The American College of Obstetricians & Gynecologists has issued new guidelines for prenatal diagnostic and screening testing for genetic disorders. These new guidelines will become the new rules by which obstetricians administer prenatal testing.
ACOG has long established the standard of care for obstetric practice in the United States. Going back to the 1980’s, ACOG issued guidelines recommending that women of advanced age be offered prenatal testing for Down syndrome and other aneuploidies. These guidelines remained in place until a new screening technology was recognized in the 2000’s.
In 2005, the First And Second Trimester Evaluation of Risk (FASTER) study published findings on the reliability of the first-trimester combined screen of nuchal translucency measurement and maternal serum analysis. Contemporaneously, other studies reported that the risk of miscarriage associated with diagnostic testing was lower than the historically cited 1% for amniocentesis and 2% for chorionic villus sampling.
Relatively soon after the publications of these studies, ACOG issued Practice Bulletins No. 77 and 88 in 2007 changing the recommendations for prenatal testing. Rather than limiting the offer of prenatal testing to mothers considered “AMA,” the then-new guidelines recommended offering diagnostic and screening testing to all women.
In the nine years since those guidelines were first published, cell free DNA screening has entered clinical practice. Prompted by this new screening option, and with the years of practice since the 2007 guidelines were issued, ACOG has now issued new guidelines concerning diagnostic and screening testing.
ACOG Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders
The first new guideline (in numerical order) concerns the relatively finite options of diagnostic testing. ACOG retains the recommendation from Practice Bulletins No. 77 and 88 that all women should be offered diagnostic testing regardless of maternal age or other risk factors. Here are the other main takeaways from Practice Bulletin No. 162 (subscription required):
- Chorionic villus sampling (“CVS”) is performed between 10 and 13 weeks. Its calculated procedure-related loss rate is 0.22%. While earlier studies had suggested an association with limb-reduction defects, the risk is not significantly greater than found in the general population provided CVS is performed at or after 10 weeks of gestation.
- Amniocentesis (“amnio”) is performed between 15 and 20 weeks; it is not recommended to be performed earlier than 15 weeks. The estimated procedure-related loss rate is approximately 0.11%. Loss rates for both amnio and CVS, though, are found in high-volume, experienced centers and ACOG notes the low loss rates “may not apply to other situations,” i.e. “among health care providers with less cumulative experience.”
- Fluorescence in situ hybridization (“FISH”) should be considered a screening test due to false-positive and false-negative results having been reported with FISH. Any clinical decision should not be based solely on FISH, but after confirmatory diagnostic results or consistent clinical information, e.g. abnormal ultrasound findings or a positive screening result for Down syndrome or trisomy 18.
- Chromosomal microarray analysis (“CMA”) should be made available to any patient choosing to undergo invasive diagnostic testing. In the case of an ultrasound finding of fetal structural abnormality, CMA is recommended as a primary test, unless the abnormality is “strongly suggestive” of a particular aneuploidy, in which case karyotype may be offered before CMA.
- Preimplantation genetic diagnosis (“PGD”) uses only a few cells and errors are possible; therefore “confirmation of results with CVS or amniocentesis is usually recommended.”
- Pre-test counseling: General information about the potentially detectable conditions should be provided patients before making a decision to have invasive diagnostic testing. When a fetal genetic abnormality is suspected, a health care professional with genetics expertise “can help with counseling, choosing the right test, and interpreting the test results.”
- Post-diagnosis counseling: “the patient should receive detailed information, to the extent that information is available, about the natural history of the specific condition. … The option of pregnancy termination should be discussed when a genetic disorder or major structural abnormality is detected prenatally. … Referral to parent support groups, counselors, social workers, or clergy may provide additional information and support for some patients.”
ACOG reiterates, and expands on this recommendation later in the guideline: “counseling should include family education and preparation; obstetric management recommendations, including fetal surveillance, intrapartum monitoring, and mode of delivery; referral to pediatric specialists and a tertiary care center for delivery, if appropriate; availability of adoption or pregnancy termination; and perinatal palliative care services and comfort care for delivery of a child with a diagnosis or fetal presentation that is incompatible with long-term survival.”
The guideline directs practitioners to a website with additional resources, but it is restricted to viewing by members of ACOG.
