Step 1. Start with baseline risk
Default opening state: no ultrasound performed and no cfDNA performed. Empty outputs display as "-" rather than "N/A," because the value is unavailable until inputs are entered.
Workflow: enter maternal age, gestational age, and target condition. Add ultrasound only if performed. Add cfDNA only if the result is known. A positive cfDNA result is screening-positive, not diagnostic.
Step 2. Ultrasound status
Use "not performed" unless an ultrasound finding is being interpreted. Specify whether the ultrasound was known before cfDNA or performed after the cfDNA result. A normal ultrasound after a screen-positive cfDNA result is reassuring for structural findings but does not by itself reclassify cfDNA as diagnostic or negative; diagnostic confirmation remains the definitive option. Structural/syndromic findings such as cardiac defect, palate/craniofacial abnormality, hypertelorism/facial dysmorphism, genitourinary anomaly, fetal growth restriction, increased NT, cystic hygroma, hydrops, or sex discordance should trigger pathway language rather than a simple isolated-marker calculation.
Fetal sex discordance pathway: Use pathway language rather than PPV. First confirm that the cfDNA report and ultrasound are referring to the same pregnancy and specimen. Review fetal fraction, Y-chromosome reporting, sex chromosome aneuploidy comments, and whether fetal sex was suppressed. Then confirm the ultrasound phenotype with targeted imaging of external genitalia and, when visible, internal genital structures, gonads, adrenal glands, urinary tract, growth, and other anomalies. If fetal diagnosis will change counseling or management, discuss genetics consultation and diagnostic testing, usually amniocentesis when confined placental mosaicism is a concern.
Pattern-specific testing options for fetal sex discordance
| Pattern | Most important considerations | Practical diagnostic approach |
|---|---|---|
| Ultrasound appears male or virilized, but cfDNA shows no Y / suggests XX | This pattern needs explicit attention. Important possibilities include true 46,XX virilization, especially congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency; maternal androgen exposure; aromatase deficiency; fetal or placental mosaicism; vanishing twin; or a reporting/sample issue. | Confirm fetal sex chromosomes with diagnostic testing. If amniocentesis confirms 46,XX or no Y and the genitalia appear male or virilized, add CYP21A2 testing for CAH. Consider endocrinology/genetics input, review maternal androgen exposure, and use a broader DSD panel or exome sequencing if CAH testing is negative or other anomalies are present. |
| Ultrasound appears female or undervirilized, but cfDNA shows Y / suggests XY | Consider 46,XY DSD, androgen insensitivity, gonadal dysgenesis, steroidogenesis defects, 5-alpha-reductase deficiency, SRY/SOX9 pathway disorders, placental mosaicism, or a cfDNA/reporting issue. | Confirm fetal sex chromosomes with amniocentesis when fetal confirmation is needed. If 46,XY is confirmed and the phenotype remains female or undervirilized, consider SRY evaluation when appropriate and a DSD gene panel covering androgen action, gonadal development, and steroid synthesis. |
| Ambiguous genitalia, with or without Y signal | Differential includes sex chromosome mosaicism, CNV, 46,XX or 46,XY DSD, severe hypospadias, cloacal/urogenital anomaly, single-gene syndrome, or imaging limitation. | Repeat targeted ultrasound. Consider fetal MRI if anatomy is unclear. Diagnostic testing generally starts with fetal karyotype or rapid aneuploidy testing plus chromosomal microarray; add SRY, CYP21A2, DSD panel, or exome sequencing based on the fetal sex chromosome result and associated anomalies. |
| Sex chromosome aneuploidy result discordant with phenotype | Consider confined placental mosaicism, fetal mosaicism, maternal sex chromosome mosaicism/CNV, vanishing twin, or true fetal SCA with variable phenotype. | Review fetal fraction and laboratory comments. Amniocentesis is preferred for fetal confirmation when placental mosaicism is possible. Karyotype is useful for mosaicism and structural sex chromosome rearrangements; microarray improves CNV detection but may miss low-level mosaicism. Consider maternal karyotype if maternal mosaicism/CNV is suspected. |
Practical note: karyotype alone may answer whether the fetus is 46,XX or 46,XY, but it does not fully evaluate a fetus whose phenotype and sex chromosome result do not match. In a male-appearing or virilized fetus with no Y signal or confirmed 46,XX, CAH testing should be specifically considered.
