Page 1
Preimplantation Genetic Diagnosis Oct 11 1
National Medical Policy Subject: Preimplantation Genetic Diagnosis in Assisted
Reproduction
Policy Number: NMP245
Effective Date*: October 2005
Updated: November 2006, November 2007, February 2011, October 2011
This National Medical Policy is subject to the terms in the
IMPORTANT NOTICE
at the end of this document
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage
guidelines first:
Use Source Reference/Website Link
National Coverage Determination
(NCD)
National Coverage Manual Citation
Local Coverage Determination (LCD)
Article (Local)
X Other CMS Manual System. Adjudication of Laboratory
Tests that are Excluded from Clinical Laboratory
Improvement Amendment (CLIA) Edits. (CPT
Codes noted)
https://www.cms.gov/transmittals/downloads/R8
82OTN.pdf
None Use Health Net Policy
Instructions
Medicare NCDs and National Coverage Manuals apply to ALL Medicare members
in ALL regions.
Medicare LCDs and Articles apply to members in specific regions. To access your
specific region, select the link provided under “Reference/Website” and follow the
search instructions. Enter the topic and your specific state to find the coverage
determinations for your region
If more than one source is checked, you need to access all sources as, on
occasion, an LCD or article contains additional coverage information than
contained in the NCD or National Coverage Manual.
Page 2
Preimplantation Genetic Diagnosis Oct 11 2
If there is no NCD, National Coverage Manual or region specific LCD/Article,
follow the Health Net Hierarchy of Medical Resources for guidance.
Current Policy Statement (Update October 2011 – A Medline search failed to
reveal any studies that would cause Health Net, Inc. to change its current position)
Many benefit plans specifically exclude in vitro fertilization (IVF) and
related procedures. Health Net does not cover IVF services associated
with preimplantation genetic diagnosis (PGD) unless the plan specifically
covers IVF.
Health Net, Inc. considers preimplantation genetic diagnosis (PGD) as an adjunct to
in vitro fertilization (IVF) medically necessary to deselect embryos affected by flawed
genetic make-up, when the results of the genetic test will impact clinical decision
making and/or clinical outcome, and any of the following are met:
1. Women > 35 years of age to test for suspected aneuploidy - one or a few
chromosomes above or below the normal chromosome number, e.g., three
number 21 chromosomes or trisomy 21 (characteristic of Down syndrome) is a form of aneuploidy.
2. Couples at high risk for aneuploid pregnancy (e.g., prior aneuploid pregnancy)
3. Couples at high risk for single gene disorders* who meet any of the following:
One partner has the diagnosis, is a known carrier or has a family history of a single gene, autosomal dominant chromosomal disorder
Both partners are known carriers of a single gene autosomal recessive chromosomal disorder
One partner is a known carrier of a single X-linked disorder
4. Couples who already have one child with a genetic problem and are at high risk of having another
5. There have been three or more prior failed attempts at IVF
6. Women with > 2 miscarriages (recurrent pregnancy losses) related to parental
structural chromosome abnormality
7. Repeated implantation failure defined as the absence of a gestational sac on
ultrasound at 5 weeks post-embryo transfer (e.g., > 3 embryo transfers with high quality embryos or the transfer of 10 embryos in multiple transfers)
8. To determine the sex of an embryo only when there is a documented history of
an X-linked disorder, such that deselection of an affected embryo can be made
on the basis of sex alone.
9. To evaluate human leukocyte antigen (HLA) status in families with a child with
a malignant cancer or genetic disorder who is likely to be cured or whose life
expectancy is expected to be substantially prolonged by a cord blood stem cell
transplant after all other clinical options have been exhausted, and in whom
there is no other source of a compatible bone marrow donor other than an HLA matched sibling.
Page 3
Preimplantation Genetic Diagnosis Oct 11 3
*Note: Single gene disorders include autosomal recessive diseases (e.g., cystic
fibrosis, beta-thalassemia, Tay-Sachs), autosomal dominant diseases (e.g., Marfan's
syndrome, myotonic dystrophy) and X-linked diseases (e.g., Duchenne and Becker's
muscular dystrophy, hemophilia, fragile-X syndrome).
Note: When the specific criteria noted above are met, we consider the polar
body biopsy / cleavage stage embryo biopsy procedure to obtain the cell and the
genetic test associated with PGD medically necessary.
List of Genetically Determined Disorders
Achondroplasia Adenosine deaminase deficiency
Alpha-1-antitrypsin deficiency Beta thalassemia
Cystic fibrosis Epidermolysis bullosa
Fanconi anemia Gaucher disease
Hemophilia A and B Huntington disease
Muscular dystrophy (Duchenne
and Becker)
Ornithine transcarbamylase
(OTC) deficiency
Neurofibromatosis type I Myotonic dystrophy
Phenylketonuria Retinoblastoma
Retinitis pigmentosa Sickle cell disease
Spinal muscular atrophy Tay Sachs disease
Fragile X syndrome Lesch-Nyhan syndrome
Rett syndrome Charcot-Marie-Tooth disease
Barth's syndrome Turner syndrome
Down's syndrome
Health Net, Inc. considers PGD not medically necessary for any of the following
because there is a paucity of peer-reviewed studies:
1. The genetic code associated with the condition is not known to allow diagnosis with current genetic testing techniques
2. Genetic diagnosis is uncertain, e.g., due to genetic/molecular heterogeneity or uncertain mode of inheritance
3. PGD for the purposes of carrier testing to determine carrier status of the
embryo (determination of carrier status is performed on individuals contemplating reproduction)
4. PGD for adult-onset/late-onset disorders (e.g., Alzheimer's disease; cancer predisposition)
Health Net, Inc. considers PGD investigational for any of the following because
although studies continue to be done, additional peer-reviewed studies are
necessary to determine the safety, efficacy and long-term outcomes for these scenarios:
Page 4
Preimplantation Genetic Diagnosis Oct 11 4
1. PGD for the purpose of HLA typing of an embryo to identify a future suitable
stem cell, tissue or organ transplantation donor; PGD has not been established
as the standard of care for assessing the suitability of embryos for stem cell
transplantation.
2. Testing of embryos for non-medical gender selection or non-medical traits
3. The affected or sick child has an acute medical condition prohibiting safe stem
cell transplantation or has extremely low life expectancy, such that there isn‟t
enough time for the PGD test to be developed, applied and the birth of the HLA-
matched sibling.
