
	Version PDF

Relationship between magnesium levels in drinking water and sudden infant death syndrome

Magnesium Research. Volume 18, Numéro 1, 12-8, March 2005, Original article

Summary

Auteur(s) : Hui-Fen Chiu, Chih-Cheng Chen, Shang-Shyue Tsai, Trong-Neng Wu, Chun-Yuh Yang , Department of Pharmacology, Kaohsiung Medical University, Kaohsiung City, Taiwan, Section of Neonatology, Department of Pediatrics, Kaohsiung Chang- Gung Medical Center, Kaohsiung County, Taiwan, Department of Health Care Administration, I-Shou University, Kaohsiung County, Taiwan, Institute of Environmental Health Science, National Yang-Ming University, Taipei, Taiwan, Institute of Public Health, Kaohsiung Medical University, Taiwan.

ARTICLE

Auteur(s) :, Hui-Fen Chiu¹, Chih-Cheng Chen², Shang-Shyue Tsai³, Trong-Neng Wu⁴, Chun-Yuh Yang^5,*

¹Department of Pharmacology, Kaohsiung Medical University, Kaohsiung City, Taiwan
²Section of Neonatology, Department of Pediatrics, Kaohsiung Chang- Gung Medical Center, Kaohsiung County, Taiwan
³Department of Health Care Administration, I-Shou University, Kaohsiung County, Taiwan
⁴Institute of Environmental Health Science, National Yang-Ming University, Taipei, Taiwan
⁵Institute of Public Health, Kaohsiung Medical University, Taiwan

Introduction

The sudden infant death syndrome (SIDS) has been defined since 1970 as “the sudden death of any infant which is unexpected by history and in which a thorough postmortem examination fails to demonstrate an adequate cause of death” [1]. SIDS remains a leading cause of death during the first year of life. It accounts for 20% of the total infant mortality in Taiwan. The death rate of SIDS was 0.67 per 1000 live births in 1997 [2]. There is a substantial geographical variation in SIDS death rates within the country [3]. Such geographical distribution may suggest an environmental risk factor.

A hypothesis published in 1972 by Caddell compared the epidemiology of SIDS with that of magnesium deficiency and suggested that SIDS may be due to magnesium deficiency shock [4]. This was the first time that the possibility that magnesium deficit may play a role in the pathogenesis of SIDS was taken into consideration.

SIDS may be due to a magnesium dependent disease of infant thermoregulation caused by the fetal consequences of maternal deficiency, which might be prevented by simple atoxic nutritional magnesium intake by the mother [5]. In a recent review, Durlach et al. [6] proposed a theory that various stresses in pregnant women or in the infant may transform a simple magnesium deficiency into magnesium depletion which may not be cured by taking a nutritional magnesium supplement, but requires a correction of its causal dysregulation. Nevertheless, there are sparse epidemiologic data to support these hypotheses. An inverse correlation between the magnesium concentration in drinking water and SIDS has been shown in one study [7] and two studies have reported a significant negative correlation between infant mortality and the drinking water hardness [8, 9].

In our previous studies, we found that there is a decreased risk, with an increasing magnesium level in drinking water, of gastric cancer [10], prostate cancer [11], breast cancer [12], stroke [13], hypertension [14], diabetes mellitus [15], ovarian cancer [16], and delivering a child of very low birth weight [17]. The objective of this study was to study the relationship between the levels of magnesium in drinking water and the risk of death from SIDS.

Methods

Study area

Taiwan is divided into 361 administrative districts, which will be referred to herein as municipalities. Excluded from the analysis were 30 aboriginal townships and 9 islets which had different life-styles and living environments. This elimination of unsuitable municipalities left 322 municipalities.

Subject selection

Data on all deaths of Taiwan residents from 1988 through 1997 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health, which is in charge of the death registration system in Taiwan. For each death, detailed demographic information, including sex, year of birth, year of death, cause of death, place of death (municipality), and residential district (municipality) were recorded on computer tapes. The case group consisted of all deaths from SIDS (International Classification of Disease, ninth revisions [ICD-9], code 798) that occurred between 28 and 364 days of age. The possible control group members consisted of all deaths from injury and poisoning ([ICD-9] codes E800-E999).

Control subjects were pair-matched to the cases by sex, month and year of birth. Each matched control was selected randomly from the set of possible controls for each case. To be eligible, all study subjects needed to have residence and place-of-death in the same municipality.