Soft-marker details, if applicable
Optional compact long-bone marker calculator
Determines whether historical short femur or short humerus marker thresholds are met. Use Biometry 5 for full growth, skeletal dysplasia, or FGR assessment.
Femur O/E ratio
-
Enter BPD and FL.
Humerus O/E ratio
-
Enter BPD and HL.
Long-bone caution: femur and humerus are correlated biometric findings. The clinical default uses the stronger long-bone marker rather than multiplying both likelihood ratios.
Step 3. cfDNA result category
Default is no cfDNA performed. Select the category that matches the report. Use the fetal sex discordance pathway when the reported fetal sex, Y-chromosome signal, or sex chromosome result does not match ultrasound anatomy or is indeterminate.
Profile note: PPV is highly dependent on prior risk and specificity. Use lab-specific performance and the lab-reported PPV when available, especially for 22q11.2 deletion and other CNV targets.
cfDNA + Ultrasound Risk Wizard
Baseline onlyNo ultrasound enteredNo cfDNA entered
Main message for counseling
Baseline risk estimate only. Enter maternal age, gestational age, and target condition to show baseline risk before ultrasound or cfDNA.
Step 1
Starting risk
-
Age/GA baseline risk.
Step 2
Risk if ultrasound added
-
No ultrasound modifier applied.
Step 3
cfDNA result
Not done
No cfDNA result entered.
Step 4
Post-cfDNA ultrasound
Not done
No ultrasound finding entered.
Best label:
Opening state is baseline-only. Do not label as PPV until cfDNA has been performed.
Opening state is baseline-only. Do not label as PPV until cfDNA has been performed.
Timing matters:
Ultrasound before cfDNA changes pretest risk. Ultrasound after cfDNA changes follow-up counseling.
Ultrasound before cfDNA changes pretest risk. Ultrasound after cfDNA changes follow-up counseling.
Patient framing:
Start with age/GA risk, then explain screening or diagnostic options.
Start with age/GA risk, then explain screening or diagnostic options.
Baseline risk
-
Enter target, age, and gestational age.
Risk before cfDNA
-
No ultrasound likelihood ratio applied.
Post-cfDNA probability
Not done
No cfDNA result entered.
Updated risk / pathway
Baseline only
No combined estimate generated.
Clinical synthesis
Structured for clinical documentation and counseling.
Clinician summary
Baseline-only estimate. No ultrasound finding and no cfDNA result have been entered.
Patient explanation
At this point, the estimate is based only on age and gestational age. No ultrasound or cfDNA result has been entered yet.
EMR-ready output
cfDNA/Ultrasound Risk Summary: Baseline risk reviewed using maternal age and gestational age. No ultrasound finding and no cfDNA result were entered.
Transparent calculation
Shown for internal review and teaching. Use lab-specific PPV when available.
Baseline-only workflow. Enter target condition, maternal age, and gestational age to calculate baseline risk.
Baseline risk table
Enter maternal age and gestational age to show starting risks.
| Condition | Starting risk | Basis |
|---|---|---|
| Baseline risk table will appear after maternal age and gestational age are entered. | ||
These are approximate counseling estimates. They are not a substitute for a validated laboratory-specific prior-risk model, diagnostic testing, or genetics consultation.
Interpretive caveats
Use these precautions before relying on the numeric output. The calculator should generate a number only when the clinical situation is appropriate for Bayesian screening-test interpretation. Otherwise, the output should switch to pathway language.
