Association of DDT with Spontaneous Abortion

Association of DDT with Spontaneous Abortion: A Case-Control Study SUSAN A. KORRICK, MD, MPH, CHANGZHONG CHEN, MD, ANDREW I. DAMOKOSH, PHD, JIATONG NI, MD, XUE LIU, BS, SUNG-IL CHO, MD, SCD, LARISA ALTSHUL, MS, LOUISE RYAN, PHD, AND XIPING XU, MD, PHD

PURPOSE: Spontaneous abortion (SAB), the most common adverse pregnancy outcome, affects 15% of clinically recognized pregnancies. Except for advanced maternal age and smoking, there are not wellestablished risk factors for SAB. Animal models associate increased fetal resorption or abortion with exposure to the pesticide dichlorodiphenyl trichloroethane (DDT), but epidemiologic investigations of DDT and SAB are inconsistent. We undertook a pilot investigation of the hypothesized association of DDT with SAB. METHODS: Participants in this case-control study were selected from a longitudinal study of reproductive effects of rotating shifts among female Chinese textile workers who were married, ages 22–34, nulliparous without history of SAB or infertility, and planning pregnancy. From 412 pregnancies, 42 of which ended in SAB, 15 SAB cases and 15 full-term controls were randomly selected and phlebotomized. Serum was analyzed for p,p-DDT, o,p-DDT, their metabolites (DDE and DDD), and other organochlorines including polychlorinated biphenyls. RESULTS: Cases and controls were nonsmokers and did not differ in age (mean 25 years), body mass index (BMI), passive smoke exposure, or workplace exposures. Cases had significantly (p  0.05) higher serum levels of p,p-DDE (22 vs.12 ng/g) and o,p-DDE (0.09 vs. 0.05 ng/g) than controls. After adjustment for age and BMI, each ng/g serum increase in p,p-DDE was associated with a 1.13 (CI, 1.02–1.26) increased odds of SAB. With adjustment of serum DDE levels for excretion via breastfeeding, DDE-associated increased odds of SAB remained significant with up to 7% declines in maternal serum DDE levels for each month of breastfeeding. CONCLUSIONS: A potential increased risk of SAB is associated with maternal serum DDE levels. Ann Epidemiol 2001;11:491–496. © 2001 Elsevier Science Inc. All rights reserved. KEY WORDS:

Pesticides, Organochlorines, DDT, DDE, PCBs, Spontaneous Abortion.

INTRODUCTION Spontaneous abortion (SAB), the most common adverse pregnancy outcome, affects approximately 15% of clinically recognized pregnancies and up to 50% of all pregnancies, including preimplantation losses. Most occur in the first trimester of pregnancy, and the majority of these losses are a consequence of abnormalities in fetal karyotype (1–3). Except for advanced maternal age and smoking, risk factors for SAB are not well established; maternal infection, alcohol

From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (S.A.K.); the Department of Environmental Health, Harvard School of Public Health, Boston, MA (S.A.K., L.A., X.X.); the Program for Population Genetics, Harvard School of Public Health, Boston, MA (C.C., A.I.D., S.-I.C., X.X.); the Anhui Institute of Biomedicine and Environmental Health, Anqing, Anhui, China (J.N., X.L.); and the Department of Biostatistics, Harvard School of Public Health, and the Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA (L.R.). Address reprint requests to: Susan Korrick, MD, MPH, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. Received November 17, 2000; revised February 28, 2001; accepted March 19, 2001. © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

and caffeine intake, parity, menstrual disorders, anatomic or immunologic abnormalities, hormonal factors, and various occupational, chemical, or radiation exposures are suspected, but not consistently demonstrated, risk factors for SAB (4). Dichlorodiphenyl trichloroethane (DDT) is a broadspectrum synthetic insecticide widely used in agriculture and residential settings since the mid-1940s. Because of its biological persistence and toxicity, DDT is banned almost worldwide, though still used for malaria vector control in some countries. The United States banned its use in 1972 (5), and agricultural uses of DDT were banned in China by 1984 (6); however, the use of DDT for malaria control in some regions of China continued after the agricultural ban. Estimated dietary DDT intake among the Chinese is higher than among populations in developed countries (6, 7). DDT and its metabolites are lipophilic, slowly metabolized, and relatively resistant to environmental degradation; thus, they continue to accumulate in the food chain and in human adipose tissue despite bans on DDT’s use. For example, the half-life of DDT in soil is estimated to be in excess of 10 years (8). Dichlorodiphenyl dichloroethene (DDE) 1047-2797/01/$–see front matter PII S1047-2797(01)00239-3

