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Lecture for
3rd Year Medical Students at the Faculty of Medicine King Fahad
Medical City, Riyadh Saudi Arabia on April 1, 2013 by Professor Omar Hasan
Kasule Sr.
Learning
objectives
- To familiarize students with the ethical and legal aspects of prenatal diagnosis
- To identify practical issues of prenatal diagnosis
Down Syndrome / trisomy 21
- Most common chromosomal anomaly due to duplication of chromosome 21
- Impaired cognitive ability with average IQ of 50, impaired physical growth, specific facies, in addition to other medical complications
- Confirmation of the diagnosis is by karyotype analysis.
- The cytogenetic abnormality can be classified into pure trisomy 21, translocation, or mosaicism
Thalassemia..1
·
Thalassemia is due to defect in either the alpha
or beta globin chains leading to abnormal red blood cells that hemolyse more
often than normal ones causing anemia and other complications such as:
pneumonia, iron overload, bone deformities[1]
and cardiovascular illness (CCF, arrhythmias), infections, enlarged spleen,
slow growth and delayed puberty.
·
In some forms of thalassemia the abnormality may
be in the delta chain. Thalassemia is one of many hemoglobinopathies. Others
are: Hb
S, Hb
C, Hb
E, Hb
D, Hb O,
·
Thalassemia can occur in combination with
other hemoglobinopathies such as hemoglobin E, hemoglobin S, and hemoglobin C.
The beta form of thalassemia is particularly prevalent among Mediterranean
peoples. South Asians are also affected
Thalassemia..2
·
Both alpha and beta thalassemia are inherited as
autosomal recessive (i.e. both parents must be carriers for the child to have
the disease). Dominant inheritance can also occur.
·
Genetic counseling is needed for carriers of the
trait. Trait requires no treatment.
·
Prevention by premarital screening and genetic
testing[4]
Man is checked first if he has microcytes the woman is tested. If both are
microcytic, their hemoglobin is tested and if positive they are referred to
counseling
Thalassemia …
3
·
A Saudi study of 329 blood samples from
suspected cases were analyzed. 35.9% had normal HB. 36.5% had iron deficiency
anemia masking the thalassemia trait. Other anomalies were: HB-F 1.5%,
beta-thalassemia 10%, beta-thalassemia and sickle cell disease 3.3%, sickle cell
disease 4%[5].
·
Since 2003 the Saudi Ministry of Health mandated
pre-marital screening for thalassemia[6]. A
Saudi study showed that the pre-marital thalassemia screening program reduced
at risk marriages[7]
·
88.2% of couples with the beta thalassemia trait
at pre-marital screening went ahead and married. Reasons given for marrying:
wedding plans could not be canceled, and fear of social stigma[8]. Another study found that 98% of screened
couples went on to marry for cultural reasons[9]
Definition of
prenatal diagnosis / prenatal screening / prenatal genetic testing
·
Examples of anomalies: neural tube defects, Down
syndrome, chromosome abnormalities, genetic
diseases and other conditions, such as spina
bifida, cleft palate, Tay
Sachs disease, sickle cell anemia, thalassemia,
cystic
fibrosis, Muscular dystrophy, and fragile X syndrome.
Prenatal screening
- Reasons for pre-natal screening: (a) Routine pre-natal identification of at-risk pregnancies (b) Early detection of congenital anomalies (c) Screening reduces the use of invasive prenatal diagnosis[10].
- Methods of pre-natal screening (a) Family history (b) Serum screening (c) Molecular tests (d) Ultrasound
Prenatal diagnosis
- Reasons for pre-natal diagnosis: (a) Reassurance (b) Desire for termination (c) Preparation for abnormal birth (financially, psychologically) (d) In utero treatment for example congenital adrenal hyperplasia
- Methods of pre-natal diagnosis: (a) Amniocentesis (Amniocentesis is feasible after week 16) (b) Chorionic villi sampling (c) Percutaneous umbilical cord sampling (d) Ultrasonography (e) CT and MRI.
