Down syndrome

DOWN'S SYNDROME (DS): FIRST TRIMESTER VERSUS SECOND TRIMESTER SCREENING STRATEGIES.

INTRODUCTION

Down syndrome is the most common chromosome abnormality in humans, with an incidence of 1 in 600 live births. Individuals with Down syndrome may have physical birth defects including heart defects and varying degrees of mental retardation. Median life expectancy of persons with Down syndrome is about 49 years (Grant 2005).

Antenatal screening strategies are used to identify patients with increased risk of having a baby with Down's Syndrome, so that more accurate diagnostic tests can be offered. They are designed for apparently healthy individuals, and limit the number of people undergoing diagnostic tests. Screening strategies are evaluated in terms of detection rate, false-positive rate and the odds of being affected given a positive result (Benn 2002).

While estimating the effectiveness of screening strategies, the following parameters need to be considered:

* Cost effectiveness

* Detection rate

* False positive values associated with a particular strategy.

* Uptake of screening strategies.

* Procedures used to terminate pregnancy, (if such a decision is reached) their associated complications and availability.

* Availability of resources and expertise required to perform the procedures (screening, diagnostic and subsequent procedures).

First-trimester screening has more benefits as it facilitates early diagnosis with consequent safer and less traumatic therapeutic abortion. They also offer an earlier reassurance, if there is low risk for Down's syndrome (Cuckle 2001).

In this review, the efficacy of first and second trimester screening strategies have been assessed in terms of cost-effectiveness, detection rate, false-positive and false-negative outcomes and their implications for patients and healthcare providers have been reviewed. Research articles which have addressed these parameters have been critically reviewed. Finally, after reviewing the evidence for using first trimester and second trimester strategies and contemplating their advantages and disadvantages, a conclusive statement has been put forward.

FIRST TRIMESTER SCREENING STEATEGIES (10-14 WEEKS):

* Nuchal translucency measurement

* First trimester double test (PAPP­A, HCG)

* First trimester combined test (nuchal translucency, PAPP­A, HCG).

* Integrated screen

* Contingent screen.

SECOND TRIMESTER SCREENING STRATEGIES (15-19 WEEKS)

* Second trimester double test (AFP, HCG)

* Triple test (AFP, HCG, uE3)

* Quadruple test (AFP, HCG, uE3, inhibin A)

METHODS AND RESULTS

1. SEARCH TERMS:

* “Down Syndrome diagnosis”

* “Down Syndrome screening test”

* “First trimester versus second trimester screening for Down Syndrome”

* “First trimester screening test”

* “Second trimester screening test”

* “Maternal age in Down Syndrome”

* “Aneuploidy”

* “Double test”

* “Nuchal translucency test”

* “Combined test”

* “Triple test”

* “Quadruple test”

* “Integrated test”

* “Cost effectiveness analysis”

* “Evidence base”

* “Efficacy”

* “First and second trimester evaluation of risk (FASTER) trial”

2. DATABASES USED:

* Pubmed.gov - U.S national Library of medicine and National Institutes of health.

* Medline (Ebscohost)

* Cochrane reviews

* Google search engine

* Google scholar search engine

* Obstetrics and Gynecology Journals

* Sciencedirect.com

* SCOPUS

* Web of Science database

* Ovid gateway

* JSTOR - Journal storage website - www.jstor.org

* JournalSeek.net

* BioMed Central database - www.biomedcentral.com

3. EXCLUSION/INCLUSION CRITERIA:

INCLUSION CRITERIA

* All research articles that published in English language from January 1950 till date were selected.

* All the articles that mentioned all or most of the search terms (mentioned in the earlier section) were selected.

* The papers which discussed screening strategies from both first trimester and second trimester were considered.

* Studies that were evidence based and showed a meta-analysis report were given special preference.

* Papers which demonstrated Computer-based cost analysis and computer based prediction performance for the screening tests were included.