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Selected Abbreviations and Acronyms DDT  dichlorodiphenyl trichloroethane DDE  dichlorodiphenyl dichloroethene DDD  dichlorodiphenyl dichloroethane HCB  hexachlorobenzene PCBs  polychlorinated biphenyls BMI  body mass index CI 95% confidence interval SAB  spontaneous abortion SD  standard deviation

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Outcome Assessment (Parent Study) Reproductive status (using contraception or not, planning pregnancy, or pregnant), pregnancy date, and pregnancy outcome are ascertained by monthly participant interviews and by review of medical records. If a first pregnancy is terminated (e.g., with induced or spontaneous abortion), participants are invited to continue in the study with subsequent pregnancies. Study Questionnaires

and dichlorodiphenyl dichloroethane (DDD) are the primary metabolites of DDT degradation, DDE being the most prevalent with an estimated half-life even longer than its parent compound (9). Indeed, DDE residues are detectable in the fat of all human populations monitored to date (10, 11). In animal models, increased fetal resorption or abortion is associated with DDT exposure (12, 13). Epidemiologic investigations of pesticides as a potential risk factor for SAB are inconsistent and limited by problems of multiple exposures (in farmers or pesticide applicators), indirect exposure assessment (by occupation), small sample size, and potential confounding (14). We undertook this pilot investigation to assess the hypothesized association of DDT with SAB among a sample of female textile workers without occupational DDT exposure.

METHODS Study Population Participants in this case-control study were recruited from a prospective cohort study begun in 1996 to assess the reproductive effects of rotating shift work among women working in the Yifang Textile Mill in Anqing, China. Women who are married, ages 22–34 years, nulliparous without history of SAB or infertility, and planning to have a child, are eligible for the parent study. In China, each married couple is permitted to have one child and must receive state permission to do so. Potential participants in the parent study are identified primarily at the time of a government-mandated premarital health exam and when state permission to have a child has been granted. Because this was a pilot study, resources were available to study 32 women. At the time of this pilot—August 1998—585 women had enrolled in the ongoing parent study, 412 (70%) of whom had clinically identified pregnancies. Sixteen of 42 women in the cohort whose first study pregnancy had ended in a clinically recognized SAB were selected randomly and agreed to phlebotomy, as were 16 women of 225 women whose first study pregnancy had reportedly resulted in a live birth. One case and one control were excluded from analysis because of missing data thereby leaving 15 cases and 15 controls for analysis.

Upon enrollment in the parent study, a baseline questionnaire is administered to all participants (both husband and wife). For those women who had a live birth before providing a blood sample for this case-control study, breastfeeding experience was ascertained by interview. Exposure Assessment In August 1998, each pilot subject had nonfasting phlebotomy with a red top VacutainerTM tube. Serum fractions were frozen at 20C until extraction. Serum samples were analyzed by the Harvard School of Public Health Organic Chemistry Laboratory (Boston, Massachusetts) for p,pand o,p isomers of DDT, DDE, and DDD and other commonly occurring organochlorine contaminants in human serum–hexachlorobenzene (HCB), oxychlordane, heptachlor epoxide, trans-nonachlor, 67 individual polychlorinated biphenyl congeners and their sum (PCB). Details of the laboratory analytic methods and quality control procedures are reported elsewhere (15). Briefly, primary analyses of serum extracts employed gas chromatography with electron capture detection with confirmatory analyses of all samples using a capillary column of different polarity. Quantitation was based on the response factor of each analyte relative to an internal standard. Final concentrations were reported in ng of analyte/g of serum after subtracting the amount of analyte measured in the procedural blank. Lipid content of the serum was not measured. For the most prevalent analyte, p,p-DDE, the within and between assay coefficients of variation were 2% and 5.5%, respectively. The analyst was blind to the case-control status of the samples and case and control samples were run in the same analytical batches. Statistical Analyses Logistic regression modeling was used to estimate the odds of SAB as a function of serum DDE and other organochlorine levels adjusted for age and BMI. Because breastfeeding is an excretory pathway for organochlorines and serum levels of these analytes were measured after breastfeeding one child for most study participants (12 controls and 7 cases), we estimated serum DDE levels before the index pregnancy. This estimate was based on the conservative assumption

