Prenatal Genetic Counseling in

Non-Invasive Prenatal Testing

(NIPT)

Muflihatul Muniroh
A Genetic Counselor, CITO Clinical Laboratory
Definition genetic counseling
• Communication process which deals with the human
problems associated with the occurrence or the risk of
occurrence of a genetic disorder in a family

• Participants: counsellor and counsellee(s)

Prenatal Genetic Counseling
• Genetic counseling in individuals, couples, or families
who have an increased chance of having a child with a
birth defect or genetic condition
• Those who are already pregnant or are considering
having a child in the future
For whom genetic counseling?
• parents with a previous child with a (possible) genetic
disorder
• one of the parents has a (possible) genetic disorder
• patient(s) in the family with a (possible) genetic disorder
• consanguinity of parents
• exposure to teratogenic/mutagenic/carcinogenic drug
Why see a prenatal genetic counselor
• A child with a genetic condition and want to have another child
• Family members with mental retardation or birth defects
• A history of infertility or pregnancy losses (miscarriages or stillbirths)
• Concerned that health or lifestyle poses a risk to the pregnancy
• Risks to the pregnancy associated with increasing parental age
• Receive abnormal prenatal screening or ultrasound results
• Increased risk of being a carrier because of ethnic background
• Pregnant and the baby has been diagnosed with a birth defect or genetic condition
• Taken a medication during pregnancy or exposed to a chemical that might cause a
problem for the baby
Process of Genetic Counseling
• Information gathering
• Family and medical history
• Risk assessment
• Actual risk vs perceived risk
• Information giving à Educators
• Psychosocial counseling
Contents of genetic counseling
• information on diagnostic, prognostic, management
• information on genetics and recurrence risk
• information on alternatives for dealing with the recurrence
risk
• helping to come to a decision about being tested and/or
having children and its realisation
• Pre- and post-diagnostic
Genetics and recurrence risk
• explain how genetics play a role (“biology
lesson”)
• give a recurrence risk and put this risk in
perspective
• 1/4 = 25% versus population risk of the
disorder
• Bayesian theory, Mendelian & Non-
Mendelian inheritance analysis
Diagnosis, prognosis, management
• diagnosis needs to be etiologic = causal, e.g. deafness = no
diagnosis, Intellectual Disability = no diagnosis à Genetic
testing (mutation analysis)
• prognosis = life expectancy, progressive vs non-progressive,
co-morbidity, etc.
• management includes all: physiotherapy, speech therapy,
special schooling/working, surgery, drugs; as yet mostly non-
curative
Goal of genetic counselling
• enable counsellees/parents to make an informed
(reproductive) choice, appropriate in view of their ethical,
cultural and religious standards and family goals
• NOT: to reduce the number of children born with a genetic
disorder nor to enhance responsible parenthood
Ethical rules governing genetic counseling
• beneficence = do well
• non-maleficence = do not harm
• respect for autonomy = be non-directive
• justice = be just and fair
• confidentiality = be trustworthy
Case 1
• A mother, age 23 y.o G1P0. at 22 weeks of gestation, intra-uterine growth
restriction and persistent left superior vena cava were detected by routine
US. Although the fetus presented with female-like external genitalia,
prenatal amniocentesis testing showed 46,XY karyotype. This implied that
the fetus had differences in sex development (DSD)
 Pre- & post natal Genetic counseling
• The parents appeared to be unaffected psychologically on
looking at the baby’s ambiguous genitalia at birth, according to
the attending physicians
• Finally, the parents themselves assigned and calmly registered
their baby’s sex as male
4 month follow-up of general condition & psychological
status

• Psychological status à stable

• Mother: “I was nervous when I searched ‘ambiguous genitalia’
on the Internet. However, after counseling, I was able to prepare
myself to address the issue of our baby’s genitalia calmly.”
• Father: “Before birth, I did not fully understand the
consequences of ambiguous genitalia, but I understood the
procedure of legal sex assignment. After counseling, I realized
that the professional team helped us.”
Case 2
• A mother, 38 y.0, G1P0. At 28 weeks of gestation,
omphalocele, bladder exstrophy, and spinal deformity were
suspected by routine US. The fetus appeared to have
ambiguous genitalia with a scrotum-like structure and no
apparent penis
Pre- & post natal Genetic counseling
• Diagnosis: an omphalocele-exstrophy-imperforate anus-spinal
defects, also defined as an OEIS complex

