Prenatal screening has become a routine part of obstetric care, aimed at identifying pregnancies at higher risk for fetal defects, including neural tube defects and chromosomal abnormalities like Down syndrome (trisomy 21) and trisomy 18. For many years, second-trimester maternal serum screening was the standard approach. However, significant advancements in medical technology now offer the possibility of earlier assessment. This updated guideline addresses the crucial question for expectant parents: Which Prenatal Test Provides The Earliest Diagnosis Of Fetal Defects? Understanding the options available in the first trimester is vital for informed decision-making and timely management of pregnancy. This article will explore the different prenatal screening and diagnostic tests, with a focus on identifying the earliest methods for detecting potential fetal abnormalities, ensuring parents have access to the most up-to-date information and choices.
Screening for Neural Tube Defects (NTDs)
Neural tube defects (NTDs), such as spina bifida and anencephaly, are serious birth defects that affect the brain and spinal cord. Maternal serum alpha-fetoprotein (MSAFP) screening has been used since the 1980s to detect pregnancies at risk for NTDs. This screening method can identify 75–90% of open NTDs and a higher percentage of anencephaly by measuring elevated MSAFP levels in the mother’s blood, typically with a screen positive rate of 5% or less. MSAFP screening can also detect a significant proportion (around 85%) of ventral wall defects.
The optimal gestational age for NTD screening using MSAFP is between 16–18 weeks, although it can be performed from 15 to 20 weeks. It’s important to note that while NTD screening is optional, identifying a fetal neural tube defect can significantly influence pregnancy management, regardless of the parents’ decision about continuing the pregnancy. Accurate interpretation of MSAFP results relies on knowing the gestational age at the time of blood collection. Laboratories use specific cutoff values to determine screen positive and screen negative results, which are detailed in the reports. For pregnancies with elevated MSAFP levels, genetic counseling and further diagnostic testing, such as detailed ultrasound examinations and amniocentesis to analyze amniotic fluid AFP and acetylcholinesterase levels, are recommended to further evaluate the findings.
Diagnosis of Fetal Aneuploidy: CVS and Amniocentesis
Historically, advanced maternal age (35 years or older at delivery) and abnormal screening test results were the primary indications for offering prenatal genetic counseling and diagnostic tests like amniocentesis or chorionic villus sampling (CVS). These diagnostic procedures directly analyze fetal chromosomes to identify aneuploidies, which are conditions where there is an abnormal number of chromosomes.
Chorionic villus sampling (CVS) is a diagnostic test performed earlier in pregnancy than amniocentesis, typically between 10 and 13 weeks of gestation in the first trimester. CVS involves taking a small sample of chorionic villi, placental tissue that shares the fetus’s genetic makeup. Amniocentesis, on the other hand, is usually performed starting from 15 weeks of gestation in the second trimester. Amniocentesis involves collecting a sample of amniotic fluid, which contains fetal cells.
CVS can be performed through the cervix (transcervical) or the abdomen (transabdominal). While the risk of pregnancy loss associated with CVS is generally low, some studies suggest that the transabdominal approach might have a slightly lower risk. However, other research indicates similar loss rates for both transcervical and transabdominal CVS procedures. Any differences in loss rates are likely influenced by the operator’s experience, particularly with transcervical procedures, and the quality of available ultrasound technology. Modern data suggests that the risk of miscarriage from ultrasound-guided amniocentesis is approximately 1 in 300–600, with some studies suggesting it might not significantly increase the baseline miscarriage risk.
Given the relative safety of CVS and amniocentesis, and recognizing that screening tests cannot detect all chromosomal abnormalities, professional guidelines recommend that all pregnant women, regardless of age, should be offered the option of invasive diagnostic testing. This recommendation respects patient autonomy and the desire for definitive diagnostic information. Diagnostic testing should be available upon request after comprehensive counseling that includes a discussion of the risks and benefits.
While maternal age is not a reliable sole screening criterion, screening tests play a crucial role in refining risk assessment for women who wish to have more information before deciding whether to undergo invasive diagnostic testing. Effective screening tests are available to adjust a woman’s age-related risk for trisomies 21 and 18. It is important to remember that prenatal screening tests are voluntary, and women who prefer not to know about the chromosomal status of their fetus should not be required to undergo screening.
First Trimester Screening: The Earliest Window for Aneuploidy Risk Assessment
First trimester screening is a significant advancement in prenatal care, offering women the earliest opportunity to assess the risk of fetal aneuploidy. This approach combines biochemical markers in maternal blood with ultrasound measurements to provide a more refined risk assessment for trisomies 21 and 18.