Each Taiwanese has his or her own unique personal identification number. Using this number, we linked the mortality database with the birth certificate database, identifying the following information for each study subject: maternal age, education level and marital status, and infant birth weight, gestational age, birth order, gender, and birth place.

Registration of births is required by law in Taiwan. It is the responsibility of the parents or the family concerned to register infant births at a local household registration office within 15 days. Computerized data on live births were obtained from the Household Registration System which is managed by the Department of the Interior. The registration forms, which ask for information on maternal age, education, parity, gestational age, date of delivery, infant sex, and birth weight, are completed by the physicians attending the deliveries. Since most deliveries in Taiwan take place in either a hospital or clinic [18] and the birth certificates are completed by physicians attending the delivery, and since it is mandatory to register all live births at local household registration offices, the birth registration data are considered to be complete and accurate. This dataset has been used in our earlier studies [19, 20].

Magnesium levels in drinking water

Information on the level of magnesium in each municipality’s treated drinking water supply was obtained from the Taiwan Water Supply Corporation (TWSC) [21], to which each waterworks is required to submit drinking water quality data, including the level of magnesium. They also conduct routine water analyses to assess the suitability of water for drinking from both the sources and at various points in the distribution system. Four finished water samples, one for each season, were collected from each waterworks. The samples were analyzed by the waterworks laboratory office using spectrophotometric methods. Since the laboratory office examines magnesium levels on a routine basis using standard methods, it was thought that the problem of analytical variability was minimal. Among the 322 municipalities, 70 were excluded as they were supplied by more than one waterworks and the exact population served by each waterworks could not be determined. Their details have already been described in earlier publications [10-17]. The final complete data consisted of magnesium data from 252 municipalities. Levels of magnesium in water remain reasonably constant for long periods of time [22]. The data collected were the annual mean levels of magnesium for the year 1995. The municipality of residence for all cases and controls was identified from death certificates and was assumed to be the source of the subject’s magnesium exposure via drinking water. The levels of magnesium of that municipality were used as an indicator of exposure to magnesium for an individual residing in that municipality.

Statistics

The Statistical Analysis System (SAS) system was used to perform the statistical analyses. A conditional logistic regression model was used to estimate the odds ratios (ORs) and their 95% confidence intervals (95% CIs) in relation to the magnesium levels in drinking water [23]. All ORs were adjusted for maternal age (< 25, ≥ 25 years), maternal education (< 12, ≥ 12 years), urbanization level of residence (metropolitan, city, town, rural), gestational age (< 37 weeks, ≥ 37 weeks), birth weight (< 2500 g, ≥ 2500g), and birth order (first, second to fourth). We calculated crude and adjusted ORs and their 95% CIs for three categories of magnesium levels: ≥ 14.1 mg/L (above the 75th percentile), 8.4-13.5 mg/L (study area median to the 75th percentile), ≤ 8.3 mg/L (below the median of the study municipalities) using the group with the lowest magnesium levels as the reference group. All statistical tests were two-sided. Values of p < 0.05 were considered statistically significant.

Results

A total of 501 SIDS cases with complete records were collected for this study. Of the 501 cases, 287 were male and 214 were female. The mean magnesium concentration in the drinking water was 9.69 mg/L for the cases, and 11.46 for the controls. Cases were born in municipalities in which 92.6% of the population was served by a waterworks. For controls this number was 89.8%. There was no noticeable difference between the case and the control groups with respect to birth order, birth place, marital status of the mother, education of the mother, and mortality season. Cases had significantly higher rates of being born in metropolitan municipalities, being born with a low birth weight (< 2500 g), and being born with a shorter gestational age (< 37 weeks). Mothers of cases had a lower rate (27.3%) of young maternal age than the controls mothers (33.9%) (table 1( Table 1 )).

table 2( Table 2 ) shows the numbers of cases and controls and ORs in relation to magnesium levels in drinking water. The crude ORs were significantly lower than 1.0 for the group with the highest levels of magnesium in their drinking water. Adjustments for possible confounders (including maternal age, urbanization levels of residence, gestational age, and birth weight) only slightly altered the ORs. The group with the highest magnesium levels (≥ 14.1 mg/L) had an OR which remained significantly less than 1.0 (0.70, 95% CI = 0.51-0.97). In addition, there was a significant trend toward a decreased SIDS risk with increasing magnesium levels in drinking water (X² for linear trend = 12.83, p < 0.05).
Table 1 Some characteristics of the study population

