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Maternal Pesticide Exposure and Neural Tube Defects in Mexican Americans
Maternal Pesticide Exposure and Neural Tube Defects in Mexican Americans JEAN D. BRENDER, PHD, MARILYN FELKNER, DRPH, LUCINA SUAREZ, PHD, MARK A. CANFIELD, PHD, AND JUDY P. HENRY, PHD
PURPOSE: The relation between maternal pesticide exposures and neural tube defects (NTDs) in offspring was evaluated in 184 Mexican American case-women and 225 comparison women. METHODS: In-person interviews solicited information about environmental and occupational exposures to pesticides during the periconceptional period. RESULTS: With adjustment for maternal education, smoking, and folate intake, women who reported using pesticides in their homes or yards were two times more likely (95% confidence interval [CI], 1.2–3.1) to have NTD-affected pregnancies than women without these reported exposures. Case-women were also more likely to report living within 0.25 mile of cultivated fields than control-women (odds ratio [OR] 3.6; 95% CI, 1.7–7.6). As sources of pesticide exposure opportunities increased, risk of NTDs also increased. The adjusted ORs and 95% CIs for one, two, and three or more exposure sources were 1.2 (0.69–1.9), 2.3 (1.3–4.1) and 2.8 (1.2–6.3) respectively, and this positive trend was stronger for risk of anencephaly than for spina bifida. CONCLUSIONS: Self-reported pesticide exposures were associated with NTD risk in this study population, especially use of pesticides within the home and a periconceptional residence within 0.25 mile of cultivated fields. Ann Epidemiol 2010;20:16–22. Ó 2010 Elsevier Inc. All rights reserved. KEY WORDS:
Anencephaly, Neural Tube Defects, Pesticides, Spina Bifida.
INTRODUCTION Various types of pesticides have been associated with neural tube defects (NTDs) in animal models (1–3), and findings from epidemiologic studies have suggested that these chemicals might also confer risk for NTDs in humans. Most epidemiologic studies have focused on occupational exposures to pesticides with positive associations noted between maternal employment in agriculture and NTDs in offspring (4–8). Fewer studies have examined the relation between household use of pesticides and other environmental exposures and these defects. White et al. (9) noted elevated standardized risk ratios for spina bifida in areas in New Brunswick, Canada with higher agricultural chemical exposure activity. In a case-control study conducted in
From the Department of Epidemiology & Biostatistics, Texas A&M Health Science Center, School of Rural Public Health, College Station (J.D.B.); Emerging and Acute Infectious Disease Branch (M.F.), Environmental Epidemiology and Disease Registries Section (L.S.), Birth Defects Epidemiology and Surveillance Branch (M.A.C.), Texas Department of State Health Services, Austin; and Health Services Division, Texas Youth Commission (J.P.H.), Austin. Address correspondence to: Jean D. Brender, PhD, Department of Epidemiology & Biostatistics. Texas A&M Health Science Center, School of Rural Public Health, 219 SRPH Administration Bldg, College Station, TX 77843-1266. E-mail: [email protected]. Received July 28, 2009; accepted September 30, 2009. Ó 2010 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
California (United States), women who reported professional pesticide applications in their homes or living within 0.25 mile of agricultural crops were at increased risk of NTD-affected pregnancies (10). Using the same casecontrol study population of infants with NTDs and nonmalformed controls, Rull et al. (11) explored the validity of maternal self-reported proximity to agricultural crops by comparing women’s responses against historical land-use survey maps. With land-use maps serving as the ‘‘gold standard’’ for proximity, case-women were noted to more accurately recall living near such crops than control women (given that the maps indicated close proximity), thereby leading to a positively biased odds ratio (OR) for self-reported proximity in relation to NTDs in offspring. These investigators then examined the relation between neural tube defects and maternal residential proximity to agricultural pesticide applications by linking historical land-use survey maps and pesticide use reports to mothers’ addresses during the periconceptional period (12). Women who lived within 1000 meters of crops that were treated with selected pesticides were more likely to have NTD-affected pregnancies than women who lived farther away from such crops. In the United States, Mexican Americans have some of the highest rates of NTDs compared with other ethnic/racial groups (13–15); in Texas, the highest rates of these defects are found among births to Mexican American residents 1047-2797/10/$–see front matter doi:10.1016/j.annepidem.2009.09.011
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Selected Abbreviations and Acronyms NTD Z neural tube defect OR Z odds ratio 95% CI Z 95% confidence interval
living in counties adjacent to the border with Mexico. In 1991, a cluster of anencephalic births was reported in one of these counties (Cameron County), and the results of a subsequent investigation showed the prevalence of NTDs to be much higher in this county than the United States (Texas Department of Health, unpublished report, 1992; Hendricks et al. [16]). In response to these findings, a surveillance project and case-control study were initiated to identify risk factors for NTDs in this population. Given the heavy agricultural activity in several regions of the Texas-Mexico border area, we explored the relation between environmental pesticide exposure and risk of NTDs among the Texas-Mexico border population. In the assessment of environmental exposures, potential occupational exposures were also taken into account, although the role of occupational exposures in this population has already been reported in a previous publication (17).
METHODS Selection of Cases and Controls This study used data from the Texas Neural Tube Defect Project, which was implemented by the Texas Department of Health in 1993. The surveillance portion of this project involved active surveillance of NTD births from multiple sources, including genetic clinics and ultrasound centers (fetuses diagnosed prenatally), hospitals, birthing centers, abortion centers, prenatal clinics, and lay and certified midwives. A case was defined as a resident of one of the 14 Texas counties along the U.S.-Mexico border who delivered or terminated an NTD-affected pregnancy from March 1995 through May 2000. Births or terminations with defects classified as anencephalus (ICD-9-CM code 740), spina bifida (741), or encephalocele (742.0) were included. Controls were identified from among women giving birth to a live-born infant without any apparent congenital malformations in one of the same 14 counties of the study area during the study period. These women were selected randomly and annually in proportion to the number of live births that occurred 2 years earlier in given facilities which included hospitals and midwifeattended birthing centers in the study area. Of the 225 Mexican American case-women and 378 Mexican American control women eligible for participation, 184 (82%) case-women and 225 (60%) control-women completed the interviews.