1. First choice rule
Before testing, counsel that screening and diagnostic testing are both options. The patient may accept or decline any option after counseling. Do not present cfDNA as the only acceptable pathway.
Before testing, counsel that screening and diagnostic testing are both options. The patient may accept or decline any option after counseling. Do not present cfDNA as the only acceptable pathway.
2. Screening, not diagnosis
A high-risk cfDNA result is not diagnostic. Positive screening results should be followed by genetic counseling, comprehensive ultrasound evaluation, and the opportunity for diagnostic testing with CVS or amniocentesis if the patient wants definitive fetal diagnosis.
A high-risk cfDNA result is not diagnostic. Positive screening results should be followed by genetic counseling, comprehensive ultrasound evaluation, and the opportunity for diagnostic testing with CVS or amniocentesis if the patient wants definitive fetal diagnosis.
3. Negative does not mean zero
A low-risk cfDNA result substantially lowers risk for the screened condition but does not exclude mosaicism, CNVs, single-gene disorders, structural malformations, or conditions outside the assay.
A low-risk cfDNA result substantially lowers risk for the screened condition but does not exclude mosaicism, CNVs, single-gene disorders, structural malformations, or conditions outside the assay.
4. Missing-input rule
If age, gestational age, target condition, or a valid custom prior is missing, display "-" and avoid PPV or residual-risk language. Do not show "0," "normal," or "N/A."
If age, gestational age, target condition, or a valid custom prior is missing, display "-" and avoid PPV or residual-risk language. Do not show "0," "normal," or "N/A."
5. PPV rule
Use PPV only for a screen-positive cfDNA result with a defined target condition, prior risk, and test-performance profile. Use lab-reported PPV when available.
Use PPV only for a screen-positive cfDNA result with a defined target condition, prior risk, and test-performance profile. Use lab-reported PPV when available.
6. Remaining-risk rule
Use "remaining risk after low-risk cfDNA," not PPV, for a screen-negative result. The residual-risk estimate is assay-specific and should be framed as approximate.
Use "remaining risk after low-risk cfDNA," not PPV, for a screen-negative result. The residual-risk estimate is assay-specific and should be framed as approximate.
7. Do not stack screening tests
Do not multiply independent results from serum screening, NT screening, and cfDNA as if they are separate diagnostic tests. If cfDNA is used after a positive serum screen, document the reason and counsel about delayed or missed diagnosis of non-screened conditions.
Do not multiply independent results from serum screening, NT screening, and cfDNA as if they are separate diagnostic tests. If cfDNA is used after a positive serum screen, document the reason and counsel about delayed or missed diagnosis of non-screened conditions.
8. Ultrasound timing rule
An ultrasound finding present before cfDNA changes the pretest probability. A finding discovered after cfDNA changes post-test counseling and may override the numeric residual-risk output.
An ultrasound finding present before cfDNA changes the pretest probability. A finding discovered after cfDNA changes post-test counseling and may override the numeric residual-risk output.
9. Isolated-marker definition
"Isolated" requires no structural anomaly, no growth restriction, no additional soft marker, and an otherwise detailed ultrasound appropriate for gestational age.
"Isolated" requires no structural anomaly, no growth restriction, no additional soft marker, and an otherwise detailed ultrasound appropriate for gestational age.
10. Negative cfDNA + isolated marker
After negative serum or cfDNA screening, do not recommend diagnostic testing solely for an isolated soft marker. Still perform marker-specific non-aneuploid follow-up when indicated.
After negative serum or cfDNA screening, do not recommend diagnostic testing solely for an isolated soft marker. Still perform marker-specific non-aneuploid follow-up when indicated.
11. Structural-anomaly override
Cardiac defect, palate/craniofacial finding, hypertelorism/facial dysmorphism, genitourinary anomaly, fetal growth restriction, multiple structural anomalies, increased NT, cystic hygroma, hydrops, or multiple findings should trigger genetics/diagnostic counseling rather than isolated-marker LR math.
