Abstract
Formaldehyde Exposure and Low Birth Weight Incidence: Regina GRAZULEVIOIENE, et aL Laboratory of Environmental Epidemiology, Institute of Cardiology-A population-based epidemiological study was undertaken to assess the prenatal formaldehyde exposure effect on the incidence of low birth weight newborns in Kaunas area in 1994. All women in childbirth were interviewed in person about their sociodemographic characteristics, habits and reproductive and medical history. We compared 244 cases of low birth weight newborns with 4,089 controls. The comparison involved questionnaire information on 26 potential risk factors in low birth weight. We employed multivariate logistic regression to adjust for potential variable effects of 12 selected low birth weight risk factors. The incidence of low birth weight newborns in Kaunas was 56.2 per 1,000 live newborns. The crude risk ratio of low birth weight babies among women subjected to formaldehyde exposure was 1.68 (95% Cl 1.24-2.27) and to TSP exposure was 1.59 (95% Cl 1.13-2.20). The population attributable risk percentages were 14.1% and 4.9%, respectively. Adjustment for age, occupation, education, marital status, hypertonic disease, last pregnancy outcome, parents smoking, hazardous work, formaldehyde, ozone and TSP exposure decreased the formaldehyde effect, OR 1.37 (95% Cl 0.90-2.09), and ozone effect, OR 1.44 (95% Cl 0.47-4.41), and increased the TSP effect, OR 2.58 (95% Cl 1.34-4.99). The study results indicate that among the ambient air pollutants examined TSP exposure had a statistically significant effect on low birth weight risk. Insufficient control of other environmental risk factors could have influenced the observed association (J Occup Health 1998; 40: 61-67) 

Epidemiological studes in the last decade have shown that, under certain conditions, environmental pollution deranges the functioning of physiological systems and causes low birth weight and abnormal births"'). It is therefore quite possible that there is a direct relation between the environmental conditions in a residential area and the major health indices of its population. The need for complex studies has been emphasized by the European Charter on Environment and Health').

Until now only about five percent of chemicals used in industry have been studied in terms of their reproductive effects. The air pollutants that have been shown to be reproductive toxicants in humans are few, including carbon monoxide, solvents, tobacco smoke and lead 4). The effect caused by toxicants has been associated with low birth weight and intrauterine growth retardation. Low birth weight infants compared with infants of higher birth weights, have been at much greater risk of prenatal mortality and morbidity5), delayed neurologic development and major handicap 6). Among chemical agents that have been associated with an excess risk in epidemiologic studies is formaldehyde? . It was reported that exposure to formaldehyde was associated with an increased risk of uveal melanomas). Considerable exposure to formaldehyde increased the proportional mortality ratio by 2.09). High levels of cumulative formaldehyde exposures of workers empolyed in the formaldehyde industry showed an increase in the risk of lung cancer'o)

There is a lack of data on the long-term prenatal formaldehyde exposure effect on the human newborn population. In animals formaldehyde causes adverse developmental effects in the fetus, fetal loss and birth defects"). Recently published data have shown that formaldehyde may cause children to develop more respiratory infections, allergies and asthma, although evidence of these effects is very controversial 12). Formaldehyde is a carcinogen, as shown in tests on animals. It was classified as a "probable human carcinogen" by the International Agency for Research on Cancer (IARC)13~. In summary, no scientific consensus has yet been reached on the dangers to human health of lowlevel exposure to formaldehyde 14>