Characteristics	Cases	Controls	P value
Total subjects	501	501
Enrollment municipality	252	252
Mean magnesium concentration (mg/L) (SD)	9.69 ± 6.74	11.46 ± 7.64	< 0.001
Sex of infant (%)
Male	287 (57.3)	287 (57.3)
Female	214 (42.7)	214 (42.7)
Drinking water served by waterworks (%)	92.6±12.8	89.8 ± 16.3	< 0.001
Urbanization level of residence (%)^a
Metropolitan	264 (52.7)	187 (37.3)
City	97 (19.3)	118 (23.5)
Town	102 (20.4)	128 (25.6)
Rural	38 (7.6)	68 (13.6)	< 0.001
Mortality season^b(%)
Cool	352 (70.3)	326 (65.1)
Warm	149 (29.7)	175 (34.9)	0.079
Maternal age (yr) (%)
< 25	137 (27.3)	170 (33.9)
≥ 25	364 (72.7)	331 (66.1)	0.024
Maternal marital status (%)
Married	488 (97.4)	488 (97.4)
Unmarried	13 (2.6)	13 (2.6)	1.00
Maternal education (%)
< 12 yr	425 (84.8)	432 (86.2)
≥ 12 yr	76 (15.2)	69 (13.8)	0.530
Birthweight (g) (%)
≥ 2500	430 (85.8)	465 (92.8)
< 2500	71 (14.2)	36 (7.2)	< 0.001
Gestational age (weeks) (%)
≥ 37	439 (87.6)	468 (93.4)
< 37	62 (12.4)	33 (6.6)	< 0.001
Birth order (%)
First child	171 (34.1)	152 (30.3)
Second to fourth	330 (65.9)	349 (69.7)	0.199
Birth place (%)
Hospital/clinic	500 (99.8)	499 (99.6)
Other	1 (0.20)	2 (0.40)	0.999

^aThe urbanization level of each municipality was based on the urban-rural classification scheme of Tzeng and Wu [44].

^bcool season = April-September; warm season = October-March.

Table 2 Odds ratios and 95% confidence intervals for sudden infant death syndrome by magnesium levels in drinking water, 1988-1997

	Magnesium, mg/L (median)
	≤ 8.3 (5.1)	8.4-13.5 (9.3)	≥ 14.1 (17.6)
No. of cases	273	127	101
No. of controls	227	125	149
Crude odds ratios	1.0	0.84(0.62-1.14)	0.57(0.42-0.78)
Adjusted odds ratios*	1.0	0.94(0.68-1.30)	0.70(0.51-0.97)
		X² for trend = 12.83, p < 0.05

Discussion

This study uses a death certificate-based case-control approach and drinking water quality ecologic study to examine the relationship between SIDS mortality and magnesium levels in drinking water in Taiwan. The results of the present study show that there seems to be a significant protective effect of magnesium intake from drinking water on the risk of SIDS.

The individual magnesium exposureARRAY(0x22afbc) from drinking water used in this study is the levelARRAY(0x22afe0) of magnesium of that municipality in which the individual resided. Information on the outcomes and covariates, however, was collected from individual death or birth records. This study design is semi-individual, which is considered a valid design as compared with tradition ecological studies [24].

Despite inherent limitations [25], studies of the ecological correlation between mortality and environmental exposures have been used widely to generate or discredit epidemiological hypotheses. Before any conclusion based on such a mortality analysis is made, however, the completeness and accuracy of the death registration system should be evaluated. In the event of death in Taiwan, the deceased’s family is required to obtain a death certificate from the hospital or local community clinic, which then must be submitted to the household registration office in order to cancel the deceased’s household registration. The death certificate is required in order to have the deceased’s body buried or cremated. Since the death certificates have to be completed by physicians and it is mandatory to register death certificates at local household registration offices, the death registration in Taiwan is considered to be reliable and complete. Although causes of death may be misdiagnosed and/or misclassified, the problem has been minimized through the improvement in the verification and classification for causes of death in Taiwan since 1972. Also since a physician’s diagnosis is based on professional knowledge and experience, his or her diagnosis is unlikely to be influenced by the deceased’s residence (i.e., deceased’s magnesium exposure). Furthermore, Taiwan is a small island with a convenient communication network, and the accessibility of medical service facilities is comparable among study municipalities. It is believed that the diagnosis of SIDS is in general reliable and mortality data differences between municipalities in this study do not appear to result from bias related to disease misclassification. Also, any misclassification should be non-differential with regard to the exposure, thus introducing a bias towards the null.