Cardiac defect, palate/craniofacial finding, hypertelorism/facial dysmorphism, genitourinary anomaly, fetal growth restriction, multiple structural anomalies, increased NT, cystic hygroma, hydrops, or multiple findings should trigger genetics/diagnostic counseling rather than isolated-marker LR math.
12. Microarray pathway
When a fetal structural anomaly is present and invasive testing is chosen, chromosomal microarray is generally the preferred diagnostic test rather than limiting analysis to common trisomies.
When a fetal structural anomaly is present and invasive testing is chosen, chromosomal microarray is generally the preferred diagnostic test rather than limiting analysis to common trisomies.
13. No-call cfDNA
No-call, nonreportable, or low fetal-fraction results are not low-risk results. Review gestational age, fetal fraction, maternal factors, ultrasound, and options for repeat cfDNA versus diagnostic testing.
No-call, nonreportable, or low fetal-fraction results are not low-risk results. Review gestational age, fetal fraction, maternal factors, ultrasound, and options for repeat cfDNA versus diagnostic testing.
14. Atypical / mosaic / rare result
Do not assign a universal PPV to atypical, mosaic, rare autosomal trisomy, genome-wide, or secondary findings. Use genetics consultation and diagnostic-pathway language.
Do not assign a universal PPV to atypical, mosaic, rare autosomal trisomy, genome-wide, or secondary findings. Use genetics consultation and diagnostic-pathway language.
15. SCA and fetal sex-discordance caution
Do not force fetal sex discordance into a universal PPV. Verify report/sample identity, review fetal fraction and sex chromosome reporting, confirm anatomy with targeted ultrasound, and obtain genetics consultation. Amniocentesis is generally preferred for fetal confirmation when confined placental mosaicism is possible. In a male-appearing or virilized fetus with no Y signal or confirmed 46,XX, specifically consider CAH testing, usually CYP21A2.
Do not force fetal sex discordance into a universal PPV. Verify report/sample identity, review fetal fraction and sex chromosome reporting, confirm anatomy with targeted ultrasound, and obtain genetics consultation. Amniocentesis is generally preferred for fetal confirmation when confined placental mosaicism is possible. In a male-appearing or virilized fetus with no Y signal or confirmed 46,XX, specifically consider CAH testing, usually CYP21A2.
16. Multifetal gestation caution
Singleton PPV and residual-risk assumptions may not apply to twins or higher-order multiples. Chorionicity, vanishing twin, and whether the result is fetus-specific must be considered.
Singleton PPV and residual-risk assumptions may not apply to twins or higher-order multiples. Chorionicity, vanishing twin, and whether the result is fetus-specific must be considered.
17. 22q11.2 / microdeletion caution
22q11.2 deletion syndrome may be listed separately because it is commonly offered as a named cfDNA microdeletion target. It should still not be treated like common-trisomy screening. Rarity lowers PPV, assay performance varies, and diagnostic testing is needed to clarify abnormal results.
22q11.2 deletion syndrome may be listed separately because it is commonly offered as a named cfDNA microdeletion target. It should still not be treated like common-trisomy screening. Rarity lowers PPV, assay performance varies, and diagnostic testing is needed to clarify abnormal results.
18. Ventriculomegaly is separate
Do not manage ventriculomegaly as a simple isolated soft marker. Use atrial diameter thresholds: mild 10-12 mm, moderate 13-15 mm, severe >15 mm; evaluate anatomy, infection, genetics, and follow-up imaging.
Do not manage ventriculomegaly as a simple isolated soft marker. Use atrial diameter thresholds: mild 10-12 mm, moderate 13-15 mm, severe >15 mm; evaluate anatomy, infection, genetics, and follow-up imaging.