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Data Collection Prior to initiating the case-control study, the Texas Department of Health Institutional Review Board reviewed and approved the study protocol, English and Spanish consent forms, and interview instruments. Women were interviewed in-person approximately 5 to 6 weeks postpartum after informed consent was obtained. They were interviewed in either English or Spanish, depending on their preference, with a questionnaire modeled after the Centers for Disease Control and Prevention Mother Questionnaire (unpublished document, 1992). The instrument elicited information about maternal health and reproductive history; residential history; use of medications; use of vitamin supplements; and environmental and occupational exposures. Before the interview, the study obstetrician-gynecologist and interviewer established the date of conception for the index pregnancy from information in the medical records. The interviewer then used a personalized calendar to focus the participant’s attention on exposures during the 6-month periconceptional period that extended from 3 months prior to conception through 3 months post-conception. The Mother Questionnaire elicited information about pesticide exposure from a variety of sources including home use, work, and residential proximity to cultivated fields during the periconceptional period. Women were specifically questioned about location of pesticide use, type of pest for which the product was used, who used the product, and the method of application. Although participants were asked about product names, most gave nonspecific information; therefore, individual products and chemical classes of pesticides could not be examined. Women were asked whether they lived near cultivated fields (crops grown) at the time that they became pregnant, about the distance lived from the fields, and whether they walked through the fields. A residence within one fourth of a mile or less was considered as living within close proximity to such fields. Women were also classified with respect to occupational exposure to pesticides, and a detailed description of this exposure assessment was reported in an earlier publication (17). Briefly, women (and fathers of the index birth if available) were questioned about place of work, jobs held, and work duties, including materials handled and machines used from 12 months before the date of conception through the first trimester. Parental occupational exposures to pesticides were classified by assessment of work histories. For the purposes of the present study, we also included self-reported occupational exposures to pesticides that were elicited from a list of potential chemical exposures that was shared with each participant. Data Analysis We used binary logistic regression to generate crude and adjusted risk estimates (ORs and their respective 95%
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confidence intervals [CIs]) for neural tube defects in relation to maternal environmental and occupational exposures to pesticides. Separate risk estimates for anencephaly and spina bifida were examined with multinomial logistic regression. Main sources of pesticide exposure (home use, application on self, yard or garden use, proximity to cultivated fields, and maternal occupational exposures) were evaluated in both single- and multiple-exposure models. ORs from all single- and multiple-exposure models were adjusted for maternal education (!7 years, 7–11 years, 12þ years), passive/active smoking during the first trimester (yes/no), and periconceptional folic acid/folate intake (combination of dietary intake and supplements less than 400 mg, 400þ mg/day). With the exception of paternal/take-home pesticide exposures (from occupational exposures among household members other than the mother), the referent group consisted of case- and control-women who did not report occupational or environmental pesticide exposures and who reported living more than one fourth of a mile from cultivated fields during the periconceptional period. We also examined the effect of pesticide exposures from multiple sources including the following: 1) pesticide use in or around the home; 2) pesticides applied on self; 3) pesticide applications on yards or in gardens; 4) living within one fourth of a mile of a cultivated field; or 5) potential job-related pesticide exposures. Because few women reported four or more sources, exposure opportunities were grouped into none, one, two, and three or more sources, with the ‘‘none’’ category serving as the referent group.
RESULTS Table 1 compares selected demographic and behavioral characteristics between the case and control participants. Among interviewed women, information was missing regarding sources of pesticide exposure for four case- and three control-women. Although case- and control-women had similar age distributions, case-women were more likely to have less education, to ingest less than 400 mg of folic acid/folate per day, and to smoke or be exposed to secondhand smoking. A total of 56 (30.4%) case-women and 100 (44.4%) control women denied using pesticides around their homes, yards, or on themselves; living within close proximity to cultivated fields at the time of conception; and being exposed to pesticides based on reported jobs and/or workplace activities. With this group of women serving as the referent category, Table 2 shows the crude and adjusted ORs of the associations between types of pesticide exposure opportunities and risk of NTDs in offspring. With adjustment for maternal education, smoking, and folic acid/folate intake, NTD risk was associated with use of pesticides
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TABLE 1. Demographic and behavioral characteristics of Mexican American case-women with NTD-affected pregnancies and control-women in Texas border counties, 1995–2000 Case-women (n Z 184) Characteristic
No.
%
Maternal age !20 46 25.0 20–24 65 35.3 25–29 42 22.8 >30 31 16.8 Education !7 35 19.0 7–11 58 31.5 >12 91 49.5 Passive/active smoking during first trimester* Yes 111 63.4 No 64 40.3 Folate intakey !400 mg 42 23.5 >400 mg 137 76.5
Control-women (n Z 225) No.
%
55 74 57 39
24.4 32.9 25.3 17.3
27 83 115
12.0 36.9 51.1
89 132
40.3 59.7
42 180
18.9 81.1
*Nine case-women and four control-women missing information on passive and/or active smoking. y Periconceptional dietary intake and supplements taken 1 month prior to 1 month postconception. Five case-women and three control-women missing information on dietary and/or supplement intake of folate.
around the home (OR 2.0; 95% CI, 1.2–3.1), in the yard or garden (OR 2.0; 95% CI, 1.1–3.7), and on self (OR 1.7; 95% CI, 0.96–2.9). Risk estimates for NTDs were similar whether women applied pesticides within the home themselves (OR 1.6; 95% CI, 0.95–2.8) or used a professional applicator (OR 1.6; 95% CI, 0.51–5.3) (data not shown in Table 2). With adjustment for multiple sources of pesticide exposure, home use (adjusted OR 1.8, 95% CI 1.1–2.9) and living near cultivated fields (adjusted OR 2.7; 95% CI, 1.4– 5.5) remained associated with NTD risk while occupational exposures and pesticides used on self or in the yard showed minimal or no association with NTD risk. In this study population, NTD risk was most strongly associated with the use of bombs or foggers within the home (OR 5.6; 95% CI, 1.1–38.0) and with living within one fourth of a mile of cultivated fields (OR 3.6; 95% CI, 1.7–7.6), especially if the women reported walking through these fields (OR 4.7; 95% CI, 1.0–30.2). Women with NTDaffected pregnancies were also more likely than comparison women (OR 3.1; 95% CI, 1.4–6.6) to report living with household members who worked in occupations with a likelihood of pesticide exposure, a potential source of take-home exposure. Reported exposure opportunities to pesticides were more strongly associated with anencephalic births in offspring than with births with spina bifida (Table 3). The strongest association was noted between a reported maternal residence within one fourth of a mile of cultivated fields
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TABLE 2. Reported maternal agricultural/pesticide exposures and NTDs in pregnancies of Mexican Americans Cases Reported exposures during periconceptional period No reported maternal occupational or environmental exposures to pesticides Used pesticide in or around home To kill bugs or flying insects To kill termites To kill rodents Used bomb or fogger Used anything on self/took anything to kill insects To protect from/kill mosquitoes Used pesticide on yard, lawn, or garden To kill bugs/insects To kill weeds To kill rodents Anyone used product in home, yard, or garden Used product self Baby’s father used product Product used by professional Lived one-fourth mile or less from fields Lived one-fourth mile and walked through field Maternal occupational pesticide exposure
Controls
No.
%*
No.
