Review of Perinatal Genetic Testing

Rita Henien Bybee, DO

DFMCH Academic Fellow

Rita.HenienBybee@fammed.wisc.edu

Objectives

1. Understand the evidence and rationale for prenatal genetic testing
2. Review genetic screening choices for patients and describe the utility of screening
3. Examine the advantages and limitations of prenatal genetic testing through case evaluation

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Importance

For patients:

• To provide patient with widest scope of reproductive options
• Help patients prepare, set expectations
• Identify risks to parents own health and future pregnancies
• Intervention: fetal surgery or specialty pediatric referrals

For providers:

• ACOG mandates a genetic screening discussion
• Practicing patient-centered medicine
• Malpractice avoidance

Importance of Shared Decision-Making Model

• We cannot screen for all potential conditions (such as autism)
• There is a broad range of phenotypes for a particular genetic disorder
• Keep in mind:
• Patient’s preferences (religious, cultural, personal, historical..)
• Reassurance when testing is normal (aka low odds)
• Identifying conditions for which prenatal intervention can occur
• Optimizing neonatal outcomes
• Location of delivery / staff presence
• Supporting pregnancy termination where appropriate

Genotype 🡪 Phenotype is Complex

• No test is perfect!
• Epigenetics > genes can be activated or silenced by modifications
• Chromosome abnormalities and gene disorders cannot always be identified by fetal tissue analysis
• 1:150 live births will have some type of chromosomal abnormality

When to Begin the Discussion?

• Ideally, preconception! (i.e. during annual physical)
• One Key Question:
• “Do you plan to become pregnant in the next calendar year?”
• Many implications:
• Pregnancy will occur for 90% +/- of people not using reliable birth control
• Adequate family planning services if needed
• Begin process of risk stratifying for the patient (SMA, CF, sickle cell, etc)

How to counsel?

• Start with relative risk due to age of birthing person
• Family history / genetic history, one vs multiple fetuses
• Explain screening vs diagnostic
• Discuss physical vs emotional risk
• FYI, ACOG recommends discussing all options despite difference in detection rate

Factors that Increase Risk

• Age of birthing parent
• Age of partner / donor
• Carrier state parent
• Aneuploidy / mosaicism in parent
• Prior child with structural birth defect
• Parental carrier genetic disorder
• Structural defect on ultrasound

Screening vs Diagnostic Tests

Screening

• Determine whether the individual is at increased risk for a disorder
• Traditionally focused on trisomy 21

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Diagnostic

• Determine with certainty (ideally) whether a condition is present in the fetus

Prenatal Screening Tests

Typical Screening Options

• 1^st prenatal visit: early counseling covering all screening options
• Primary screening:
• Option 1: cfDNA + 11-14 week US/NT (recommended)
• Option 2: 1^st tri serum markers + 11-14 week US/NT
• Next step:
• 2^nd tri Anatomy US (18 – 22 weeks), +/- 2^nd tri MSAFP (NTD screening)
• NTD screening, structural anomalies, and soft markers of aneuploidy
• If 1^st tri serum markers were chosen, can still do MSAFP, however, Canadian guidelines suggest unnecessary if high quality 2^nd tri US is available
• Notably -
• cfDNA can be done anytime >/= 10 weeks
• If abnormal NT, predictor of subsequent structural anomalies 🡺 should get fetal echocardiogram

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Cell free DNA (NIPT)

• Fragments of placental cells in birthing person’s circulation after 9-10 weeks gestation
• Derived from placental trophoblasts
• Fetal fraction
• 3 – 13% of total cell free DNA in blood and increases throughout gestation
• Minimum threshold to run test is 2-4%
• Results are more reliable with higher fetal fraction
• Low fetal fraction = increased risk of aneuploidy
• Quantity depends on:
• Early GA/ incorrect dating
• Birthing person’s BMI
• Birthing person’s conditions / medications
• Single vs multiple
• IVF conception
• Increasing fetal fraction means less failure

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Diagnostic Testing

Chorionic Villus Sampling

• 10-13 weeks
• Culture failure 0.5%
• TV or TA (no difference in accuracy)
• Risks:
• Loss rate 0.22%
• Limb reduction (very low)
• Spotting – 32% TC sample patients

Amniocentesis

• 15-20 weeks, or up to term
• 20-30 cc fluid
• Culture failure 0.1%
• Loss rate 0.13 – 0.27%

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When to offer diagnostic testing

• Positive serum screening
• Anomalies found on anatomy ultrasound
• Obstetric or family history
• Birthing person positive for single gene disorder
• Chromosomal aneuploidy
• Stillbirth – microarray is recommended
• Can use any fetal or placental tissue or amniotic fluid not contaminated by blood from birthing person