19. Normal ultrasound after positive cfDNA
A normal ultrasound after a screen-positive cfDNA result is reassuring for structural findings, but it does not negate, cancel, or reclassify the positive cfDNA screen as negative. The post-cfDNA probability/PPV remains the screen-positive estimate unless a validated assay- and condition-specific modifier is intentionally applied. Genetic counseling and the opportunity for diagnostic testing should still be offered.
A normal ultrasound after a screen-positive cfDNA result is reassuring for structural findings, but it does not negate, cancel, or reclassify the positive cfDNA screen as negative. The post-cfDNA probability/PPV remains the screen-positive estimate unless a validated assay- and condition-specific modifier is intentionally applied. Genetic counseling and the opportunity for diagnostic testing should still be offered.
When the calculator should switch from number to pathway
| Clinical scenario | Recommended output behavior | Reason |
|---|---|---|
| Cardiac defect, palate/craniofacial finding, hypertelorism/facial dysmorphism, genitourinary anomaly, structural anomaly, increased NT, cystic hygroma, hydrops, or FGR | Show "diagnostic/genetics pathway" rather than a single PPV or remaining risk. Add fetal echocardiography when a cardiac defect is present. | cfDNA does not exclude CNVs, single-gene disorders, mosaicism, infection, or syndromic etiologies. |
| Multiple soft markers | Use pathway language or strongest-marker teaching calculation only; do not imply independent multiplication is clinically validated. | Markers may be correlated and may reflect a shared fetal condition. |
| Negative cfDNA + isolated EIF or CPC | Reassuring counseling; no additional aneuploidy evaluation solely for the marker. | SMFM #57 treats these as normal variants after negative screening when isolated. |
| Negative cfDNA + isolated echogenic bowel, urinary tract dilation, or short long bone | No diagnostic testing solely for aneuploidy; add marker-specific follow-up. | Non-aneuploid causes and follow-up differ by marker. |
| 22q11.2 deletion screen-positive result | Show 22q11.2-specific counseling and offer diagnostic confirmation; use lab-reported PPV when available. | It is a named microdeletion target, but prevalence and assay performance differ from common trisomies. |
| Normal ultrasound after positive cfDNA | Keep the post-cfDNA probability/PPV visible and add a clear statement that the normal ultrasound is reassuring for anatomy but does not negate the positive cfDNA screen. | SMFM/ACOG-style management remains genetic counseling, comprehensive ultrasound review, and offering diagnostic confirmation; there is no universal validated negative likelihood ratio for a normal post-cfDNA ultrasound across cfDNA targets. |
| No-call or atypical cfDNA | Do not report as low risk; provide counseling pathway. | These results have different etiologies and are not interpretable as negative screens. |
| Fetal sex discordance or unusual fetal-sex/SCA cfDNA finding | Use the dedicated discordance pathway, not a universal PPV. Confirm report/sample identity, review fetal fraction and sex chromosome reporting, confirm anatomy with targeted ultrasound, and offer genetics consultation. If fetal diagnosis will affect counseling or management, amniocentesis is generally preferred when confined placental mosaicism is possible. For ultrasound male/virilized with no Y or confirmed 46,XX, specifically add CAH evaluation, usually CYP21A2 testing. | Differential includes fetal, placental, maternal, and technical explanations. The male-appearing or virilized phenotype with no Y/XX result is the pattern in which CAH must be clearly addressed. |
Marker-specific management layer
| Finding | After negative cfDNA / serum screen | Additional non-aneuploid follow-up |
|---|---|---|
| Isolated EIF | No further aneuploidy evaluation; normal variant language. | No fetal echo, follow-up imaging, or postnatal evaluation solely for EIF. |
| Isolated choroid plexus cyst | No further aneuploidy evaluation after negative screening. | No follow-up imaging or postnatal evaluation solely for CPC. |
| Isolated echogenic bowel | No further aneuploidy evaluation after negative screening. | Evaluate for cystic fibrosis and CMV; third-trimester ultrasound for reassessment/growth. |
| Isolated urinary tract dilation | No further aneuploidy evaluation after negative screening. | Follow UTD classification and renal follow-up pathway. |
| Isolated short femur / humerus | No further aneuploidy evaluation after negative screening. | Third-trimester ultrasound for growth; evaluate separately if severe, progressive, or disproportionate. |
| Thickened nuchal fold or absent/hypoplastic nasal bone | After negative cfDNA: no further aneuploidy evaluation solely for isolated marker. | Confirm isolation and consider context, patient preference, and any additional findings. |
| Ventriculomegaly | Not treated as SMFM #57 isolated soft-marker shortcut. | Use SMFM #45 evaluation and surveillance pathway. |
Teaching Module - 11 questions
Select the best answer for each question, then click "Score quiz." Explanations reinforce the calculator's guardrails and show selected Bayesian calculations.
