The American College of Obstetricians & Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM) have issued new guidelines replacing previous guidance on prenatal genetic screening. The guidelines are restricted to subscribers and members. This post summarizes Practice Bulletin No. 226, offers brief commentary, and invites your thoughts on the new guidelines.
PB 226 is titled “Screening for Fetal Chromosomal Abnormalities”; however, the guidance extends to physiological conditions as well. The preface recognizes there are a “wide variety of prenatal screening and diagnostic tests” available, but that “no one test is superior in all circumstances.” Given this range of options, “nuanced, patient-centered counseling from the obstetric care professional and complex decision making by the patient” is needed. Continuing, “[t]esting for chromosomal abnormalities should be an informed patient choice based on provision of adequate and accurate information, the patient’s clinical context, accessible health care resources, values, interests, and goals.” Consistent with guidelines since 2007, ACOG and SMFM recommend that all patients should be offered prenatal screening and diagnostic testing and all patients have the right to accept or decline testing.
Cell-free DNA Screening
After a brief background section, the Practice Bulletin addresses each genetic screening method. It leads off with cell-free DNA screening (cfDNA), and this is the section that is making news. Changing from previous guidance, (summarized here), ACOG/SMFM now recommends that all patients should be offered cfDNA screening regardless of baseline risk level.
Consistent with every guidance on cfDNA screening, PB 226 recognizes that “cell-free DNA testing is not equivalent to diagnostic testing.” Further, PB 226 recommends that patients who receive no call test results be counseled that they are “at an increased risk for chromosomal abnormalities.” Lab tests that report fetal fraction are preferred.
CfDNA labs have been offering expanded screening beyond the major trisomies (21, 18, and 13) for years, with some offering whole genome screening. PB 226 recommends when the test results report a microdeletion, it should be confirmed through diagnostic testing “as most positive results will be false-positive results because of the low prevalence of these disorders.” PB 226 does not recognize whole genome cfDNA screening as being clinically validated.
First-Trimester Screening: Serum Analytes Plus Ultrasound
Nuchal translucency combined (NT-combined) testing is what prompted ACOG to change the standard of care in 2007. Up until that time, prenatal genetic screening was not recommended unless the mother was of “advanced maternal age” or had other factors that would increase her age-based probability. Consistent with guidance since then, PB 226 recognizes that “[i]ndependent credentialing and ongoing quality assurance of individuals performing these measurements is required to maintain screening performance.”
AFP was the initial prenatal genetic screening test in the 1980’s. Since then, the quadruple marker screen (“quad” screen) has become the norm, though some labs offer the “penta” screen, adding yet another marker. PB 226 does not recognize the penta screen as superior to the quad screen, but does recognize the quad screen’s superiority in detection over just AFP.
Combined First-Trimester and Second-Trimester Screening Tests
The guidelines regarding the various combinations of first and second-trimester screening options–integrated, sequential, or contingent screening–have not changed. Integrated has a higher detection rate and a lower false positive rate as compared to the other options, but its results are not reported until the second trimester. Sequential and contingent provide some information in the first trimester “to allow for earlier diagnostic testing and reproductive management options.”
Regardless of whether patients have accepted cfDNA or serum screening, ACOG/SMFM recommend that “all patients should be offered a second-trimester ultrasound for fetal structural defects, ideally performed between 18 and 22 weeks of gestation.” Often, these anatomic ultrasounds can identify “soft markers.” PB 226 states that “soft markers for aneuploidy are most commonly identified in euploid fetuses.” If soft markers are seen, the patient’s record should be checked to see if aneuploidy screening had been performed: if not, offer aneuploidy screening; if so, the soft markers are to “be placed in context with those results.”
Clinical Considerations and Recommendations
All patients should be offered screening and diagnostic testing for chromosomal abnormalities. Patients “should be provided with general information about the disorders” detectable and not detectable with screening before making a decision to undergo the tests offered. “Counseling should be performed in a clear, objective, and nondirective fashion, allowing patients sufficient time to understand and make informed decisions regarding testing.” “Prenatal genetic testing may be desired to obtain information before delivery or to inform a decision for pregnancy termination.”
Regarding cfDNA screening, patients should be counseled about the possibility of “incidental findings affecting the patient, including medical conditions such as her own chromosomal aneuploidy, mosaicism, or malignancy.” If aneuploidy screening is chosen, only one method, analyte screening or cfDNA screening, should be used to avoid discordant results.
Screen Positive Results
Practitioners are recommended when delivering screen positive results to advise patients of their revised probability of the tested-for condition. “Information regarding the characteristics of the condition should be reviewed to aid decision making.” Patients “should undergo genetic counseling” and offered diagnostic testing to confirm results. Again, ACOG/SMFM caution that screening results “should not be used as the sole basis on which to make critical clinical decisions.”
Somewhat contradicting the earlier statement of not using both serum and cfDNA screening due to possible divergent results, following a serum screen positive, cfDNA screening is an option for patients wishing to avoid diagnostic testing. If diagnostic testing is declined, “management of the pregnancy should be based on the sonographic features identified and the patient’s preferences.”