* Research articles outlining results from the FASTER trial (First and second trimester evaluation of risk) and SURUSS study (Serum Urine and Ultrasound Screening Study) were included.

EXCLUTION CRITERIA

* Articles that reviewed only one or two methods of screening were discarded.

* Meta-analysis performed for either just the first trimester or the second trimester screening test was discarded.

* Research papers which discussed first and second trimester screening for conditions other than Down's Syndrome were discarded.

* Research articles that did not provide a clear conclusive remark about the better screening test, were also discarded.

TABLE 1: SUMMARY OF OUTCOMES

No.

AUTHORS

TYPE OF STUDY

RESULTS

ACCURATE?

RELEVANT?

EFFECTIVE?

1.

(Cuckle 2005)

Computer modeling using published meta-analyses.

1st trimester screen had higher detection rate than 2nd trimester.

Yes. Conclusions were derived from published meta-analyses.

Yes. Detection rates are compared for 1st & 2nd trimester screens.

Yes, because it clearly stated that 1st trimester screen had higher detection rate.

2.

(Cusick, Buchanan et al. 2003)

Mathematical modeling applied to a hypothetical population.

Combined 1st trimester screening was

more cost-effective than the 2nd trimester triple screen.

No. The results are similar to other published studies, but there are some assumptions.

Yes. A cost-analysis study has been performed for both the 1st and 2nd trimester screens.

Yes, the results state that 1st trimester screen is more cost-effective.

3.

(Gekas 2009)

Computer simulated study

Screen in 1st trimester was cost effective with fewer euploid miscarriages and unnecessary

terminations.

Yes. Data was populated from the SURUSS trial and real unit costs for healthcare

Interventions were considered.

Yes. It compares cost effectiveness and miscarriages associated with both screening strategies.

Yes, because the results indicate higher cost-effectiveness and lower fetal losses for 1st trimester screens.

4.

(Gilbert 2001)

Analysis of incremental cost effectiveness using decision model

The 1st trimester combined test and the quadruple test are cost effective.

Yes. Estimates used in the model are based on a systematic review and other published sources.

Yes. Includes screening tests from first and second semester.

Relevant but it does not say definitively that first trimester screen is more cost effective.

5.

(Cuckle 2008)

Retrospective study from FASTER trial data.

The contingent screening decreases the need for second trimester testing.

Yes. Down syndrome risks were retrospectively calculated from FaSTER trial data.

Yes. Compares between 1st and 2nd trimester screening policies.

Relevant, as it states contingent screening in 1st trimester reduces the need to screen again in the 2nd trimester.

6.

(Malone 2005)

A study of 42367 patients conducted between 1999 and 2002 at 15 U.S centres.

1st trimester combined screening is better than 2nd trimester quadruple screening.

Yes. Results are based on a large number of subjects with actual observations.

Yes. Compares screening in 1st and 2nd trimester.

Yes. This study concludes that 1st trimester screen, if performed at 11 weeks has highest detection rates and least false positive results.

7.

(Rosen 2005)

Meta-analyses.

1st trimester screening is as accurate as 2nd trimester testing.

Yes. Results are based on large data bases obtained from FASTER trial.

Yes. Compares Down syndrome screening in 1st and 2nd trimester.

Yes. This review concludes that first trimester is at least as accurate as the second trimester screen.

8.

(Wald 2005)

Prospective study of 47,053 singleton pregnancies

Screening in 1st trimester is most cost effective and safe method.

Yes, as it involves a large number of patients with real observed results.

Yes, because it looks at the best tests available in the 1st and 2nd trimester.

Yes. This study states that screening in 1st trimester is more cost effective and safe.

9.

(Wald 2003)

A study of pregnant women in 25 UK centres.

Screening performance in the 1st trimester was same as in 2nd trimester.

Yes. Has a large patient number includes follow-up for pregnancies with DS.

Yes. It compares most cost effective and safe screenings in 1st and 2nd trimester.

Yes. Screening strategies integrated from both first and second trimester are more cost effective and safe (Conflicting views).

