Living in a stable and nurturing home for over 73% of life
Being diagnosed with FAS before age six
Never having experienced violence
Remaining in each living situation for at least 2.8 years
Experiencing a "good quality home" (meeting 10 or more defined qualities) from age 8 to 12 years old
Having been found eligible for developmental disability (DD) services
Having basic needs met for at least 13% of life
Having a diagnosis of FAS (rather than another FASD condition)
Malbin (2002) has identified the following areas of interest and
talents as strengths that often stand out for those with FASD and should
be utilized, like any strength, in treatment planning:
Participation in non-impact sports or physical fitness activities
Lifespan
One study found that the people with FAS had a significantly shorter life expectancy.
With the average life span of 34 years old, a study found that 44% of
the deaths were of "external cause", with 15% of deaths being suicides.
Epidemiology
Globally, one in 10 women drinks alcohol during pregnancy. Out of this population, 20% binge drink and have four or more alcoholic drinks per single occasion.
The use of alcohol during pregnancy occurs at different rates across
the world, potentially due to various cultural differences and
legislation. The five countries with the highest prevalence of alcohol
use during pregnancy are Ireland (60%), Belarus (47%), Denmark (46%),
the UK (41%), and the Russian Federation (37%).
In a recent count, the prevalence of having any FASD disorder was
1 person out of 20, but some people estimate it could be as high as 1
in 7.
The rates of FAS and FASD are likely to be underestimated, because of
the difficulty in making the diagnosis and the reluctance of clinicians
to label children and mothers.
FASD among Australian youth is more common in indigenous Australians. The only states that have registered birth defects in Australian youth are Western Australia, New South Wales, Victoria and South Australia. In Australia, only 12% of Australian health professionals are aware of the diagnostics and symptoms of FASD.
In Western Australia, the rate of births resulting in FASD is 0.02 per
1,000 births for non-Indigenous Australians, however among indigenous
births the rate is 2.76 per 1,000 births.
In Victoria, there have been no registered FASD related births for
indigenous Australians, but the rate for the general population in
Victoria is 0.01–0.03 per 1000 births.
There have been no dedicated FASD clinics within Western Australia, but
there are also no nationally supported diagnostic criteria anywhere in
Australia.
Passive surveillance is a prevention technique used within Australia to
assist in monitoring and establishing detectable defects during
pregnancy and childhood.
Canada
A
2015 review article estimated the overall costs to Canada from FASD at
$9.7 billion (including from crime, healthcare, education, etc.).
South Africa
In South Africa, some populations have rates as high as 9%.
United States
In the United States, alcohol use at some point during pregnancy is common and appears to be rising in prevalence.
In 2006–2010, an estimated 7.6% of pregnant women used alcohol, while
1.4% of pregnant women reported binge drinking during their pregnancy.
The highest prevalence estimates of reported alcohol use during
pregnancy were among women who are aged 35–44 years (14.3%), white
(8.3%), college graduates (10.0%), or employed (9.6%). In 2015, about 10% of pregnant women drank alcohol in the past month, and 20% to 30% drank at some point during the pregnancy. Of pregnant American women, 3.6% met criteria for an alcohol use disorder in a 2001 epidemiological study.
As of 2016, the US Centers for Disease Control estimated 3 million
women in the United States are at risk of having a baby with FASD.
FASD is estimated to affect between 1-2% and 5% of people in the United States and Western Europe. FAS is believed to occur in between 0.2 and 9 per 1,000 live births in the United States.
Using medical and other records, CDC studies have identified 0.2 to 1.5
infants with FAS for every 1,000 live births in certain areas of the
United States.
A more recent CDC study of 2010 data analyzed medical and other records
and found FAS in 0.3 out of 1,000 children from 7 to 9 years of age.
The lifetime cost per child with FAS in the United States was
estimated at $2 million (for an overall cost across the country of over
$4 billion) by the CDC in 2002.
History
Before designation
Some hold that ancient sources describe the negative effects of alcohol during pregnancy, identifying admonitions from ancient Greek, Roman, the Talmud, and the Bible. For example, Plato writes in his fourth-century B.C. Laws
(6.775): "Drinking to excess is a practice that is nowhere seemly ...
nor yet safe. ... It behooves both bride and bridegroom to be sober ...
in order to ensure, as far as possible, in every case that the child
that is begotten may be sprung from the loins of sober parents." The
sixth-century AD Talmud (Kethuboth
60b) cautions, "One who drinks intoxicating liquor will have ungainly
children." However, ancient sources rarely, if ever, distinguish
maternal alcohol consumption from paternal, and are more concerned with
conception than pregnancy. The sources can often be viewed as expressing
heredity,
that children are likely to turn out like their (alcoholic) parents,
rather than presenting the modern viewpoint that alcohol itself has an
impact.