Codes Related To This Policy ICD-9 Codes
270.0-279.9 Other metabolic and immunity disorders
277.00-277.09 Cystic fibrosis
282.41-282.49 Thalassemias
282.60-282.69 Sickle-cell disease
284.0 Constitutional aplastic anemia
298.81 Primary hypercoagulable state
330.1 Cerebral lipidoses
359.0 Congenital hereditary muscular dystrophy
359.1 Hereditary progressive muscular dystrophy
653.70 Other fetal abnormality causing disproportion; unspecified as to
episode of care or not applicable, delivered, with or without
mention of antepartum condition, or antepartum condition or
complication
655.00-655.90 Known or suspected fetal abnormality affecting management of
mother; unspecified as to episode of care or not applicable,
delivered, with or without mention of antepartum condition, or
antepartum condition or complication
569.89.1 Elderly primigravida; unspecified as to episode of care or not
applicable, delivered, with or without mention of antepartum
condition, or antepartum condition or complication
659.60, 1, 3 Elderly multigravida
741.00-742.9 Spina bifida and other congenital anomalies of nervous system
758.0 - 758.9 Chromosomal anomalies
759.82 Marfan syndrome
793.9 Other nonspecific abnormal findings on radiological and other
examination of body structure
V17.2 Family history of other neurological diseases
V18.1 Family history of other endocrine and metabolic diseases
V18.2 Family history of anemia
V18.3 Family history of other blood disorders
V18.4 Family history of mental retardation
V19.5 Family history of congenital anomalies
V19.8 Family history of other condition
V23.81 Supervision of elderly primigravida
V23.82 Supervision of elderly multigravida
V23.89 Supervision of other high-risk pregnancy
V28.0 Screening for chromosomal anomalies by amniocentesis
Page 5
Preimplantation Genetic Diagnosis Oct 11 5
V28.1 Screening for raised alpha-fetoprotein levels in amniotic fluid
V28.2 Other screening based on amniocentesis
V28.8 Other specified antenatal screening
V82.4 Maternal postnatal screening for chromosomal anomalies
V83.31 Cystic fibrosis gene carrier
V83.89 Other genetic carrier status
CPT Codes
83898 Molecular diagnostics; amplification of patient nucleic acid (e.g.
PCR, LCR), single primer pair, each primer pair
88365 Tissue in situ hybridization, interpretation and report
89290 Biopsy, oocyte polar body or embryo blastomere, microtechnique
(for preimplantation genetic diagnosis); less than or equal to 5
embryos
89291 Biopsy, oocyte polar body or embryo blastomere, microtechnique
(for preimplantation genetic diagnosis); greater than 5 embryos
HCPCS Codes
S3625 Maternal serum triple marker screen including alpha-fetoprotein
(AFP), estriol, and human chorionic gonadotropin (hCG)
S3835 Complete gene sequence analysis for cystic fibrosis genetic testing
S3837 Complete gene sequence analysis for hemochromatosis genetic
testing
S3840 DNA analysis for germline mutations of the ret proto-oncogene for
susceptibility to multiple endocrine neoplasia type 2
S3841 Genetic testing for retinoblastoma
S3842 Genetic testing for von Hippel-Lindau disease
S3843 DNA analysis of the F5 gene for susceptibility to Factor V Leiden
thrombophilia
S3845 Genetic testing for alpha-thalassemia
S3846 Genetic testing for hemoglobin E beta-thalassemia
S3847 Genetic testing for Tay-Sachs disease
S3848 Genetic testing for Gaucher disease
S3849 Genetic testing for Niemann-Pick disease
S3851 Genetic testing for Canavan disease
S3853 Genetic testing for myotonic muscular dystrophy
S4011-S4022 In vitro fertilization
Scientific Rationale Update – October 2011 Colls et al. (2009) Preimplantation genetic diagnosis (PGD) for gender selection for
non-medical reasons has been considered an unethical procedure by several authors
and agencies in the Western society on the basis that it could disrupt the sex ratio,
that it discriminates against women and that it leads to disposal of normal embryos
of the non-desired gender. In this study, the analysis of a large series of PGD
procedures for gender selection from a wide geographical area in the USA shows
that, in general, there is no deviation in preference towards any specific gender
except for a preference of males in some ethnic populations of Chinese, Indian and
Middle Eastern origin that represent a small percentage of the US population. In
cases where only normal embryos of the non-desired gender are available, 45.5% of
the couples elect to cancel the transfer, while 54.5% of them are open to have
embryos transferred of the non-desired gender, this fact being strongly linked to
cultural and ethnic background of the parents. In addition this study adds some
Page 6
Preimplantation Genetic Diagnosis Oct 11 6
evidence to the proposition that, in couples with previous children of a given gender,
there is no biological predisposition towards producing embryos of that same gender.
El-Toukhy et al. (2010) completed a review to inform the clinician about the
application, success rates and limitations of preimplantation genetic diagnosis (PGD)
for hematologic disease to enable clinicians to offer couples with reproductive risk a
realistic view of possible treatments. The history and ethics involved in performing
PGD together with human leukocyte antigen (HLA) testing (PGD-H) to create
matched siblings suitable for hematopoietic stem cell transplant (HSCT) are
discussed. The greatest diagnostic hurdle in PGD is the paucity of molecular material
in the single embryonic cell. PGD to exclude embryos carrying serious hematologic
disease is a viable alternative to prenatal diagnosis for couples whom wish to avoid
having affected children and for whom therapeutic termination of affected
pregnancies is unacceptable. PGD is not available for all hematologic mutations, is
expensive, time consuming and does not guarantee a pregnancy. PGD-H is more
diagnostically and ethically challenging, especially when there is the time constraint
of urgent provision of HLA-matched stem cells for a sick sibling. To date there is only
a handful of reported cases of successful HSCT from siblings created by embryo
selection.
Pre-implantation genetic diagnosis (PGD) has been proposed as a method for
selecting HLA-matched embryos in order to create a tissue matched child that can
serve as a stem cell donor. After delivery of the HLA-matched baby, umbilical cord
blood (UCB) cells can be collected and cryopreserved for transplantation to the sick
sibling or the affected child. Using pre-implantation HLA typing to have a tissue-
matched child that can serve as a haematopoietic stem cell donor to save a loved
one‟s life. This is generally known as the creation of „saviour siblings‟.
Haematopoietic stem cells are found in the umbilical cord blood, bone marrow and
peripheral blood. Despite recent promising results of using stem cells from the
umbilical cord blood of so called saviour siblings for curing patients with blood
diseases and certain types of cancer, this method has been met with much
opposition. Concerns related to the risks of preimplantation genetic diagnosis (PGD)
for the child to be born, the intention to have a donor child, the limits that should be
placed on what cells or organs can be used from the child and whether the recipient
can be someone other than a sibling). Preimplantation tissue typing has been
proposed as a method for creating a tissue matched child that can serve as a
haematopoietic stem cell donor to save its sick sibling in need of a stem cell
transplant. Despite recent promising results, many people have expressed their
disapproval of this method.
Scientific Rationale Update – February 2011 Tay Sachs Disease
Per Hayes Genetic Testing Overview, (2008) “New molecular technologies for gene
amplification and detection are emerging. These new technologies may improve
preimplantation genetic diagnosis of Tay Sachs Disease (TSD), which employ single
cells to detect specific alleles on single chromosomes”. In order to develop a reliable,
robust test to generate stronger signals for single-cell preimplantation genetic
diagnosis of TSD, a new single-reaction primer system to amplify two mutation sites
simultaneously was developed. New nested primers were designed to optimize
detection of two major TSD mutations. Based on PCR-amplified product analysis, a
total efficiency of amplification was 85.3%, with an allele dropout rate (ADO) of
4.8% and 5.8% for both mutations. Although there is no evidence to suggest that
Page 7
Preimplantation Genetic Diagnosis Oct 11 7
DNA mutation analysis would not be feasible for standard prenatal diagnosis or for
preimplantation analysis prior to implantation of embryos during assisted
reproduction, no clinical trials addressing this application were identified in the
literature search.
Per Hayes, the genetic test overview of the „Ashkenazi Jewish Genetic Screening
Panel for Risk Assessment‟:
For the inclusion of Tay-Sachs disease – Rated „A‟ for the Hayes Genetic Test
Rating. (i.e. A - Established benefit. A high level of positive published evidence
regarding safety and efficacy supports use of the technology for the cited
application(s). Drugs, biologics, and devices with an A rating have FDA approval,
but not necessarily for the specific clinical application).
Altaruscu et al. (2007) Preimplantation genetic diagnosis (PGD) for single gene
defects is described for a family in which each parent is a carrier of both Tay-Sachs
(TS) and Gaucher disease (GD). A multiplex fluorescent polymerase chain reaction
protocol was developed that simultaneously amplified all four familial mutations and
10 informative microsatellite markers. In one PGD cycle, seven blastomeres were
analysed, reaching a conclusive diagnosis in six out of seven embryos for TS and in
five out of seven embryos for GD. Of the six diagnosed embryos, one was wild type
for both TS and GD, and three were wild type for GD and carriers of TS. Two
remaining embryos were compound heterozygotes for TS. Two transferable embryos
developed into blastocysts (wt/wt and wt GD/carrier TS) and both were transferred
on day 5. This single cycle of PGD resulted in a healthy live child. Allele drop-out
(ADO) was observed in three of 34 reactions, yielding an 8% ADO rate. The
occurrence of ADO in single cell analysis and undetected recombination events are
primary causes of misdiagnosis in PGD and emphasize the need to use multiple
polymorphic markers. So far as is known, this is the first report of concomitant PGD
for two frequent Ashkenazi Jewish recessive disorders.
