Inorganic arsenic is a ubiquitous environmental pollutant. People can be exposed to arsenic from occupational activities, eating contaminated foods, and from industrial sources [1]. The most common route of exposure, however, is from drinking groundwater that is contaminated with naturally occurring arsenic [2,3]. In the United States, a survey of all major aquifers estimated that 7% of households equating to approximately 4.2 million people are exposed to arsenic concentrations that exceed the United States Environmental Protection Agency’s maximum contaminant level of 10 μg/L [4]. However, arsenic-contaminated drinking water is a global health concern particularly for Bangladesh. This is because public health interventions designed to reduce waterborne disease switched the population’s source of drinking water from surface water to groundwater [5]. Unfortunately, the shallow groundwater aquifer under Bangladesh is contaminated with naturally-occurring arsenic [5]. As a result of this intervention, 46% of the population are exposed to arsenic concentrations above the World Health Organization’s recommended limit of 10 μg/L and 27% are exposed to concentrations above 50 μg/L which is the Bangladesh government’s drinking water recommendation (and previous U.S. limit) [6].

There is consistent evidence that chronic exposure to arsenic from drinking water increases the risk of skin lesions, cardiovascular disease, neuropathy, and type 2 diabetes and cancers of the skin, bladder, lung and kidney cancer, [7-14]. Data from epidemiological studies also show that chronic exposure to arsenic contaminated drinking water is associated with adverse reproductive health effects [15-19]. These reproductive health studies focused on the effect of arsenic on fetal loss, preterm birth, and/or birthweight. None have reported on the effect of chronic arsenic exposure on maternal health.

We decided, therefore, to examine the association between arsenic exposure and maternal health, as assessed by self-reported symptoms during pregnancy. We conducted this study in a large population-based prospective cohort of pregnant women recruited in Bangladesh. In this prospective reproductive health cohort, women were asked questions about their health and followed throughout the course of their pregnancy. We hypothesized that arsenic exposure measured in maternal drinking water at the time of enrollment into the cohort would be associated with increased self-reported symptoms of illness reported during the pregnancy.

We compared socio-demographic characteristics between the 1,262 women with complete follow up information with the 196 women who were lost to follow up. There was no significant difference in the age (22.8 vs 22.9 years, p-value = 0.51), ln drinking water arsenic (1.3 vs 1.7 μg/L, p-value 0.27), parity (0.7 vs 0.7, p-value = 0.76), BMI at the time of enrollment (20.8 vs 20.5, p-value = 0.42), or maternal education (p-value = 0.14) among participants who were lost to follow up and those who were included in this analysis. Clinic staff attempted to re-contact the women who were lost to follow up by going to their homes to determine why they did not complete the study protocols. None of these women could be re-contacted so reasons for lost to follow up could not be ascertained.

At the time of enrollment, the overall mean and median concentration of arsenic in participant’s drinking water was 38 μg/L (standard deviation, 92.7 μg/L) and 2 μg/L (interquartile range, 30 μg/L), respectively. Sixty-three percent of the women reported experiencing at least one health symptom during their pregnancy. The most common symptom reported by women was nausea/vomiting (39.2%) followed by abdominal cramping (37.1%), headache (32.7%), cold/flu/infection (18.0%), vaginal bleeding (1.0%), and swollen ankles (1.0%). Women who reported having any symptom during pregnancy were exposed to significantly higher concentrations of arsenic in their water compared to women who reported no symptoms (Table 1). Additionally, women who reported any symptom during pregnancy were more likely to be underweight, exposed to second hand tobacco smoke, have lower educational attainment, have anemia and lower ferritin status, lack sanitary latrines, take medication, and have lower household incomes compared to women who reported no adverse symptoms during pregnancy.

Frequencies of specific symptoms by categories of arsenic exposure and select characteristics are presented in Table 2. Overall, participants who reported nausea/vomiting and abdominal cramping were exposed to higher concentrations of arsenic in their drinking water compared to women who did not report these symptoms. No difference in arsenic exposure was observed between participants who reported cold/flu/respiratory infection or severe headache compared to women who did not report these symptoms. No difference in arsenic exposure was observed between participants who reported vaginal bleeding or swollen ankles. It should be noted that only 12 participants reported vaginal bleeding or swollen ankles resulting in small sample sizes that limited statistical inference (data not shown).

