Association Between Low Unconjugated Estriol in Second Trimester Screening and Genetic Issues
Low unconjugated estriol (uE3) levels in second trimester screening are strongly associated with increased risk of Down syndrome (trisomy 21), trisomy 18, and other adverse pregnancy outcomes including fetal growth restriction and fetal death.
Genetic Associations of Low uE3
Trisomy 21 (Down Syndrome)
- Low uE3 is a key marker in multiple marker screening (MMS) for Down syndrome 1
- In most cases of Down syndrome, both AFP and uE3 levels are lower than normal, while hCG and inhibin-A levels are higher 1
- When combined with maternal age, MSAFP, hCG, and inhibin-A (quadruple screen), this screening approach detects approximately:
- 75% of Down syndrome cases in women younger than 35 years
- Over 80% of Down syndrome cases in women 35 and older 1
Trisomy 18
- Low uE3 combined with low AFP and low hCG is characteristic of trisomy 18 1
- In most cases of trisomy 18, all three analytes (AFP, hCG, uE3) are low 1
- The detection rate for trisomy 18 using these markers is at least 70% 1
Other Chromosomal Abnormalities
- Very low uE3 levels (below assay sensitivity) have been associated with various chromosomal abnormalities 2
- While the MMS primarily screens for trisomies 21 and 18, it does not reliably detect other forms of aneuploidy such as trisomy 13 and Klinefelter syndrome (47,XXY) 1
Non-Genetic Associations of Low uE3
Fetal Death
- Very low uE3 levels (at or below assay sensitivity) are most commonly associated with fetal death (37.1% of cases) 2
- Six cases of early fetal death followed uneventful prenatal visits in a study of women with very low uE3 2
Fetal Growth Restriction (FGR) and Low Birth Weight
- Low uE3 levels (<5th percentile) significantly increase the risk of:
- Women with uE3 ≤0.75 MoM have significantly higher odds of developing:
- Fetal growth restriction (OR: 6.73,95% CI: 2.55-17.74)
- Low amniotic fluid index (OR: 3.85,95% CI: 1.53-9.68)
- Small for gestational age infants (OR: 2.89,95% CI: 1.27-6.57) 4
Placental Sulfatase Deficiency
- Unexplained very low uE3 levels have been associated with placental sulfatase deficiency 2
- This condition has a strong male predominance (p=0.03) 2
Clinical Implications and Management
Screening Protocols
- Multiple marker screening (MMS) using three analytes (MSAFP, hCG, uE3) raises the sensitivity for Down syndrome to approximately 65% (triple test) 1
- Adding inhibin-A (quadruple screen) further improves detection rates 1, 5
- Optimal timing for second trimester screening is between 15-20.9 weeks gestation 1
Follow-up for Low uE3
- Genetic counseling and additional testing are recommended for pregnancies with abnormal screening results 1
- Patients should be informed that MMS is only a screening test and not a replacement for diagnostic procedures like CVS or amniocentesis 1
- For unexplained low uE3 without genetic abnormalities, careful monitoring for:
Diagnostic Testing
- Diagnostic testing options include:
- Amniocentesis (after 15 weeks)
- Chorionic villus sampling (CVS) (10-13 weeks) 5
- These tests carry approximately 0.5% risk of pregnancy loss 5
Important Considerations
- Accurate gestational dating is crucial for proper interpretation of screening results 1, 5
- If there is a discrepancy in gestational age of 2 or more weeks after ultrasound, test results must be reinterpreted 1
- Other factors that should be considered when interpreting results include maternal weight, race, presence of insulin-dependent diabetes, and number of fetuses 1
Remember that while low uE3 is associated with increased risk of genetic abnormalities and adverse pregnancy outcomes, it is a screening test that requires follow-up diagnostic testing for definitive diagnosis.