Fragile X Syndrome
Per Hayes (2008) Current evidence suggests that the use of the genetic test to
identify carriers of the premutation, or for preimplantation and prenatal genetic
testing may benefit carriers and assist family planning. There is no evidence for the
clinical utility of a general population-screening program.
Preimplantation and prenatal genetic testing for fragile X syndrome has been
investigated in several studies that provide sufficient evidence to support the validity
of the test. Furthermore, there is evidence that prenatal genetic testing informs
decision-making and provides the option of terminating affected pregnancies.
Successful unaffected pregnancies have also been achieved using preimplantation
genetic diagnosis.
Hayes rating for genetic testing for fragile x syndrome:
B – for preimplantation testing for CGG repeat length in embryos from carrier
mothers with a known premutation in the FMR1 gene.
Malcov et al. (2007) Fragile X syndrome is caused by a dynamic mutation in the
FMR1 gene. Normal individuals have <55 CGG repeats in the 5 untranslated region,
premutation carriers have 55-200 repeats and a full mutation has >200 repeats.
Female carriers are at risk of having affected offspring. A multiplex nested
polymerase chain reaction protocol is described for preimplantation genetic diagnosis
(PGD) of fragile X syndrome with simultaneous amplification of the CGG-repeat
Page 8
Preimplantation Genetic Diagnosis Oct 11 8
region, the Sry gene and several flanking polymorphic markers. The amplification
efficiency was > or =96% for all loci. The allele dropout rate in heterozygotic females
was 9% for the FMR1 CGG-repeat region and 5-10% for the polymorphic markers.
Amplification failure for Sry occurred in 5% of single leukocytes isolated from males.
PGD was performed in six patients who underwent 15 cycles. Results were confirmed
in all cases by amniocentesis or chorionic villous sampling. Five clinical pregnancies
were obtained (31% per cycle), four of which resulted in a normal delivery and one
miscarried. This technique is associated with high efficiency and accuracy and may
be used in carriers of full mutations and unstable high-order premutations.
Spinal Muscular Atrophy (SMA)
Hayes (2008) Prenatal diagnosis is typically performed by PCR-RFLP, but may also
involve sequence analysis and/or linkage studies. To avoid false-negative results,
testing for maternal cell contamination is often performed by analysis of polymorphic
markers. Preimplantation genetic diagnosis (PGD) has also been carried out using
PCR-RFLP or allele-specific PCR.
The confirmation of SMA in an individual by genetic testing may also affect the
reproductive decision-making of family members. Meldrum et al. (2007) inquired
about the effect of a child‟s SMA diagnosis on the future reproductive decisions of the
parents. Of 103 respondents questioned in this retrospective analysis, 53% reported
that they chose to limit future pregnancies, while 21% chose to undergo prenatal
diagnosis in a subsequent pregnancy, either by CVS, amniocentesis, and/or PGD. In
addition to affecting future pregnancies, families perceived that the genetic diagnosis
of SMA also helped them connect with appropriate support resources.
A total of 11 open studies involving SMA patients are listed on the ClinicalTrials.gov
website. Of these, 9 are designed to study disease progression, prognosis, or
treatment. Two studies are examining specific methodologies for the genetic
diagnosis of SMA; these are listed below:
Quantitative Analysis of SMN1 and SMN2 Gene Based on DHPLC System:
Establishing a Novel Highly Efficient and Reliable SMA Carrier Screening Test
(NCT00155168)
Establishing Novel Detection Techniques for Various Genetic-Related Diseases by
Applying DHPLC Platform (NCT00154960)
Hayes (2009) rates Spinal Muscular Atrophy (SMA) for Progressive Muscle Weakness
as noted below:
For the prenatal diagnosis or preimplantation genetic diagnosis of SMA in the
pregnancy of two known carriers – Rated as B
Giardet et al. (2008) Two multiplex PGD protocols were developed allowing the
detection of the common homozygous deletion of the telomeric spinal muscular
atrophy gene (SMN1), together with two microsatellites located on each side of
SMN1. The molecular genetics laboratory of the university hospital in Montpellier.
PATIENT(S): A couple who had already given birth to a child affected with SMA.) In
vitro fertilization using intracytoplasmic sperm injection (ICSI) and blastomere
biopsy. MAIN OUTCOME MEASURE(S): Improvement of PGD for SMA. Two different
multiplex protocols were set up on 81 (multiplex A) and 64 single cells (multiplex B)
from normal controls, affected patients, and individuals with homozygous SMN2
deletion. In one PGD cycle that used one of these protocols, two embryos were
Page 9
Preimplantation Genetic Diagnosis Oct 11 9
transferred, which resulted in the birth of a healthy baby. Analysis of microsatellite
markers in addition to the SMN1 deletion allows the detection of contamination, the
study of ploidy of the biopsied blastomeres, and the performance of an indirect
genetic diagnosis, thereby increasing the reliability of the results. This PGD assay
may be applied to all families with the common deletion of SMN1 and also to couples
in whom one of the partners carries a small intragenic mutation in SMN1, identified
in about 6% of affected individuals who do not lack both copies of SMN1.
Shaw et al. (2008) Thirty-three members of 7 families participated in carrier test and
disease detection of SMA. Prenatal genetic diagnosis was performed if both parents
were carriers or any family members had SMA. DNA extracted from blood, chorionic
villi and amniotic fluid was amplified and used for DHPLC. Twenty SMA carriers,
seven SMA affected cases, and six normal individuals were identified. SMA status
was demonstrated by genotyping and total copy number determinations of SMN1
and SMN2. Families 1-3 were classified as group one (SMA affecting previously born
child). Group two, comprising families 4 and 5, had lost a child due to an unknown
muscular disease. Group three (SMA-affected parent) comprised families 6 and 7;
carrier testing was done. DHPLC prenatal genetic diagnosis was made in seven
pregnancies, one in each family (affected, n=2; carrier, n=3; normal, n=2).
Pregnancy was terminated for the two affected fetuses. The others were delivered
uneventfully and SMA free. DHPLC prenatal diagnosis of SMA and determination of
SMA status in adults is possible, and SMN1 and SMN2 copy numbers can be
determined.
Alpha-1-antitrypsin deficiency
Alpha-1 antitrypsin (AAT) deficiency emphysema is an inherited disorder affecting
approximately 100,000 Americans. Affected patients have little or no blood and
tissue levels of AAT (also called alpha-1 protease inhibitor, alpha1-PI, or A1-PI),
which protects the lung from destruction by enzymes in the lung that normally digest
bacteria and other invaders. Unchecked, this enzyme progressively damages healthy
lung tissue leading to decreased lung function and emphysema. The prognosis for
patients with high-risk phenotypes for AAT deficiency emphysema is poor although
symptomatic treatments and more definitive lung surgery are options.
Cystic Fibrosis
Norton et al. (2008) Recent advances in genetic technology have substantial
implications for prenatal screening and diagnostic testing. The past year has also
seen important changes in recommendations surrounding the genetic counseling that
occurs in the provision of such testing. Multiple screening tests for single gene
disorders, chromosomal abnormalities, and structural birth defects are now routinely
offered to all pregnant women. Ethnicity-based screening for single gene disorders
includes Tay Sachs disease, cystic fibrosis, and hemoglobinopathies. Recent
discussions have involved, not only additional disorders that warrant screening, but a
re-evaluation of the paradigm of selecting disorders for population-based screening.
Testing for chromosomal abnormalities has seen the introduction of first-trimester
screening, as well as strategies to improve detection through sequential testing.
Changes in recommendations for screening compared with diagnostic testing, and a
move away from maternal age-based dichotomizing of testing, have had major
implications for provision of genetic counseling by providers of prenatal care.
Advances in genetic testing have resulted in tremendous benefits to patients, and
challenges to providers. New approaches to education and counseling are needed to
assure that all patients receive a complete and balanced review of their prenatal
genetic-testing options.
