Prenatal Genetic Screening: An Update

One of our very first podcasts covered prenatal genetic screening and testing. Since then, ACOG has updated the former PB 163 to the new PB 226. For today, we’ll cover some changes/updates and get more into diagnostic testing, which we didn’t cover in depth on our previous episode. Diagnostic testing info remains well-covered by PB 162.

How do you provide genetic counseling to a patient? 

• Every pregnancy has a risk for genetic abnormality and review that this risk increases with increasing age

  • Average rate is 1/150 live births. There is also risk based on family history. 

    • Review family history of birth defects, genetic diagnoses in the family, etc. prior to discussion

  •  Risk of abnormalities based on age:

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• Review options for genetic screening for patients.

  • All types of genetic screening is limited, and all genetic screening tests detect fewer abnormalities than diagnostic tests with microarray. Diagnostic tests include CVS and amniocentesis.

• Screening and diagnostic testing should be discussed and offered to all patients early in pregnancy regardless of maternal age or baseline risk

What are the available tests?

• Preimplantation genetic testing/screening 

  • PGT-A (also called PGS previously) - preimplantation genetic testing for aneuploidies 

    • Biopsy of an embryo at the blastocyst stage, usually around day 5-6 of development 

    • Cells are taken from the outer layer of cells (trophectoderm) that will eventually become the placenta 

    • PGT-A just screens for aneuploidy, and the idea is to increase the chances of live birth by screening for embryos that have aneuploidy.

  • PGT-M - preimplantation genetic testing for monogenetic/single gene mutations

    • Same as above in terms of how the cells are gotten, but in this case, tests are done for monogenic disease or single gene mutations 

    • Can be used to choose embryos that do not have a genetic disease, like screening for embryos that do not have Huntington’s or cystic fibrosis 

    • Disease and mutation must be known beforehand — this is a highly targeted screening.

  • PGT-SR - preimplantation genetic testing for structural rearrangements 

    • Useful when there are parental structural chromosomal abnormalities.

    • Detects things like translocation, inversion, deletions, insertions, etc.

  • With PGT, because the cells biopsied are destined to become placenta, other forms of pregnancy genetic screening should still be offered due to risk of mosiacism - that is, different genetic material in different cell lines.

• Screening and Testing During Pregnancy 

  • Discuss that many screening tests are sensitive for T21, but may have less sensitivity for other chromosomal disorders. 

  • Review these tests cannot detect other genetic abnormalities like point mutations, deletions, translocations, etc. 

  • Types of screening tests: 

    • NIPT (cell free DNA) – test any time around 9-10 weeks to term. 99% detection rate for trisomy 21. It has the highest DR of all tests and lowest false positive rate, but also may detect maternal aneuploidy or disease. Highest sensitivity and specificity. Does NOT test for open neural tube defects.

      • Someone with a screen positive serum analyte test may choose cfDNA for follow up if they want to avoid a diagnostic test, but they should be informed that it is still a screening test, meaning it can still fail to identify some chromosomal abnormalities and may delay definitive testing if positive.

    • Integrated screen – two tests. First is at 10w-13w6d. Then 15-22w. DR for T21 is 96%, but you need two samples and no first trimester results. Method: NT + PAPP-A in first trimester, then quad screen (hCG, AFP, uE3, inhibin A)

    • Sequential – 10w-13w6d, then 15-22 w. 95% DR for T21. Still need two samples, with first trimester NT + BHCG, PAPP-A and +/- AFP. Then quad screen.

    • Quad screen – 15w-22w. 81% DR for T21. It’s a one-time test, but also has lower DR than integrated

    • Other options with lower detection rates: first trimester screen (NT+PAPP-A, bHCG, AFP), Serum integrated (Integrated just without NT), NT alone

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ACOG PB 226

Diagnostic Testing

• The gold standard for detecting genetic abnormalities and should be offered after abnormal genetic screening tests.

• Chorionic villi sampling – done between 10-13 weeks. 

  • Get placental villi transabdominally or transcervically. 

  • Pregnancy loss rate 1/500. Limb reduction defect is super low, around 6/10,000. 

  • Can cause spotting/bleeding. Also the tissue is placental, so there is still possibility of mosaicism (ie. placenta doesn’t have abnormalities, but fetus does). 

    • Because of this, sometimes after CVS can still recommend amnio.

• Amniocentesis – done between 15-20 weeks usually, but can be done any time later too. 

  • Reason not to do too early: amnion and chorion not fused, increasing anomalies/loss rate.