We studied the hypothesis that environmental prenatal formaldehyde exposure increases the risk of low birth weight newborns.
Study Area and Methods
Kaunas, with an area of 132 km2 and a population of more than 400,000, is the second largest city in Lithuania. Since 1993, air pollution measurements in the city have been performed by the National Environmental Department and Kaunas Municipal environment monitoring posts. The monitoring of major air pollutants has revealed that environmental exposure of the population residing in different areas of the city differs significantly. It provided the basis for a population-based study of the effects of long-term prenatal environmental formaldehyde exposure on the risk of low birth weight in newborns.
Study Area and Methods
The study involved all women in childbirth who were Kaunas city residents in 1994. We made computer maps of all city administrative districts with street codes and population distribution according to gender and age to assess the low birth weight incidence in the areas. Air pollution data, derived from twelve ecological monitoring posts, were used for the characterization of area exposure. The annual mean of total suspended particulate (TSP), sulphur dioxide (SO2), nitrogen dioxide (NO2), ozone (03), lead (Pb) and formaldehyde (HCHO) concentrations in the districts provided a basis for classifying them as areas with low or high exposure levels.
Study Area and Methods
The data analyzed in this study were collected as a part of the Kaunas Municipal newborns' registry. Sociodemographic characteristics, reproductive and medical history, health behavior and marital status were obtained through a personal prenatal interview. Data on infant birth weight and sex were obtained from hospital delivery records. Gestational age at delivery was calculated from the last menstrual period. Ultrasound analysis was performed in 85.1% of all events. Trained research nurses abstracted data and registrated infants according to the mother's residential area with a standardized registration form in an attempt to identify all low birth weight in newborns (<2,500 g). The completeness of the registration was a check up on statistical hospital discharge forms, coded by 764-765 codes of the 9th revision of International Classification of Diseasesls)
Study Area and Methods
The study population includes all women in Kaunas residents who had delivered a live infant between January 1, 1994 and December 31, 1994. Among 4,343 delivery data, 13 were excluded from analysis because of missing of mothers' medical record (n = 10) or incomplete address (n = 3). Twelve potential risk factors were selected for analysis on the basis of previous findings in the epidemiologic literature on low birth weight' 6,17) * To identify risk factors in low birth weight we calculated crude risk ratios of 26 variables along with their corresponding 95% confidence intervals (CI). Variables that we considered for potential inclusion in the multivariate models include the mothers' age, occupational status, education, marital status, parents smoking, hazardous work, hypertonic disease, pregnancy outcome, TSP, formaldehyde and ozone exposure. We used multivariate models to adjust for potential variable effects of risk factors with p-values below 0.05.
Study Area and Methods
We assessed the incidence of 0.5-2.5 kg babies per 1,000 live newborns per year. This index was assessed in the districts and in three formaldehyde exposure level areas. The low birty weight baby risk ratio in the areas and population attributable risk percent were assessed according to the methods proposed by Beaglehole et al.18 ). The population attributable risk percent (PAR%) was calculated as : PAR% _ ((Rp -Ro)/Rp) X 100, where Rp is the incidence of low birth weight in the total newborns' population and Ro is that in the unexposed population. In our study the risk ratio (RR) is the ratio of the risk of low birth weight in the population of exposed women (Re) to that in the unexposed (Ro) : RR = Re/Ro.
Results
In 1994, there were 4,343 live births in Kaunas, and 244 of them weighted 0.5 to 2.5 kg at birth ( Table 1 ). The incidence of low birth weight babies per 1,000 live newborns was 56.2. This index varied significantly, from district to district, and reached the highest proportion in the industrial district of Palemonas, 115.9. Complex air pollution in Kaunas districts is shown in Fig. 1 . Ambient air exposure monitoring data showed significant fluctuation in yearly mean concentrations in the districts. The formaldehyde concentration was highest in the Centras district, 5.28 ,ug/m3, whereas in Silainiai it was 1.36,ug/m3 (Table 1) . According to the formaldehyde concentration in the districts, three exposure level areas were determined as follows : low exposure-1.94 ,ug/m3 (95% CI 1.35-2.52), moderate exposure-3.48 ug/m3 (95% CI 3.13-3.84) and high exposure-4.67 ,ug/m3 (95% CI 4.04-5.29). In these areas we assessed the incidence of low birth weight. In the low formaldehyde exposure area the incidence of low birth weight was 48.3 per 1,000, in the moderate area it was 49.5 and in the high exposure area the incidence was 81.1. The crude risk ratio in the high formaldehyde exposure area to compare with the low exposure area was 1.68 ; 95% CI 1.24 -2 .27, p for X2 trend 0.001.