Page 10
Preimplantation Genetic Diagnosis Oct 11 10
Fanconi Anemia
Modern Ashkenazi Jewish (AJ) populations (Ashkenazic Jews or Ashkenazim)
descended from the Jewish communities of Germany, Poland, Austria, and Eastern
Europe. Approximately 90% of the 5.7 million individuals of Jewish descent in the
USA today are of AJ origin. Certain childhood-onset autosomal recessive genetic
disorders are more common among the AJ community including Tay-Sachs disease,
Canavan disease, familial dysautonomia, Bloom syndrome, Fanconi anemia group C,
Gaucher disease, mucolipidosis type IV, Niemann-Pick disease type 1A, cystic
fibrosis, and primary dystonia type 1 (torsion dystonia). Over the last few decades,
the molecular basis of these diseases has been elucidated providing the tools and the
opportunity to perform preconceptual carrier screening for these disorders in this
ethnic group. The relatively homogeneous genetic make-up of the AJ population has
resulted in there being a relatively limited number of disease-causing sequence
variants accounting for the majority of cases of each disease which has allowed for
the development of screening panels with a high level of sensitivity and specificity for
the AJ population. As a result of the autosomal recessive mode of inheritance for
these disorders, if both members of a couple are carriers, they have a 25% chance
of having a child with the disorder. Fifteen autosomal recessive disorders were
reviewed in order to determine whether or not they should be included in an AJ
screening panel. The 15 disorders are: alpha-1-antitrypsin deficiency (AAD), Bloom
syndrome (BLM), Canavan disease (CD), CF, deafness neurosensory autosomal
recessive 1 (DFNB1), FD, familial hyperinsulinism (FHI), Fanconi anemia type C
(FAC), Gaucher disease type 1 (GD), glycogen storage disease type 1A (GSD), maple
syrup urine disease type 1b (MSUD), mucolipidosis type IV (MLIV), Niemann-Pick
disease types A and B (NPDA&B), nonclassical congenital adrenal hyperplasia
(NCAH), and Tay-Sachs disease (TSD). There is controversy, however, surrounding
which diseases should be included in such screening panels. While serious, generally
fatal disorders such as Tay-Sachs disease and Canavan disease are clear candidates
for screening; the argument is not as clear for disorders with variable clinical
presentation and reduced penetrance such as Gaucher disease or primary dystonia.
Fares et al. (2008) completed a study, with a database containing the results of 410
genotyping assays was screened. Ten thousand seventy eight nonselected healthy
members of the AJ population were tested for carrier status for the following
diseases; Gaucher disease (GD), cystic fibrosis (CF), Familial dysautonomia (FD),
Alpha 1 antitrypsin (A1AT), Mucolipidosis type 4 (ML4), Fanconi anemia type C
(FAC), Canavan disease (CD), Neimann-Pick type 4 (NP) and Bloom syndrome
(BLM). The results demonstrated that 635 members were carriers of one mutation
and 30 members were found to be carriers of two mutations in the different genes
related to the development of the above mentioned diseases. GD was found to have
the highest carrier frequency (1:17) followed by CF (1:23), FD (1:29), A1AT (1:65),
ML4 (1:67) and FAC (1:77). The carrier frequency of CD, NP and BLM was 1:82,
1:103 and 1:157, respectively. The frequency of the disease-causing mutations
screened routinely among the AJ population indicated that there are rare mutations
with very low frequencies. The screening policy of the disease-causing mutations
should be reevaluated and mutations with a high frequency should be screened,
while rare mutations with a lower frequency may be tested in partners of carriers.
Hemophilia A for Hemophilia A/Factor 8 Deficiency
Laurie et al. (2010) Preimplantation genetic diagnosis (PGD) is an option for couples
at risk of having a child with hemophilia A (HA). Although many clinics offer PGD for
HA by gender selection, an approach that detects the presence of the underlying F8
Page 11
Preimplantation Genetic Diagnosis Oct 11 11
mutation has several advantages. The objection was to develop and validate analysis
protocols combining indirect and direct methods for identifying F8 mutations in single
cells, and to apply these protocols clinically for PGD. A panel of microsatellite
markers in linkage disequilibrium with F8 were validated for single-cell multiplex
polymerase chain reaction. For point mutations, a primer extension genotyping assay
was included in the multiplex. Amplification efficiency was evaluated using buccal
cells and blastomeres. Four clinical PGD analyses were performed, for two families.
Results: Across all validation experiments and the clinical PGD cases, approximately
80% of cells were successfully genotyped. Following one of the PGD cycles, healthy
twins were born to a woman who carries the F8 intron 22 inversion. The PGD
analysis for the other family was complicated by possible germline mosaicism
associated with a de novo F8 mutation, and no pregnancy was achieved.
Conclusions: PGD for the F8 intron 22 inversion using microsatellite linkage analysis
was validated by the birth of healthy twins to one of the couples. The other family's
situation highlighted the complexities associated with de novo mutations, and
possible germline mosaicism. As many cases of HA result from de novo mutations,
these factors must be considered when assessing the reproductive options for such
families.
Neurofibromatosis Type 1 (NF1)
Per Hayes (2010) NF1 gene testing is a complex, multistep process that may involve
protein truncation testing (PTT) to identify variants leading to premature truncation
of the NF1 protein, and sequence analysis of genomic DNA and/or messenger RNA
(mRNA) to look for base-pair substitutions, small deletions or insertions, and variants
affecting splicing of the NF1 gene. It may also involve multiplex ligation-dependent
probe amplification (MLPA), fluorescence in situ hybridization (FISH), and/or array-
based comparative genomic hybridization (aCGH) to test specifically for larger
genomic imbalances such as multiexon or whole-gene deletions. NF1 gene testing
may be considered for patients exhibiting the classic signs of NF1, for either
diagnostic confirmation or for identification of the causative gene variant in cases
where the testing of family members (including at-risk fetuses) is desired. It may
also be used to establish a diagnosis in patients demonstrating features of NF1 who
do not yet fulfill the clinical diagnostic criteria (including infants and children who
have not yet developed enough features for a diagnosis, or patients with an atypical
clinical presentation). In addition, prenatal and preimplantation genetic diagnosis
may be used to diagnose NF1 in the offspring of affected individuals.
Currently, genetic testing is considered unnecessary for confirming a diagnosis of
NF1 in clinically diagnosed individuals or for managing their care. However, it has
been suggested that NF1 gene testing may be useful in cases with an atypical
presentation or in individuals who are suspected of having NF1 but do not fulfill the
criteria for a clinical diagnosis (for example, in young children who have not yet
developed enough features to establish a diagnosis). In these cases, a positive gene
test may also allow for earlier genetic counseling and risk assessment, earlier
monitoring for complications, and earlier initiation of interventions for developmental
delays or intellectual disabilities. While data supporting the utility of NF1 gene testing
in the above cases were not identified, studies do support the use of NF1 gene
testing in patients desiring prenatal or preimplantation genetic diagnosis.
The main limitation of studies demonstrating the clinical utility of NF1 gene testing in
reproductive decision making is that most were case series involving few NF1
patients, although obtaining larger patient populations is unlikely due to the nature
Page 12
Preimplantation Genetic Diagnosis Oct 11 12
of the testing (i.e., prenatal and preimplantation genetic diagnosis are much less
common than the testing of symptomatic individuals)
HAYES RATING FOR GENETIC TEST for Neurofibromatosis Type 1 (NF1)
For identification of the causative gene variant in NF1 patients desiring prenatal
or preimplantation genetic diagnosis (or the testing of other at-risk family
members) – rated C.
For the prenatal or preimplantation genetic diagnosis of NF1 in the pregnancies
of affected individuals – Rated C
Huntington’s Disease (HD)
Per Hayes (2008) Genetic testing for HD is used for diagnostic, predictive, and
prenatal or preimplantation genetic diagnosis purposes. Symptomatic patients with
or without a family history may benefit from diagnostic testing for HD. Asymptomatic
individuals with a family history may undergo predictive testing to define personal
risk or risk of transmission. Prenatal testing for HD may be indicated for
asymptomatic couples with a family history of HD. Preimplantation testing to
deselect embryos with HD allele(s) may be indicated for couples carrying penetrant
HD alleles.