The most effective first-trimester screening test involves measuring two biochemical markers in maternal serum: pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG). Blood collection for these markers is typically performed between 9 and 13 6/7 weeks of gestation (when the fetus’s crown-rump length is 24–84 mm). Simultaneously, an ultrasound assessment of nuchal translucency (NT) measurement is conducted between 11 and 13 6/7 weeks (fetal crown-rump length 45–84 mm). Nuchal translucency refers to the sonolucent space at the back of the fetal neck, which is present in all fetuses. An increased NT measurement is associated with a higher risk of trisomy 21 and other aneuploidies.
Studies have demonstrated high detection rates for Down syndrome with first-trimester screening, ranging from 79 to 90% with a 5% false-positive screen rate. In cases of trisomy 21, PAPP-A levels are typically reduced, and hCG levels are elevated. While free β-hCG may offer slightly better sensitivity compared to intact hCG, access to free β-hCG has been limited, leading many programs to use intact hCG. In contrast, both free β-hCG and intact hCG levels are reduced in trisomy 18.
It is important to note that women undergoing first-trimester screening and/or CVS should still be offered MSAFP screening between 15 and 20 weeks’ gestation and/or an ultrasound examination for NTDs between 15 and 20 weeks’ gestation. First trimester screening primarily focuses on aneuploidy risk and does not replace NTD screening.
While NT measurement alone can detect approximately 70% of Down syndrome cases with a 5% false-positive rate, it is generally considered less effective as a standalone test compared to combined first-trimester screening that includes serum markers (PAPP-A and hCG). However, in specific situations, such as when the NT measurement is significantly increased (4 mm or greater) or in cases of cystic hygroma, the addition of serum markers may not substantially alter the risk for Down syndrome. In such cases, offering diagnostic testing directly may be a reasonable approach.
In multifetal gestations (twins, triplets, etc.), combined first-trimester serum screening is less sensitive (around 70%) than in singleton pregnancies. NT measurement alone shows similar detection rates for Down syndrome in multiple pregnancies. However, an increased or discordant NT measurement in multiple gestations, particularly monochorionic twins, may indicate a higher risk of adverse pregnancy outcomes.
Increased NT measurements are also associated with other fetal structural anomalies, including congenital heart defects, diaphragmatic hernias, skeletal dysplasias, and various genetic syndromes. Therefore, current guidelines recommend that patients with a fetal NT measurement of 3.5 mm or higher should be offered a detailed targeted ultrasound and/or a fetal echocardiogram to further investigate potential structural abnormalities.
Second Trimester Screening: Multiple Markers for Aneuploidy and NTDs
Second-trimester screening, typically performed between 15–20 weeks, utilizes multiple marker screening to assess the risk for trisomies 21 and 18, as well as open neural tube defects. The most common second-trimester screening test is the quad screen, which measures four biochemical markers: alphafetoprotein (AFP), hCG, unconjugated estriol (uE3), and dimeric inhibin-A.
Using a Down syndrome risk cutoff of 1 in 270, the quad screen combined with maternal age detects approximately 75% of Down syndrome cases in women younger than 35 years with a 5% positive screening rate. The detection rate is slightly higher, over 80%, in women 35 years and older. In most cases of Down syndrome, AFP and uE3 levels are lower, while hCG and dimeric inhibin-A levels are elevated. The “triple test,” which includes only AFP, hCG, and uE3, has a lower sensitivity, detecting approximately 65% of Down syndrome cases and 70% of trisomy 18 cases. In trisomy 18, levels of all three analytes are typically low.
Second-trimester maternal serum screening is a validated and appropriate screening test for both Down syndrome and trisomy 18. However, in twin pregnancies, its detection rate for affected fetuses is reduced to around 50%, and interpretation can be complex as a normal twin might mask the results of an affected twin. Risk calculations in twin pregnancies rely on mathematical models due to limited prospective studies.
Second-trimester multiple marker screening is less reliable in detecting other aneuploidies that become more frequent with increasing maternal age, such as trisomy 13 and Klinefelter syndrome (47,XXY). These conditions are typically diagnosed through cytogenetic analysis of amniocytes or villi obtained via amniocentesis or CVS.
Similar to first-trimester screening, accurate gestational age is crucial for interpreting second-trimester screening results. Laboratories require information on gestational age at the time of sample collection. Ultrasound measurements, particularly crown-rump length in the first trimester or biparietal diameter in the second trimester, provide more accurate gestational age estimates compared to relying solely on the last menstrual period.
Second-trimester ultrasonography can identify fetal anatomical defects and sonographic markers suggestive of aneuploidy, such as thickened nuchal fold, absent nasal bone, renal pyelectasis, or echogenic bowel. However, these markers have low sensitivity and specificity for aneuploidy detection and are not recommended as primary screening tools for aneuploidy.
