The implications of a false positive second-trimester serum screen for Down syndrome

doi:10.1016/S0029-7844(03)00235-7

Obstetrics & Gynecology

Volume 101, Issue 6, June 2003, Pages 1301-1306

https://doi.org/10.1016/S0029-7844(03)00235-7 Get rights and content

Abstract

Objective

To investigate the genetic and obstetric implications of false positive Down syndrome serum screening results.

Methods

The study population comprised 162,774 women underwent triple marker screening in the Ontario Maternal Serum Screening program between October 1995 and September 1998, with outcomes obtained from the Canadian Institute of Health Information. The study compares the incidence of chromosomal abnormalities other than Down syndrome in screen positive women with background incidence from the literature. It also compares the risks of having a fetus with congenital abnormalities or of developing obstetric complications in 11,549 screen positive women with their matched controls.

Results

A higher incidence of trisomy 13 (12.4 per 10,000) was seen in screen positive women; the incidence of other chromosomal abnormalities in screen positive women was not increased relative to the general population. The higher incidence of trisomy 13 may have been biased by the selective uptake of amniocentesis in women who had high risks for Down syndrome or abnormal ultrasound findings. Incidences of fetal congenital abnormality in screen positive and negative women were similar. Women who screened positive for Down syndrome had increased risk of spontaneous fetal loss (odds ratio 1.80; 95% confidence interval 1.54, 2.07) but no other obstetric complications.

Conclusion

Among women who screened positive for Down syndrome, we found a higher number of spontaneous fetal losses and a possibly higher risk of having a fetus with trisomy 13. We did not find an increased risk for other chromosomal abnormalities, congenital abnormalities, or other adverse obstetric outcomes.

Section snippets

Materials and methods

Second-trimester triple marker maternal serum screening has been routinely offered to women in the province of Ontario since July 1993. As part of the Ontario Maternal Serum Screening program, a maternal serum screening database was established to audit screening performance. The current study uses information collected for this database.

Database information includes screen utilization, results, follow-up, and pregnancy outcomes. The demographic information and test results for all pregnancies

Results

Table 2 compares the incidence of certain chromosomal abnormalities other than Down syndrome in women with false positive maternal serum screening results with the background incidence of these anomalies obtained from the literature.

Of the chromosomal abnormalities studied, trisomy 13 was the only one that had a significantly higher incidence in screen positive women. Based on our data, the overall risk for a woman to have a fetus with trisomy 13 if she screened positive for Down syndrome would

Discussion

There is an innate bias in comparing women with positive and negative Down syndrome screening results in terms of their risks of having a fetus with non–Down syndrome chromosomal anomalies. This is particularly true for viable anomalies such as the sex chromosome aneuploidies as well as those aneuploidies associated with a high miscarriage rate such as Turner syndrome, trisomy 13, and trisomy 18. This problem is highlighted by the use of Canadian Institute of Health Information data that rely

Acknowledgements

The authors thank the members of the Ontario Maternal Serum Screening consultative committee, participating centers, and the women of Ontario for their contributions to the Maternal Serum Screening program.