The recommended dietary amount (RDA) of magnesium is about 350 mg/day for adults [26-28]. In the general population, the major proportion of magnesium intake is through food, and a smaller proportion is through drinking water [29]. Nonetheless, in the modern world intake of dietary magnesium is often lower than the RDA [26]. Taiwan is an island nation and its people have access to an abundant supply of seafood. Seafood is also a major source of magnesium. There are no available data about the mean daily intake of dietary magnesium in the present study. However, seafood is more expensive than other foods in Taiwan and is not a mainstay in most resident’s daily diet. Therefore we think that the people of Taiwan have a slightly deficient diet and also we assume that their dietary magnesium intake is less than the recommended amount.

Magnesium, which is mainly intracellularly concentrated, is reduced during pregnancy [30], i.e., there is a pregnancy-induced hypomagnesemia because the formation of new tissue (maternal and fetal) during pregnancy requires a higher magnesium intakeARRAY(0x21b058) than that of the normal nonpregnant woman of a comparable age [30]. Therefore during pregnancy additional magnesium is needed. The recommended daily allowance for dietary magnesium during pregnancy seems little higher than RDA [26-28, 31], but most pregnant women do not obtain enough of the required amounts. The fetus is more severely affected than the mother by maternal magnesium deficiency [5]. Infants born to ethnic groups whose mothers have traditionally high dietary magnesium have lower rates of SIDS, while infants born to ethnic groups whose mothers have low dietary magnesium have higher rates of SIDS [32]. This finding confirms the importance of maternal magnesium intake in protecting the offspring from SIDS [6].

Ashe et al. [33] observed that in middle-class pregnant women, the magnesium intake was only 270 mg/day, which is 60% of the recommended allowance of pregnant women (450 mg/day). If the mean daily dietary intake of magnesium of pregnant women is 270 mg/day (60% of the RDA) in Taiwan, and if we assume that people drank an average of 2 liters of water per day, the percentage of magnesium contribution from water for residents in municipalities with the highest water magnesium levels (median, 17.6 mg/L) is about 13% (35.2/270). The percentages would be 6.9% (18.6/270) for the group residing in areas with water magnesium levels between 8.4 and 13.5 mg/L (median, 9.3 mg/L) and 3.8% (10.2/270) for the group in areas with water magnesium levels of 8.3 mg/L or less (median, 5.1 mg/L). The relative contribution of water magnesium would be even more important among persons with lower dietary intakes of magnesium. The fact that a significantly protective effect of magnesium intake via drinking water was found in the group with the highest levels of intake suggested that only subjects with magnesium intake via drinking water above a certain level receive a beneficial effect on their risk of SIDS.

The question has been raised of how the relatively small intake of magnesium via drinking water can have critical significance for the amount of magnesium in the body. However a recent review which dealt with waterborne magnesium at a level of about 10 percent of the total daily magnesium intake supported this hypothesis [34]. It may be that magnesium in water, which appears as hydrated ions, is more easily absorbed than magnesium in food [26, 35]. It is also possible that waterborne magnesium could correct an insufficient dietary magnesium level [36]. Nutritionists and pharmacologists should conduct studies using quantitative pharmacokinetic models to suggest how it would be possible to become substantially depleted with a slightly deficient diet. Additionally, studies should examine how waterborne magnesium could have such a marked effect when it constitutes only a small percentage of total intake [34]. There are a number of major risk factors for SIDS in Taiwan, including maternal age, maternal education, birth order, low birth weight, and prematurity [37], which should be taken into account when investigating the possible role of an additional factor (magnesium levels in drinking water). In this study, we found a significant protective effect of magnesium intake from drinking water on the risk of SIDS after controlling for the above mentioned variables.

Several stresses, including parental smoking, maternal alsoholism, bottle feeding, sleeping position, bedding, and wrapping, may be associated with maternal magnesium deficiency which may induce SIDS in various subgroups with magnesium depletion [6]. There is unfortunately no information available on these variables for individual study subjects and they could not be adjusted for directly in the analysis. However, there is no reason to believe that there would be any correlation between these confounders and the levels of magnesium in drinking water. It is also unlikely that there would be a direct relationship between other risk factors and the level of magnesium in drinking water. We think that the degree to which not controlling for other causal or protective factors may have affected our results is not significant.