Integrated and Sequential Screening Approaches
To improve overall aneuploidy detection rates, several integrated and sequential screening approaches have been developed, combining first and second-trimester screening tests.
Integrated screening provides a single, comprehensive risk assessment based on first-trimester NT measurement and PAPP-A, combined with the second-trimester quad screen results. Studies show that integrated screening has the highest detection rate for trisomy 21 (93–96%). However, a drawback of integrated screening is that first-trimester results are withheld until the second-trimester tests are completed, preventing women from having the option of earlier diagnostic testing if first-trimester results indicated a high risk.
Serum integrated screening provides a single age-adjusted risk assessment for trisomies 18 and 21, using first-trimester PAPP-A and second-trimester serum screening results. This approach has a detection rate of approximately 88% and is useful when NT measurement is not feasible or unavailable.
Sequential screening approaches, including stepwise and contingency screening, allow for the disclosure of first-trimester results. Both sequential methods offer high detection rates (around 90%) with low positive screening rates (2–3%). Stepwise screening involves disclosing first-trimester results, enabling women at high risk to undergo CVS and consider earlier termination if the fetus is affected. Women with low or moderate risk proceed to second-trimester screening for a final risk assessment. Contingency screening involves second-trimester testing only for women with first-trimester results in a laboratory-defined intermediate range.
Directly comparing first and second-trimester screening results independently is discouraged due to high false-positive rates. It is important to note that the improved detection rates reported for combined screening methodologies are primarily based on mathematical modeling, rather than large prospective cohort studies like those available for first-trimester or second-trimester screening alone. A practical disadvantage of serum integrated and sequential screening is the potential for patient attrition, as women may not return for the second blood sample required in the second trimester.
Recommendations: Earliest Diagnosis and Screening Options
Considering the available evidence and the desire for early diagnosis, the following recommendations are important for prenatal care providers and expectant parents:
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Offer Diagnostic Testing: All women should be offered the option of invasive diagnostic testing for fetal aneuploidy, such as CVS (if available in the first trimester) or amniocentesis. These tests provide definitive diagnoses for major aneuploidies and large chromosomal rearrangements. CVS, performed in the first trimester (10-13 weeks), provides the earliest diagnostic option.
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Screening for Aneuploidy and NTDs: For women who initially decline diagnostic testing, screening for aneuploidy and neural tube defects should be offered to all pregnant women presenting for prenatal care before 20 weeks of gestation, regardless of maternal age. Documenting the reason for declining screening is important in cases where women choose not to receive information about fetal aneuploidy status.
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First Trimester Screening as an Effective Early Option: First-trimester screening (combining NT measurement, PAPP-A, and hCG) is an acceptable and effective approach for screening for fetal aneuploidy, particularly for women who present early in pregnancy (before 14 weeks’ gestation). This is the earliest screening option available.
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Follow-up for Combined Screening Approaches: Providers offering integrated, serum integrated, or sequential screening approaches must ensure adequate follow-up to complete both first and second-trimester components and provide comprehensive risk assessments. For integrated screening, it is crucial to ensure patient acceptance of nondisclosure of first-trimester results until the combined result is available. Sequential or contingency screening, with the disclosure of first-trimester results, may be preferable for some providers and patients seeking earlier information.
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Informed Decision-Making Based on Adjusted Risk: Women should receive information about their adjusted risk for aneuploidy and be empowered to make individual decisions regarding diagnostic testing based on their personal risk perception and preferences. The interpretation of numerical risk and the decision to pursue diagnostic testing are personal choices.
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NTD Screening for Women Undergoing First Trimester Aneuploidy Screening: Women who choose first-trimester screening and/or CVS should still be offered MSAFP screening and/or ultrasound for neural tube defect detection between 15 and 20 weeks of gestation, as first-trimester aneuploidy screening does not assess NTD risk.
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Screening in Multifetal Pregnancies: First-trimester or second-trimester screening can be used in multifetal pregnancies. However, women should be informed about the limitations of screening accuracy in these situations compared to singleton pregnancies.
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Further Evaluation for Increased NT Measurement: An increased NT measurement of 3.5 mm or greater, even with low aneuploidy risk from screening or a normal fetal karyotype, warrants a detailed anatomical ultrasound and/or fetal echocardiogram to investigate potential structural anomalies.
In conclusion, for the earliest possible diagnosis of fetal defects related to aneuploidy, Chorionic Villus Sampling (CVS) is the prenatal test that can be performed earliest in pregnancy, within the first trimester. First-trimester screening offers the earliest window for risk assessment, allowing for informed decisions about further diagnostic testing and pregnancy management. Understanding these options empowers both healthcare providers and expectant parents to navigate prenatal care effectively and make choices that align with their individual needs and values.