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False positive results of trisomy 21 prenatal screening as a surrogate marker for adverse pregnancy outcome
2013, Diagnostico Prenatal
Citation Excerpt :
Detection rate reaches 85–90%, but this is achieved with 3–5% false positive rates.1,2 Previous studies3–5 showed an increased incidence of pregnancy complications with direct or indirect involvement of the placenta in false positive screenings. This agrees with the association between placental dysfunction and changes in maternal levels of screening biochemical markers: hCG increases in response to placental hypoxia,6 there is an association between reduction of PAPP-A and fetal growth retardation7,8 and transfer of AFP to the maternal blood is impaired by decreased placental function.9,10
Hypertensive disorders of pregnancy, intrauterine growth restriction (IUGR) and preterm delivery are pathologies associated with significant fetal and maternal morbidity and mortality. This study evaluates the usefulness of false positive results for trisomy 21 prenatal screening and isolated changes in biochemical screening markers for the identification of increased risk for those pregnancy complications.
Two case–control studies were performed: the association of those pathologies with a false positive screening (Integrated or Double) and the distribution of the biochemical markers, PAPP-A, free beta-hCG and alpha-Fetoprotein (AFP), in affected and unaffected pregnant women. The population included all the 4224 pregnant women who underwent prenatal screening for trisomy 21 in Hospital S. Francisco Xavier, Lisbon, between March 2003 and August 2007.
The association was significant (P < 0.05) between IUGR and false positives for Integrated and 2nd trimester screening and between IUGR and isolated changes in the three biochemical markers. Isolated changes of PAPP-A and AFP were significantly associated with preterm delivery and hypertensive disorders of pregnancy, respectively.
Screening false positive results or isolated changes in biochemical screening markers are surrogate markers of increased risk for placental pathology. This information is available before 20 weeks of gestation and can be used in follow-up.
La hipertensión del embarazo, el retraso del crecimiento intrauterino (RCIU) y el parto prematuro son enfermedades asociadas a morbimortalidad maternofetal significativa. Este estudio evalúa la utilidad de los falsos positivos y de los cambios aislados en los marcadores bioquímicos del cribado prenatal de la trisomía 21 para la identificación de un mayor riesgo para estas enfermedades.
Se hicieron 2 estudios caso-control: uno de la asociación entre los falsos positivos por el cribado (integrado y del segundo trimestre) y aquellas enfermedades y otro de la distribución de los marcadores bioquímicos, PAPP-A, fracción libre de la beta-hCG y alfa-fetoproteína (AFP), en mujeres embarazadas afectadas y no afectadas. La población de estudio incluyó todos los 4.224 cribados realizados en el Hospital S. Francisco Xavier (Lisboa), entre marzo de 2003 y agosto de 2007.
La asociación fue significativa (p < 0,05) entre el RCIU y los falsos positivos del cribado integrado y del segundo trimestre y entre el RCIU y los cambios aislados de los 3 marcadores bioquímicos. Los cambios aislados de PAPP-A y AFP se asociaron significativamente con el parto prematuro y la hipertensión del embarazo, respectivamente.
Los falsos positivos en el cribado o cambios aislados en los marcadores bioquímicos son marcadores indirectos de un mayor riesgo de efermedad placentaria. Esta información está disponible antes de las 20 semanas de gestación y puede ser utilizada en el seguimiento del embarazo.
Prenatal Screening for Neural Tube Defects and Aneuploidy
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
QF-PCR-based prenatal detection of common aneuploidies in the Czech population: Five years of experience
2008, European Journal of Medical Genetics
Citation Excerpt :
A positive result from second trimester serum screening for Down syndrome is often significant part of indication for cytogenetic examination of amniotic fluid (AF). With the exception of a higher incidence of trisomy 13, there is no significant risk of CHA other than trisomy 21 in this group [19]. In some prenatal programs, RAD is directed towards trisomy 21 in screen positive cases, and all common aneuploidies are only tested after ultrasonographic indications [20].
We present the results from the largest clinical application of QF-PCR for antenatal rapid aneuploidy detection (RAD) in routine prenatal diagnosis in the Czech Republic. QF-PCR was performed in addition to karyotyping (dual testing) in two settings: the first was a single multiplex reaction testing only trisomy 21 and amelogenin X/Y alleles in the second trimester screened positive cases (T21 test), and the second setting consisted of two multiplexes (2M test) for common aneuploidies (13, 18, 21, X and Y) in cases with other RAD indications such as ultrasound findings, late booking or maternal anxiety.
Dual testing was performed in 6349/12,778 (49.7%) of prenatal samples using either T21 or 2M test between 2002 and 2007. The clinical acceptability of our dual testing policy, methodological efficiency of RAD and residual risks of other chromosomal aberrations (CHAs) were evaluated.
QF-PCR detected 92% (175/190) of significant CHAs. The 2M test identified 93.5% and the T21 test identified 87.5% of the significant CHAs with complete specificity. The residual risk of significant CHA was 1/231 in the 2M test and 1/565 in the T21 test. If RAD for all common aneuploidies is used as the sole prenatal diagnosis method, the odds of missing a CHA of any type are 1:90 and the odds of missing significant CHA with no ultrasound findings are 1:1513. If prenatal karyotyping were used as an additional procedure to RAD in cases only with ultrasound findings, 186/190 (97.8%) of the significant CHAs would be detected when 15.7% cases were karyotyped, according to our data.
We consider RAD directed towards trisomy 21 alone (our T21 test) as an economically and clinically acceptable part of second trimester screening for Down syndrome. Both RAD tests allow fast alleviation of maternal anxiety with low residual risk when the test results are negative, and allow fast decision making if the results are positive. However, replacement of dual testing with only the RAD procedure in specific indications accepted in some countries (Great Britain) remains in the Czech Republic a theme for debate.
Obstetrical complications associated with abnormal maternal serum markers analytes
2008, Journal of Obstetrics and Gynaecology Canada
Obstetrical Complications Associated With Abnormal Maternal Serum Markers Analytes
2008, Journal of Obstetrics and Gynaecology Canada
The identification of risk of spontaneous fetal loss through second-trimester maternal serum screening
2005, American Journal of Obstetrics and Gynecology
The purpose of this study was to investigate associations between risk of spontaneous fetal loss and risk estimates for Down syndrome, trisomy 18, and neural tube defects assigned by second-trimester maternal serum screening.
The study involved 264,653 women with available pregnancy outcomes who were screened between 15 and 20 weeks of gestation in the Ontario Maternal Serum Screening Program between October 1995 and September 2000. Pregnancies complicated by fetal chromosomal or structural abnormalities, insulin-dependent diabetes mellitus, and multiple pregnancies were excluded. Spontaneous fetal loss was defined as spontaneous miscarriage and intrauterine fetal demise as classified by the ICD-9 system, but including only those ≥15 weeks of gestation. Women were grouped according to risk estimates for Down syndrome, trisomy 18, and neural tube defects, respectively. Spontaneous fetal loss rates by each risk group were evaluated after adjusting for losses associated with maternal age and amniocentesis.
Fetal loss rates increased in women with risk estimates of ≥1 in 1110 for trisomy 18 or neural tube defects, and ≥1 in 130 for Down syndrome. The excessive fetal loss rates for these 3 groups of women were 14.4%, 3.2%, and 1.5% respectively.
Fetal loss rate markedly increased in women with high-risk estimates for trisomy 18, neural tube defects, and Down syndrome. Risk estimates assigned by triple marker screening may provide an early means of stratifying pregnancies into risk for fetal loss.

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Original researchThe implications of a false positive second-trimester serum screen for Down syndrome

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Am J Obstet Gynecol

Am J Obstet Gynecol

Maternal serum screening for Down’s syndrome in early pregnancy

BMJ

Serum screening for Down’s syndrome and adverse pregnancy outcomesA case-controlled study

Prenat Diagn

Pregnancy outcome and long term prognosis in 868 children born after second trimester amniocentesis for maternal serum positive triple test screening and normal prenatal karyotype

J Med Genet

Inherited structural cytogenetic abnormalities detected incidentally in fetuses diagnosed prenatallyFrequency, parental-age associations, sex-ratio trend, and comparison with rate of mutants

Am J Hum Genet

Second trimester screening for Down’s syndrome7 years experience

J Med Screen

Original research
The implications of a false positive second-trimester serum screen for Down syndrome