Genetic testing for HD may be categorized by three purposes, which include
diagnostic (with or without family history), predictive (personal or risk of
transmission), and prenatal or preimplantation; in all, six groups of patients may
benefit:
Diagnostic:
Patients (probands) suspected of having HD in the absence of a family history of
HD to confirm diagnosis.
Patients (probands) suspected of having HD from families in which there is a
history of HD to confirm diagnosis.
Predictive:
Asymptomatic individuals from families in which there is a history of HD to
define personal risk.
Asymptomatic individuals from families in which there is a history of HD to
define risk of transmission.
Prenatal or preimplantation:
Fetuses from families in which there is a history of HD to define risk by prenatal
testing.
Embryos from parents with penetrant genetic variation for HD to avoid risk for
offspring by preimplantation testing
Genetic Test Evaluation Overview (April 29, 2008)
For testing for CAG repeat length for diagnosis of HD in patients (probands)
suspected of having HD in the absence of a family history of HD - rated C
For testing for CAG repeat length for diagnosis of HD in patients (probands)
suspected of having HD from families in which there is a history of HD – Rated
D1
For predictive testing for CAG repeat length in asymptomatic individuals from
families in which there is a history of HD to define personal risk - rated D2
Page 13
Preimplantation Genetic Diagnosis Oct 11 13
For predictive testing for CAG repeat length in asymptomatic individuals from
families in which there is a history of HD to define risk of transmission – rated B
For prenatal testing for CAG repeat length in fetuses from families in which there
is a history of HD - rated B
For preimplantation testing for CAG repeat length in embryos from parents with
penetrant genetic variation for HD- rated C
Myotonic Dystrophy Types 1 and 2 (DM1 / DM2)
Per Hayes (2009) The clinical circumstances in which genetic testing for DM1 and
DM2 may be appropriate are: when DM is suspected, or to definitively confirm a
clinical diagnosis; for asymptomatic adults at risk for DM through a family history of
the disorder; prenatal diagnosis in pregnant women at risk for offspring with
congenital DM; and preimplantation genetic diagnosis (PGD) of DM.
Genetic Test Evaluation Overview Hayes (2009, updated 2010)
For prenatal diagnosis or preimplantation genetic diagnosis of DM1 in couples in
which one or more members have been confirmed to be affected with, or be a
presymptomatic carrier of, DM1 through genetic testing – rated B
For prenatal diagnosis or preimplantation genetic diagnosis of DM2 – rated D2
Charcot-Marie-Tooth Type 1A (CMT1)
Per Hayes (2009) Individuals with a differential diagnosis of CMT1 may undergo this
test to confirm the diagnosis and establish CMT subtype. Asymptomatic individuals
with a family history of CMT1A may pursue testing to clarify their personal risk and
risk of transmission to offspring. Prenatal diagnosis and preimplantation genetic
diagnosis for CMT1A provides options for couples at risk to pass on a CMT1A
duplication.
Identifying the genetic cause can also provide reproductive options such as prenatal
diagnosis or preimplantation genetic diagnosis, which could prevent the birth of an
affected offspring if desired. CMT1A duplication testing can confirm the presence of a
familial deletion and could be the first step in the process of identifying
asymptomatic family members at risk to pass the duplication on to their children.
Prenatal and preconception testing for CMT1A has been shown to potentially have
clinical utility. Prenatal diagnosis for a variable, adult-onset disorder such as CMT1A
is not commonly requested, although this decision is patient-specific. On the other
hand, preimplantation genetic diagnosis has been shown to be successful for couples
at risk of having a child with CMT1A, and has clinical utility for individuals with
CMT1A in the process of family planning.
Molecular genetic testing for CMT1A may be appropriate for the following individuals:
For a couple planning a pregnancy and interested in prenatal or preimplantation
genetic diagnosis.
Genetic Test Evaluation Overview Hayes (2010 updated)
For prenatal or preimplantation genetic diagnosis of CMT1A – rated B.
Per the American Congress of Obstetricians and Gynecologists (ACOG). ACOG
Committee Opinion. Number 430 • March 2009. Preimplantation Genetic Screening
for Aneuploidy states the following:
“Preimplantation genetic screening differs from preimplantation genetic diagnosis for
single gene disorders and was introduced for the detection of chromosomal
Page 14
Preimplantation Genetic Diagnosis Oct 11 14
aneuploidy. Current data does not support a recommendation for preimplantation
genetic screening for aneuploidy using fluorescence in situ hybridization solely
because of maternal age. Also, preimplantation genetic screening for aneuploidy
does not improve in vitro fertilization success rates and may be detrimental. At this
time there are no data to support preimplantation genetic screening for recurrent
unexplained miscarriage and recurrent implantation failures; its use for these
indications should be restricted to research studies with appropriate informed
consent. Preimplantation genetic screening differs from preimplantation genetic
diagnosis (PGD) for single gene disorders. In order to perform genetic testing for
single gene disorders, PGD was introduced in 1990 as a component of in vitro
fertilization programs. Such testing allows the identification and transfer of embryos
unaffected by the disorder in question and may avoid the need for pregnancy
termination. Assessment of polar bodies as well as single blastomeres from cleavage
stage embryos has been reported, although the latter is the approach most widely
practiced. Preimplantation genetic diagnosis has become a standard method of
testing for single gene disorders, and there have been no reports to suggest adverse
postnatal effects of the technology. Preimplantation genetic diagnosis has been used
for diagnosis of translocations and single-gene disorders, such as cystic fibrosis, X-
linked recessive conditions, and inherited mutations, which increase one‟s risk of
developing cancer.
In contrast, in the latter half of the 1990s, preimplantation genetic screening was
introduced for the detection of chromosomal aneuploidy (2–4). Aneuploidy leads to
increased pregnancy loss with increasing maternal age and also was thought to be a
major cause of recurrent pregnancy loss in patients using assisted reproductive
technologies. However, when compared with the molecular diagnostics available for
PGD of single gene disorders, the current technologies available for preimplantation
genetic screening for aneuploidy are more limited. Preimplantation genetic screening
using fluorescence in situ hybridization is constrained by the technical limitations of
assessing the numerical status of each chromosome. Typically assessed are the
chromosome abnormalities associated with common aneuploidies found in
spontaneous abortion material, and because of this, and other limitations noted in
this Committee Opinion, a significant false-negative rate exists. Therefore, this form
of testing should be considered a screening test, and not a diagnostic test, as is the
case for PGD for single gene disorders.
Because preimplantation chromosome assessment tests a single cell, there are
certain limitations:
Testing a single cell prohibits confirmation of results.
There is a limit to the number of tests that can be done with a single cell.
Embryo mosaicism of normal and aneuploid cell lines may not be clinically
significant.
Guidelines for counseling on limitations of this screening have been developed by the
American Society for Reproductive Medicine.
Recommendations of ACOG:
Current data does not support a recommendation for preimplantation genetic
screening for aneuploidy using fluorescence in situ hybridization solely because
of maternal age.
Preimplantation genetic screening for aneuploidy does not improve in vitro
fertilization success rates and may be detrimental.
Page 15
Preimplantation Genetic Diagnosis Oct 11 15
At this time there are no data to support preimplantation genetic screening for
recurrent unexplained miscarriage and recurrent implantation failures; its use for
these indications should be restricted to research studies with appropriate
informed consent.
Scientific Rationale Initial With recent advances in genetics, there are a good number of inherited disorders,
which can now be diagnosed at a molecular level. For couples who are carriers or
affected by any of a variety of genetic diseases and are at high risk for transmitting
it to their offspring, it is currently possible to detect the disorder during pregnancy.
This is done by one of two approaches: chorionic villus sampling in the first trimester
or amniocentesis in the second trimester. However the couples have the dilemma of
whether or not to terminate the pregnancy if the genetic abnormality is present. In
some cases this may also not be a viable option for religious or moral reasons. An
alternative would then be to diagnose the condition in embryos before the pregnancy
is established. Only the unaffected embryos would then be transferred to the uterus.
This new technique that combines advances in molecular genetics and assisted
reproductive technologies is referred to as preimplantation genetic diagnosis (PGD).