%*
Crude OR (95% CI)
Adjustedy singleexposure OR (95% CI)
Adjustedy,z multipleexposure OR (95% CI)
56
30.4
100
44.4
1.0 (Referent)
1.0 (Referent)
1.0 (Referent)
99 76 7 18 8 50 48 40 31 11 7 129 79 25 15 30 9 6
53.8 41.3 3.8 9.8 4.3 27.2 26.1 21.7 16.8 6.0 3.8 70.1 42.9 13.6 8.2 16.3 4.9 3.3
82 63 4 10 3 50 50 31 22 8 3 122 71 38 11 16 3 5
36.4 28.0 1.8 4.4 1.3 22.2 22.2 13.8 9.8 3.6 1.3 54.2 31.6 16.9 4.9 7.1 1.3 2.2
2.2 (1.4–3.3) 2.2 (1.4–3.4) 3.1 (0.88–11) 3.2 (1.4–7.4) 4.8 (1.2–19) 1.8 (1.1–3.0) 1.7 (1.0–2.9) 2.3 (1.3–4.1) 2.5 (1.3–4.8) 2.5 (0.93–6.5) 4.2 (1.0–17) 2.2 (1.4–3.4) 2.3 (1.4–3.7) 1.2 (0.64–2.1) 2.5 (1.1–5.9) 3.3 (1.7–6.7) 5.4 (1.4–21) 2.1 (0.63–7.3)
2.0 (1.2–3.1) 1.8 (1.1–3.0) 4.0 (0.88–22) 3.3 (1.3–8.3) 5.6 (1.1–38) 1.7 (0.96–2.9) 1.6 (0.95–2.8) 2.0 (1.1–3.7) 2.1 (1.0–4.2) 2.1 (0.63–7.2) 4.1 (0.75–29) 1.9 (1.2–3.4) 2.0 (1.2–3.0) 1.1 (0.56–2.1) 2.2 (0.84–5.5) 3.6 (1.7–7.6) 4.7 (1.0–30) 1.9 (0.50–7.1)
1.8 (1.1–2.9)
1.0 (0.61–1.7) 1.3 (0.69–2.3)
2.7 (1.4–5.5) 0.94 (0.25–3.6)
OR Z odds ratio; CI Z confidence interval; NTDs Z neural tube defects. *Percentages based on 184 case-women and 225 control-women interviewed. Four case- and three control-women had missing information. y Adjusted for maternal education, passive/active smoking, and folic acid/folate intake. z Adjusted for other reported pesticide exposures (home use; use on self; use on yard, lawn, or garden; proximity to fields; and maternal occupational exposure).
and anencephalic births (OR 6.0; 95% CI, 2.4–14.9). With adjustment for multiple sources of pesticide exposure, reported residential proximity to fields remained strongly associated with anencephaly (OR 3.4; 95% CI, 1.5–7.5) and spina bifida (OR 2.5; 95% CI, 1.1–5.9), whereas home use was only significantly associated with anencephaly (OR 2.4; 95 % CI, 1.3–4.2). As sources of reported pesticide exposure opportunities increased, risk estimates of NTDs also increased. For all NTDs combined (data not shown in Table 4), the adjusted ORs and 95% CIs for one, two, and three or more types of exposures were 1.2 (95% CI, 0.69–1.9), 2.3 (95% CI, 1.3– 4.1), and 2.8 (95% CI, 1.2–6.3), respectively (p value for trend ! 0.001). A stronger trend was noted for risk of anencephalic births than for risk of births with spina bifida with increasing sources of pesticide exposure opportunities (Table 4).
DISCUSSION Results of this study suggest that maternal exposure to pesticides during the periconceptional period may confer risk for NTDs among offspring in Mexican American women, particularly exposures within the home or those associated with living in close proximity to cultivated fields. Maternal
pesticide exposure was more strongly associated with risk for anencephaly than for spina bifida. For both types of defects, however, risk appeared to increase as the sources of exposure opportunities increased. In a study of maternal pesticide exposures and NTDaffected pregnancies among California women (10), pest treatment of the home was associated with NTDs with professional applications (OR 1.6; 95% CI, 1.1–2.5), but showed only minimal association among women applying the pesticides themselves (OR 1.1; 95% CI, 0.8–1.7). In the present study, we noted essentially the same risk estimate for professional home applications as the California study. Among the Texas border population, however, similar associations with NTDs were noted with both professional and self-applications of pesticides to the home. Women in the California study population were 1.5 times more likely (95% CI, 1.1–2.1) than control mothers to report living within one fourth of a mile of agricultural or commercial crops (10). Rull et al. (11) detected differential recall between case- and control-women in the California study when they compared effect estimates obtained from land-use maps and self-reports of proximity to agricultural crops. In their subsequent study that used agricultural pesticide use reports and crop maps, elevated risks of NTDs were found with maternal residential proximity
17 (20.5) 16 (7.1)
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OR Z odds ratio; CI Z confidence interval. *Percentages based on 83 case-women with anencephalic births, 84 case-women with births having spina bifida, and 225 control-women. Four case-women (one with an anencephalic birth and three with births having spina bifida) and three control-women had missing information. y Adjusted with multinomial logistic regression for maternal education, passive/active smoking, and folic acid/folate intake. z Adjusted for other reported sources of pesticide exposures (home use; use on self; use on yard, lawn, or garden; proximity to fields; maternal occupational exposure).
2.5 (1.1–5.9) 2.7 (1.1–6.6) 2.4 (1.0–5.7) 12 (14.3) 3.4 (1.5–7.5) 6.0 (2.4–15)
16 (19.3) 31 (13.8)
5.6 (2.4–13)
1.8 (0.89–3.8) 2.0 (0.96–4.3) 2.1 (1.0–4.2) 20 (23.8) 0.91 (0.42–2.0) 2.3 (0.97–5.3)
25 (30.1) 50 (22.2)
2.7 (1.2–5.9)
0.84 (0.44–1.6) 1.2 (0.61–2.4) 1.3 (0.67–2.5) 20 (23.8) 1.1 (0.59–2.1) 2.3 (1.1–4.7)
19 (22.9) 48 (57.8) 100 (44.4) 82 (36.4)
None reported Used pesticides in/around home Used pesticide on self Used pesticide on yard, lawn, garden Lived within one-fourth mile from cultivated fields
N (%)* N (%)* Pesticide exposure opportunity
2.6 (1.3–5.2)
1.0 (Referent) 1.4 (0.77–2.5) 1.0 (Referent) 1.5 (0.82–2.6) 1.0 (Referent) 1.7 (0.96–2.9) 31 (36.9) 42 (50.0) 1.0 (Referent) 2.4 (1.3–4.2) 1.0 (Referent) 2.9 (1.5–5.4)
N (%)* Adjusted multipleexposure ORy,z (95% CI) Adjusted singleexposure ORy (95% CI) Crude OR (95% CI)
Anencephaly cases Controls
1.0 (Referent) 3.1 (1.7–5.6)
Adjusted singleexposure ORy (95% CI) Crude OR (95% CI)
Spina bifida cases
Adjusted multipleexposure ORy,z (95% CI)
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TABLE 3. Maternal pesticide exposure and risk of anencephaly and spina bifida in offspring
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within 1,000 meters of pesticide applications of benomyl, methomyl, and other selected chemicals (12). Compared with the risk estimates found in the California study based on maternal self-reports of proximity to agricultural crops (10), a stronger association (OR 3.6) was noted in the Texas Neural Tube Defect Project between residential proximity to cultivated fields and NTD risk. Anencephaly and spina bifida were both associated with maternal residence near crops. In contrast, White et al. (9) noted a significant trend (p Z 0.01) between living in areas with a higher likelihood of agricultural chemical exposures and risk of spina bifida, but not with anencephaly. Numerous studies have found an association between maternal work in agriculture and risk for NTDs in offspring, including anencephaly (8) and spina bifida (4–7, 18). In our study, 4 out of the 11 women (36%) in occupations with potential pesticide exposure lived within a quarter of a mile of cultivated fields compared with 42 of 391 women (11%) who worked in other occupations or were homemakers. With adjustment for other sources of pesticide exposure, occupational pesticide exposure was not associated with NTDs in the study population. This study had several limitations, including relatively lower study participation of eligible