  • Rate of loss is about 1:300 – 1:750 depending on studies. 

  • Other complications include spotting or loss of fluid. 

  • Cells are from sloughed off fetal skin cells, so can actually get fetal DNA.

• Type of tests that can be sent from diagnostic testing - a question you might get: what are you sending it for? 

  • Karyotype

    • Detects aneuploidies, like trisomies, 45X, 47 XXY.

    • Need culturable cells, so takes longer (7-10 days).

    • Cannot usually be done on dead tissue (ie. stillbirth), because the cells likely won’t grow 

  • Microarray

    • Can find major aneuploidies and submicroscopic changes that you can’t see just with karyotype.

    • Can’t detect balanced translocations and triploidy.

    • Can be done on cultured cells or uncultured tissue.

    • Can also be done on copy number variants If done on uncultured cells.

    • Can be fast turn-around (3-7 days).

  • FISH

    • Uses probes for specific chromosomes or chromosomal regions (ie, can detect T21 but also can detect 22q11.2 deletion).

    • Can be done on uncultured cells, so can get results in as few as 2 days.

    • Good to use if someone screens positive for T21 or other aneuploidy on serum analytes or cfDNA and you want a quick results before you get the full karyotype/microarray results

    • Often start with FISH, then reflex to microarray if normal, or karyotype if abnormal (to confirm).

Cervical Cancer Screening and Prevention

Today we discuss one of the basic screening tools of the OB-GYN office: the Pap smear. Named for Georgios (George) Papanikolau, credited for its creation around 1923, it is a test that has singlehandedly changed the face of cancer screening. With its widespread use, the incidence of cervical cancer in the US has dropped from 14.8 / 100k women in 1975, to 6.7 / 100k women in 2011. The converse also demonstrates the importance of this routine test: 50% of those diagnosed with cervical cancer have never had Pap screening, and 10% have not had screening within the preceding 5 years.

We also now know and can test for the presence of oncogenic strains of human papilloma virus, or HPV. Types 16 and 18 account for over 70% of cervical cancer worldwide, and 12 other strains account for the remaining majority of cases. Ongoing trials are looking at whether HPV screening may ultimately supplant cytology as the preferred 1st test, but HPV screening has added another excellent tool to help OB-GYNs discuss risk and prevent cancer in their patients.

Follow along with ACOG PB 168!

So what are the screening guidelines?
In the immunocompetent patient, they are as follows:

• < 21 years: Screening should not be performed, even in the presence of behavior-related risk factors.

  • Only 0.1% of cervical cancer cases occur before age 20.

  • Women younger than 21 with no immunocompromising conditions generally clear HPV infection between 8-24 months after exposure. 

  • This population should have discussion about safe sex practices to avoid exposure to STIs including HPV, and strong consideration for HPV vaccination.

• 21 - 29 years: Screening should be performed using cytology alone every 3 years.

  • Annual screening is discouraged in this group, as it exposes patients to a much more significant number of unnecessary procedures for minimal improvement in outcomes. 

  • HPV co-testing is not recommended in this group; however, HPV reflex testing in the event of an ASC-US Pap smear may be considered to determine need for colposcopy.

• 30 - 65 years: Screening should be performed with cytology alone every 3 years, or cytology with HPV co-testing every 5 years. 

  • In this population, with a negative cytology and negative HPV test, the risk of developing CIN 2 or 3 in the next 4-6 years is extremely low, based on large database studies (approximately 0.08% risk over 5 years). The risk is higher, but also quite low, with cytology alone (0.26% over 5 years). This is the rationale for the screening interval being extended.

  • RCTs have demonstrated in this population that cotesting has a number of distinct advantages:

    • Cotesting has a higher detection rate of high-grade dysplasia in first round of screening, and decreases risk of CIN3 or cancer in subsequent screening.

    • Cotesting likely has a better pickup rate for cervical adenocarcinomas (vs. squamous cell) than cytology alone.

• > 65 years, or post-benign hysterectomy: Screening should be discontinued, provided that:

  • There has been no history of CIN2, CIN3, or AIS in the preceding 20 years, and:

  • There are adequate negative prior results:

    • 3 consecutive negative cytology results within last 10 years, or

    • 2 consecutive negative cotest results within the last 10 years, with the most recent test performed within the past 5 years.

  • Women in this age group do get cervical cancer; however, the majority of these cases occur in women who are not screened, or in those who are underscreened.

  • The changes of menopause may also cause false positive Pap tests in this group, leading to likely unnecessary additional and invasive testing and procedures.