It does not involve the manipulation of genes in embryos; rather, it selects among
embryos. PGD involves several steps: the creation of an embryo via IVF; the removal
of one or two cells from the embryo; the genetic testing of these cells for specific
genetic conditions; and the subsequent transfer of unaffected embryos to a woman‟s
uterus.
Currently, IVF is the only available technique for obtaining an embryo in the very
early stages of development. One to two single cells, blastomeres, are removed from
early cleavage stage embryos (6–8-cell stage) at approximately 3 days' post-
fertilization. The blastomere contains genetic material that can be analyzed to
identify three categories of disorders, including aneuploidy and structural
chromosomal abnormalities, single-gene disorders, and X-linked disorders. Although
couples with a high risk of transmitting a genetic defect to their offspring may have
normal fertility, they would need to go through the IVF procedure to provide
embryos for screening. Fertility specialists can use the results of this analysis to
select only mutation-free embryos for implantation into the mother's uterus, hence
preventing the physical and psychological trauma associated with possible
termination. Clinical and practical considerations include that the embryo must be
healthy enough to survive the procedure. It is estimated that only 2.5% of eggs
collected will form a viable unaffected pregnancy. Maternal age is an important
factor, particularly for aneuploidy screening in women older than 35 years of age, as
this increases the likelihood of finding a chromosomal abnormality and decreases the
success rate of IVF. With PGD, couples are much more likely to have healthy babies.
Although PGD has been practiced for years, only a few specialized centers worldwide
offer this procedure.
PGD should be offered for 3 major groups of disease, including (1) sex-linked
disorders, (2) single gene defects, and (3) chromosomal disorders. X-linked diseases
are passed to the child through a mother who is a carrier. They are passed by an
abnormal X chromosome and manifest in sons, who do not inherit the normal X
chromosome from the father. Affected fathers have sons who are not affected, and
their daughters have a 50% risk of being carriers if the mother is healthy. Sex-linked
recessive disorders include hemophilia, fragile X syndrome, most of the
neuromuscular dystrophies (currently > 900 neuromuscular dystrophies are known),
and hundreds of other diseases. Sex-linked dominant disorders include Rett
Page 16
Preimplantation Genetic Diagnosis Oct 11 16
syndrome, incontinentia pigmenti, pseudohyperparathyroidism, and vitamin D–
resistant rickets. This genetic test is currently available to couples whose offspring
are at a high risk (25-50%) for a specific genetic condition due to one or both
parents being carriers or affected by the disease. Also the genetic code associated
with the condition must be known in order to allow diagnosis. Currently, it is not
feasible to routinely screen women at lower risks, such as women over age 35 for
Downs Syndrome, since the means of establishing a pregnancy is with the help of
IVF.
PGD is used to identify single gene defects such as cystic fibrosis, Tay-Sachs disease,
sickle cell anemia, and Huntington disease. In such diseases, the molecular
abnormality is detectable with molecular techniques using PCR amplification of DNA
from a single cell. Although progress has been made, some single gene defects have
a wide variety of rare mutations (e.g., cystic fibrosis has approximately 1000 known
mutations). Only 25 of these mutations are currently routinely tested. Because most
of these rare mutations are not routinely tested, a parent without any clinical
manifestations of cystic fibrosis could be a carrier. This allows the possibility for a
parent carrying a rare mutation gene to be tested as negative but still have the
ability to pass on the mutant cystic fibrosis gene. The last group includes
chromosomal disorders in which a variety of chromosomal rearrangements, including
translocations, inversions, and deletions, can be detected using FISH. Some parents
may have never achieved a viable pregnancy without using PGD because previous
conceptions resulted in chromosomally unbalanced embryos and were spontaneously
miscarried.
The risk of aneuploidy in children increases as women age. The chromosomes in the
egg are less likely to divide properly, leading to an extra or missing chromosome in
the embryo. The rate of aneuploidy in embryos is greater than 20% in mothers aged
35-39 years and is nearly 40% in mothers aged 40 years or older. The rate of
aneuploidy in children is 0.6-1.4% in mothers aged 35-39 years and is 1.6-10% in
mothers older than 40 years. The difference in percentages between affected
embryos and live births is due to the fact that an embryo with aneuploidy is less
likely to be carried to term and will most likely be miscarried, some even before
pregnancy is suspected or confirmed. Therefore, using PGD to determine the
chromosomal makeup of embryos increases the chance of a healthy pregnancy and
reduces the number of pregnancy losses and affected offspring with so-called serious
inherited disorders such as Tay Sachs; Trisomies 13, 18, and 21; cystic fibrosis;
muscular dystrophy; Huntington disease; Lesch-Nyhan; and neurofibromatosis.
PDG is also presently has much wider indications than prenatal diagnosis, including
common diseases with genetic predisposition and preimplantation human leukocyte
antigen typing, with the purpose of establishing potential donor progeny for stem cell
treatment of siblings. Many hundreds of apparently healthy, unaffected children have
been born after preimplantation genetic diagnosis, presenting evidence of its
accuracy, reliability and safety. Preimplantation genetic diagnosis appears to be of
special value for avoiding age-related aneuploidies in patients of advanced
reproductive age, improving reproductive outcome, particularly obvious from their
reproductive history, and is presently an extremely attractive option for carriers of
balanced translocations to have unaffected children of their own. Many people fear
that PGD will be used to select a child of a preferred sex. PGD could also be used in
attempts to select a future child's cosmetic, behavioral, and other non-disease traits.
However, the genetic laws of independent assortment make it difficult for PGD to be
used for any traits that depend on two or more genes. Thus, PGD provides an
Page 17
Preimplantation Genetic Diagnosis Oct 11 17
alternative to germline modification as a way to prevent the births of children with
serious genetic diseases, most of which are single-gene disorders, but does not open
the door to escalating and species-altering applications.
Research continues in the area of PGD. There is now a rapidly growing list of
disorders for which PGD has been applied successfully, including cystic fibrosis, Tay-
Sachs disease, hemophilia A and B, retinitis pigmentosa, numerous inborn errors of
metabolism, fragile X syndrome, Duchenne muscular dystrophy, and chromosomal
abnormalities, to name a few. The risks of PGD are similar to risks for IVF, namely
multiple-fetal pregnancies and the twofold increased risk for major birth defects and
low birth weight. Preliminary studies show no increased risk for spontaneous
abortions. The data from long-term follow-up of children conceived after PGD,
however, have yet to be collected.
Review History
October 2005 Medical Advisory Council initial approval
November 2006 Medical Advisory Council - no changes
November 2007 Update – no revisions
February 2011 Update. Added Medicare Table. No revisions.
October 2011 Update. No revisions
Patient Education Websites
English
1. MedlinePlus. Genetic counseling and prenatal diagnosis. Available
at:http://www.nlm.nih.gov/medlineplus/ency/article/002053.htm
2. Human Genome Program. Gene Testing. Available at:
http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetest.shtml
3. Medical World Search. Preimplantation Genetics Diagnosis for Preventing Birth
Defect, Making Designer Babies or Creating Babies To Help Sick Siblings -- Why?
What? How? Right or Wrong? Available at:
http://www.mwsearch.com/creatingbaby.html
4. Office of Genomics & Disease Prevention, Centers for Disease Control and
Prevention. Available at: http://www.cdc.gov/genomics/
Spanish
1. MedlinePlus. Asesoramiento genético y diagnóstico prenatal. Available at:
http://www.nlm.nih.gov/medlineplus/spanish/ency/article/002053.htm
2. Información sobre la Oficina de Genómica y Prevención de Enfermedades de los
CDC. Available at: http://www.cdc.gov/genomics/spanish/aboutsp.htm
3. March of Dimes Birth Defects. Available at: http://www.nacersano.org/
This policy is based on the following evidence-based guidelines:
1. American College of Obstetricians and Gynecologists, American College of
Medical Genetics: Preconception and Prenatal Carrier Screening for Cystic
Fibrosis: Clinical and Laboratory Guidelines. Washington, DC; American College
of Obstetrics and Gynecology; October, 2001. Available at: http://www.mlo-
online.com/ce/pdfs/oct02.pdf
2. American Society for Reproductive Medicine, Society for Assisted Reproductive
Technology: A practice committee report: Preimplantation genetic diagnosis.