control-women than case-women, the potential for recall bias of periconceptional pesticide exposures, and inadequate information on specific pesticides used in the home, yard, or nearby fields. Participating control-women were similar to all TexasMexico border Hispanic women giving birth during the study years with respect to education attainment of fewer than 7 years (12.0% vs. 12.1%), 7 to 11 years (36.9% vs. 37.0%), and 12 or more years (51.1% vs. 50.0%). Participating control-women also had similar household incomes as women who participated in a 1997 survey of the population living in six of the most populous border counties in the study area (19). Differential recall of pesticide exposures between women with NTD-affected pregnancies and women giving birth to normal infants cannot be ruled out. As already discussed, Rull et al. (11) found evidence of recall bias in a California study population regarding residential proximity to crops during the periconceptional period. In that study, case- and control-women were interviewed, on average, 3.7 years and 3.8 years, respectively, after delivery, regarding various pesticide exposures, including proximity to agricultural crops (10). Because women in the Texas Neural Tube Defect Project were interviewed within 2 months after delivery about periconceptional pesticide exposures, it is possible that the extent of recall bias might differ between the two studies. Some evidence suggests that accuracy of recall of events during pregnancy decreases as the time lapse between events during pregnancy and maternal interviews increases (20, 21). With land-use survey-based proximity within one fourth of a mile used as
19 (22.9) 29 (34.9) 25 (30.1) 9 (10.8) 100 (44.4) 74 (32.9) 35 (15.6) 13 (5.8) None One Two Three to five
OR Z odds ratio; CI Z confidence interval. *Percentages based on 83 case-women with anencephalic births, 84 case-women with births having spina bifida, and 225 control-women. Four case-women (one with an anencephalic birth and three with births having spina bifida) and three control-women had missing information. y Adjusted with multinomial logistic regression for maternal education, passive/active smoking, and folic acid/folate intake. z p Value for trend Z 0.001. x p Value for trend Z 0.028.
1.0 (Referent) 0.75 (0.38–1.5) 1.6 (0.79–3.3) 2.7 (1.1–6.8) 1.0 (Referent) 0.87 (0.46–1.6) 1.8 (0.88–3.5) 2.7 (1.1–6.7) 31 (36.9) 20 (23.8) 19 (22.6) 11 (13.1) 1.0 (Referent) 1.9 (0.97–3.7) 3.4 (1.6–7.1) 3.5 (1.3–9.7)
Adjusted ORy,z (95% CI) Crude OR (95% CI) N (%)* Controls N (%) No. of pesticide exposure opportunities reported
Anencephaly cases
TABLE 4. Maternal pesticide exposure opportunities and risk of anencephaly and spina bifida in offspring
1.0 (Referent) 2.1 (1.1–4.0) 3.8 (1.8–7.6) 3.6 (1.4–9.7)
Crude OR (95% CI)
Adjusted ORy,x (95% CI)
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N (%)*
Spina bifida cases
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the ‘‘gold standard’’ in the study of Rull et al. (11), sensitivities of case- and control-women for self-reported proximity to agricultural crops displayed differences (65.7% and 50.0%, respectively), but the specificities for exposure classification were similar (87.5% and 89.3%, respectively) between the two groups. To better understand the potential impact of recall bias on the association between residential proximity to fields and NTDs, we conducted a sensitivity analysis for various scenarios of exposure misclassification with methods suggested by Greenland and Lash (22). With the use of the same specificities obtained for cases and controls in the Rull et al. study (11), ORs for the association between maternal residential proximity to fields and NTDs remained above 2.0, even with the extreme scenario of 90% sensitivity for case exposures and 30% for control exposures, and did not decline to 1.0 unless the exposure specificity for cases fell below 78% with these specified sensitivities. Overall, the sensitivity analysis indicated sustained positive associations between self-reported proximity to fields and NTDs in offspring for a wide range of sensitivities and specificities, except for the most extreme differences in accuracy of reporting. It would have been informative to compare specific biomarkers of pesticide exposure between cases and controls. In this study, urine and blood specimens were collected for pesticide biomarkers from a small proportion of participants approximately 1 year after conception, and laboratory analyses were conducted for a limited number of pesticide analytes (including those of chlorinated hydrocarbon insecticides and methyl parathion). Results from that phase of the study are not presented herein because of low participation of the cases and controls (<28% and <34%, respectively, depending on the biomarker analyzed). Of participants tested, the majority had results below the level of laboratory detection. In conclusion, this study found that Mexican American women with NTD-affected pregnancies were more likely than comparison women to report home use of pesticides and living near cultivated fields shortly before and after conception. McDiarmid et al. (23) noted that pesticides are among the most likely chemical hazards that women will encounter in the home. More studies that measure a wide range of pesticide biomarkers are needed, however, to understand which pesticides might increase risk of adverse pregnancy outcomes such as NTDs.
Funding for this study was provided in part by Centers for Disease Control and Prevention, Birth Defects Branch Cooperative Agreement U85/ CCU608761-05 and Cooperative Agreement U50/CCU613232 through The Texas Center for Birth Defects Research and Prevention, Texas Department of Health. We wish to thank Dr. Kate Hendricks for the conceptualization and implementation of the Texas Neural Tube Defect Project.
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18. Blatter BM, Roeleveld N, Bermejo E, Martinez-Frias ML, Siffel C, Czeizel AE. Spina bifida and parental occupation: results from three malformation monitoring programs in Europe. Eur J Epidemiol. 2000; 16:343–351.
7. Blatter BM, Lafeber AB, Peters PW, Roeleveld N, Verbeek AL, Gabreels FJ. Heterogeneity of spina bifida. Teratology. 1997;55:224–230. 8. Lacasana M, Vazquez-Grameix H, Borja-Aburto VH, Blanco-Munoz J, Romieu I, Aguilar-Garduno C, et al. Maternal and paternal occupational exposure to agricultural work and the risk of anencephaly. Occup Environ Med. 2006;63:649–656. 9. White FM, Cohen FG, Sherman G, McCurdy R. Chemicals, birth defects and stillbirths in New Brunswick: associations with agricultural activity. Can Med Assoc J. 1988;138:117–124. 10. Shaw GM, Wasserman CR, O’Malley CD, Nelson V, Jackson RJ. Maternal pesticide exposure from multiple sources and selected congenital anomalies. Epidemiology. 1999;10:60–66. 11. Rull RP, Ritz B, Shaw GM. Validation of self-reported proximity to agricultural crops in a case-control study of neural tube defects. J Expo Sci Environ Epidemiol. 2006;16:147–155. 12. Rull RP, Ritz B, Shaw GM. Neural tube defects and maternal residential pesticide proximity to agricultural pesticide applications. Am J Epidemiol. 2006;163:743–753.