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that serum DDE levels decline by a fixed percentage for each month of breastfeeding regardless of duration of breastfeeding, although there is evidence that DDE excretion abates with increased duration of lactation (16, 17). Prelactation DDE levels were calculated with a multiplicative model: DDEprelactation  (DDEmeasured)/(1  P)BF where P  %decline in serum DDE/month of breastfeeding and BF  months of breastfeeding times the proportion of feedings each month with breastmilk (a value of 1 means one month of 100% breastfeeding). Multiple estimates of prelactation DDE concentrations were calculated assuming 1–15% declines in maternal serum levels per month of lactation. Sensitivity analyses employed repeated logistic regression models using these estimated DDE levels. Although there are limited data available from which to estimate potential lactation-associated changes in maternal serum DDE levels, use of up to 15% decline was based on results from Rogan et al.’s study of over 700 lactating women (16), suggesting that maternal milk or serum DDE levels may decline by approximately 7–15% per month for the first 6 weeks of lactation and by 3–4% per month thereafter. This study was approved by the Human Research Committees of Harvard School of Public Health, Boston, Massachusetts, and Beijing Medical University, Beijing, China. Written informed consent was obtained from study subjects before participation.

RESULTS Study Population The 15 case and 15 control women assessed in this analysis did not differ significantly with regard to demographic characteristics, BMI, or workplace exposures from the 27 women with SAB and 210 with live births not included in the study. Consistent with population characteristics reported for this region of China (18), both case and control women were lean (Table 1). Except for greater breastfeeding and a shorter time between their index event (SAB or birth) and phlebotomy among controls (commensurate with the time to complete a term pregnancy), cases and controls did not differ from each other (Table 1). However, because blood samples for DDT analyses were not collected until almost two years after initiation of the parent study, some women whose first study pregnancy ended with SAB had a second pregnancy prior to phlebotomy; specifically, 11 (73%) cases had become pregnant subsequent to SAB, seven of whom had live births and breastfed, and four of whom were still pregnant at phlebotomy. All participating cases had an SAB within the first trimester of pregnancy (mean  SD gestation 7.5  2.2 weeks). With the exception of one infant born at 36.4

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TABLE 1. Demographic and lifestyle characteristics of study participants: 15 women with spontaneous abortion (cases) and 15 women with live births (controls) Mean  SD

Age (years)a Husband’s agea Age at menarche BMI (kg/m2) Tea intake (gm/month) Breastfeeding (months)b Time to phlebotomy (months)c

Case (n  15)

Control (n  15)

25.3  1.6 27.2  1.5 14.2  1.2 20.1  2.3 90  115 3.7  1.8 (n  7) 14.8  4.8

25.0  1.2 27.3  1.8 14.7  1.5 19.3  1.7 77  84 4.6  1.8 (n  12) 6.5  1.6d N (%)

Current smoker Passive smoke exposure Missing Drink alcohol Breastfed prior to phlebotomy Missing Hx. gynecologic disordere Work exposures Shift work Dust Noise Vibration

0 10 (77%) 2 0 7 (47%) 0 0

0 11 (79%) 1 0 12 (86%)d 1 0

13 (87%) 10 (67%) 10 (67%) 5 (33%)

15 (100%) 9 (60%) 12 (80%) 3 (20%)

a

Age at time of index pregnancy. Breastfeeding based on self-reported months of breastfeeding (prior to phlebotomy) times proportion of feedings with breastmilk; a value of ‘1’ means one month of 100% breastfeeding. Mean (SD) based on non-zero values. c Time between index event (SAB or birth) and phlebotomy. d p 0.05; Wilcoxon 2-sample test for means, Fisher’s exact test for frequencies. e History of gynecologic disorder includes infection (cervicitis, vaginitis), malignant and benign gynecologic tumors, pelvic inflammatory disease, uterine prolapse, and irregular menses. b

