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-centeredcounseling 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.
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.
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.
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.”
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.
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.”
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.
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.
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.
“[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.”
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.
Ethnic-specific, pan-ethnic, and expanded carrier screening are acceptable strategies for pre-pregnancy and prenatal carrier screening. Each obstetrician–gynecologist or other healthcare provider or practice should establish a standard approach that is consistently offered to and discussed with each patient, ideally before pregnancy. After counseling, a patient may decline any or all carrier screening. If a patient requests a screening strategy other than the one used by the obstetrician–gynecologist or other healthcare provider, the requested test should be made available to her after counseling on its limitations, benefits, and alternatives.
All patients who are considering pregnancy or are already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for cystic fibrosis and spinal muscular atrophy, as well as a complete blood count and screening for thalassemias and hemoglobinopathies. Fragile X premutation carrier screening is recommended for women with a family history of fragile X–related disorders or intellectual disability suggestive of fragile X syndrome, or women with a personal history of ovarian insufficiency. Additional screening also may be indicated based on family history or specific ethnicity. Couples with consanguinity should be offered genetic counseling to discuss the increased risk of recessive conditions being expressed in their offspring and the limitations and benefits of carrier screening. Carrier screening will not identify all individuals who are at risk of the screened conditions. Patients should be counseled regarding residual risk with any test result. Prenatal carrier screening does not replace newborn screening, nor does newborn screening diminish the potential benefit of prenatal carrier screening.
All patients who are considering pregnancy or are already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for cystic fibrosis and spinal muscular atrophy, as well as a complete blood count and screening for thalassemias and hemoglobinopathies. Fragile X premutation carrier screening is recommended for women with a family history of fragile X–related disorders or intellectual disability suggestive of fragile X syndrome, or women with a personal history of ovarian insufficiency. Additional screening also may be indicated based on family history or specific ethnicity. Couples with consanguinity should be offered genetic counseling to discuss the increased risk of recessive conditions being expressed in their offspring and the limitations and benefits of carrier screening. Carrier screening will not identify all individuals who are at risk of the screened conditions. Patients should be counseled regarding residual risk with any test result. Prenatal carrier screening does not replace newborn screening, nor does newborn screening diminish the potential benefit of prenatal carrier screening.
If a woman is found to be a carrier for a specific condition, her reproductive partner should be offered screening to provide accurate genetic counseling for the couple with regard to the risk of having an affected child. Additional genetic counseling should be provided to discuss the specific condition, residual risk, and options for prenatal testing.
If a carrier couple (ie, carriers for the same condition) is identified before pregnancy, genetic counseling is encouraged so that reproductive options (eg, donor gametes, pre-implantation genetic diagnosis, prenatal diagnosis) can be discussed.
Individuals with a family history of a genetic disorder may benefit from the identification of the specific familial mutation or mutations rather than carrier screening. Knowledge of the specific familial mutation may allow for more specific and rapid prenatal diagnosis.
Given the multitude of conditions that can be included in expanded carrier screening panels, the disorders selected for inclusion should meet several of the following consensus-determined criteria: have a carrier frequency of 1 in 100 or greater, have a well-defined phenotype, have a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life. In addition, screened conditions should be able to be diagnosed prenatally and may afford opportunities for antenatal intervention to improve perinatal outcomes, changes to delivery management to optimize newborn and infant outcomes, and education of the parents about special care needs after birth. Carrier screening panels should not include conditions primarily associated with a disease of adult onset. ACOG notes that these recommendations are not a substitute for other important routine testing, including newborn screening, and they do not identify all individuals who are at risk of a condition.
Committee Opinion No. 690 Summary: Carrier Screening in the Age of Genomic Medicine. Obstet Gynecol. March 2017
Prenatal sex determination & sex selection is illegal in India and not done here. It is a punishable offence.
© 2021. All right reserverd. Baufici Genetic Laboratory