Development of prenatal screening—A historical overview

doi:10.1053/j.semperi.2015.11.003

Seminars in Perinatology

Volume 40, Issue 1, February 2016, Pages 12-22

https://doi.org/10.1053/j.semperi.2015.11.003 Get rights and content

Abstract

The first prenatal screening test to be introduced was based on a single maternal serum marker of neural tube defects. Since then various prenatal screening concepts have been developed, the most successful being Down syndrome risk estimation using multiple serum and ultrasound markers. Today a completely new approach to aneuploidy screening is available based on maternal plasma cell-free DNA testing. This has the potential to markedly improve screening performance but routine testing is currently too expensive in a public health setting. However, it can be cost-effective when used in combination with existing multi-maker tests. Some are beginning to broaden prenatal screening to include pregnancy complications such as pre-eclampsia that can be prevented using soluble low-dose aspirin treatment started before 16 weeks of gestation. Prenatal screening for cardiac abnormalities, fragile X syndrome and recessive genetic disorders is underutilized and public health planners should considered a more widespread application of available methods.

Section snippets

Neural tube defects

In the mid-1970s the large multi-center UK Collaborative AFP Study examined maternal serum AFP levels in nearly 300 affected and almost 20,000 unaffected pregnancies.¹ The smallest overlap in the distribution of results between affected and unaffected pregnancies was at 16–18 weeks of gestation when, on average, the AFP level was 6.4 multiples of the normal gestation-specific median (MoM) in anencephaly and 3.8 MoM in “open” spina bifida cases, with some exposure of neural tissue or a lesion

Aneuploidies—Established screening protocols

The focus of prenatal screening since the 1980s has been for the detection of trisomy 21 (Down syndrome). Such screening leads to the incidental diagnosis of a large proportion of the other common trisomies, trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome), as well as rare lethal abnormalities such as triploidy and common but clinically less significant sex chromosome abnormalities (SCAs).¹² Some trisomy 21 screening programs incorporate a specific cutoff for trisomy 18 and 13

Aneuploidies—Improved screening protocols

The established screening protocols can be improved by the use of additional ultrasound and biochemical markers. The most well-developed additions are four first-trimester ultrasound markers: absent fetal nasal bone (NB), increased frontal-maxillary facial (FMF) angle, Doppler blood flow of the tricuspid valve showing regurgitation (TR), and of the ductus venosus (DV) showing absent or reversed flow. The likelihood ratios for the occurrence of each marker, and the opposite state, from

Aneuploidies—DNA screening

In recent years, the discovery that there is sufficient fetal cell-free (cf) DNA in maternal plasma to detect Down syndrome has led to the rapid growth of commercial screening for this and other types of aneuploidy. Most tests are based on counting DNA fragments, assigning them to a chromosome and quantifying the proportion assigned to chromosome 21. The results are expressed as a z score computed by comparison to an expected proportion for a euploid sample. Another commercial method uses

Adverse pregnancy outcomes

Adverse maternal–fetal complications of pregnancy are much more common than NTDs and aneuploidy combined. While these complications generally present late in pregnancy, many have been shown to originate from events in the first trimester and as such are candidates for early screening.

The most thoroughly studied adverse outcome with the potential for screening and prevention is pre-eclampsia (PE), a common cause of fetal and maternal morbidity and mortality. In normal pregnancies, at about 8–17

Cardiac abnormalities

Congenital cardiac abnormalities are common and the major abnormalities have an incidence comparable to Down syndrome. Serious cardiac abnormalities are identified at the 18–20-week anomaly scan but the detection rate is low—only 39% in a large European collaborative study.⁵¹ Comparable or better results can be found using the results of a first-trimester NT scan, particularly if this includes the Doppler determination of tricuspid valve and DV blood flow.

In a meta-analysis of first-trimester

Public health considerations

Although the cost of cfDNA is currently very high, there are expectations that, as seen with other emerging technologies, this is likely to fall considerably. If so, difficult choices will need to be made regarding first-trimester public health screening policy.