Mobility from a municipality of high magnesium levels to one with low magnesium exposure or vice versa could have introduced misclassification bias or bias in our risk estimates [38-40]. Two american studies reported that about 25% [41] and 37% [42] of women moved during pregnancy. No data were available about the proportion of women who have moved during pregnancy in Taiwan. However, this misclassification of exposure is most likely to be nondifferential (random), which would be more likely to reduce the observed magnitude of association than to introduce a positive bias in the association. For polytomous exposure categorizations, nondifferential misclassification could also attenuate or obliterate a true trend [43].

Conclusions

In summary, the results of the present study show that there is a significant trend towards a decreased risk of SIDS with an increasing Mg level in drinking water. This is an important finding for the Taiwan water industry and human risk assessment. Future studies should use precise estimates of the individual’s intake of magnesium, through both food and water.

Acknowledgments

This study was partly supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC-89-2320-B-037-023). The authors gratefully acknowledge the Taiwan Water Supply Corporation for supplying the data on the magnesium levels in drinking water in Taiwan.

References

1 Russel-Jones DL. Sudden infant death in history and literature. Arch Dis Child 1985; 60: 278-81.

2 Taiwan Provincial Maternal and Child Health Institute (TPMCHI). Statistics relating to maternal and child health in Taiwan. Taichung: TPMCHI. Taiwan Provincial Government, 1999.

3 Knobel HH, Yang WS, Ho MS. Urban and regional differences in infant mortality in Taiwan. Soc Sci Med 1994; 39: 815-22.

4 Caddell JL. Magnesium deprivation in sudden unexpected infant death. Lancet 1972; i: 258-62.

5 Durlach J, Durlach V, Rayssiguier Y, Ricquier D, Goubern M, Bertin R, Bara M, Guiet-Bara A, Olive G, Mettey R. Magnesium and thermoregulation. I. Newborn and infant. Is suddent infant death syndrome a magnesium-dependent disease of the transition from chemical to physical thermoregulation? Magnes Res 1991; 4: 137-52.

6 Durlach J, Pages N, Bac P, Bara M, Guiet-Bara A. Magnesium deficit and suddent infant death syndrome (SIDS): SIDS due to magnesium deficiency and SIDS due to various forms of magnesium depletion: possible importance of the chronopathological form. Magnes Res 2002; 15: 269-78.

7 In: Seelig MS, ed. Magnesium deficiency in the pathogenesis of disease. New York: Plenum Publishing Corporation, 1980.

8 Crawford MD, Gardner MJ, Morris JN. Mortality and hardness of local water supplies. Lancet 1968; i: 827-31.

9 Crawford MD, Gardner MJ, Sedwick PA. Infant mortality and hardness of local water supplies. Lancet 1972; i: 988-92.

10 Yang CY, Cheng MF, Tsai SS, Hsieh YL. Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality. Jpn J Cancer Res 1998; 89: 124-30.

11 Yang CY, Chiu HF, Tsai SS, Cheng MF, Lin MC, Sung FC. Calcium and magnesium in drinking water and the risk of death from prostate cancer. J Toxicol Environ Res 2000; 60: 17-26.

12 Yang CY, Chiu HF, Cheng BH, Hsu TY, Cheng MF, Wu TN. Calcium and magnesium in drinking water and the risk of death from breast cancer. J Toxicol Environ Res 2000; 60: 231-41.

13 Yang CY. Calcium and magnesium in drinking water and risk of death from cerebrovascular disease. Stroke 1998; 29: 411-4.

14 Yang CY, Chiu HF. Calcium and magnesium in drinking water and the risk of death from hypertension. Am J Hypertens 1999; 12: 894-9.

15 Yang CY, Chiu HF, Cheng MF, Tsai SS, Hung CF, Tseng YT. Magnesium in drinking water and the risk of death from diabetes mellitus. Magnes Res 1999; 12: 131-7.

16 Chiu HF, Chang CC, Yang CY. Magnesium and calcium in drinking water and risk of death from ovarian cancer. Magnes Res 2004; 17: 28-34.

17 Yang CY, Chiu HF, Tsai SS, Chang CC, Sung FC. Magnesium in drinking water and the risk of delivering a child of very low birth weight. Magnes Res 2002; 15: 207-13.