ACOG Practice Bulletin No. 163: Screening for Fetal Aneuploidy
Unlike diagnostic testing, there are a panoply of screening methodologies and combinations thereof. Moreover, while diagnostic testing is just that, diagnostic, the screening options do not all test for the same conditions, which adds to the number of options of screening offerings for patients to consider. As with Practice Bulletins No. 77 and 88, ACOG recommends that screening testing be offered to all expectant mothers and ideally at their first prenatal visit. Here are the summarized takeaways from Practice Bulletin No. 163 (subscription required):
- First trimester combined screening can be performed between 10 and 13 6/7 weeks. It is commonly referred to as “nuchal translucency” or “NT” screening, however it is key to appreciate that NT alone is not what is recommended. Rather, NT combined with maternal serum screening is the recognized first trimester screen. Because slight mismeasurements can cause wide variation in accuracy of the calculations, “meticulous technique … is essential.”
- Second trimester screening can be performed between 15 and 22 6/7 weeks, with the optimal screening time frame being 16 – 18 weeks of gestation. Typically, second trimester screening is the “quad” screen, which tests a blood sample from the mother. Unlike first trimester combined screening, second trimester screening tests not only for aneuploidy but open neural defects like spina bifida. Therefore, second trimester screening should be offered for open neural defects regardless of whether first trimester screening was conducted. HOWEVER, and this is a key note in the guidelines, multiple screenings for aneuploidy should not be conducted independently of each other since they each have a higher chance of reporting a false positive and creating confusion. The guideline recognizes that one laboratory (so far) is offering what has been called “Penta” screening, adding a fifth element to the quad screen, but that there is limited date to compare Penta with quad screening’s accuracy.
- Integrated and sequential screening: these are combinations of the first trimester combined screen and the second trimester screening. Integrated has the highest detection rate of all non-cfDNA screening protocols, but its results are not reported until the second trimester. Sequential screening has a higher detection rate than individual screen results and reports first trimester results, which then determine if second trimester screening should be done.
- Ultrasound screening: while ultrasound may detect the physical attributes associated with trisomy 13 and 18, “Down syndrome is more elusive.” Therefore, ultrasound should not be used in isolation to diagnose or exclude Down syndrome. If a soft marker is identified by ultrasound, serum screening should be offered if it had not been already.
- Cell free DNA screening: may be offered anytime from 10 weeks on through the duration of the pregnancy–it is the only screen available in the third trimester. The fetal component of cfDNA is primarily from placental cells. Though cfDNA screening has the highest reported detection rate among high risk mothers, comparisons of which cfDNA screen has the highest is not capable of being done due to how the cfDNA labs choose what information is shared publicly. It therefore remains a screening test with false positives and false negatives. Further, in the instance when no reportable results are available from a serum sample, because these unreportable results have shown to have a higher association with being true positives, unreportable results should be treated as a report of increased risk. Due to a lack of clinical validation, cfDNA screening is not recognized for microdeletions. In the case of multiple gestations, cfDNA screening is not recommended.
- Preimplantation genetic screening (“PGS”): in an IVF cycle, PGS may be performed, but it still may have false positives and false negatives. As a result, pregnancies conceived through IVF, even if they had PGS, should be offered the same screening and diagnostic offerings as all other pregnancies.
- Pre-test counseling: ACOG recommends that patients be counseled on the prenatal testing options that are available, with it being explained the relative advantages and disadvantages of each screening test, along with the screening test’s detection rate, positive and false positive rates, and limitations. Patients should also be counseled about having diagnostic testing. After counseling, patients may decline for any reason.
- Post-test counseling: Screening test results “should be reported as either positive or negative, and the adjusted numerical risk should be provided.” Patients should receive “detailed counseling” and if the positive screen result is conventional serum screening, patients should be offered cfDNA screening and/or CVS or amniocentesis. Patients with a positive conventional screen result but a negative cfDNA screen should be informed that there is still a 2% residual risk of a chromosomal abnormality. “All patients with a positive cfDNA result should have a diagnostic procedure before any irreversible action, such as pregnancy termination, is taken.” As with Practice Bulletin No. 162, ACOG refers practitioners to a website for further information and resources regarding screening, but it too is available only to ACOG members.
Practice Bulletins No. 162 and 163 will set the new standard of care for administering prenatal testing. They will also influence the coverage of prenatal testing as insurers regularly rely on and cite ACOG’s practice bulletins as justifications for their coverage determinations. Given the length of this post, I’ll leave it at just this factual reporting on the new recommendations, but your comments, questions, and critiques are welcomed by leaving a comment to this post.
What do you think of the new recommendations? What is done well and what, if anything, could use improvements?