19. Dutton RJ, Weldon M, Shannon J, Bowcock C, Tackett-Gibson M, Blakely C, et al. Survey of Health and Environmental Conditions in Texas Border Counties and Colonias. Austin (TX): Texas Department of Health. 2000 (TDH Publication No. 79–10828). 20. Koren G, Maltepe C, Navioz Y, Wolpin J. Recall bias of the symptoms of nausea and vomiting of pregnancy. Am J Obstet Gynecol. 2004;190:485– 488. 21. Wilcox AJ, Horney LF. Accuracy of spontaneous abortion recall. Am J Epidemiol. 1884;120:727–733. 22. Greenland S, Lash TL. Bias analysis. In: Rothman KJ, Greenland S, Lash TL, eds. Modern epidemiology. 3rd ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008:353–357. 23. McDiarmid MA, Gardiner PM, Jack BW. The clinical content of preconception care: environmental exposures. Am J Obstet Gynecol. 2008;199(6 Suppl. 2):S357–361.
PURPOSE: The relation between maternal pesticide exposures and neural tube defects (NTDs) in offspring was evaluated in 184 Mexican American case-women and 225 comparison women. METHODS: In-person interviews solicited information about environmental and occupational exposures to pesticides during the periconceptional period. RESULTS: With adjustment for maternal education, smoking, and folate intake, women who reported using pesticides in their homes or yards were two times more likely (95% confidence interval [CI], 1.2–3.1) to have NTD-affected pregnancies than women without these reported exposures. Case-women were also more likely to report living within 0.25 mile of cultivated fields than control-women (odds ratio [OR] 3.6; 95% CI, 1.7–7.6). As sources of pesticide exposure opportunities increased, risk of NTDs also increased. The adjusted ORs and 95% CIs for one, two, and three or more exposure sources were 1.2 (0.69–1.9), 2.3 (1.3–4.1) and 2.8 (1.2–6.3) respectively, and this positive trend was stronger for risk of anencephaly than for spina bifida. CONCLUSIONS: Self-reported pesticide exposures were associated with NTD risk in this study population, especially use of pesticides within the home and a periconceptional residence within 0.25 mile of cultivated fields. Ann Epidemiol 2010;20:16–22. Ó 2010 Elsevier Inc. All rights reserved. KEY WORDS:
Anencephaly, Neural Tube Defects, Pesticides, Spina Bifida.
INTRODUCTION Various types of pesticides have been associated with neural tube defects (NTDs) in animal models (1–3), and findings from epidemiologic studies have suggested that these chemicals might also confer risk for NTDs in humans. Most epidemiologic studies have focused on occupational exposures to pesticides with positive associations noted between maternal employment in agriculture and NTDs in offspring (4–8). Fewer studies have examined the relation between household use of pesticides and other environmental exposures and these defects. White et al. (9) noted elevated standardized risk ratios for spina bifida in areas in New Brunswick, Canada with higher agricultural chemical exposure activity. In a case-control study conducted in
From the Department of Epidemiology & Biostatistics, Texas A&M Health Science Center, School of Rural Public Health, College Station (J.D.B.); Emerging and Acute Infectious Disease Branch (M.F.), Environmental Epidemiology and Disease Registries Section (L.S.), Birth Defects Epidemiology and Surveillance Branch (M.A.C.), Texas Department of State Health Services, Austin; and Health Services Division, Texas Youth Commission (J.P.H.), Austin. Address correspondence to: Jean D. Brender, PhD, Department of Epidemiology & Biostatistics. Texas A&M Health Science Center, School of Rural Public Health, 219 SRPH Administration Bldg, College Station, TX 77843-1266. E-mail: [email protected]. Received July 28, 2009; accepted September 30, 2009. Ó 2010 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
California (United States), women who reported professional pesticide applications in their homes or living within 0.25 mile of agricultural crops were at increased risk of NTD-affected pregnancies (10). Using the same casecontrol study population of infants with NTDs and nonmalformed controls, Rull et al. (11) explored the validity of maternal self-reported proximity to agricultural crops by comparing women’s responses against historical land-use survey maps. With land-use maps serving as the ‘‘gold standard’’ for proximity, case-women were noted to more accurately recall living near such crops than control women (given that the maps indicated close proximity), thereby leading to a positively biased odds ratio (OR) for self-reported proximity in relation to NTDs in offspring. These investigators then examined the relation between neural tube defects and maternal residential proximity to agricultural pesticide applications by linking historical land-use survey maps and pesticide use reports to mothers’ addresses during the periconceptional period (12). Women who lived within 1000 meters of crops that were treated with selected pesticides were more likely to have NTD-affected pregnancies than women who lived farther away from such crops. In the United States, Mexican Americans have some of the highest rates of NTDs compared with other ethnic/racial groups (13–15); in Texas, the highest rates of these defects are found among births to Mexican American residents 1047-2797/10/$–see front matter doi:10.1016/j.annepidem.2009.09.011
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Selected Abbreviations and Acronyms NTD Z neural tube defect OR Z odds ratio 95% CI Z 95% confidence interval
living in counties adjacent to the border with Mexico. In 1991, a cluster of anencephalic births was reported in one of these counties (Cameron County), and the results of a subsequent investigation showed the prevalence of NTDs to be much higher in this county than the United States (Texas Department of Health, unpublished report, 1992; Hendricks et al. [16]). In response to these findings, a surveillance project and case-control study were initiated to identify risk factors for NTDs in this population. Given the heavy agricultural activity in several regions of the Texas-Mexico border area, we explored the relation between environmental pesticide exposure and risk of NTDs among the Texas-Mexico border population. In the assessment of environmental exposures, potential occupational exposures were also taken into account, although the role of occupational exposures in this population has already been reported in a previous publication (17).
METHODS Selection of Cases and Controls This study used data from the Texas Neural Tube Defect Project, which was implemented by the Texas Department of Health in 1993. The surveillance portion of this project involved active surveillance of NTD births from multiple sources, including genetic clinics and ultrasound centers (fetuses diagnosed prenatally), hospitals, birthing centers, abortion centers, prenatal clinics, and lay and certified midwives. A case was defined as a resident of one of the 14 Texas counties along the U.S.-Mexico border who delivered or terminated an NTD-affected pregnancy from March 1995 through May 2000. Births or terminations with defects classified as anencephalus (ICD-9-CM code 740), spina bifida (741), or encephalocele (742.0) were included. Controls were identified from among women giving birth to a live-born infant without any apparent congenital malformations in one of the same 14 counties of the study area during the study period. These women were selected randomly and annually in proportion to the number of live births that occurred 2 years earlier in given facilities which included hospitals and midwifeattended birthing centers in the study area. Of the 225 Mexican American case-women and 378 Mexican American control women eligible for participation, 184 (82%) case-women and 225 (60%) control-women completed the interviews.