• Parents appeared calm on observing the baby’s abdomen and

external genitalia (according to the attending nurses)

• Finally, the parents themselves assigned and calmly registered their

baby’s sex as male
6 month follow-up of general condition &
psychological status
• Psychological status à stable
• Mother: “When I saw him at birth, I was upset to some
extent, although I had received genetic counseling. Without
counseling, I would have been more upset and worried.”
• Father: “We were assured that multidisciplinary experts
supported us. Of course, we were worried, but we trusted
you.”
Non-Invasive Prenatal Test (NIPT)
Non-Invasive Prenatal Testing
• a screening test from 9 or 10 weeks gestation until the end
• chance of having a baby with aneuploidy à trisomy 21
(Down syndrome), 18 (Edward syndrome), 13 (Patau
syndrome), and other chromosome differences
• more accurately compared to conventional screening test
(enhanced First Trimester Screening (eFTS) or Maternal
Serum Screening (MSS))
• Small fragments of DNA How NIPT Works
from the placenta that free-
floating in the bloodstream
à cell-free DNA (cfDNA)
• DNA in placental cells is
usually identical to DNA of
fetus
• Provides for early detection
of genetic or chromosome
abnormality without
harming fetus
• is a screening test
NIPT Performance
Chromosome difference Detection rate False positive rate
Trisomy 21 More than 99% 0.1%
Trisomy 18 95% Less than 0.1%
Trisomy 13 88% Less than 0.1%

Notes
• Detection rate = how many pregnancies where the baby really DOES have
the chromosome difference will be flagged as high risk by this test
• False positive rate = how many pregnancies will this test flag as high risk
but the baby does NOT really have the chromosome difference
Microdeletion Syndromes
• additional genetic conditions, called microdeletion syndromes
• missing pieces of chromosomes (ie. deletions) and vary in severity,
ranging from no symptoms to serious health and developmental
concerns
• The chance for a baby having a microdeletion is not related to
maternal age
• individually rare in the general population and difficult to study
Benefits of NIPT
• Accuracy: NIPT is a more accurate screening test for trisomies 21, 18
and 13 than traditional screening (eFTS and MSS)
à Next Generation Sequencing (NGS)

• Timing: NIPT can be done as early as 9 weeks of pregnancy.

• Non-invasive: Because NIPT is a simple blood test from mother, it

poses no risk to pregnancy.
Limitations of NIPT
• Not diagnostic: a very good screening test but cannot give a definite
“yes” or “no” answer à invasive diagnostic testing (e.g. chorionic
villus sampling or amniocentesis)

• Unexpected findings: Some of the DNA in blood sample is from the

mother (maternal DNA) à rarely may identify a genetic difference in
mother
When NIPT is not Available
• if there is a "vanishing" twin: loss of the embryo in one of the
pregnancy sacs à can be residual DNA in the mother's blood from
the fetus that miscarried à affect the interpretation for ongoing
pregnancy.

• if there are more than two babies (triplets, quadruplets, etc.)

NIPT Results
• typically reported within 7-10 working days
• NIPT results are reported as either a “high risk” or “low risk” result.
• In a small percentage of cases, the result is reported as “no call” or
“failed” à the laboratory may ask for a repeat blood draw.
• It is important to know that a low-risk NIPT result does not guarantee
a healthy baby.
High risk NIPT result
• Means the chance of trisomy 21, 18, 13 or a sex difference is
significantly increased
• Not all high risk results are equal à NIPT more accurate for
trisomy 21
• Positive predictive value (PPV)
• A 25 y.o mother with high risk NIPT for trisomy 21 will
truly have a baby with trisomy 21 is approximately 33%
• A 40 y.o mother à 87%
• The baseline risk is higher for 40 y.o than 25 y.o
Next steps for High risk NIPT result
• Post-NIPT genetic counseling
• Referred to OBGYN
• Diagnostic testing
• chorionic villus sampling or amniocentesis
• can also be performed after delivery , if invasive diagnostic testing
is not pursued during pregnancy
Low risk NIPT result
• Means the chance for trisomy 21, 18, 13 is less than
1:10.000
• The chance are not zero
Next steps for Low risk NIPT result
• Post-NIPT genetic counseling
• Continue for routine check up
• Referred to OBGYN
• Recommended for a nuchal translucency (NT)
ultrasound between 11-14 weeks gestational age
• Multiple marker screening is not needed
Aneuploidy screening at
10-14 weeks gestation