Some localities implementing primary cfDNA screening may consider that there is little or no need to continue funding a first-trimester ultrasound examination that includes NT. However, the scan has benefits other than aneuploidy

Fragile X syndrome

FXS is the second most common cause of severe learning disability after Down syndrome and the most frequent cause of inherited learning disability, affecting about 1 in 6000 births. Despite the frequency, severity and a test with good performance, prenatal screening is not widespread. A national public health screening program has only been established in Israel.

The disorder, previously called Martin–Bell syndrome, has been known since the 1940s to be inherited but in a non-Mendelian fashion.

Cystic fibrosis

CF is common recessive disorder in North European populations with a prevalence of about 1 in 2500. The aim of prenatal screening is to identify carrier couples rather than individual carriers since the chance of an affected fetus in a given pregnancy is 1 in 4. A contingent strategy is most efficient: test the mother using blood drawn for other reasons in early pregnancy and test the father only if she is found to be a CF carrier. This is best done by obtaining a saliva sample from the father

Other genetic disorders

Spinal muscular atrophy is a recessive disorder, which though less common than CF with a birth prevalence of about 1 in 10,000, it is a severe condition and the main genetic cause of infant mortality. The SMA carrier frequency in Caucasians is about 1 in 45 and 95% of carriers can be detected using a multiplex PCR.⁶⁶ In this population model predicted screening performance is—detection rate, 90%; false-positive rate, 0.04%; and PPV, 25%. The carrier frequency is lower in those with African

Conclusions

A series of technical and conceptual developments over the last 4 decades have led to the widespread introduction of prenatal screening programs. As a result, in countries with optimal screening policies most NTD and common aneuploidy births can be avoided. Newer technical developments continue to be made. These will have a further impact on affected births but it is not necessarily simple to take advantage of the potential advance without disrupting existing services and cost can be a major

References (67)

J.-P. Bernard et al.
Screening for fetal spina bifida by ultrasound examination in the first trimester of pregnancy using fetal biparietal diameter
Am J Obstet Gynecol
(2012)
J. Sonek et al.
Additional first-trimester markers
Clin Lab Med
(2010)
H.S. Cuckle et al.
NIPT for aneuploidy as a clinical service
Clin Biochem
(2015)
H.S. Cuckle
Screening for pre-eclampsia—lessons from aneuploidy screening
Placenta
(2011)
H. Grandjean et al.
The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study
Am J Obstet Gynecol
(1999)
A.J. Verkerk et al.
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome
Cell
(1991)
A. Angelis et al.
Socio-economic burden of rare diseases: asystematic review of cost of illness evidence
Health Policy
(2015)
N.J. Wald et al.
Maternal serum alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of the U.K. Collaborative Study on Alpha-Fetoprotein in Relation to Neural-Tube Defects
Lancet
(1977)
N.J. Wald et al.
Maternal serum alphafetoprotein screening for open neural tube defects: revised statistical parameters
BJOG
(2000)
H.S. Cuckle et al.
Antenatal diagnosis and management of neural tube defects

R. Chaoui et al.

Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11–13-week scan

Ultrasound Obstet Gynecol

(2009)

K.W. Fong et al.

Retrospective review of diagnostic performance of intracranial translucency in detection of open spina bifida at the 11–13-week scan

Ultrasound Obstet Gynecol

(2011)

R. Chaoui et al.

Prospective detection of open spina bifida at 11–13 weeks by assessing intracranial translucency and posterior brain

Ultrasound Obstet Gynecol

(2011)

R. Garcia-Posada et al.

Cisterna magna width at 11–13 weeks in the detection of posterior fossa anomalies

Ultrasound Obstet Gynecol

(2013)

R. Mangione et al.

Screening for fetal spina bifida at the 11–13-week scan using three anatomical features of the posterior brain

Ultrasound Obstet Gynecol

(2013)

R. Lachmann et al.

Posterior brain in fetuses with open spina bifida at 11 to 13 weeks

Prenat Diagn

(2011)

A. Iuculano et al.

Brain stem/brain stem occipital bone ratio and the four-line view in nuchal translucency images of fetuses with open spina bifida

J Matern Fetal Neonatal Med

(2014)

C. Davis et al.

Screening for Down syndrome—incidental diagnosis of other aneuploidies

Prenat Diagn

(2014)

H. Cuckle

Down syndrome fetal loss rate in early pregnancy

Prenat Diagn

(1999)

H. Cuckle et al.

Multianalyte maternal serum screening for chromosomal defects

H.S. Cuckle et al.

Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level

Br J Obstet Gynaecol

(1987)

H. Cuckle et al.

Age-standardisation when target setting and auditing performance of Down syndrome screening programmes

Prenat Diagn

(2004)

J. Miguelez et al.

Model predicted performance of second trimester Down syndrome screening with ultrasound prenasal thickness

J Ultrasound Med

(2010)

S. Cicero et al.

Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11–14-week scan

Ultrasound Obstet Gynecol

(2004)

T. Huang et al.

First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy-associated plasma protein A, free-β human chorionic gonadotrophin, placental growth factor and α-fetoprotein

Prenat Diagn

(2015)

H. Cuckle et al.

Down syndrome risk calculation for a twin fetus taking account of the nuchal translucency in the co-twin

Prenat Diagn

(2010)

D. Wright et al.

Screening for trisomies in dichorionic twins by measurement of fetal nuchal translucency thickness according to the mixture model

Prenat Diagn

(2011)

K.H. Nicolaides et al.

Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies, results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening

Ultrasound Obstet Gynecol

(2005)

M. Agathokleous et al.

Meta-analysis of second-trimester markers for trisomy 21

Ultrasound Obstet Gynecol

(2013)

K.M. Aagaard-Tillery et al.

Role of second-trimester genetic sonography after Down syndrome screening

Obstet Gynecol

(2009)

Y.M. Chan et al.

Women’s uptake of non-invasive DNA testing following a high-risk screening test for trisomy 21 within a publicly funded healthcare system: findings from a retrospective review

Prenat Diagn

(2015)

S. Chetty et al.

Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening

Prenat Diagn

(2013)

F. Shah et al.

Impact of cell-free fetal DNA screening on patients’ choice of invasive procedures after a positive california prenatal screen result

J Clin Med

(2014)

Cited by (57)