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Data Collection Prior to initiating the case-control study, the Texas Department of Health Institutional Review Board reviewed and approved the study protocol, English and Spanish consent forms, and interview instruments. Women were interviewed in-person approximately 5 to 6 weeks postpartum after informed consent was obtained. They were interviewed in either English or Spanish, depending on their preference, with a questionnaire modeled after the Centers for Disease Control and Prevention Mother Questionnaire (unpublished document, 1992). The instrument elicited information about maternal health and reproductive history; residential history; use of medications; use of vitamin supplements; and environmental and occupational exposures. Before the interview, the study obstetrician-gynecologist and interviewer established the date of conception for the index pregnancy from information in the medical records. The interviewer then used a personalized calendar to focus the participant’s attention on exposures during the 6-month periconceptional period that extended from 3 months prior to conception through 3 months post-conception. The Mother Questionnaire elicited information about pesticide exposure from a variety of sources including home use, work, and residential proximity to cultivated fields during the periconceptional period. Women were specifically questioned about location of pesticide use, type of pest for which the product was used, who used the product, and the method of application. Although participants were asked about product names, most gave nonspecific information; therefore, individual products and chemical classes of pesticides could not be examined. Women were asked whether they lived near cultivated fields (crops grown) at the time that they became pregnant, about the distance lived from the fields, and whether they walked through the fields. A residence within one fourth of a mile or less was considered as living within close proximity to such fields. Women were also classified with respect to occupational exposure to pesticides, and a detailed description of this exposure assessment was reported in an earlier publication (17). Briefly, women (and fathers of the index birth if available) were questioned about place of work, jobs held, and work duties, including materials handled and machines used from 12 months before the date of conception through the first trimester. Parental occupational exposures to pesticides were classified by assessment of work histories. For the purposes of the present study, we also included self-reported occupational exposures to pesticides that were elicited from a list of potential chemical exposures that was shared with each participant. Data Analysis We used binary logistic regression to generate crude and adjusted risk estimates (ORs and their respective 95%
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confidence intervals [CIs]) for neural tube defects in relation to maternal environmental and occupational exposures to pesticides. Separate risk estimates for anencephaly and spina bifida were examined with multinomial logistic regression. Main sources of pesticide exposure (home use, application on self, yard or garden use, proximity to cultivated fields, and maternal occupational exposures) were evaluated in both single- and multiple-exposure models. ORs from all single- and multiple-exposure models were adjusted for maternal education (!7 years, 7–11 years, 12þ years), passive/active smoking during the first trimester (yes/no), and periconceptional folic acid/folate intake (combination of dietary intake and supplements less than 400 mg, 400þ mg/day). With the exception of paternal/take-home pesticide exposures (from occupational exposures among household members other than the mother), the referent group consisted of case- and control-women who did not report occupational or environmental pesticide exposures and who reported living more than one fourth of a mile from cultivated fields during the periconceptional period. We also examined the effect of pesticide exposures from multiple sources including the following: 1) pesticide use in or around the home; 2) pesticides applied on self; 3) pesticide applications on yards or in gardens; 4) living within one fourth of a mile of a cultivated field; or 5) potential job-related pesticide exposures. Because few women reported four or more sources, exposure opportunities were grouped into none, one, two, and three or more sources, with the ‘‘none’’ category serving as the referent group.
RESULTS Table 1 compares selected demographic and behavioral characteristics between the case and control participants. Among interviewed women, information was missing regarding sources of pesticide exposure for four case- and three control-women. Although case- and control-women had similar age distributions, case-women were more likely to have less education, to ingest less than 400 mg of folic acid/folate per day, and to smoke or be exposed to secondhand smoking. A total of 56 (30.4%) case-women and 100 (44.4%) control women denied using pesticides around their homes, yards, or on themselves; living within close proximity to cultivated fields at the time of conception; and being exposed to pesticides based on reported jobs and/or workplace activities. With this group of women serving as the referent category, Table 2 shows the crude and adjusted ORs of the associations between types of pesticide exposure opportunities and risk of NTDs in offspring. With adjustment for maternal education, smoking, and folic acid/folate intake, NTD risk was associated with use of pesticides
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TABLE 1. Demographic and behavioral characteristics of Mexican American case-women with NTD-affected pregnancies and control-women in Texas border counties, 1995–2000 Case-women (n Z 184) Characteristic
No.
%
Maternal age !20 46 25.0 20–24 65 35.3 25–29 42 22.8 >30 31 16.8 Education !7 35 19.0 7–11 58 31.5 >12 91 49.5 Passive/active smoking during first trimester* Yes 111 63.4 No 64 40.3 Folate intakey !400 mg 42 23.5 >400 mg 137 76.5
Control-women (n Z 225) No.
%
55 74 57 39
24.4 32.9 25.3 17.3
27 83 115
12.0 36.9 51.1
89 132
40.3 59.7
42 180
18.9 81.1
*Nine case-women and four control-women missing information on passive and/or active smoking. y Periconceptional dietary intake and supplements taken 1 month prior to 1 month postconception. Five case-women and three control-women missing information on dietary and/or supplement intake of folate.
around the home (OR 2.0; 95% CI, 1.2–3.1), in the yard or garden (OR 2.0; 95% CI, 1.1–3.7), and on self (OR 1.7; 95% CI, 0.96–2.9). Risk estimates for NTDs were similar whether women applied pesticides within the home themselves (OR 1.6; 95% CI, 0.95–2.8) or used a professional applicator (OR 1.6; 95% CI, 0.51–5.3) (data not shown in Table 2). With adjustment for multiple sources of pesticide exposure, home use (adjusted OR 1.8, 95% CI 1.1–2.9) and living near cultivated fields (adjusted OR 2.7; 95% CI, 1.4– 5.5) remained associated with NTD risk while occupational exposures and pesticides used on self or in the yard showed minimal or no association with NTD risk. In this study population, NTD risk was most strongly associated with the use of bombs or foggers within the home (OR 5.6; 95% CI, 1.1–38.0) and with living within one fourth of a mile of cultivated fields (OR 3.6; 95% CI, 1.7–7.6), especially if the women reported walking through these fields (OR 4.7; 95% CI, 1.0–30.2). Women with NTDaffected pregnancies were also more likely than comparison women (OR 3.1; 95% CI, 1.4–6.6) to report living with household members who worked in occupations with a likelihood of pesticide exposure, a potential source of take-home exposure. Reported exposure opportunities to pesticides were more strongly associated with anencephalic births in offspring than with births with spina bifida (Table 3). The strongest association was noted between a reported maternal residence within one fourth of a mile of cultivated fields
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TABLE 2. Reported maternal agricultural/pesticide exposures and NTDs in pregnancies of Mexican Americans Cases Reported exposures during periconceptional period No reported maternal occupational or environmental exposures to pesticides Used pesticide in or around home To kill bugs or flying insects To kill termites To kill rodents Used bomb or fogger Used anything on self/took anything to kill insects To protect from/kill mosquitoes Used pesticide on yard, lawn, or garden To kill bugs/insects To kill weeds To kill rodents Anyone used product in home, yard, or garden Used product self Baby’s father used product Product used by professional Lived one-fourth mile or less from fields Lived one-fourth mile and walked through field Maternal occupational pesticide exposure
Controls
No.