weeks’ gestation, control infants were full term (mean  SD gestation 39.7  1.5 weeks). Organochlorine Exposure The predominant form of DDT in this population was p,pDDE. Cases had higher serum levels of all detected isomers of DDT and their metabolites than controls (Table 2). Serum concentrations of other analytes were either nondetectable or very low and did not differ between cases and controls (Table 2). Spontaneous Abortion Risk After adjustment for age and BMI, each ng/g serum increase in p,p-DDE and ng/100 g increase in o,p-DDE was associated, respectively, with 1.1 CI 1.0–1.3, p  0.03 and 1.6 (CI 1.1–2.3, p  0.01) increased odds of SAB (Table 3). Exclusion of the four cases who were pregnant at phlebotomy produced similar but borderline nonsignificant effect

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TABLE 2. DDT, hexachlorobenzene (HCB), oxychlordane, and polychlorinated biphenyl (PCB) serum levels (ng/g) in women with spontaneous abortion and control women Case (n  15) p,p-DDE p,p-DDT p,p-DDD o,p-DDE o,p-DDT Total DDTb HCB Oxychlordane PCBc

Control (n  15)

Mean (SD)

25%

50%

75%

Mean (SD)

25%

50%

75%

p-valuea

22 (12) 0.8 (0.7) 0.12 (0.09) 0.09 (0.04) 0.13 (0.09) 23 (13) 0.4 (0.1) 0.01 (0.01) 0.2 (0.1)

11 0.5 0.07 0.05 0.05 11 0.3 0.00 0.1

23 0.6 0.09 0.09 0.11 24 0.4 0.00 0.2

31 0.8 0.11 0.10 0.19 33 0.5 0.01 0.3

12 (6) 0.4 (0.2) 0.08 (0.04) 0.05 (0.02) 0.08 (0.04) 13 (6) 0.3 (0.1) 0.00 (0.01) 0.2 (0.1)

8 0.3 0.06 0.04 0.06 9 0.3 0.00 0.1

11 0.4 0.09 0.05 0.08 11 0.3 0.00 0.2

16 0.6 0.12 0.06 0.12 17 0.4 0.01 0.3

0.01 0.06 0.22 0.005 0.10 0.01 0.06 0.34 0.64

a

t-test comparison of means. Total DDT  p,p-DDT p,p-DDE p,p-DDD o,p-DDT o,p-DDE. c PCB  sum of 67 PCB congeners. b

estimates. Specifically, each ng/g serum increase in p,pDDE and ng/100 g increase in o,p-DDE was associated, respectively, with 1.1 (CI 1.0–1.2, p  0.11) and 1.4 (CI 1.0– 2.0, p  0.05) increased odds of SAB. In sensitivity analyses including all cases, increased risk of SAB associated with maternal serum p,p-DDE levels remained statistically significant if each month of lactation resulted in no more than 7% decline in maternal serum DDE level. Specifically, after allowing for 7% per month decline in maternal serum DDE level during lactation, each ng/g increase in maternal serum p,p-DDE was associated with 1.1 increased odds of SAB (CI 1.0–1.2, p  0.049).

DISCUSSION Results of this study support findings in animal models suggesting that exposure to DDT and its metabolites is a potential source of increased risk for SAB (12, 13, 19). Although the mechanism of these associations is unknown, DDT’s potential for endocrine activity is hypothesized to explain some of its reproductive toxicities. For example, DDT and DDE are structurally similar to various hormones, including estrogens, and o,p-DDT and DDE isomers act analogously to estradiol (20). P,p-isomers of DDT and its metabolites have anti-androgen effects. Alternatively, DDT and its metabolites have been hypothesized to interfere with normal endocrine function via their ability to induce hepatic cytochrome P-450 enzymes, some of which metabolize endogenous steroid hormones (21, 22). Lastly, DDT and its metabolites alone, or in combination with other pesticides, have been associated with chromosomal abnormalities in occupationally exposed cohorts (23, 24) and in vitro models (25), another possible mechanism of increasing the risk of SAB. However, human epidemiologic data for the hypothesized DDT-associated risk of SAB are limited, and results of published studies are inconsistent—elevated maternal blood DDE levels have been associated with SAB in some