10.

(Benn 2002)

Review article

First trimester screening is very effective for DS.

Yes, as it considers observations and finding from a large number of publications (73).

Yes. Serum markers from 1st and 2nd trimester are discussed.

Yes. This review validates screening in first trimester.

11.

(Biggio 2004)

Computer simulated analysis and mathematical modeling.

Sequential screening was most cost-effective but had the highest euploid loss rate.

No. Because although it may be more cost-effective, it fails to justify unnecessary terminations.

Yes. Screening tests for 1st and 2nd trimesters have been analysed for their cost effectiveness.

Sequential screen (results from 1st and 2nd trimester) is most cost-effective (conflicting views).

12.

(Cuckle 2001)

Expert Opinion/Commentary.

1st trimester screening is better than

2nd trimester screening.

Yes. The author refers to other publications that validate these observations.

Yes. Predicted detection rates for screening tests in 1st and 2nd trimester mentioned.

Yes. Emphasizes the importance of screening in first trimester & suggests adding more parameters will increase efficiency of screens.

DISCUSSION

Some screening strategies are predominantly performed in the first trimester and some work best in the second trimester. The aims of these screening strategies are:

* To evaluate risk factors for Down Syndrome.

* Reduce the number of uptake for diagnostic tests as these invasive tests include risk of miscarriage

* Provide women with positive diagnosis a choice of terminating or continuing with the pregnancy.

If such a decision is reached, it is safer and easier to terminate in the first trimester. Hence, it is beneficial if the screening strategies used in first trimester are more efficient and cost-effective.

A literature search was conducted to look for evidence for screening strategies in first and second trimester. Twelve research publications, which compared the screening strategies in first and second trimester were shortlisted, and reviewed. Data was extracted from these publications and their quality was evaluated based on pre-defined criteria (clarity, consistency, quality, statistical calculation, accounts for missing data etc). The data extraction sheets and quality scoring sheets for all the publications have been attached at the end.

TABLE 2: Records supporting first trimester, combined 1st and 2nd trimester strategies and records with conflicting views.

Record No.

1st trimester is better

2nd trimester is better

1st and 2nd trimester are same

Both 1st and 2nd together are better than 1st

Additional information.

1

YES

NO

2

YES

NO

3

YES

NO

5

YES

NO

6

YES

NO

YES

8

YES

NO

10

YES

NO

12

YES

NO

YES

4

YES

7

YES

9

YES

11

YES

PAPERS SUPPORTING 1ST TRIMESTER STRATEGIES:

Eight out of twelve publications (white background in SUMMARY OF OUTCOMES table) were in strong agreement and advocated screening strategies in first trimester. Of these, three studies were based on computer simulations (Cusick, Buchanan et al. 2003; Cuckle 2008; Gekas 2009), one paper was a review of current screening strategies (Benn 2002), one was a prospective study of over 47000 pregnancies (Wald 2005), one was a retrospective study (Cuckle 2008), one was a study of over 40000 patients (Malone 2005) and one was an expert opinion/commentary (Cuckle 2001).

These articles have compared the cost-effectiveness, detection rates, false positive values and specific serum markers for DS in the first and second trimester. All of them support and advocate first trimester screening strategies.

ARTICLE SUPPORTING NEITHER FIRST NOR SECOND TRIMESTER STRATEGY:

A meta-analysis (Rosen 2005) based on results obtained from the FAsTER trial (pink background in SUMMARY OF OUTCOMES table) concludes that both strategies are equally efficient. A mathematical simulation study (Gilbert 2001) has compared the cost-effectiveness of first and second trimester strategies, but it did not conclude which strategy was better.