Down Syndrome detection with Swin Transformer architecture
2023, Biomedical Signal Processing and Control
Down Syndrome, also known as Trisomy 21, is a severe genetic disease caused by an extra chromosome 21. For the detection of Trisomy 21, despite those statistical methods have been widely used for screening, karyotyping remains the gold standard and the first level of testing for diagnosis. Due to karyotyping being a time-consuming and labour-intensive procedure, Computer Vision methodologies have been explored to automate the karyotyping process for decades. However, few studies have focused on Down Syndrome detection with the Transformer technique. This study develops a Down-Syndrome-Detector (DSD) architecture based on the Transformer structure, which includes a segmentation module, an alignment module, a classification module, and a Down Syndrome indicator.
The segmentation and classification modules are designed by homogeneous transfer learning at the model level. Transfer learning techniques enable a network to share weights learned from the source domain (e.g., millions of data in ImageNet) and optimize the weights with limited labeled data in the target domain (e.g., less than 6,000 images in BioImLab). The Align-Module is designed to process the segmentation output to fit the classification dataset, and the Down Syndrome Indicator identifies a Down Syndrome case from the classification output.
Experiments are first performed on two public datasets BioImLab (119 cases) and Advanced Digital Imaging Research (ADIR, 180 cases). Our performance metrics indicate the good ability of segmentation and classification modules of DSD. Then, the DS detection performance of DSD is evaluated on a private dataset consisting of 1084 cells (including 20 DS cells from 2 singleton cases): 90.0% and 86.1% for cell-level TPR and TNR; 100% and 96.08% for case-level TPR and TNR, respectively.
This study develops a pipeline based on the modern Transformer architecture for the detection of Down Syndrome from original metaphase micrographs. Both segmentation and classification models developed in this study are assessed using public datasets with commonly used metrics, and both achieved good results. The DSDproposed in this study reported satisfactory singleton case-specific DS detection results. Significance: As verified by a medical specialist, the developed method may improve Down Syndrome detection efficiency by saving human labor and improving clinical practice.
Financial contribution as reason to opt out of non-invasive prenatal testing
2023, European Journal of Obstetrics and Gynecology and Reproductive Biology
First trimester non-invasive prenatal testing (NIPT) provides pregnant women with a reliable, non-invasive method to screen for fetal aneuploidies. In the Netherlands, there is a nationwide prenatal screening program in which pregnant women and their partners are counseled about their options around 10 weeks of pregnancy. The first trimester and second trimester scan are fully reimbursed but the NIPT has an own financial contribution of €175 per participant, irrespective of type of insurance. The arguments for this own contribution are fear of uncritical use of NIPT or routinization. NIPT has a relatively stable uptake of 51%, against over 95% for second trimester anomaly scan. We aimed to explore the effect of this financial contribution on the decision to opt out of NIPT.
We performed a survey among 350 pregnant women undergoing a second trimester anomaly scan in our center, Amsterdam UMC, between January 2021 and April 2022. All pregnant women who declined NIPT in the first trimester, were asked to participate and answered 11–13 questions about the decision-making process, the reasons to opt out and the financial contribution.
Information about NIPT was desired in 92% of women and 96% felt sufficiently informed. Most women took the decision not to perform NIPT with their partner and did not experience difficulties in taking this decision. The most important reason to decline NIPT was: “Every child is welcome” (69%). “The test was too expensive” was answered in 12% and was significantly correlated with lower maternal age. Additionally, one in five women (19%) said they would have done NIPT if it had been for free, which was significantly higher in younger women.
The own financial contribution plays a role in the decision-making to decline NIPT and partly explains the low uptake in the Netherlands. This suggests that there is no equal access to fetal aneuploidy screening. To overcome this inequality, this own contribution should be abandoned. We speculate that this will have a positive effect on the uptake, which will increase to at least 70% and potentially 94%.
Do online decision aids reflect new prenatal screening and testing options? An environmental scan and content analysis
2022, PEC Innovation
Decision aids have been developed to help prospective parents make informed, shared decisions about medical tests, but these options are rapidly changing. This study aimed to identify and evaluate publicly available decision aids written in English for prospective parents seeking prenatal test information.
A systematic review process was followed using 3 sources: known decision aid repositories, fetal medicine organisations and Google. The search, screening process, quality assessment, and data extraction was performed by two independent researchers. The quality assessment of the decision aids was based on the International Patient Decision Aids Standards (IPDAS v.4.0).
We identified 13 decision aids, which varied in the screening and diagnostic tests that they discussed. No decision aid met all the IPDAS v.4.0. criteria and no decision aid reported updated risk of miscarriage for amniocentesis and chorionic villus sampling (CVS). There was a lack of decision aids for some common decisions in the prenatal context.
We identified outdated content in current prenatal decision aids. The findings will inform healthcare professionals of the quality of current prenatal decision aids, which may facilitate their patients’ informed decision-making about prenatal tests.
Considerations for improving future decision aids are outlined.
Trends and predictors of eclampsia among singleton and multiple gestations in the United States, 1989–2018
2021, Pregnancy Hypertension
Citation Excerpt :
A limitation of the present study is our inability to include a comparison of temporal trends between preeclampsia and eclampsia; however, this was not possible because the natality datasets did not contain preeclampsia information for any of the study years. Further, we were only able to consider covariates for which data was available for most of the study period, which is potentially problematic as the diagnostic criteria for pregnancy-induced hypertensive disorders have broadened over time [28,29]. In conclusion, we found elevated rates of eclampsia among women with multiple pregnancies, and this association was modified by maternal race, age, obesity, and marital status.
To examine temporal trends of eclampsia by plurality in the US spanning three decades (1989–2018); and to investigate risk factors for eclampsia among singleton and multiple pregnancies in the US during the study period.
Study design: We conducted a retrospective cohort study using the Natality data files, including information on all births within the gestational age of 20–42 weeks from 1989 through 2018. We used joinpoint regression analysis to evaluate trends in rates of eclampsia over the study period. We employed logistic regression models to examine the association between plurality and eclampsia after adjusting for socio-demographic and gestational factors.
Main outcome measures: The primary outcome was eclampsia among singleton and multiple pregnancies.
Findings: There was a 2.8% (95% CI: −5.4, −0.1) average annual reduction in eclampsia rates among singletons, whereas among multiples there was a decline of about 3.7% (95% CI: −6.4, −1.0) annually. Mothers with multiple pregnancies had three-fold increased adjusted odds (OR = 95% CI: 2.95–3.21) of experiencing eclampsia when compared to those with singleton gestations. Non-Hispanic (NH) Black mothers with singletons had 37% greater adjusted odds of developing eclampsia than their NH-White peers (95%CI: 1.33–1.42).
There was an overall decreasing trend in eclampsia incidence in the US from 1989 to 2018, regardless of plurality. The occurrence of eclampsia was associated with plurality, race/ethnicity, maternal age and maternal BMI. Given the heterogeneity in clinical presentations of eclampsia, personalized/standardized risk prediction models are needed to enable consistent diagnosis and timely intervention.
Universal screening for thyroid disease during pregnancy should be performed
2020, Best Practice and Research: Clinical Endocrinology and Metabolism
Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening – the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.
The Evolving Landscape of Genetic Carrier Screening: Clinical Considerations and Challenges
2023, Obstetrical and Gynecological Survey