Quiz not scored.
References
- Snijders RJM, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol. 1999;13(3):167-170. doi: 10.1046/j.1469-0705.1999.13030167.x.
- Snijders RJM, Sebire NJ, Nicolaides KH. Maternal age and gestational age-specific risk for chromosomal defects. Fetal Diagn Ther. 1995;10(6):356-367.
- Cuckle HS, Wald NJ, Thompson SG. Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol. 1987;94(5):387-402. doi: 10.1111/j.1471-0528.1987.tb03115.x.
- Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983;249(15):2034-2038.
- Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol. 1998;12(6):380-384. doi: 10.1046/j.1469-0705.1998.12060380.x.
- Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372(17):1589-1597. doi: 10.1056/NEJMoa1407349.
- American College of Obstetricians and Gynecologists. Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities. Obstet Gynecol. 2020;136(4):e48-e69.
- Society for Maternal-Fetal Medicine. Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester. Am J Obstet Gynecol. 2021;225(4):B2-B15.
- Society for Maternal-Fetal Medicine Consult Series #74. Cell-free DNA screening for aneuploidies: updated guidance. SMFM Publications Committee, 2025. Use to support that cfDNA is screening, abnormal results require confirmatory diagnostic counseling, and ultrasound context does not convert a screen-positive result into a diagnostic or negative result.
- Smet ME, Scott FP, McLennan AC. Discordant fetal sex on NIPT and ultrasound. Prenat Diagn. 2020;40(6):685-690. doi: 10.1002/pd.5681.
- Finney EL, Finlayson C, Rosoklija I, et al. Prenatal detection and evaluation of differences of sex development. J Pediatr Urol. 2021;17(2):149-155. doi: 10.1016/j.jpurol.2020.12.004.
- Chitayat D, Glanc P. Diagnostic approach in prenatally detected genital abnormalities. Ultrasound Obstet Gynecol. 2010;35(6):637-646. doi: 10.1002/uog.7679.
- Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088.
- American College of Obstetricians and Gynecologists. Committee Opinion No. 682: Microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol. 2016;128(6):e262-e268.
Baseline-risk implementation note: Trisomy 21 uses the updated Snijders 1999 Table 4 40-week maternal-age risk and gestational-age relative-prevalence formula. Trisomy 18, trisomy 13, Turner syndrome, and triploidy are based on the broader Snijders 1995 chromosomal-defect tables; this cfDNA wizard includes Turner syndrome as the modeled sex chromosome aneuploidy. 47,XXX, 47,XXY, and 47,XYY do not have individualized Snijders maternal-age/gestational-age calculator outputs in this implementation. Cuckle and JAMA/Hook are retained as historical maternal-age baseline-risk sources; Matias is cited for first-trimester ultrasound-marker literature but is not used as a multiplier in this cfDNA wizard. Values are theoretical baseline estimates before cfDNA, serum screening, ultrasound markers, or diagnostic testing.
Implementation note: numeric likelihood ratios in this educational tool are simplified teaching aids. Guideline pathway language should override a numeric estimate when high-risk ultrasound, structural anomaly, no-call/atypical cfDNA, sex discordance, or non-isolated findings are present.