%*
No.
%*
Crude OR (95% CI)
Adjustedy singleexposure OR (95% CI)
Adjustedy,z multipleexposure OR (95% CI)
56
30.4
100
44.4
1.0 (Referent)
1.0 (Referent)
1.0 (Referent)
99 76 7 18 8 50 48 40 31 11 7 129 79 25 15 30 9 6
53.8 41.3 3.8 9.8 4.3 27.2 26.1 21.7 16.8 6.0 3.8 70.1 42.9 13.6 8.2 16.3 4.9 3.3
82 63 4 10 3 50 50 31 22 8 3 122 71 38 11 16 3 5
36.4 28.0 1.8 4.4 1.3 22.2 22.2 13.8 9.8 3.6 1.3 54.2 31.6 16.9 4.9 7.1 1.3 2.2
2.2 (1.4–3.3) 2.2 (1.4–3.4) 3.1 (0.88–11) 3.2 (1.4–7.4) 4.8 (1.2–19) 1.8 (1.1–3.0) 1.7 (1.0–2.9) 2.3 (1.3–4.1) 2.5 (1.3–4.8) 2.5 (0.93–6.5) 4.2 (1.0–17) 2.2 (1.4–3.4) 2.3 (1.4–3.7) 1.2 (0.64–2.1) 2.5 (1.1–5.9) 3.3 (1.7–6.7) 5.4 (1.4–21) 2.1 (0.63–7.3)
2.0 (1.2–3.1) 1.8 (1.1–3.0) 4.0 (0.88–22) 3.3 (1.3–8.3) 5.6 (1.1–38) 1.7 (0.96–2.9) 1.6 (0.95–2.8) 2.0 (1.1–3.7) 2.1 (1.0–4.2) 2.1 (0.63–7.2) 4.1 (0.75–29) 1.9 (1.2–3.4) 2.0 (1.2–3.0) 1.1 (0.56–2.1) 2.2 (0.84–5.5) 3.6 (1.7–7.6) 4.7 (1.0–30) 1.9 (0.50–7.1)
1.8 (1.1–2.9)
1.0 (0.61–1.7) 1.3 (0.69–2.3)
2.7 (1.4–5.5) 0.94 (0.25–3.6)
OR Z odds ratio; CI Z confidence interval; NTDs Z neural tube defects. *Percentages based on 184 case-women and 225 control-women interviewed. Four case- and three control-women had missing information. y Adjusted for maternal education, passive/active smoking, and folic acid/folate intake. z Adjusted for other reported pesticide exposures (home use; use on self; use on yard, lawn, or garden; proximity to fields; and maternal occupational exposure).
and anencephalic births (OR 6.0; 95% CI, 2.4–14.9). With adjustment for multiple sources of pesticide exposure, reported residential proximity to fields remained strongly associated with anencephaly (OR 3.4; 95% CI, 1.5–7.5) and spina bifida (OR 2.5; 95% CI, 1.1–5.9), whereas home use was only significantly associated with anencephaly (OR 2.4; 95 % CI, 1.3–4.2). As sources of reported pesticide exposure opportunities increased, risk estimates of NTDs also increased. For all NTDs combined (data not shown in Table 4), the adjusted ORs and 95% CIs for one, two, and three or more types of exposures were 1.2 (95% CI, 0.69–1.9), 2.3 (95% CI, 1.3– 4.1), and 2.8 (95% CI, 1.2–6.3), respectively (p value for trend ! 0.001). A stronger trend was noted for risk of anencephalic births than for risk of births with spina bifida with increasing sources of pesticide exposure opportunities (Table 4).
DISCUSSION Results of this study suggest that maternal exposure to pesticides during the periconceptional period may confer risk for NTDs among offspring in Mexican American women, particularly exposures within the home or those associated with living in close proximity to cultivated fields. Maternal
pesticide exposure was more strongly associated with risk for anencephaly than for spina bifida. For both types of defects, however, risk appeared to increase as the sources of exposure opportunities increased. In a study of maternal pesticide exposures and NTDaffected pregnancies among California women (10), pest treatment of the home was associated with NTDs with professional applications (OR 1.6; 95% CI, 1.1–2.5), but showed only minimal association among women applying the pesticides themselves (OR 1.1; 95% CI, 0.8–1.7). In the present study, we noted essentially the same risk estimate for professional home applications as the California study. Among the Texas border population, however, similar associations with NTDs were noted with both professional and self-applications of pesticides to the home. Women in the California study population were 1.5 times more likely (95% CI, 1.1–2.1) than control mothers to report living within one fourth of a mile of agricultural or commercial crops (10). Rull et al. (11) detected differential recall between case- and control-women in the California study when they compared effect estimates obtained from land-use maps and self-reports of proximity to agricultural crops. In their subsequent study that used agricultural pesticide use reports and crop maps, elevated risks of NTDs were found with maternal residential proximity
17 (20.5) 16 (7.1)
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OR Z odds ratio; CI Z confidence interval. *Percentages based on 83 case-women with anencephalic births, 84 case-women with births having spina bifida, and 225 control-women. Four case-women (one with an anencephalic birth and three with births having spina bifida) and three control-women had missing information. y Adjusted with multinomial logistic regression for maternal education, passive/active smoking, and folic acid/folate intake. z Adjusted for other reported sources of pesticide exposures (home use; use on self; use on yard, lawn, or garden; proximity to fields; maternal occupational exposure).
