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Ultrasound suggest a girl, NIPT predicts a boy?!

On the accuracy of gender determination by NIPT

Almost parallel with the large-scale implementation of NIPT, we have seen the arrival of a new phenomenon amongst couples expecting a baby:  gender reveal parties.  During a gender reveal party, the couples announce the sex of the future baby to friends and family.  The parties come in all flavors but the main colors are, needless to say, blue and pink.

Why is the success of gender reveal parties associated with the implementation of NIPT?  Before the widespread introduction of NIPT, fetal gender was mainly determined by ultrasonographic analyses.   During the first ultrasound which, in the Western world takes place between 10-12 weeks, gender is determined.  But often this analysis remains ambiguous and only when there are obvious male characteristics, the obstetrician will confidentially reveal the gender.    With the introduction of NIPT, this ambiguity has largely disappeared.  In addition to trisomy 21, most NIP tests allow for a very accurate gender determination.  The presence of Y chromosomal reads can almost unequivocally determine the presence or absence of a Y chromosome and hence, identify the gender.

Despite the great NIPT accuracy to determine gender, there are a number of reasons why the party may crash.  Information about the failure rates for fetal sex determination of NIPT while the overall test results are confidently reported, remain largely lacking.  The overall focus for NIPT companies has been on trisomy 21 detection.  However, the overall focus of pregnant couples may well be on gender determination.    A small poll amongst colleagues and in my own laboratory tells me that between 0.3% and 2% of reports lack unequivocal sex determinations.  The success rates seem to vary depending on the NIPT platform and lab performance parameters.

In addition to purely technical reasons, there are several biological reasons why sex determination is confounded.  First, sex chromosomal anomalies are the most frequent chromosomal abnormalities. While before the screening era trisomy 21 occurred in about 0.14% live births, sex chromosomal anomalies are present in about 0.16% live births.  The large majority of sex chromosomal anomalies (0.15% of live births) are the sex chromosomal trisomies XXX, XXY and XYY.  The phenotypic consequences are limited and fetal viability is not compromised.  Monosomy X, the cause of Turner syndrome, is next to trisomy 21 the main viable chromosomal anomaly.  Importantly, monosomy X is the most frequent abnormality seen in spontaneous abortions.

How would a sex chromosomal anomaly influence the fetal sex determination? In contrast to trisomy 21, the incidence of those sex chromosomal anomalies are not associated with maternal age.   Rather, they most frequently occur by mitotic non-disjunction post fertilization.  As a consequence, some cells in the placenta may be normal whereas other cells can be present with only a monosomy.  In that case, some cells could be normal male whereas others contain only a single X chromosome.  The amount of Y chromosomal fragments which will shed into the maternal bloodstream will be less than expected.  Hence, the algorithms have difficulty assigning the gender.   In case of a trisomy a similar ambiguity occurs: there are too many X chromosomal fragments in relation to the number of Y chromosomal fragments.  This will lead to ambiguity in the gender determination.  In addition to traditional mosaicism, often mosaicism for a rearranged Y chromosome can be observed.  Such a rearranged Y will equally confound sex determination.

Sometimes, there is a difference between the obstetric gender determination and the NIPT based gender determination.   Also, this can have biological reasons.   These are mainly caused by disorders of sex differentiation, rare genetic disorders causing XY persons to develop as females or reversely, XX individuals to develop as males.  Luckily, the incidence of sex reversal is very rare occurring only about one in every 20000 births.   Another cause for ambiguous sex determination has been the occurrence of vanishing twins.   If the male twin is vanishing, Y chromosome specific signals can be present and lead to an inaccurate fetal sex determination. Finally, there may be some other reasons why the NIPT test is at odds with the ultrasound.  I was confused by an obstetrician arguing that the women carried a female fetus whereas the NIPT very clearly reported a male, even upon repeated blood drawings.  However, the extremely high ‘fetal fraction’ pointed to another cause for the maleness:  the woman had received a liver transplant from a male donor.  During her pregnancy, rejection of the transplant started to occur, releasing large amounts of the liver tissue DNA in the bloodstream resulting in large amounts of Y chromosomal fragments, thus skewing the NIPT results.

In conclusion, NIPT is very powerful for the fetal sex determination.  However, no test is 100% reliable and it can be wise to combine both obstetric and molecular data to counsel the prospective parents and choose the color of your cake.