Fall 2003: Down Syndrome

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Unchanged Prevalence of Trisomy 21
With Folic Acid Food Fortification in Canada

Submitted by Joel G Ray, MD, MSc, FRCPC¹, Chris Meier, BSc², Marian J Vermeulen, BScN, MHSc³, David EC Cole, MD, PhD, PFCPC⁴, Philip R Wyatt, MD, PhD, FRCPC²

¹ Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario.
² Department of Genetics, North York General Hospital, Toronto, Ontario.
³ Department of Emergency Services, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
⁴ Departments of Laboratory Medicine and Pathobiology, Medicine and Paediatrics (Genetics), University of Toronto, Toronto, Ontario.

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Introduction

Folic acid supplementation and food fortification are associated with a significant reduction in the risk of neural tube defects (NTD) ^{1, 2}. Genetic polymorphisms for enzymes that remethylate homocysteine to methionine, a pathway dependent on normal folate metabolism, have been associated with trisomy 21 ³, and a familial clustering of NTD and trisomy 21 has also been seen ⁴. Since the nondisjunction of trisomy 21 may arise either during oocyte maturation or at the time of oocyte fertilization ⁵, it is hypothesized that higher folic acid intake might reduce the likelihood of such chromosomal aberrations ⁶. By January 1998, most Canadian cereal grains (e.g., flour) were being fortified with folic acid, providing an additional daily average of about 0.2 mg of synthetic folic acid ⁷ . This enabled us to study whether food fortification was associated with a decline in the prevalence of trisomy 21.

Methods

We performed a retrospective population-based study of 336,963 consecutive Ontarian women who underwent antenatal maternal serum screening (MSS) for trisomy 21 between January 1994 and August 2000 ⁸. We evaluated the monthly prevalence of antenatally and postnatally diagnosed trisomy 21 before and after January 1998, and defined the time point of screening and the diagnosis of trisomy 21 as the date of conception, estimated by menstrual history, or more commonly by an early dating ultrasound.

All women with a positive MSS for fetal trisomy 21 were referred for counseling at one of 17 genetic counseling centers across Ontario, and offered amniocentesis. Each center contributes all follow-up data to the Ontario MSS Database, located at the North York General Hospital (Toronto, Ontario). Antenatally diagnosed cases were confirmed using the follow-up records collected by each regional genetics center. Postnatally diagnosed cases were derived using data-linkage between the mother’s provincial health insurance number and that of her infant, through the Canadian Institute for Health Information Discharge Abstract Database. The data from one genetics center was incomplete, and were therefore excluded from the data set.

Autoregressive integrated moving average (ARIMA) methods were used to model the effect of fortification after January 1998 by means of a ramp function ². The overall prevalence of trisomy 21 pre-fortification period was compared to that post-fortification, using a crude and a maternal age-adjusted prevalence ratio (PR), the latter calculated using Poisson regression analysis. The Research Ethics Board of the North York General Hospital granted permission to conduct this study.

Results

There were 375 identified cases of trisomy 21 before fortification (1.71 per 1000), compared to 201 cases thereafter (1.70 per 1000) - a crude PR of 0.99 (95% confidence interval [CI] 0.84-1.18) (Table). The associated risk of trisomy 21 did not change after adjustment for mean maternal age (adjusted PR 0.99 [95% CI 0.82-1.19). Similarly, no significant decline in the monthly prevalence of trisomy 21 was observed using ARIMA time series analysis (P = 0.24).

Discussion

Despite the limited sensitivity of MSS for detecting trisomy 21 ⁸, our study consistently included both antenatally and postnatally detected cases, thereby reducing the risk of ascertainment bias ⁹. Furthermore, the prevalence of trisomy 21 during the pre-fortification period was the same as in other studies ^{10, 11}. Clearly, we were not able to detect those aneuploid pregnancies spontaneously aborted earlier than 14 week's gestation.

We previously observed a significant and large rise in red cell folate concentrations among Ontarian women of reproductive age within 12 months of complete food fortification ¹², as well as a 50% decline in the prevalence of open neural tube defects ². Although 0.2 mg daily of extra synthetic folic acid may not be enough to prevent most cases of trisomy 21 cases, we would have expected some reduction, which was not so.

These preliminary findings do not support the hypothesis that increased folic acid intake can substantially lower the population risk of fetal trisomy 21. Given the limitations of our study design, however, we believe that the hypothesis deserves further testing, including an evaluation of the interactions between maternal age, folate and homocysteine status, and the genetic polymorphisms influencing these environmental interactions.

Acknowledgements: We would like to thank both the Ontario provincial laboratories and genetics clinics for contributing data to the Ontario MSS Database, and the women of Ontario for supporting the maternal serum screening program.

References

1. Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2000; (2):CD001056.

2. Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DEC. Association of neural tube defects and folic acid food fortification. Lancet 2002; 360:2047–2048.

3. Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, Rozen R, James SJ. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000; 67:623-630.

4. Barkai G, Arbuzova S, Berkenstadt M, Heifetz S, Cuckle H. Frequency of Down's syndrome and neural-tube defects in the same family. Lancet 2003; 361:1331-1335.

5. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001; 2:280-291.

6. Fenech M, Aitken C, Rinaldi J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 1998; 19:1163-1171.

7. Health Canada. Regulations Amending the Food and Drug Regulations. Schedule No. 1066 (Flour Fortification). Part II Canada Gazette November 25 1998.

8. Meier C, Huang T, Wyatt PR, Summers AM. Accuracy of expected risk of Down syndrome using the second-trimester triple test. Clin Chem 2002; 48:653-655.

9. Bower C, Ryan A, Rudy E. Ascertainment of pregnancies terminated because of birth defects: effect on completeness of adding a new source of data. Teratology 2001; 63:23-25.

10. Howe DT, Gornall R, Wellesley D, Boyle T, Barber J. Six year survey of screening for Down's syndrome by maternal age and mid-trimester ultrasound scans. BMJ 2000; 320:606-610.

11. Beaman JM, Goldie DJ. Second trimester screening for Down's syndrome: 7 years experience. J Med Screen 2001; 8:128-131.

12. Ray JG, Vermeulen MJ, Boss SC, Cole DEC. Increased red cell folate concentrations in women of reproductive age after Canadian folic acid food fortification. Epidemiology 2002; 13:238-240.

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TABLE.  Maternal features and prevalence of trisomy 21 before and after mandatory folic acid food fortification

Observation	Period of observation
	Pre-fortification (January 1994 to December 1997)	Post-fortification (January 1998 to May 2000)
Number of months of observation	48	29
Mean (SD) maternal age, years	30.1 (0.19)	30.3 (0.10)
Total number of women screened	218 977	117 986
Number of women with a trisomy 21 affected fetus	375	201
Prevalence of trisomy 21 (per 1000 screened)	1.71	1.70
Unadjusted prevalence ratio (95% CI)*	0.99 (0.84-1.18)
Age-adjusted prevalence ratio (95% CI)*	0.99 (0.82-1.19)

* Post- versus pre-fortification periods
CI confidence interval

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