View all citing articles on Scopus

^☆: Howard Cuckle is a consultant to PerkinElmer Inc., Ariosa Diagnostics Inc., and Natera Inc., and a director of Genome Ltd. Ron Maymon has no conflicts of interest.

View full text

Development of prenatal screening—A historical overview☆

Abstract

Section snippets

Neural tube defects

Aneuploidies—Established screening protocols

Aneuploidies—Improved screening protocols

Aneuploidies—DNA screening

Adverse pregnancy outcomes

Cardiac abnormalities

Public health considerations

Fragile X syndrome

Cystic fibrosis

Other genetic disorders

Conclusions

Am J Obstet Gynecol

Clin Lab Med

Clin Biochem

Placenta

Am J Obstet Gynecol

Cell

Health Policy

Maternal serum alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of the U.K. Collaborative Study on Alpha-Fetoprotein in Relation to Neural-Tube Defects

Lancet

Maternal serum alphafetoprotein screening for open neural tube defects: revised statistical parameters

BJOG

Antenatal diagnosis and management of neural tube defects

Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11–13-week scan

Ultrasound Obstet Gynecol

Retrospective review of diagnostic performance of intracranial translucency in detection of open spina bifida at the 11–13-week scan

Ultrasound Obstet Gynecol

Prospective detection of open spina bifida at 11–13 weeks by assessing intracranial translucency and posterior brain

Ultrasound Obstet Gynecol

Cisterna magna width at 11–13 weeks in the detection of posterior fossa anomalies

Ultrasound Obstet Gynecol

Screening for fetal spina bifida at the 11–13-week scan using three anatomical features of the posterior brain

Ultrasound Obstet Gynecol

Posterior brain in fetuses with open spina bifida at 11 to 13 weeks

Prenat Diagn

Brain stem/brain stem occipital bone ratio and the four-line view in nuchal translucency images of fetuses with open spina bifida

J Matern Fetal Neonatal Med

Screening for Down syndrome—incidental diagnosis of other aneuploidies

Prenat Diagn

Down syndrome fetal loss rate in early pregnancy

Prenat Diagn

Multianalyte maternal serum screening for chromosomal defects

Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level

Br J Obstet Gynaecol

Age-standardisation when target setting and auditing performance of Down syndrome screening programmes

Prenat Diagn

Model predicted performance of second trimester Down syndrome screening with ultrasound prenasal thickness

J Ultrasound Med

Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11–14-week scan

Ultrasound Obstet Gynecol

First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy-associated plasma protein A, free-β human chorionic gonadotrophin, placental growth factor and α-fetoprotein

Prenat Diagn

Down syndrome risk calculation for a twin fetus taking account of the nuchal translucency in the co-twin

Prenat Diagn

Screening for trisomies in dichorionic twins by measurement of fetal nuchal translucency thickness according to the mixture model

Prenat Diagn

Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies, results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening

Ultrasound Obstet Gynecol

Meta-analysis of second-trimester markers for trisomy 21

Ultrasound Obstet Gynecol

Role of second-trimester genetic sonography after Down syndrome screening

Obstet Gynecol

Women’s uptake of non-invasive DNA testing following a high-risk screening test for trisomy 21 within a publicly funded healthcare system: findings from a retrospective review

Prenat Diagn

Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening

Prenat Diagn

Impact of cell-free fetal DNA screening on patients’ choice of invasive procedures after a positive california prenatal screen result

J Clin Med