(26–28) but not all (29, 30) previous studies. In one of the largest such studies, maternal blood concentrations of total DDE did not differ significantly between 120 women hospitalized for SAB (5.2 ppb) and 120 women hospitalized with a term pregnancy (4.6 ppb) (30). In contrast, among a more heavily, nonoccupationally exposed population in India, Saxena and colleagues (26) noted significant increases in mean maternal blood p,p-DDE levels across birth outcomes—13 ppb (25 full-term deliveries), 58 ppb (15 preterm deliveries), and 164 ppb (10 cases of SAB). Maternal blood p,p-DDT levels were also high (mean 5–137 ppb) and followed the same pattern relative to birth outcome suggesting that a DDT-associated increased risk of SAB may only be apparent at high exposure levels or among those with recent or direct exposure to DDT itself. Independent of the potential for a threshold effect, a major limitation of most previous analyses is the absence of adjustment for potential confounders. For example, older age is a risk factor for SAB and is generally associated with higher blood DDE levels (31, 32). Similarly, the potential for greater parity and lactation experience in women with full-term deliveries than in women with SAB could acTABLE 3. Odds of spontaneous abortion (SAB) as a function of serum levels of DDT, HCB, and PCB in 15 women with SAB and 15 women with live births Pesticide p,p-DDE (ng/g) p,p-DDT (ng/100 g) o,p-DDE (ng/100 g) o,p-DDT (ng/100 g) Total DDT (ng/g) HCB (ng/100 g) PCB (ng/100 g)b a

Odds Ratioa

95% CI

p-value

1.13 1.04 1.56 1.13 1.13 1.06 0.96

1.02–1.26 0.99–1.08 1.08–2.25 0.98–1.29 1.02–1.25 1.00–1.14 0.87–1.05

0.025 0.11 0.017 0.09 0.026 0.07 0.36

Adjusted for age and body mass index (kg/m2). Odds ratio expressed per ng/g increase in p,p-DDE and total DDT; odds ratio expressed per ng/ 100g increase in p,p-DDT, o,p-DDE, o,p-DDT, HCB, and PCB. b PCB  sum of 67 PCB congeners.

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count for differences since lactation is an important excretory pathway for DDT and its metabolites. In contrast, the women we studied were a relatively homogeneous group vis-à-vis these confounders. Specifically, cases and controls did not differ significantly in age, occupation, or other SAB risk factors (e.g., all were nonsmokers). Because of Chinese laws governing childbearing, no one in the study had parity greater than one. No one in the study had a history of previous SAB. Furthermore, DDE levels in this analysis were relatively high—roughly comparable to those described 30 years ago among U.S. cohorts (29)—thereby improving the potential sensitivity of the analysis. An important limitation of our analysis—and of previous studies—was its cross-sectional exposure assessment. Blood was collected almost two years after the index pregnancy for some participants such that both cases and controls had the opportunity to breastfeed, and likely excrete DDT, before exposure assessment. Although no one breastfed more than one child, controls were more likely to have breastfed a child than were cases, thereby introducing a potential for bias in our analyses. To address this possible bias, we did a sensitivity analysis that estimated serum DDE levels before the index pregnancy. An increased risk of SAB was still present with up to 7% decline in serum DDE levels with each month of breastfeeding. In summary, our results suggest a modest increased risk of SAB in association with maternal serum DDE levels. Although serum exposure measurements were made after the index event (SAB or birth), results of sensitivity analyses support the significance of these findings even after accounting for moderate DDE excretion via breastfeeding. But because of both uncertainty regarding the proper way to model lactation-related changes in serum DDE and small sample size, these results must be interpreted with caution. Larger studies with prospective exposure assessment are warranted to address these uncertainties. This research was supported by grants from the National Institute of Child Health and Human Development (NICHD HD32505) and National Institute of Environmental Health Sciences (NIEHS ES00002, ES05947) with funding for the latter provided by the U.S. Environmental Protection Agency (EPA). Dr. Korrick was additionally supported by NIEHS grant ES08074 and a Harvard Medical School Edward and Amalie Kass 50th Anniversary Scholars in Medicine Fellowship. This manuscript’s contents are the sole responsibility of the authors and do not necessarily represent the official views of NIH or EPA. We thank Raisa Stolyar and Christine Rutherford for support with chemical analyses. Most important, we thank the families who generously participated in this research.

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