Results
The relative importance of formaldehyde exposure to the entire Kaunas newborn population, estimated by calculating the population attributable risk percent, was found to be 14.1%.
Results
The three TSP exposure level areas estimated were as follows : low exposure-65.83 (95% CI 62.57 -69 .09), moderate exposure-76.35 (95% CI 71.67-80.04) and high exposure-87.66 (95% CI 79.72-95.60). In the low TSP exposure area the incidence of low birth weight was 53.5 per 1,000, in the moderate it was 52.0 and in high exposure area it was 81.8. The population attributable risk percent was 4.9%. We consider that if interaction with other variables did not have any effect, we could expect a 14% decrease in low birth weight risk by reducing formaldehyde exposure, and a 5 % decrease by reducing TSP exposure in the city.
Results
To assess whether the characteristics of mothers who delivered newborns in the high formaldehyde exposure area are different from those in the low exposure area, we compared the prevalence of risk factors for low birth weight ( Table 2 ). The majority of 20 maternal characteristics studied did not differ much from one exposure area to another. The prevalence of five of them, that is, education, husband smoker, maternal hazardous work, parity and infectious diseases differed significantly. To remove differences in the prevalence of independent variables we used a multivariable model and assessed the adjusted odds ratios (OR,) of low birth weight newborns among exposed women. Table 3 shows prevalence by categories of the risk factors, crude risk ratios, and 95% confidence intervals in cases and controls. A higher proportion Df mothers who delivered low birth weight newborns, reported extremes of age, lower education, single women, smoking, hazardous work, hypertonic disease and unfavourable last pregnancy outcome. The crude risk ratios were higher in high formaldehyde, TSP and ozone exposure areas. To remove the effect of differences in the mothers' characteristics, in the analysis we used multivariate logistic models. Estimates of the independent effects of the risk factors for low birth weight come from the full multivariate logistic model that contained 12 potential risk factors, predetermined to be important (p <0.05). To obtain an adjusted OR,, we adjusted for identified predictors of low birth weight : maternal age, occupation, education, marital status, parents smoking, hazardous work, hypertonic disease, pregnancy outcome, formaldehyde, TSP and ozone exposure. Table 4 shows the adjusted ORS and 95% confidence intervals for each factor. After adjustment for the predictors of low birth weight, the increased risk was associated with maternal age, marital status, hazardous work, husbands smoking, hypertonic disease, unfavourable last pregnancy outcome. Women exposed to TSP had an excess low birth weight risk (OR 2.58; 95% CI 1.34-4.99), Table 2 .
Results
Characteristics of mothers residing in high and low formaldehyde exposure areas 'Formaldehyde . "Risk ratios of all newborns in high and low formaldehyde exposure areas. tConfidence interval. t tLow birth weight, whereas in women exposed to ozone and formalc hyde the adjusted OR, was reduced to significance.
Discussion
The study was designed as a population-based epidemiological study aimed at the detection of low birth weight incidence and assessment of formaldehyde impact. The case register technique was used to cover all Kaunas women in chidbirth. Such an approach had the advantage of reducing the selection bias.
Discussion
Another advantage of the present study included the homogeneity of the study population with respect to ethnic culture, unified prenatal care and the health care system. The results presented are derived from the entire population of pregnant women who completed questionnaires (99.7% of Table 3 . Crude risk ratios and 95% confidence intervals for potential risk factors for low birth weight total). As many as 26 possible risk factors for low birth weight were studied. The use of questionnaires to assess occupational exposure and total smoking is a limitation of our study. We cannot rule out the possibility that women are exposed to different levels of environmental tobacco smoke, formaldehyde or other indoor air pollutants. Since in our study ambient air monitoring data are used to estimate the average in districts' residents exposure, the individual exposures will be subject to some error. These and another variables may be the reason why the statistical association that we detected between ambient air pollution and low birth weight risk may not represent a causal association. ' 22) , history of preterm delivery in the preceding pregnancy and recurrent spontaneous abortions23). Maternal smoking is known to influence fetal growth and there is accumulating evidence that gestation duration is also decreased by maternal smoking22). Previous studies have observed a relation between maternal occupation and pregnancy outcome 24), hypertensive disease and maternal employment25 ' 26) , so that a wide range of agents could increase the risk of low birth weight, and insufficient control of other environmental risk factors could have influenced the observed association.

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