Birmingham, Ala. June 2001. Available at:
www.asrm.org/Media/Practice/practice.html
Page 18
Preimplantation Genetic Diagnosis Oct 11 18
3. National Ethics Committee on Assisted Human Reproduction. Guidelines for
Preimplantation Genetic Diagnosis in New Zealand. Consultation Document.
September 2004. Available at:
http://www.newhealth.govt.nz/necahr/guidelines/preimplantationgeneticdiagnos
is-consultation0904.pdf
4. Thornhill AR, deDie-Smulders CE, Geraedts JP, et al. European Society of Human
Reproduction and Embryology (ESHRE) PGD Consortium. Best practice guidelines
for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic
screening (PGS). 2005. Available at:
http://humrep.oxfordjournals.org/cgi/content/full/20/1/35#SEC4
5. Developments in infertility therapy. Diagnosis of genetic disease in embryos.
Australian Family Physician Vol. 34, No. 3, March 2005. Available at:
www.asrm.org/Media/Practice/practice.html
6. International Working Group on Preimplantation Genetics, International
Congress of Human Genetics: Preimplantation Genetic Diagnosis: Experience of
Three Thousand Cycles. Report of the 11th Annual Meeting of International
Working Group on Preimplantation Genetics, in association with 10th
International Congress of Human Genetics. Vienna, Austria; May, 2001.
Available at: http://216.242.209.125/11m.shtml
7. American Society For Reproductive Medicine. Preimplantation Genetic Diagnosis
Fact Sheet. 12/96. Available at: http://www.hygeia.org/pgd.htm
8. Preimplantation genetic testing: a Practice Committee opinion. Practice
Committee of the Society for Assisted Reproductive Technology; Practice
Committee of the American Society for Reproductive Medicine. Fertil Steril
2007;88:1497–504.
9. Hayes. Medical Technology Directory. Genetic Testing for Tay-Sachs Disease.
Updated March 6, 2008.
10. Hayes. Genetic Test Overview. Fragile X Syndrome (FMR1) for Mental
Retardation. August 7, 2008
11. Hayes. Genetic Test Overview. Y Chromosome Microdeletion Analysis for Male
Infertility. November 14, 2008.
12. American Congress of Obstetricians and Gynecologists (ACOG). ACOG
Committee Opinion. Number 430 • March 2009. Preimplantation Genetic
Screening for Aneuploidy. Available at:
http://www.acog.org/publications/committee_opinions/co430.cfm
13. Hayes. Genetic Test Overview. Spinal Muscular Atrophy (SMA) for Progressive
Muscle Weakness. January 23, 2009.
14. Hayes. Genetic Test Evaluation Overview. Ashkenazi Jewish Genetic Screening
Panel for Risk Assessment. February 18, 2009
15. Hayes. Genetic Test Overview. COL1A1 and COL1A2 Testing for Osteogenesis
Imperfecta Types I to IV. February 20, 2009.
16. Hayes. Genetic Test Overview. GTE Report: Charcot-Marie-Tooth Type 1A
(PMP22). Published: August 5, 2008. Latest Update Search: Aug 23, 2010
17. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 1 (SCA1) for
Movement Disorders. March 3, 2010.
18. Hayes. Genetic Test Overview. GTE Report: Myotonic Dystrophy Types 1 and 2
Published: March 9, 2009. Latest Update Search: Mar 31, 2010
19. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 2 (SCA2) for
Movement Disorders. March 3, 2010.
20. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 3 (SCA3; Machado-
Joseph Disease) for Movement Disorders. March 3, 2010.
21. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 6 (SCA6) for
Movement Disorders. March 31, 2010.
Page 19
Preimplantation Genetic Diagnosis Oct 11 19
22. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 7 (SCA7) for
Movement Disorder. April 29, 2010.
23. Hayes. Genetic Test Overview. GTE Report: Huntington Chorea/Disease (HD) for
Diagnostic, Predictive, and Prenatal or Preimplantation Genetic Diagnosis
Purposes. Published: April 29, 2008. Updated May 6, 2010
24. Hayes. Genetic Test Overview. Comparative Genomic Hybridization (CGH)
Microarray for Chromosomal Imbalance. April 12, 2010.
25. Hayes. Genetic Test Overview. Marfan Syndrome. May 7, 2010.
26. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 12 (SCA12) for
Movement Disorders. June 15, 2010.
27. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 17 (SCA17) for
Movement Disorders. June 17, 2010.
28. Hayes. Genetic Test Overview. GTE Report: Neurofibromatosis Type 1 (NF1).
Published: November 17, 2010
29. Hayes. Genetic Test Overview. GTE Synopsis: Hemophilia A (Factor VIII
Deficiency). Published: January 24, 2011
30. American College of Obstetricians and Gynecologists (ACOG). Committee
Opinion. Family History as a Risk Assessment Tool. Number 478. March 2011.
Available at: http://www.acog.org/publications/committee_opinions/co478.cfm
References Update – October 2011
1. Colls P, Silver L, Olivera G, et al. Preimplantation genetic diagnosis for gender
selection in the USA. Reprod Biomed Online. 2009;19 Suppl 2:16-22.
2. Cooper AR, Jungheim ES. Preimplantation Genetic Testing: Indications and
Controversies. Clinics in Laboratory Medicine. Volume 30, Issue 3, September
2010.
3. Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for
aneuploidy of embryos after in vitro fertilization in women aged at least 35
years: a prospective randomized trial. Fertil Steril 2010; 93:364.
4. El-Toukhy T, Bickerstaff H, Meller S. Preimplantation genetic diagnosis for
haematologic conditions. Current Opinion in Pediatrics. 2010 Feb;22(1):28-34.
5. Fischer J, Colls P, Escudero T, Munné S, et al. Preimplantation genetic diagnosis
(PGD) improves pregnancy outcome for translocation carriers with a history of
recurrent losses. Fertil Steril. 2010;94(1):283.
6. Harper JC, Harton G. The use of arrays in preimplantation genetic diagnosis and
screening. Fertil Steril 2010; 94:1173.
7. Human Fertilisation and Embryology Authority. Authority decision on the use of
PGD for lower penetrance, later onset inherited conditions. London (UK): HFEA;
2006. Available at: http://www.hfea.gov.uk/docs/SCAG_ELC_June05.pdf 8. Liebaers I, Desmyttere S, Verpoest W, et al. Report on a consecutive series of
581 children born after blastomere biopsy for preimplantation genetic diagnosis.
Hum Reprod 2010; 25:275.
9. Musters AM, Twisk M, Leschot NJ, et al. Perspectives of couples with high risk of
transmitting genetic disorders. Fertil Steril 2010; 94:1239.
10. Raby BA. Principles of molecular genetics. May 31, 2011. Available at:
http://www.uptodate.com/contents/principles-of-molecular-
genetics?source=see_link
11. Schattman GL. Preimplantation genetic screening (PGS) for aneuploidy. March
15, 2011. Available at: http://www.uptodate.com/contents/preimplantation-
genetic-screening-pgs-for-aneuploidy?view=print
Page 20
Preimplantation Genetic Diagnosis Oct 11 20
12. Schattman GL. Preimplantation genetic diagnosis. May 31, 2011. Available at:
http://www.uptodate.com/contents/preimplantation-genetic-
diagnosis?view=print
References Update – February 2011
1. Laurie AD, Hill AM, Harraway JR, et al. Preimplantation genetic diagnosis for
hemophilia A using indirect linkage analysis and direct genotyping approaches.
Journal of Thrombosis and Haemostasis. 8 (4) (pp 783-789), 2010.
2. Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for
aneuploidy of embryos after in vitro fertilization in women aged at least 35
years: a prospective randomized trial. Fertil Steril. 2010 Feb;93(2):364-73.
Epub 2009 Feb 26.
3. Vanneste E, Melotte C, Debrock S, et al. Preimplantation genetic diagnosis using
fluorescent in situ hybridization for cancer predisposition syndromes caused by
microdeletions. Hum Reprod. 2009;24(6):1522-1528.