PAPERS SUPPORTING FIRST TRIMESTER STRATEGIES AND PROVIDING ADDITIONAL INFORMATION:

An expert opinion (Cuckle 2001) and an actual study of over 40000 pregnancies (Malone 2005) strongly validate screening strategies in the first trimester and also have added new parameters to the study (Dark green background in SUMMARY OF OUTCOMES table). The commentary by (Cuckle 2001) suggests making the first trimester strategies more robust and efficient by adding more parameters along with serum markers such as nasal bone and ultrasound studies. A study based on 40000 pregnancies (Malone 2005) was well conducted with a detailed description of statistical procedures adopted and reasons were provided for excluding patients. This study provided additional information about the accurate gestational period when first trimester strategies would work best.

PAPERS WITH CONFLICTING VIEWS:

These articles have been given a maroon background in the SUMMARY OF OUTCOMES table. A study conducted for 25 UK centres (Wald 2003) mentions that the outcomes are same for both trimester strategies in terms of detection rates. This article also mentions that if results are combined from 1st and 2nd trimester strategies, the detection rates get higher.

A computer simulated analysis (Biggio 2004) has compared five screening strategies for cost-effectiveness. It has concluded that when results from first and second trimester screens are put together, the detection rates are higher. It also stated that this strategy also had higher number of euploid fetal losses due to false positive values.

LIMITATIONS OF PAPERS WITH CONFLICTING VIEWS:

Although these articles claim higher detection rates for the combination of 1st and 2nd trimester strategies, they have failed to consider the following:

* Many women may not like to turn up for 2nd trimester screen.

* Performing two screens instead of one would certainly add to the overall costs.

* A high risk estimate for DS in the second trimester increases the costs for termination and requires higher level of expertise.

* Being informed very late may lead to women deciding to have babies with DS anyway, and this in turn will add to the cost of bringing up a child with DS.

* Loss of healthy babies due to false positive results.

QUALITY SCORING:

All the research publications selected for this evidence based review were given scores according to a predefined scoring system. Points were awarded for:

* clear description

* equal allocation

* comparable conditions between groups

* blinding

* allocation

* adequate numbers

* duration

* description of recruitment

* consistency

* control values

* consistency of outcomes

* statistical analysis

* description of statistical analysis

* accounting for missing data

* whether reason was provided for withdrawal.

TABLE 3: Table showing quality scores for all the articles reviewed.

RECORD NO.

SCORE

QUALITY

1

8

ADEQUATE

2

10

GOOD

3

11

GOOD

4

12

GOOD

5

14

HIGH QUALITY

6

15

HIGH QUALITY

7

7

ADEQUATE

8

16

HIGH QUALITY

9

16

HIGH QUALITY

10

8

ADEQUATE

11

16

HIGH QUALITY

12

5

LOW QUALITY

CRITICAL REMARKS:

Currently, the emerging trend has been in favour of strategies that incorporate results from both the 1st and 2nd trimester screening strategies. These strategies have a higher detection rate and a fixed number of procedure-related euploid losses.

Although the strategies that combine both 1st and 2nd trimester screens have higher detection rates, they fail to provide an early diagnosis and early reassurance, if the risks are low. A high risk evaluation in the second trimester adds to the complications in termination, management, and increases risks during diagnostic procedures. Also, high false positive values lead to loss of normal fetuses.

The research articles that demonstrate better efficiency of combined 1st and 2nd trimester strategies also fail to realize that women may not prefer repeated screenings and tests for the same condition. In countries where healthcare costs are relatively high, the implications for multiple screenings would not be cost-effective or popular.

For the integrated screen, the practice of with-holding the first trimester results from patients is unjustified and unethical. It is important to discuss abnormal results in first trimester, as this would enable the patient to be more informed and prepared and in a better position to make the ultimate decision.

Some of the studies estimated Detection Rates and False Positive Results using statistical modeling and some presented directly observed data to support these observations. Some articles had a common limitation of not using case-control design (especially for those considering new markers) and retrospective designs (only one retrospective study was found). It is also not known how multiple pregnancies would impact the biochemical measurements. A population-based screening programme will need to include quality control measures to ensure that serum measurements are accurate. It will also need to consider the use of Ultrasound Screening Study to correct for uncertain dates, and to ensure software is able to accurately determine an individual's risk of DS.