In 1725, in the midst of the Gin Craze, British physicians petitioned the House of Commons
on the effects of strong drink when consumed by pregnant women saying
that such drinking is "too often the cause of weak, feeble, and
distempered children, who must be, instead of an advantage and strength,
a charge to their country". There are many other such historical references during that period.
Gin specifically was implicated as affecting children's health and
causing stillbirth and infant mortality, as depicted in William
Hogarth's Gin Lane. In contrast, Hogarth's Beer Street shows commerce and happiness, suggesting that the alcohol in beer was not known to have deleterious effects at this time.
In the 19th century, Benjamin Rush and Thomas Trotter lobbied against alcohol consumption during pregnancy to avoid dependence and mental deficiency in children. The teetotalism and temperance movements popularized these and other claims, including the teratogenic effects of alcohol on animal embryos, but they were often sensationalized, so much so that any finding that alcohol was harmful was largely denounced as propaganda.
A prominent observation of possible links between maternal alcohol use
and fetal damage was made in 1899 by Dr. William Sullivan, a Liverpool prison physician who noted higher rates of stillbirth for 120 alcoholic female prisoners than their sober female relatives. He suggested the causal agent to be alcohol use.
This contradicted the predominant belief at the time that heredity
caused intellectual disability, poverty, and criminal behavior, which
contemporary studies on the subjects usually concluded. A case study by Henry H. Goddard of the Kallikak family—popular in the early 1900s—represents this earlier perspective, though later researchers have suggested that the Kallikaks almost certainly had FAS. General studies and discussions on alcoholism throughout the mid-1900s were typically based on a heredity argument. Researchers were often temperance advocates and funded by like-minded organizations such as the Anti-Saloon League,
so clinicians viewed all such research with heavy skepticism. The
temperance movement effectively shut down serious research into the
subject for nearly 50 years after Prohibition. In the 1940s it was generally dismissed as superstition.
From the 1960s to the 1980s, alcohol was commonly used as a tocolytic, a method to stop preterm labor (born at less than 37 weeks gestation). The method originated with Dr. Fritz Fuchs, the chairman of the department of obstetrics and gynecology at Cornell University Medical College.
Doctors recommended a small amount of alcohol to calm the uterus during
contractions in early pregnancy or Braxton Hicks contractions. In later
stages of pregnancy, the alcohol was administered intravenously and
often in large amounts. "Women experienced similar effects as occur with
oral ingestion, including intoxication, nausea and vomiting, and
potential alcohol poisoning, followed by hangovers when the alcohol was
discontinued." Vomiting put the mother at a high risk for aspiration and was "a brutal procedure for all involved".
Because the alcohol was being given intravenously, the doctor could
continue giving the treatment to the mother long after she had passed
out, resulting in her being more intoxicated than would otherwise be
possible. Such heavy intoxication was highly likely to contribute to
FASD.
In a 2015 review, ethanol was found to be no better than a placebo
(sugar water) in suppressing preterm birth and neonatal mortality. Not
only was ethanol worse than other beta-mimetic drugs (tocolytic agents)
at postponing birth, it also led to a higher rate of low birthweight
babies, babies with breathing problems at birth, and neonatal death.
Recognition as a syndrome
In
France in 1957, Jacqueline Rouquette had described 100 children whose
parents were alcoholics in a thesis, which was not published. "She gave a
good description in certain cases of the facies" according to her
mentor, Paul Lemoine.
In 1968, Paul Lemoine of Nantes, published a study in a French medical journal about children with distinctive features whose mothers were alcoholics.
Independently, in the U.S., Christy Ulleland at University of Washington
Medical School conducted an 18-month study in 1968–1969 documenting the
risk of maternal alcohol consumption among the offspring of 11
alcoholic mothers. This study is arguably the true source of the modern understanding. The infants were studied by dysmorphologists Kenneth Lyons Jones and David Weyhe Smith, colleagues of Ulleland at University of Washington,
who identified a pattern of "craniofacial, limb, and cardiovascular
defects associated with prenatal onset growth deficiency and
developmental delay" in eight children. The pattern of malformations
indicated that the damage was prenatal. They named these defects "fetal
alcohol syndrome". News of the discovery shocked some, while others were skeptical of the findings. While many syndromes are eponymous,
i.e. named after the physician first reporting the association of
symptoms, Smith named FAS after the causal agent of the symptoms.
He reasoned that doing so would encourage prevention, believing that if
people knew maternal alcohol consumption caused the syndrome, then
abstinence during pregnancy would follow from patient education and public awareness. At the time, nobody was aware of the full range of possible birth defects from FAS or its rate of prevalence.