- Target groups of prenatal genetic testing: (a) History of congenital anomalies (b) Family history (c) Identification from screening
- Optimum time for diagnosis
Prenatal genetic testing
- This is characterization of the genetic anomaly
- Confirmatory of the diagnosis
Prenatal treatment
- Intrauterine fetal transfusion
- Intra-uterine / fetal surgery
- Intrauterine drug treatment of cardiac arrhythmias and thyroid disorders
- Neonatal surgery/treatment
Reasons for
prenatal diagnosis
·
To enable timely medical or surgical treatment
of a condition before or after birth,
·
To give the parents the chance to abort a fetus
with the diagnosed condition,
·
To give parents the chance to
"prepare" psychologically, socially, financially, and medically for a
baby with a health problem or disability, or for the likelihood of a
stillbirth.
Approaches of prenatal
diagnosis / prenatal screening / prenatal genetic testing
·
Invasive: amniocentesis
with karyotyping, chorionic villi sampling[11]
(trans abdominal or the more risky trans cervical), embryoscopy, fetoscopy, and
percutaneous umbilical cord sampling
·
Non-invasive[12] [13]
1. Ultrasonography 2. Maternal serum
screens biomarkers 3. Fetal DNA or fetal RNA in maternal serum detecting
fetal DNA in maternal blood 4. Other tests to detect fetal hemoglobin in
maternal serum.
Targets of prenatal diagnosis
/ prenatal screening / prenatal genetic testing
·
Women
over the age of 35 (advanced maternal age[14])
- Women who have previously had premature babies or babies with a birth defect, especially heart or genetic problems
- Women who have high blood pressure, lupus, diabetes, asthma, or epilepsy
- Women who have family histories or ethnic backgrounds such as HBs and thalassemia prone to genetic disorders, or whose partners have these
- Women who are pregnant with multiples (twins or more)
- Women who have previously had miscarriages
Down syndrome: screening, diagnosis, genetic testing
- Pre-natal screening of DS: (a) Use of serum markers for DS like alpha feto protein, PAPPA-A, serum unconjugated estriol and chorionic gonadotropin[15] [16] [17]. Other serum markers are: inhibin-A[18], inhibin-D[19], ADAM12.[20] The search is continuing for new biomarkers[21] (b) Ultra sound[22] with emphasis on nuchal transparency (NT)[23] which is not reliable[24] but beyond a certain threshold can lead to the decision to skip other screening tests[25] and proceed to diagnostic tests. Trimester 1 and 2 markers modestly predict adverse obstetric outcome.[26] (c) Fetal RNA in maternal serum[27]
- Prenatal diagnosis of DS: chromosomal analysis (karyotyping) from amniotic fluid[28] .
- Prenatal genetic testing of DS: DNA analysis. (a) Test for trisomy in maternal blood. (b) Use of epigenetic markers and real time PCR[29] [30] (d) Array of genetic tests based on the genome raises issues of informed consent since the scope of the results cannot be determined in advance[31]
Thalassemia: screening, diagnosis, genetic testing
·
Inadequate
parental knowledge of beta thalassemia screening[32]
·
Prenatal screening: fetal DNA in maternal serum
for beta thalassemia[33]
and alpha thalassemia[34].
·
Prenatal diagnosis: (a) Capillary
electrophoresis[35]. Hb
typing is as accurate as DNA analysis[36]
Ethico-legal issues in pre-natal procedures
- Full disclosure
- Autonomy and informed consent:
- Justice
- Privacy and confidentiality
- Pregnancy termination
- Issues relating to the testing procedure
- Other issues
Full disclosure
- 2 aspects of disclosure (a) disclosure of the procedures to be used, benefits, and risks (b) disclosure of bad news after screening and diagnosis
- Families must be given up to date balanced information about DS in a supportive and respectful manner. Health care worker with specific knowledge of DS should deliver DS prenatal diagnosis news in person[37].
Autonomy and informed
consent…1
- Physician’s duty to inform patient about prenatal diagnosis. It should not be assumed patients know.
