Pocket ObGyn – Genetic Screening
See Abbreviations
Maternal Serum Aneuploidy Screening (Obstet Gynecol 2007;109:217)
- Aneuploidy screening should be offered to all Counseling includes what is being screened for, potential results, advantages/disadvantages (including cost), & how the results might impact their decisions about the Preg.
- Reported as “risk” of aneuploidy (w/ regard to trisomy 21 & trisomies 13/18) compared to age-matched reference, not as positive or negative (except for cellfree fetal DNA, see below). Overall: 5% positive screen rate (predetermined).
- Screening parameters: Combination of values used in various screening approaches
NT: Defined anatomic area behind fetal neck measured sonographically as width (mm) btw ~11–14 w. in aneuploidy & other conditions. Lower false positive rate if combined w/ serum markers. Useful in multiples when serum markers not accurate (ie, each fetus evaluated).
NB: Used w/ NT for trisomy 21 eval
Serum markers: Preg hormones used in combination to calculate risk (AFP, bhCG, PAPP-A, inhibin A, UE3)
- 1st trimester screening: NT, PAPP-A, & b-hCG in mat serum at 11–14 Comparable detection rates to 2nd trimester screen but higher screen positive rate in women >35 yo compared to 2nd trimester screen. Advantages:Time for CVS as diagnostic test & earlier termination options. Disadvantages: More costly
approach. In case of sequential strategy, pts must wait for results until 2nd trimester.
- 2nd trimester screening: AFP, hCG, unconjugated estriol (UE3), and inhibin A in screen at 15–18 w & some labs up to 24+ Detection 69% for triple screen, 81% for quadruple screen (using inhibin A). Advantages: Does not rely on NT (operator dependent test). Serum markers may suggest other problems (eg, AFP for NTD). Disadvantages: Only screening ® amniocentesis for dx. Given later GA, if anomaly found, options may be more limited.
| Second trimester maternal serum analytes | ||||
| AFP | UE3 | hCG | Inhibin A | |
| T21 | ¯ | ¯ | | |
| T18 | ¯ | ¯ | ¯ | ¯ |
| NTD | | N/A | N/A | N/A |
- Combined approaches: Uses both 1st & 2nd trimester screening When
1st & 2nd trimester protocols used independently, false positive rate .
Integrated screening: Integrates 1st & 2nd trimesters ® results given in 2nd trimester
94–96% detection rate w/ full integrated (NT, PAPP-A, quad screen)
Sequential screening: 1st & 2nd trimester screens performed w/ results reported after 1st & then altered after 2nd trimester. Benefits: Allows CVS for those at highest risk & ¯ anxiety of waiting. 95% detection rate by 2nd trimester.
Cell-free Fetal DNA
- Definition: Free fetal DNA in mat circulation likely from syncytiotrophoblast cells, extracted from mat serum, & proportion of target genetic material measured by sequencing. Imbalance of genetic material sugg extra or missing
- Commercial testing for screening for trisomy 21 & trisomy 18 Single bld test w/ >99% sens & spec for T21 & T18. Rapidly evolving technology.
- Applications: Aneuploidy, sex determination (presence of Y chromo), Rh typing. Performed after 10
Screening for Hemoglobinopathies (Obstet Gynecol 2007;109:229)
- Offered to individuals of African, Southeast Asian, & Mediterranean If a woman is aware of her status, screening does not need to be repeated. Many US-born women were screened at birth. See Chap. 16.
- Sickle cell: Screen w/ CBC & HbEP in African HbEP allows for detection of HbS & other variants. If positive, partner should undergo carrier screening. Dx: If both partners positive for HbS, refer for genetic counseling to discuss CVS or amniocentesis for diagnostic genetic testing of fetus.
- Thal: Screen w/ CBC & MCV in Southeast Asian & Mediterranean descent
Beta-thalassemia: In pts w/ anemia, MCV < 80, & nml iron status (nml ferritin) HbEP should be performed for screening for thal. HbEP shows elevated HbA & HbF for beta-thalassemia. If positive, partner requires screening.
Alpha-thalassemia: HbEP unable to detect alpha-thalassemia, if of Southeast Asian ancestry w/ microcytic anemia, nml iron studies, & nml HbEP offer DNA testing for abn alpha-globin gene. If positive, partner requires screening.