4. Meyer LR, Klipstein S, Hazlett WD, et al. A prospective randomized controlled
trial of preimplantation genetic screening in the “good prognosis” patient. Fertil
Steril. 2009 May;91(5):1731-8. Epub 2008 Sep 18.
5. Van de Velde H, De Rycke M, De Man C, et al. The experience of two European
preimplantation genetic diagnosis centres on human leukocyte antigen typing.
Hum Reprod. 2009 Mar;24(3):732-40. Epub 2008 Dec 5.
6. Checa MA, Alonso-Coello P, Sola I, et al. IVF/ICSI with or without
preimplantation genetic screening for aneuploidy in couples without genetic
disorders: a systematic review and meta-analysis. J Assist Reprod Genet. 2009
May;26(5):273-83. Epub 2009 Jul 24.
7. Shaw SW. Cheng PJ. Chang SD, et al. Rapid prenatal diagnosis of spinal
muscular atrophy by denaturing high-performance liquid chromatography
system. Acta Obstetricia et Gynecologica Scandinavica. 87(9):960-8, 2008.
8. Girardet A. Fernandez C. Claustres M. Efficient strategies for preimplantation
genetic diagnosis of spinal muscular atrophy. Fertility & Sterility. 90(2):443.e7-
12, 2008 Aug.
9. Kakourou G, Dhanjal S, Mamas T, et al. (2008). Preimplantation genetic
diagnosis for myotonic dystrophy type 1 in the UK. Neuromuscul Disord.
2008;18(2):131-136.
10. Fares F. Badarneh K. Abosaleh M, et al. Carrier frequency of autosomal-recessive
disorders in the Ashkenazi Jewish population: should the rationale for mutation
choice for screening be reevaluated? Prenatal Diagnosis. 28(3):236-41, 2008
Mar.
11. Fritz MA. Perspective on the efficacy and indications for preimplantation genetic
screening: where are we now? Hum Reprod 2008; 23(12):2617-21.
12. Fauser BC. Preimplantation genetic screening: the end of an affair? Hum Reprod
2008; 23 (12): 2622-5.
13. Altarescu G. Brooks B. Margalioth E, et al. Simultaneous preimplantation genetic
diagnosis for Tay-Sachs and Gaucher disease. Reproductive Biomedicine Online.
15 (1): 83-8, 2007 Jul.
14. Malcov M, Naiman T, Yosef DB, et al. Preimplantation genetic diagnosis for
fragile X syndrome using multiplex nested PCR. Reprod Biomed Online. 2007;14
(4):515-521.
15. Meldrum C, Scott C, Swoboda KJ. Spinal muscular atrophy genetic counseling
access and genetic knowledge: parents' perspectives. J Child Neurol.
2007;22(8):1019-1026.
Page 21
Preimplantation Genetic Diagnosis Oct 11 21
16. ClinicalTrials.gov. Quantitative Analysis of SMN1 and SMN2 Gene Based on
DHPLC System. NCT00155168. Updated September 9, 2005. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00155168
17. ClinicalTrials.gov. Establishing Novel Detection Techniques for Various Genetic-
Related Diseases by Applying DHPLC Platform. NCT00154960. Updated
November 25, 2005. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00154960
References Initial
1. Marik JJ. eMedicine. Preimplantation genetic diagnosis. 2005. Available at:
http://www.emedicine.com/med/topic3520.htm
2. Devolder K. Preimplantation HLA typing: having children to save our loved ones.
J Med Ethics. 2005 Oct;31(10):582-6.
3. Kuliev A, Rechitsky S, Verlinsky O, et al. Preimplantation diagnosis and HLA
typing for haemoglobin disorders. Reprod Biomed Online. 2005 Sep;11(3):362-
70.
4. Harper JC, Boelaert K, Geraedts J, et al. ESHRE PGD Consortium data collection
V: Cycles from January to December 2002 with pregnancy follow-up to October
2003. Hum Reprod. 2005 Sep 19.
5. Shenfield F. Preimplantation genetic diagnosis in order to choose a saviour
sibling. Gynecol Obstet Fertil. 2005 Oct;33(10):833-4.
6. Sugiura-Ogasawara M, Suzumori K. Can preimplantation genetic diagnosis
improve success rates in recurrent aborters with translocations? Hum Reprod.
2005 Aug 25;
7. Rao R. Preimplantation genetic diagnosis and reproductive equality. Gend Med.
2004 Dec;1(2):64-9.
8. Platteau P, Staessen C, Michiels A, et al. Preimplantation genetic diagnosis for
aneuploidy screening in women older than 37 years. Fertil Steril. 2005
Aug;84(2):319-24.
9. Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis in assisted reproduction.
Expert Rev Mol Diagn. 2005 Jul;5(4):499-505.
10. Crockin SL. Reproduction, genetics and the law. Reprod Biomed Online. 2005
Jun;10(6):692-704.
11. Aittomaki K, Bergh C, Hazekamp J, et al. Genetics and assisted reproduction
technology. Acta Obstet Gynecol Scand. 2005 May;84(5):463-73.
12. Kahraman S, Karlikaya G, Sertyel S, et al: Clinical aspects of preimplantation
genetic diagnosis for single gene disorders combined with HLA typing. Reprod
Biomed Online 2004 Nov; 9(5): 529-32.
13. Zhuang GL, Zhang D. Preimplantation genetic diagnosis. Int J Gynecol Obstet
2003;82:419-23.
14. Baird DD, Weinberg CR, McConnaughey DR, Wilcox AJ: Rescue of the corpus
luteum in human pregnancy. Biol Reprod 2003 Feb; 68(2): 448-56.
15. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after
intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med
2002;346(10):725-30.
16. Schieve LA, Meikle SF, Ferre C, et al. Low and very low birth weight in infants
conceived with use of assisted reproductive technology. N Engl J Med
2002;346(10):731-7.
17. Munne S, Cohen J, Sable D: Preimplantation genetic diagnosis for advanced
maternal age and other indications. Fertil Steril 2002 Aug; 78(2): 234-6.
18. Flinter FA. Preimplantation genetic diagnosis. Br Med J 2001;322:1008-9.
19. Findlay I. Pre-implantation genetic diagnosis. Br Med Bull 2000;56:672-90.
Page 22
Preimplantation Genetic Diagnosis Oct 11 22
20. Soussis I, Harper JC, Handyside AH, et al. Obstetric outcome of pregnancies
resulting from embryos biopsied for pre-implantation diagnosis of inherited
disease. Br J Obstet Gynaecol 1996;103:784-8.
21. Kristjansson K, Chong SS, Van den Veyver IB, et al. Preimplantation single cell
analyses of dystrophin gene deletions using whole genome amplification. Nat
Genet 1994;6:19-23.
22. Snabes MC, Chong SS, Subramanian SB, et al. Preimplantation single-cell
analysis of multiple genetic loci by whole-genome amplification. Proc Natl Acad
Sci USA 1994;91:6181-5.
23. Handyside AH, Lesko JG, Tarin JJ, et al. Birth of a normal girl after in vitro
fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med
1992;327:905-9.
24. Handyside AH, Pattinson JK, Penketh RJ, et al: Biopsy of human preimplantation
embryos and sexing by DNA amplification. Lancet 1989 Feb 18; 1(8634): 347-9.
Important Notice
General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net‟s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member‟s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, new or revised policies require prior notice or posting on the website before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative.
Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, new or revised policies require prior notice or website posting before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage.
Page 23
Preimplantation Genetic Diagnosis Oct 11 23
The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member’s Contract Controls Coverage Determinations. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member‟s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member‟s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member‟s contract shall govern. Coverage decisions are the result of the terms and conditions of the Member‟s benefit contract. The Policies do not replace or amend the Member‟s contract. If there is a discrepancy between the Policies and the Member‟s contract, the Member‟s contract shall govern. Policy Limitation: Legal and Regulatory Mandates and Requirements. The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Policy Limitations: Medicare and Medicaid. Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid
members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.