18 Wu SC, Young CL. Study of the birth reporting system. J Natl Public Health Assoc 1986; 6: 15-27; (ROC).

19 Yang CY, Cheng BH, Tsai SS, Wu TN, Lin MC, Lin KC. Association between chlorination of drinking water and adverse pregnancy outcome in Taiwan. Environ Health Perspect 2000; 108: 765-8.

20 Lin MC, Yu HS, Tsai SS, Cheng BH, Hsu TY, Wu TN, Yang CY. Adverse pregnancy outcome in a petrochemical polluted area in Taiwan. J Toxicol Environ Health 2001; 63: 565-74.

21 Taiwan Water Supply Corporation. The statistical data of water quality, Taiwan. Taichung: Taiwan Water Supply Corporation, 1996.

22 Bell JA, Doege TC. Drinking water and human health. Chicago: American Medical Association, 1984.

23 Breslow NE, Day NE. Statistical methods in cancer research: the analysis of case-control studies. Lyon: IARC Scientific publications, 1980.

24 Kunzli N, Tager IB. The semi-individual study in air pollution epidemiology: a valid design as compared to ecologic studies. Environ Health Perspect 1997; 105: 1078-83.

25 Morgenstern H. Uses of ecologic analysis in epidemiological research. Am J Public Health 1982; 72: 1336-44.

26 Durlach J. Recommended dietary amounts of magnesium: Mg RDA. Magnes Res 1989; 2: 195-203.

27 Durlach J, Bac P, Bara M, Guiet-Bara A. Apports alimentaires de reference (DRIs americains) et apports nutritionnels conseilles (ANCc francais) de magnesium: un consensus sur une consommation alimentaire magnesique sans danger et adequate. Med et Nutr 1998; 34: 197-202.

28 Durlach J. Nutritional magnesium supplementation for chronic marginal magnesium deficiency. Magnes Res 2000; 13: 65.

29 Rubenowitz E, Axelsson G, Rylander R. Magnesium in drinking water and death from acute myocardial infarction. Am J Epidemiol 1996; 143: 456-62.

30 Itokawa Y, Durlach J. Magnesium in health and disease. London: John Libbey, 1989.

31 Graber TW. Role of magnesium in health and disease. Compr Ther 1987; 13: 29-35.

32 Caddell JL. The apparent impact of gestational magnesium deficiency on the sudden infant death syndrome. Magnes Res 2001; 14: 291-303.

33 Ashe JR, Schofield FA, Gram MR. The retention of calcium, iron, phosphorus, and magnesium during pregnancy: the adequacy of prenatal diets with and without supplementation. Am J Clin Nutr 1979; 32: 286-91.

34 Marx A, Neutra RR. Magnesium in drinking water and ischemic heart disease. Epidemiol Rev 1997; 19: 258-72.

35 Theophanides T, Angiboust JF, Polissiou M. Possible role of water structure in biological magnesium systems. Magnes Res 1990; 3: 5-13.

36 Altura BM, Altura BT. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. I. Clinical aspects. II. Experimental aspects. Magnesium 1985; 4: 226-71.

37 Knobel HH, Yang WS, Chen CJ. Risk factors of sudden infant death in Chinese babies. Am J Epidemiol 1996; 144: 1070-3.

38 Bentham G. Migration and morbidity: implications for geographical studies of disease. Soc Sci Med 1980; 26: 49-54.

39 Gladen B, Rogan W. Misclassification and the design of environmental studies. Am J Epidemiol 1979; 109: 607-16.

40 Polissar L. The effect of migration on comparison of disease rates in geographic studies in the United states. Am J Epidemiol 1980; 111: 175-82.

41 Shaw GM, Malcoe LH. Residential mobility during pregnancy for mothers of infants with or without congenital cardiac anomalies: a reprint. Arch Environ Health 1992; 47: 236-8.

42 Khoury M, Stewart W, Weinstein A, Panny S, Lindsay P, Eisenberg M. Residential mobility during pregnancy: implications for environmental teratogenesis. J Clin Epidemiol 1988; 41: 15-20.

43 Brenner H. Notes on the assessment of trend in the presence of nondifferential exposure misclassification. Epidemiology 1992; 2: 420-7.

44 Tzeng GH, Wu TY. Characteristics of urbanization levels in Taiwan districts. Geograph Res 1986; 12: 287-323.