2.5 (1.1–5.9) 2.7 (1.1–6.6) 2.4 (1.0–5.7) 12 (14.3) 3.4 (1.5–7.5) 6.0 (2.4–15)
16 (19.3) 31 (13.8)
5.6 (2.4–13)
1.8 (0.89–3.8) 2.0 (0.96–4.3) 2.1 (1.0–4.2) 20 (23.8) 0.91 (0.42–2.0) 2.3 (0.97–5.3)
25 (30.1) 50 (22.2)
2.7 (1.2–5.9)
0.84 (0.44–1.6) 1.2 (0.61–2.4) 1.3 (0.67–2.5) 20 (23.8) 1.1 (0.59–2.1) 2.3 (1.1–4.7)
19 (22.9) 48 (57.8) 100 (44.4) 82 (36.4)
None reported Used pesticides in/around home Used pesticide on self Used pesticide on yard, lawn, garden Lived within one-fourth mile from cultivated fields
N (%)* N (%)* Pesticide exposure opportunity
2.6 (1.3–5.2)
1.0 (Referent) 1.4 (0.77–2.5) 1.0 (Referent) 1.5 (0.82–2.6) 1.0 (Referent) 1.7 (0.96–2.9) 31 (36.9) 42 (50.0) 1.0 (Referent) 2.4 (1.3–4.2) 1.0 (Referent) 2.9 (1.5–5.4)
N (%)* Adjusted multipleexposure ORy,z (95% CI) Adjusted singleexposure ORy (95% CI) Crude OR (95% CI)
Anencephaly cases Controls
1.0 (Referent) 3.1 (1.7–5.6)
Adjusted singleexposure ORy (95% CI) Crude OR (95% CI)
Spina bifida cases
Adjusted multipleexposure ORy,z (95% CI)
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TABLE 3. Maternal pesticide exposure and risk of anencephaly and spina bifida in offspring
20
within 1,000 meters of pesticide applications of benomyl, methomyl, and other selected chemicals (12). Compared with the risk estimates found in the California study based on maternal self-reports of proximity to agricultural crops (10), a stronger association (OR 3.6) was noted in the Texas Neural Tube Defect Project between residential proximity to cultivated fields and NTD risk. Anencephaly and spina bifida were both associated with maternal residence near crops. In contrast, White et al. (9) noted a significant trend (p Z 0.01) between living in areas with a higher likelihood of agricultural chemical exposures and risk of spina bifida, but not with anencephaly. Numerous studies have found an association between maternal work in agriculture and risk for NTDs in offspring, including anencephaly (8) and spina bifida (4–7, 18). In our study, 4 out of the 11 women (36%) in occupations with potential pesticide exposure lived within a quarter of a mile of cultivated fields compared with 42 of 391 women (11%) who worked in other occupations or were homemakers. With adjustment for other sources of pesticide exposure, occupational pesticide exposure was not associated with NTDs in the study population. This study had several limitations, including relatively lower study participation of eligible control-women than case-women, the potential for recall bias of periconceptional pesticide exposures, and inadequate information on specific pesticides used in the home, yard, or nearby fields. Participating control-women were similar to all TexasMexico border Hispanic women giving birth during the study years with respect to education attainment of fewer than 7 years (12.0% vs. 12.1%), 7 to 11 years (36.9% vs. 37.0%), and 12 or more years (51.1% vs. 50.0%). Participating control-women also had similar household incomes as women who participated in a 1997 survey of the population living in six of the most populous border counties in the study area (19). Differential recall of pesticide exposures between women with NTD-affected pregnancies and women giving birth to normal infants cannot be ruled out. As already discussed, Rull et al. (11) found evidence of recall bias in a California study population regarding residential proximity to crops during the periconceptional period. In that study, case- and control-women were interviewed, on average, 3.7 years and 3.8 years, respectively, after delivery, regarding various pesticide exposures, including proximity to agricultural crops (10). Because women in the Texas Neural Tube Defect Project were interviewed within 2 months after delivery about periconceptional pesticide exposures, it is possible that the extent of recall bias might differ between the two studies. Some evidence suggests that accuracy of recall of events during pregnancy decreases as the time lapse between events during pregnancy and maternal interviews increases (20, 21). With land-use survey-based proximity within one fourth of a mile used as
19 (22.9) 29 (34.9) 25 (30.1) 9 (10.8) 100 (44.4) 74 (32.9) 35 (15.6) 13 (5.8) None One Two Three to five
OR Z odds ratio; CI Z confidence interval. *Percentages based on 83 case-women with anencephalic births, 84 case-women with births having spina bifida, and 225 control-women. Four case-women (one with an anencephalic birth and three with births having spina bifida) and three control-women had missing information. y Adjusted with multinomial logistic regression for maternal education, passive/active smoking, and folic acid/folate intake. z p Value for trend Z 0.001. x p Value for trend Z 0.028.
1.0 (Referent) 0.75 (0.38–1.5) 1.6 (0.79–3.3) 2.7 (1.1–6.8) 1.0 (Referent) 0.87 (0.46–1.6) 1.8 (0.88–3.5) 2.7 (1.1–6.7) 31 (36.9) 20 (23.8) 19 (22.6) 11 (13.1) 1.0 (Referent) 1.9 (0.97–3.7) 3.4 (1.6–7.1) 3.5 (1.3–9.7)
Adjusted ORy,z (95% CI) Crude OR (95% CI) N (%)* Controls N (%) No. of pesticide exposure opportunities reported
Anencephaly cases
TABLE 4. Maternal pesticide exposure opportunities and risk of anencephaly and spina bifida in offspring
1.0 (Referent) 2.1 (1.1–4.0) 3.8 (1.8–7.6) 3.6 (1.4–9.7)
Crude OR (95% CI)
Adjusted ORy,x (95% CI)
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N (%)*
Spina bifida cases
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the ‘‘gold standard’’ in the study of Rull et al. (11), sensitivities of case- and control-women for self-reported proximity to agricultural crops displayed differences (65.7% and 50.0%, respectively), but the specificities for exposure classification were similar (87.5% and 89.3%, respectively) between the two groups. To better understand the potential impact of recall bias on the association between residential proximity to fields and NTDs, we conducted a sensitivity analysis for various scenarios of exposure misclassification with methods suggested by Greenland and Lash (22). With the use of the same specificities obtained for cases and controls in the Rull et al. study (11), ORs for the association between maternal residential proximity to fields and NTDs remained above 2.0, even with the extreme scenario of 90% sensitivity for case exposures and 30% for control exposures, and did not decline to 1.0 unless the exposure specificity for cases fell below 78% with these specified sensitivities. Overall, the sensitivity analysis indicated sustained positive associations between self-reported proximity to fields and NTDs in offspring for a wide range of sensitivities and specificities, except for the most extreme differences in accuracy of reporting. It would have been informative to compare specific biomarkers of pesticide exposure between cases and controls. In this study, urine and blood specimens were collected for pesticide biomarkers from a small proportion of participants approximately 1 year after conception, and laboratory analyses were conducted for a limited number of pesticide analytes (including those of chlorinated hydrocarbon insecticides and methyl parathion). Results from that phase of the study are not presented herein because of low participation of the cases and controls (<28% and <34%, respectively, depending on the biomarker analyzed). Of participants tested, the majority had results below the level of laboratory detection. In conclusion, this study found that Mexican American women with NTD-affected pregnancies were more likely than comparison women to report home use of pesticides and living near cultivated fields shortly before and after conception. McDiarmid et al. (23) noted that pesticides are among the most likely chemical hazards that women will encounter in the home. More studies that measure a wide range of pesticide biomarkers are needed, however, to understand which pesticides might increase risk of adverse pregnancy outcomes such as NTDs.
Funding for this study was provided in part by Centers for Disease Control and Prevention, Birth Defects Branch Cooperative Agreement U85/ CCU608761-05 and Cooperative Agreement U50/CCU613232 through The Texas Center for Birth Defects Research and Prevention, Texas Department of Health. We wish to thank Dr. Kate Hendricks for the conceptualization and implementation of the Texas Neural Tube Defect Project.
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