In 1978, within nine years of the Washington discovery, animal
studies, including non-human monkey studies carried out at the
University of Washington Primate Center by Sterling Clarren, had confirmed that alcohol was a teratogen.
By 1978, 245 cases of FAS had been reported by medical researchers, and
the syndrome began to be described as the most frequent known cause of intellectual disability. In 1979, the Washington and Nantes findings were confirmed by a research group in Gothenburg, Sweden.
Researchers in France, Sweden, and the United States were struck by how
similar these children looked, though they were not related, and how
they behaved in the same unfocused and hyperactive manner.
"Spectrum" rather than Syndrome
Over
time, subsequent research and clinical experience suggested that a
range of effects could arise from prenatal alcohol exposure. The term fetal alcohol effects (FAE) was used for alcohol-related neurodevelopmental disorder and alcohol-related birth defects.
It was initially used in research studies to describe humans and
animals in whom teratogenic effects were seen after confirmed prenatal
alcohol exposure (or unknown exposure for humans), but without obvious
physical anomalies.
Smith (1981) described FAE as an "extremely important concept" to
highlight the debilitating effects of brain damage, regardless of the
growth or facial features.
This term fell out of favor with clinicians in the 1990s because it was
often regarded by the public as a less severe disability than FAS, when
in fact its effects could be just as detrimental.
In 1996, the replacement terms ARBD and ARND were introduced. In 2002,
the US Congress mandated that the CDC develop diagnostic guidelines for
FAS and in 2004 a definition of a term that already had been used by
some in the nineties, the Fetal Alcohol Spectrum Disorder (FASD) was
adopted, to include FAS as well as other conditions resulting from prenatal alcohol exposure.
Currently, FAS is the only expression of prenatal alcohol exposure defined by the International Statistical Classification of Diseases and Related Health Problems and assigned ICD-9 and diagnoses.
Alcohol-related birth defects (ARBD), formerly known as possible fetal alcohol effect (PFAE), was a term proposed as an alternative to FAE and PFAE.
The IOM presents ARBD as a list of congenital anomalies that are linked
to maternal alcohol use but have no key features of FASD.
PFAE and ARBD have fallen out of favor because these anomalies are not
necessarily specific to maternal alcohol consumption and are not
criteria for diagnosis of FASD.
In 2013, the American Psychiatric Association introduced neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE).
Society and culture
Criminalization
Criminalization of substance use during pregnancy because of harm to the fetus or child is fiercely debated.
Elizabeth Armstrong has questioned the zero-tolerance approach taken
towards alcohol consumption during pregnancy, describing it as a moral panic.
While heavy alcohol consumption during pregnancy is known to be
damaging to the unborn child, the effects of low intakes remain
debatable, particularly in the absence of randomized controlled trials
(c.f. § Causes).
The UK's abstinence recommendation was not chosen based on scientific
evidence, but rather because it was simple advice that would ensure no
one underestimated the risk. Tennessee's 2014 fetal assault law (which expired in 2016) was criticized for not addressing alcohol use.
The law criminalized opioid use during pregnancy and resulted in women
avoiding professional medical care for fear of prosecution. A wide variety of professional organizations oppose criminalization.
Minnesota, North Dakota, Oklahoma, South Dakota, and Wisconsin have
statutory authorization for the involuntary civil commitment of women
who abuse alcohol during pregnancy.
2016 CDC controversy
In 2016, a CDC press release and infographic entitled "More than 3 million US women at risk for alcohol-exposed pregnancy" caused controversy. The CDC release contained the message "The risk is real. Why take the chance?".
Darlena Cunha of Times Magazine interpreted the infographic as telling
all women of child-bearing age not to drink at all, in case they might
accidentally fall pregnant, and called them "scare tactics" and "shaming
recommendations".
Julie Beck said that the infographic insinuated that "your womb is a
Schrodinger's box and you shouldn't pour alcohol into it unless you've
peeked in there to be 100 percent sure the coast is clear".
The CDC later clarified that the infographic was not intended to make
any new guidelines or recommendations for women who are pre-pregnant,
but rather to encourage conversations about alcohol with health
professionals.
Nonetheless, half of the pregnancies in developed countries and over
80% in developing countries are unplanned. Many women do not realize
they are pregnant during the early stages and continue drinking when
pregnant.
In fiction
In Aldous Huxley's 1932 novel Brave New World (where all fetuses are gestated in vitro in a factory), lower caste
fetuses are created by receiving alcohol transfusions (Bokanovsky
Process) to reduce intelligence and height, thus conditioning them for
simple, menial tasks. Connections between alcohol and incubating embryos
are made multiple times in the novel.