Case Example

• 30 year old female G1P0000 seen for initial OB visit after transfer of care from Illinois at 18w5d
• NIPT negative (low risk) for trisomy 21, 18, 13, monosomy X (Turner), XYY (Jacob’s), XXY (Klinefelter), XXX (Triple X); normal male fetus (10w0d)
• Anatomy scan (22w3d): right club foot, dilated rectum, ambiguous genitalia, inadequate visualization of fetal bladder
• MSAFP negative for open spina bifida (18w5d)
• Amniocentesis performed same day as anatomy ultrasound

Follow up plans

• Follow up:
• Follow up ultrasounds q4 weeks
• Genetics referral
• Pediatric ortho referral / club foot clinic
• Interval growth ultrasounds:
• 30w5d US: Notable for normal growth (72%ile), continued abnormally small fetal bladder, persistent right clubbed foot, normal rectum (no longer dilated), abnormal male genitalia, new aliasing in the aortic arch, and increased caliber in the umbilical vein with concern for hepatomegaly
• Next step: fetal echocardiogram
• Fetal echo: normal cardiac anatomy, cardiac output slightly elevated
• Postnatal echocardiogram around 24h of life
• Continued monitoring for fetal hydrops on scheduled q4w growth US

Further follow up plans: GDM, fetal anomalies

• Weekly antenatal testing initiated at 32w – AFI and NST
• 34w5d US:
• Suspected fetal urogenital anomaly 🡪 peds urology referral
• Continued negative hydrops checks which were negative
• Infant plan at birth: C2, placenta to pathology (club foot, abnormal genitalia)
• Peds uro: immediate post-natal inspection, prompt consult if significant anomalies, consider urology consult if anuria persists 24-36 hrs post-birth, renal & bladder US within 1^st week, defer circumcision if hypospadias
• Peds cardio: NB echo around 24h of life or sooner if clinically indicated
• Peds ortho: assess for club feet, referral to peds ortho for outpatient management

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Findings At Birth

• Bladder exstrophy - epispadias complex
• Ambiguous genitalia
• Plan
• Admitted to NICU postnatally
• Pediatric urology consult
• Renal and bladder ultrasound > R pelviectasis
• Prophylactic amoxicillin
• Wound protection
• Staged surgeries:
• Initial bladder closure (between 2 weeks and 3 months)
• Kelly procedure (between 12 – 18 months)

Summary

1. Discussed the evidence and rationale for prenatal genetic testing
2. Reviewed the screening choices for patients and describe the utility of screening
3. Examine a case of fetal anomalies found on anatomy ultrasound in the context of normal genetic testing – highlighting the advantages and limitations of prenatal genetic testing

Example Genetic Screening Counseling�

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• Deciding whether to pursue genetic screening is a personal one. None of the tests are required. For some patients, because the available blood tests are not DIAGNOSTIC, the stress over whether the results are “correct” is too much to bear.
• For others, it helps them decide whether they would want to look more thoroughly, even sometimes invasively, for a potential problem
• Your insurance may cover cell free DNA testing This test can detect placental cell fragments in your blood stream, and then a probability of whether the fetus may be affected with a chromosomal issue is reported. It doesn’t test for every chromosomal abnormality, but it has a less than 1% false positive rate. And it detects 99.5% of Down’s syndrome cases correctly, for instance.
• If you are younger than 35 or your insurance does not cover cell free DNA, some decide on the serum integrated screen. This test may require a special ultrasound of the baby’s neck as well as blood tests at two different times in the pregnancy, once in the first trimester and once in the second. The tests look to see whether your hormones are in range compared to other similar persons at the same gestational age. Results can tell you your potential chance for a problem compared to other persons who look like you, are of similar weight, ethnicity, gestational age, etc. This test is less accurate at predicting the likelihood of a diagnosis than cell free DNA, as only one in 10 that screen positive will have an affected fetus with a chromosomal issue.
• True accurate diagnosis of a chromosomal abnormality requires chorionic villus sampling or amniocentesis, which requires sampling of tissue that will eventually become the placenta, or amniotic fluid from the sac surrounding your baby, respectively. These tests are nearly 100% accurate in determining the presence of an affected fetus, but have more risk, anywhere from a 1/100 to 1/400 rate of pregnancy loss associated with obtaining the material for the test.
• Other conditions that may be inherited such as cystic fibrosis (a condition that can make it difficult for babies to breathe) , spinal muscular atrophy (a condition associated with very poor muscle tone in the baby) or abnormalities of hemoglobin (which can make it difficult for a baby’s blood to carry oxygen to his or her tissues), can also be tested for in pregnancy. In most cases, both parents must carry an abnormal gene to have an affected baby. We can test you to see if you are a carrier. If you indeed are, we would recommend carrier testing for the partner/donor to predict the chance of the baby inheriting the condition in question.

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