Non-Invasive Prenatal Testing for Fetal Sex Determination

NIPT Performance and Clinical Implications

NIPT for fetal sex determination can be performed after 9-10 weeks gestation, as approximately 10-15% of the total cell-free DNA in maternal plasma is of placental origin by this time, according to the American College of Obstetricians and Gynecologists 1
The American College of Obstetricians and Gynecologists recommends NIPT as a reliable non-invasive alternative to invasive testing for sex determination in pregnancies at risk of sex-linked genetic disorders 1, 2
If a "no-call" result occurs with NIPT at 9 weeks, repeat testing at a slightly later gestational age provides a result in approximately 75-80% of cases, as reported by Genetics in Medicine 3
The American College of Obstetricians and Gynecologists recommends offering diagnostic testing to individuals with persistent no-call results 3

Approximately 1% of initial samples submitted for NIPT result in "no-call" results, with insufficient fetal fraction being the most common cause, according to Genetics in Medicine 3
Maternal factors that can reduce accuracy at 9 weeks include high maternal BMI, which is strongly associated with low fetal fraction and may result in test failure in up to 20% of women with high BMI, as noted by the American College of Medical Genetics and Genomics 4
Fetal factors that may affect accuracy include presence of certain chromosomal abnormalities, particularly trisomies 13 and 18, which can be associated with low fetal fraction, as reported by Genetics in Medicine 2
Multiple gestations or vanishing twin syndrome can affect fetal fraction measurements and interpretation, according to Genetics in Medicine 2

NIPT for fetal sex determination should be performed in the context of appropriate pre-test and post-test genetic counseling, as recommended by Genetics in Medicine 5
Patients should be informed that while highly accurate, NIPT is a screening test, not a diagnostic test, and any abnormal or uncertain results should be confirmed with diagnostic testing, according to the American College of Medical Genetics and Genomics 2, 6
The American College of Medical Genetics and Genomics strongly recommends NIPT over traditional screening methods for both singleton and twin pregnancies 6, 7

The American College of Radiology recommends that NIPT should be performed after 10 weeks gestation, when approximately 10-15% of total cell-free DNA in maternal plasma is of placental origin, providing sufficient fetal fraction for accurate analysis 8, 9
First trimester use (10-14 weeks) is the standard and evidence-based application of NIPT, with detection rates for trisomy 21 of 99% and false positive rates of 0.5% in women who receive results 8, 9

Risk assessment has transitioned to the first trimester using NIPT and nuchal translucency measurements, making later screening less relevant from a clinical decision-making standpoint 8, 9, 10
The primary value of NIPT is early reassurance or early diagnosis, allowing time for diagnostic confirmation and reproductive decision-making 11
Earlier screening provides greater safety and lower costs if pregnancy termination is elected, and allows for safer selective reduction in twin pregnancies when performed in the first trimester 11

NIPT remains a screening test, not diagnostic, and all positive results require confirmation with chorionic villus sampling (CVS) or amniocentesis regardless of when performed 11, 12
Maternal factors affecting test performance include obesity (associated with low fetal fraction and up to 20% test failure in high BMI women) 11

For pregnancies presenting in first trimester (before 14 weeks), NIPT is the appropriate screening modality, and should be offered at 10 weeks or later for optimal fetal fraction 8, 9
For pregnancies presenting in second or third trimester, NIPT is not the appropriate screening modality, and standard anatomic ultrasound screening at 18-22 weeks is recommended for structural anomalies 8, 9
If aneuploidy screening is desired in the second or third trimester, proceed directly to diagnostic testing (amniocentesis) rather than screening 8, 12

NIPT cannot replace ultrasound for detection of structural anomalies and does not screen for neural tube defects, making it complementary to, not a replacement for, anatomic ultrasound evaluation regardless of timing 8, 9, 11

NIPT analyzes cell‑free DNA fragments (< 200 bp) circulating in maternal plasma to assess fetal genetic material. 13
After 10 weeks gestation, roughly 10–15 % of total cell‑free DNA originates from the placenta, providing enough fetal DNA for reliable analysis. 13, 14
The assay employs next‑generation sequencing (massively parallel shotgun or targeted sequencing) to count chromosome‑specific DNA fragments. 13

The optimal window for performing NIPT is after 10 weeks gestation, when the fetal DNA fraction is typically sufficient for accurate results. 14
When an adequate fetal fraction is present, sex determination by NIPT is highly accurate, though the test remains a screening tool rather than a definitive diagnostic test. 13

NIPT is a screening test; any abnormal or uncertain findings should be confirmed with diagnostic procedures such as amniocentesis or chorionic villus sampling. 13, 15
In rare cases where the fetal sex reported by NIPT disagrees with physical examination at birth, confirmatory blood chromosome analysis is recommended. 16, 17

Initially developed for aneuploidy screening (e.g., Down syndrome, trisomy 13, trisomy 18), NIPT now also screens for sex‑chromosome abnormalities and selected microdeletion syndromes. 13, 14
Determining fetal sex via NIPT is especially valuable in pregnancies at risk for X‑linked genetic disorders, as it guides subsequent diagnostic decision‑making. 13