CONCLUSION

The evidence obtained from the research publications being reviewed here indicate better cost-effectiveness, detection rates, low false positive values and better uptake by women for the screening strategies in FIRST TRIMESTER. A majority of these publications support the first trimester screening strategy and their conclusions are relevant to this study.

* Eight out of twelve research publications reviewed for this subject supported first trimester screening strategies for Down Syndrome.

* Two articles mentioned that efficacy of first trimester screens was the same as second trimester screens. If these findings are combined with the added costs of termination in second trimester and/or added costs of raising Down Syndrome child, the first trimester strategies become more cost-effective.

* Two articles stated that when results were combined from 1st and 2nd trimester, higher detection rates could be achieved.

* Some of the studies lacked case-control designs.

* A population-based screening programme will have to be performed that includes quality control measures to ensure that serum measurements are accurate.

* Ultrasound Screening Study should be used to correct for uncertain dates, and to ensure individual's risk of DS.

* More parameters should be evaluated along with maternal serum biomarkers to make first trimester screening strategies more efficient (e.g. nasal bone presence/absence and ultrasound studies).

* Finally, there is a need to have non-invasive diagnostic tests. Screening cell-free fetal DNA from maternal plasma offers promising approaches to non-invasive and safer diagnosis.

REFERENCES

Benn, P. A. (2002). "Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions." Clinica Chimica Acta 324(1-2): 1-11.

Biggio, J. R., Morris, T. C., Owen, J., Stringer, J. S. (2004). "An outcomes analysis of five prenatal screening strategies for trisomy 21 in women younger than 35 years." American Journal of Obstetrics and Gynecology 190(3): 721-729.

Cuckle, H. (2001). "Time for total shift to first-trimester screening for Down's syndrome." The Lancet 358(9294): 1658-1659.

Cuckle, H., Benn, P., Wright, D. (2005). "Down Syndrome Screening in the First and/or Second Trimester: Model Predicted Performance Using Meta-Analysis Parameters." Seminars in Perinatology 29(4): 252-257.

Cuckle, H. S., Malone, F. D., Wright, D., Porter, F., Nyberg, D.A. (2008). "Contingent screening for Down syndrome-results from the FaSTER trial." Prenatal Diagnosis 28(2): 89-94.

Cusick, W., P. Buchanan, et al. (2003). "Combined first-trimester versus second-trimester serum screening for Down syndrome: A cost analysis." American Journal of Obstetrics and Gynecology 188(3): 745-751.

Gekas, J., Gagne, G., Bujold, E., Douillard, D., Forest, J. C., Reinharz, D., Rousseau, F. (2009). "Comparison of different strategies in prenatal screening for Down's syndrome: cost effectiveness analysis of computer simulation." BMJ 338(feb13_1): b138-.

Gilbert, R. E., Augood, C., Gupta, R., Ades, A. E., Logan, S., Sculpher, M. (2001). "Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies Commentary: Results may not be widely applicable Authors' response." BMJ 323(7310): 423-.

Grant, S. S. (2005). "Options for Down Syndrome Screening: What Will Women Choose?" Journal of Midwifery & Women's Health 50(3): 211-218.

Malone, F., D., Canick, J. A., Ball, R. H., Nyberg, D. A., Comstock, C. H. (2005). "First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome." N Engl J Med 353(19): 2001-2011.

Rosen, T., D'Alton, M. E. (2005). "Down Syndrome Screening in the First and Second Trimesters: What Do the Data Show?" Seminars in Perinatology 29(6): 367-375.

Wald, N. J., Rodeck, C., Hackshaw, A. K., Rudnicka, A. (2005). "SURUSS in Perspective++." Seminars in Perinatology 29(4): 225-235.

Wald, N. J., Rodeck, C., Hackshaw, A. K., Rudnicka, A., Walters, J., Chitty, L., Mackinson, A. M. (2003). "First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS)." J Med Screen 10(2): 56-57.

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