Screen Negative Results
Patients should be counseled on the limited range of conditions tested-for and that there remains a chance of untested-for conditions to affect the fetus.
Interpretation of Cell-Free DNA Test Failures and Low Fetal Fraction
ACOG/SMFM refers to the ACMG statement on cfDNA screening (reported on here) calling for cfDNA screen results to include the fetal fraction. For no-calls, patients should be counseled on their increased probability of a condition, offered genetic testing, comprehensive ultrasound evaluation and diagnostic testing.
Role of Ultrasound
With first-trimester ultrasound, an increased NT measurement has been associated with a higher chance for genetic syndromes as well as anomalies like heart and abdominal wall defects, diaphragmatic hernia, even with euploid chromosomes. Patients should be offered genetic counseling, comprehensive ultrasound and diagnostic testing.
“independent of screening or diagnostic testing, all patients should be offered a second-trimester sonogram to assess for structural abnormalities.” Same recommendations as above if soft markers are detected.
Serum screening, including the first- and second-trimester combination options, should be available for twin gestations, though few data on test performance are available. CfDNA screening can be performed in twin gestations. All reports give one test result for a twin pregnancy. In the case of one twin’s demise or anomaly identified in one fetus, “there is a significant risk of an inaccurate result” with serum or cfDNA screening; diagnostic testing should be offered.
Preimplantation Genetic Testing
“[B]ecause preimplantation genetic testing is not uniformly accurate, prenatal screening and prenatal diagnosis should be offered to all patients regardless of previous preimplantation genetic testing.”
Additional or Incidental Information
Abnormal serum screen results, even with unaffected fetuses, can identify pregnancies at risk for obstetric complications like fetal and neonatal loss, fetal growth restriction, preeclampsia, placental abruption, and preterm delivery.
CfDNA screening can identify maternal mosaicism and malignancy, i.e. cancerous tumors, in the mother.
PB 226’s recommendation that cfDNA screening be offered to all patients is a position that the for-profit cfDNA testing laboratories have been lobbying ACOG/SMFM and state legislatures for years. Public and private insurers, including Medicaid, typically base coverage decisions on ACOG guidelines. With PB 226, it can be expected that cfDNA screening will be widely covered, allowing for cfDNA labs to market their tests as “safe. accurate. & free.” Removing one more barrier can also be expected to expand the pool of patients who will accept prenatal screening. A review of the references cited for the change in offering cfDNA screening to all patients reveals just three studies published after the 2016 PB 163. This relative few number of studies justifying the change may suggest other, unstated reasons were factors in ACOG/SMFM’s decision.
With more patients being offered screening and more expected to accept it, the significance of PB 226’s recommendations on patient informed decision making cannot be overstated. PB 226 recognizes that ultimately screening decisions can lead to decisions whether to continue or terminate the pregnancy. Compiling the relevant statements from PB 226, it recommends that “informed patient choice [be] based on provision of adequate and accurate information”. “Pretest and posttest counseling is essential.” Pre-test counseling should “inform pregnant patients about chromosomal disorders” and post-test counseling should include information on “the conditions targeted in screening”. Pre-test, “[p]atients should be provided with general information about the disorders that are potentially detectable … and the disorders that are not detectable”. Following a positive screen result, “[i]nformation regarding the characteristics of the condition should be reviewed to aid decision making”. Yet, unlike the guideline PB 226 replaces (PB 163), it does not include an addendum of recognized informational resources for practitioners to access.
The absence of information determined to be helpful just four years ago is puzzling since little–if anything–has changed about the actual conditions tested-for. Moreover, ACOG/SMFM include in the references the study many of us in PIRC participated in, which found none of the cfDNA laboratories comport with all the guidelines set forth by ACMG in 2016. ACOG/SMFM not only includes this study in the references, but specifically cites it for reporting out fetal fraction. ACOG/SMFM issues this statement, then, knowing that the cfDNA laboratories that will financially benefit from the revised guidelines are not abiding by existing professional recommendations. Specifically, as the chart maintained on this site from our study shows, at the time of PB 226’s publication, only two labs provided recommended patient resources and only one provided the recommended resources for practitioners to aid in counseling their patients.
This analysis reveals a troubling logic: cfDNA laboratories have been lobbying for offering their tests to all patients in order to gain insurance coverage to pay for their tests; ACOG/SMFM changes its recommendations, providing this expanded offering, but recognizing patient informed decision making is mandatory and, specifically, information about the conditions tested-for is needed for that decision-making; and, ACOG/SMFM does so knowing the cfDNA laboratories are not providing the recommended informational resources for patients and providers AND ACOG/SMFM chooses to exclude the reference to the information ACOG/SMFM compiled just four years ago that they recognized was helpful for patients and providers to exercise informed decision making.
Invitation to Share Your Thoughts
Your comments are welcomed on these new guidelines and the concerns raised in the brief commentary.