Compare 2 methods:
• Standard screening
(nuchal translucency &
biochemical analysis
• Cell-free DNA (cfDNA)

Trisomy 21 = 38 cases
cfDNA identified 47 (38 cases)
- 9 false positive (0.06%)
- PPV 80.9%
Standard screening identified
884 (30)
- 854 false positive (5.4%)
- PPV 3.4%
Trisomy 18 = 10 cases
cfDNA identified 10 (9 cases)
- 1 false positive (0.01%)
- PPV 90%
Standard screening identified
57 (8 cases)
- 49 false positive (0.31%)
- PPV 14%
Trisomy 13 = 2 cases
cfDNA identified 3 (2 cases)
- 1 false positive (0.02%)
- PPV 50%
Standard screening identified
29 (1 case)
- 28 false positive (0.25%)
- PPV 3.4%
• 720/781 cases positive for T21
• 167/218 cases positive for T18
• 22/67 cases positive for T13
• Nine false negatives: 6 cases of
T21 and 3 of T18
• Sensitivity was 99.17% (T21),
98.24% (T18) and 100%(T13)
• Specificity was 99.95% (T21),
99.95% (T18), and 99.96% (13)
570 pregnant mother
- NIPT
- Amniocentesis
- Sex chromosomal
aneuploidy
Important in advance maternal age à risk assessment in genetic counseling
Non-Invasive Prenatal
Test (NIPT)
Pemeriksaan NIPT dilakukan
untuk mengetahui resiko
kelainan genetik
tertentu pada bayi.
Kelainan genetik
yang paling umum adalah
TRISOMI.
Kelainan ini berdampak bagi
kesehatan bayi.
Apa itu Trisomi?

Materi genetic kita tersusun dalam 23 pasang kromosom (46, XX

untuk perempuan dan 46, XY untuk laki-laki).
Jika ada penambahan pada salah satu pasangan kromosom, kita
namakan sebagai TRISOMI.
Kapan harus periksa NIPT? Bagaimana cara periksa NIPT?
Dianjurkan bagi semua ibu • Ibu hamil dapat membawa
hamil (terutama yang surat rujukan dari dokter
beresiko) pada usia atau datang sendiri
• Pengambilan darah vena
kehamilan mulai 10 minggu ibu (10 mL) à aman bagi
janin
• Hasil à 7-10 hari kerja
Metode NIPT
Next Generation Sequencing (NGS)
Ø Sensitivitas > 99%
Ø Spesifitas > 99%
Apa yang dilakukan setelah mendapat hasil
NIPT?
• Ibu membawa hasil NIPT kepada dokter yang merujuk
• Jika ibu melakukan pemeriksaan sendiri, Ibu dapat
berkonsultasi dengan konselor genetika Laboratorium
Klinik Cito
• Konselor genetika merujuk ke dokter Sp.OG
Laboratorium Klinik Cito untuk layanan NIPT
• Pusat: Indraprasta Semarang

• 17 Cabang: Semarang (Setia Budi, dr. Cipto), Demak,

Kudus, Jogja, Bantul, Wates, Magelang, Solo,
Surabaya, Pekalongan, Tegal, Jakarta, Bogor,
Purwokerto, Pemalang, Jayapura
Take-home messages
• Genetic counselling is integral part of the management of
patients with a genetic disorder
• Not to reduce the number of children born with a genetic
disorder nor to enhance responsible parenthood
• Not only of patients but also of their families
• NIPT is a promising screening test at early pregnancy
with higher sensitivity, a lower false positive rate, and higher
positive predictive value compared with standard screening
test to detect aneuploidy T21, 18, 13, and sex chromosome