Behavioral risks, such as cigarette smoking, new or multiple sexual partners, or early sexual debut, may increase risk of HPV acquisition or persistence, but do not alter screening recommendations.

However, two particular conditions do merit changes to screening:

• In utero diethylstilbestrol (DES) exposure:

• DES was an estrogen that was manufactured and prescribed in the US during the 1930s until 1971. It was thought that the medication helped with premature birth or history of miscarriage, though by the 1950s it had been demonstrated to be ineffective.

• ACOG states that annual cytology is reasonable in women exposed to DES in utero, as cohort studies have demonstrated a much higher incidence of clear cell adenocarcinoma of the vagina in women born to mothers who took DES or similar medications. DES has also been associated with other health problems in both men and women.

• You can find a list of DES and related medications online at the CDC, and there is an interactive tool for patients to use to determine if they may be at risk.

• HIV or immunocompromising conditions:

  • Women infected with HIV or with other immunocompromising conditions are less readily able to clear HPV infections. Thus, the recommendations in this population differ:

• Screening should begin within 1 year of sexual activity, and no later than age 21.

• In women less than 30, If the first screen is negative, it should be repeated in 12 months. If three consecutive annual screens are normal, screening may be spaced to regular intervals (i.e., q3 year cytology). HPV cotesting is not recommended.

• In women older than 30, three annual tests should be normal, before moving to cytology alone or co-testing. Screening intervals should be every 3 years in this population, regardless of the method chosen. 

• Screening should continue for the lifetime of the woman, and not stop at age 65.

What about HPV vaccination?

HPV vaccination has been an incredible advance for primary prevention of cancer. Currently available include a bivalent vaccine, a quadrivalent vaccine, and a 9-valent vaccine. All of these cover HPV types 16 and 18. The 9-valent vaccine covers up to 50% additional cases of cervical cancer versus the bivalent vaccine. The 9-valent vaccine should be given to boys and girls ages 9-26. 

• For those receiving their first dose before age 15, only two doses given 6 months apart are needed. 

• For those receiving it after age 15, 3 doses given at 0, 1-2, and 6 months apart are recommended. 

HPV vaccination is not recommended during pregnancy, but also hCG screening is not necessary prior to initiating the dose. If pregnancy interrupts the schedule, it should be resumed postpartum without need for redosing. Studies are ongoing to determine the safety of HPV vaccination during pregnancy. 

In June 2019, the CDC’s advisory council on immunization practices (ACIP) updated its HPV vaccination recommendations, to extend recommendation for vaccination for all persons up through age 45, after the FDA approved this in October 2018. While this hasn’t made it into official ACOG practice guidance yet, it’s safe to say that this is forthcoming!

Further Reading from the OBG Project:

USPSTF Releases Final Cervical Cancer Screening Guidelines – Including ‘HPV Only’ Option
Screening for Cervical Cancer in the Woman at Average Risk
What is the Most Efficient Method for Cervical Cancer Screening?
Cervical Cytology and HPV Screening in the HIV Positive Woman
Cervical Cancer Screening Strategies and Cost-Effectiveness: Which is the Best?

Intimate Partner Violence and Gun Violence

Today we are spending some time on IPV/DV and gun violence. These are topics every OB/GYN should be familiar with; IPV accounts for 250,000 hospital visits, 2,000 deaths, and $8 billion in direct care costs annually on a conservative estimate. 1 in 3 American women is victimized by IPV during their lifetimes, and 1 in 5 report being the victim of sexual assault.

ACOG CO 518 serves as essential reading for our conversation today. Important points from the reading and today’s episode include:

• OBGYNs see women at risk for IPV/DV commonly, and should be regularly screening. Higher-risk is associated with pregnancy, adolescence, immigration status, and elderly age or disability.

• Screening questions should allow the patient to perform screening alone, in a safe location, with non-stigmatizing language. Systems should be in place to deal with positive screening, if identified. Offering a safe space in the office to allow the patient to contact the National Domestic Violence Hotline is a good place to start: 1-800-799-SAFE (7233).

• Mandatory reporting requirements vary by jurisdiction:

  • For IPV/DV: www.futureswithoutviolence.org/userfiles/file/HealthCare/MandReport2007FINALMMS.pdf.

  • For elder abuse: www.ncea.aoa.gov/NCEAroot/Main_Site/Find_Help/State_Resources.aspx.

Finally, check out ACOG’s stance and legislative priority list surrounding gun violence. Be active and get involved today — this is our lane!