Dx: If both parents are carriers & have described genetic mutations ® offer CVS or amniocentesis for fetal genetic testing
Other Inherited Diseases (Obstet Gynecol 2010;116:1008)
- CF: Autosomal recessive condition due to >1700 of mutations in CFTR gene. Routine testing for common mutations offered to all pts (regardless of ethnicity) after appropriate education regarding the implications of testing & results. Detection rate of test related to prevalence in Pts w/ personal Hx or FHx of CF or related conditions should undergo genetic counseling to determine if expanded mut screens are warranted. If pt positive, partner should be screened & consider amniocentesis/CVS.
- Fragile X: Most common inherited form of Due to triplet repeats on FMR1 gene. Offer carrier testing in FHx of fragile X-related disorders, unexplained MR, autism, or premature ovarian failure.Variable penetrance based on number of triplet repeats. Only test for FMR1 triplet rpt is diagnostic test using CVS or amniocentesis for known carriers.
- Tay–Sachs: Ashkenazi Jewish, French Canadian, or Cajun descent
- Familial dysautonomia or Canavan dz: Ashkenazi Jewish descent
- Offer other screening tests (musc dystrophy, Huntington’s) based on FHx
Amniocentesis and Chorionic Villus Sampling (CVS)
Invasive Prenatal Diagnostic Testing
- Definitive diagnoses for specific Discuss the difference btw screening & diagnostic tests, risks & benefits, alternate screening tests, & interpretation of results.
Amniocentesis (Obstet Gynecol 2007;110:1459)
- Definition: Removal of AF using transabdominal Procedure performed using spinal needle typically w/ US guidance. For both diagnostic & therapeutic indications. Genetic amniocentesis typically btw 15 & 20 w.
- Diagnostic amniocentesis: Usually for prenatal genetic testing, but several
Genetics: Allows for culture of fetal cells & dx of aneuploidy via karyotype FISH or CGH
Infxn: AF can be used for cell count, gluc, & culture for suspected chorio or can be used to perform diagnostic tests for infxn such as CMV
Hemoglobin: Fetal hemoglobin can be obtained for eval of fetal anemia, fetal bld type, or eval of hemoglobinopathies
Other indications: Can be used to test fetal lung maturity or for NTDs.
- Therapeutic amniocentesis: Amnioreduction (removal of AF) can be therapeutic for pts w/ twin-to-twin xfusion syn & preterm CTX from
- Risks: Higher w/ early amniocentesis (11–13 w; not recommended). 1 in 300–500 Preg loss, lower at experienced 1–2% vaginal spotting or LOF; <1:1000 for chorio. AF cells can fail to culture leading to nondiagnosis after amniocentesis. Small risk of transmission of HCV or HBV but data limited. Small risk of transmission of HIV if pt on antiretroviral therapy/undetectable viral load. Rh-negative women should get anti-D RhIg prior to procedure to prevent sensitization
Chorionic Villus Sampling (CVS)
- Definition: Removal of chorionic villi via TA or TC catheter w/ needle under sono Typically used for dx using karyotype analysis, FISH, or genetic testing for specific alleles. Performed btw 9 & 16 w gest.
- Risks: Complication rate of TA-CVS lower than rates of TC-CVS. Fetal loss (0.7–1.3%) higher than amniocentesis but background rate of fetal loss at earlier GA is Rates of loss at similar GAs are the same btw amniocentesis & CVS. Up to 30% vaginal spotting w/ TC-CVS, less after TA-CVS. Limb reduction or oromandibular defects after 9 w, risk = 6 in 10000 (similar to risk in general pop). Rh-negative women should get anti-D RhIg prior to procedure to prevent sensitization. Nondiagnostic procedure due to operator failure or cell culture failure; higher than for amniocentesis. Higher rate of chromosomal mosaicism (presence of more than one cell line) in CVS compared to amniocentesis (1% vs. 0.25%); if mosaicism, amniocentesis may be indicated. Infxn or leakage of amniotic fluid <0.5%.
- Counseling: Offer to pts interested in 1st trimester diagnostic Advantage of CVS is early GA at dx = more options.