- Information given before informed decision on DS screening[38] either pre conception[39]. Experiential information helps couples decide about DS screening[40]. Having knowledge did not lead to participation in DS screening[41]. Attitude affects women’s decisions[42]
- Risk: Algorithm for risk determination to select those for DS screening based on maternal age, fetal NT, maternal PAPP-A and free beta-hCG levels.[43] Risk score is the chance a baby has a birth defect the most common is 1:270. The decision to undergo a high risk test is based on the risk score. Information about the numerical risk score after DS screening influenced uptake of diagnostic test.[44]
Autonomy and informed
consent…2
- Decision making is a shared responsibility between the physician and the woman. Women and family physicians willing to engage in shared decision making for DS screening[45]. Family physicians in Quebec exerted minimal effort to involve women in decision making on DS screening.[46] Midwives could book DS screening[47].
- The decision before the woman is between producing an abnormal baby vs procedure-related miscarriage[48]
- Testing minors and adolescents should we wait. Adolescent mothers less likely than older women to make an informed decision about DS screening[49]
Justice.
- Disparities in screening by socio economic status persist[50].
- Asian women in England less likely to be offered DS screening[51]
- Ethnic minorities less likely to participate in DS screening[52]
- Cost barriers to screening, diagnosis, and testing
- In Holland ethnic differences were found in knowledge about DS screening[53]
Privacy and confidentiality
- Disclosure to family after permission of the woman
- Disclosure to the husband?
- Self-disclosure could implicate family members
Pregnancy termination
- Prenatal screening and diagnosis: a slippery slope to abortion, eugenics, and genocide?
- US 1995-2011 termination rate after DS screening was 67%[54] Pregnancy termination: 86% in Iran favored termination in case of fetus affected by thalassemia[55]
- Factors of termination decision: Multiple factors affected the termination decision after prenatal diagnosis of DS[56] An external moral authority needed to make termination decisions after prenatal diagnosis normal professional ethics not sufficient[57]. Consideration of the qquality of life for the mentally or physically disabled. Technical and legal limits for termination
- Post-termination support and counseling
Issues related
to the test
- Performance characteristics of the test: sensitivity, specificity. Safety. False positive and false negative
- Funding: cost effective to screen DS and neural tube defects together[58]
- Perceived disability burden versus procedural risk. Risk of abortion from amniocentesis
- Anxiety in women undergoing DS screening[59]
- DS screening related miscarriage is 13 per 100,000[60]
- Counseling before and after the procedure. Time between counseling and the procedure. Discuss impact of results.
Other Issues
in prenatal diagnosis
- Limitations of diagnosis i.e. informative ways of testing
- DS screening is not increasing co-morbidities by longer survival[61]
Case studies
on DS
- Case #1:a 38-year old mother with one live delivery of a Down syndrome baby is pregnant for the second time. The husband insists on a pre-natal diagnosis but she refuses.
- Case #2:A 40-year old gynecologist recently married and became pregnant. Her husband insists on prenatal diagnosis but she refuses
- Case #3: 35-year old mother of 2 previous normal children asks for amniocentesis to discover if the baby is normal. The director of the health clinic refuses fearing she may consider abortion
- Case #4: Down syndrome society petitioned the Ministry of Health to make down syndrome screening mandatory for pregnant women aged 30 and above
- Case #5: A doctor obtained consent to do Down screening in a 45-year old pregnant woman. When she came for the results he refused to disclose because nurses had told him she had talked about aborting abnormal fetii while in the waiting room.
Case studies
on Thalassemia
- Case #1: two first cousins wanted to marry. The geneticist told them that they were both carriers and 1 in every 4 children would get the disease. They went ahead and married because a proportion of 25% was too low a risk
- Case #2: a 4-year old child had repeated episodes of anemia that responded to transfusion. The doctors without getting parental permission carried out and found a positive test for thalassemia disease. Problems occurred in the family because both parents had results of pre-marital testing that showed that neither was a carrier of thalassemia
REFERENCES
[15] NEJM 1992; 327;588-593
[18] prenatal disgnosis 1996; 16(2):143-153
[28] Prenatal diagnosis 2002; 22(1): 29-33.
[30] Clin Biochem. 2009
May;42(7-8):672-5