The association between symptoms and quartiles of arsenic exposure from adjusted logistic regression models are presented in Table 3. The odds of a woman reporting any symptom during pregnancy were higher among those participants with the highest arsenic concentration in their drinking water. There was a significant trend for increasing odds of symptoms with increasing arsenic exposure (P for trend < 0.0001). Compared to the lowest quartile of arsenic, the adjusted odds ratio for any symptom during pregnancy was 0.62 (95% CI: 0.44, 0.88) for the second quartile, 1.83 (95% CI: 1.25, 2.69) for the third quartile, and 2.11 (95% CI: 1.42, 3.13) for the fourth quartile. Upon examining individual symptoms, only nausea/vomiting and abdominal cramping showed consistent associations with arsenic exposure. The odds of self-reported nausea/vomiting was 0.98 (95% CI: 0.68, 1.41), 1.52 (95% CI: 1.05, 2.18), and 1.81 (95% CI: 1.26, 2.60) in the second, third and fourth quartile of arsenic relative to the lowest quartile after adjusting for age, body mass index, second-hand tobacco smoke exposure, educational status, parity, anemia, ferritin, medication usage, type of sanitation at home, and household income. A significant increased odds of abdominal cramping, on the other hand, was only observed in the highest arsenic quartile (aOR: 1.62, 95% CI: 1.13, 2.32) compared to the lowest quartile.

Table 4 shows the adjusted odds of self-reported symptoms when arsenic exposure was dichotomized below and above 50 μg/L. Among participants whose drinking water contained arsenic greater than or equal to 50 μg/L, odds of reporting any symptom were two-fold higher than participants whose drinking water contained less than 50 μg/L after adjusting for age, BMI, second-hand tobacco exposure, educational status, parity, anemia, ferritin, household sanitation, medication usage, and household income (aOR: 2.11; 95% CI: 1.47, 3.02). The adjusted odds of nausea/vomiting (aOR: 1.47; 95% CI: 1.09, 1.98) and abdominal cramping (aOR: 1.79; 95% CI: 1.31, 2.45) was also significantly higher among participants whose drinking water contained arsenic ≥50 μg/L compared < 50 μg/L.

Table 5 shows the adjusted odds of self-reported symptoms when arsenic exposure was dichotomized below and above 10 μg/L. These results were consistent with the previous analyses. The adjusted odds of reporting any symptom was approximately two-fold higher than participants whose drinking water contained less than 50 μg/L (aOR: 2.99; 95% CI: 2.21, 4.04). The adjusted odds of nausea/vomiting (aOR: 1.62; 95% CI: 1.25, 2.10) and abdominal cramping (aOR: 2.39; 95% CI: 1.83, 3.13) was also significantly higher among participants whose drinking water contained arsenic ≥10 μg/L compared to < 10 μg/L. Interestingly, the adjusted odds of cold/flu/infections was significantly lower among participants whose drinking water contained arsenic greater than or equal to 10 μg/L compared to participants whose drinking water contained less than 10 μg/L (aOR: 0.61, 95% CI: 0.43, 0.86).

We also examined the potential for effect modification by parity and observed no significant interactions between parity status (primiparous vs multiparous) and arsenic quartile for any symptom (p = 0.78), nausea/vomiting (p = 0.22) or abdominal cramping (p = 0.61). This indicated that the odds of reporting symptoms did not differ between primigravid and multigravid participants in relationship to arsenic exposure.

To determine if taking medication during pregnancy influenced the observed relationship between arsenic and self-reported symptoms during pregnancy, we conducted a restricted analysis (Table 6). In a subset of women who did not report taking any prescription or herbal medications during pregnancy (n = 1,166), we observed similar results where increasing arsenic exposure was significantly associated with increased odds of any symptom (p-value < 0.001), nausea/vomiting (p-value = 0.0007), and abdominal cramping (p-value <0.0001). However, there was no significant trend between arsenic exposure and cold/flu/infection (p-value = 0.39) or severe headaches (p-value = 0.37). Similar associations were also observed when the analysis was restricted to only live births (data not shown).

We observed that the likelihood that a women reported adverse health symptoms during pregnancy increased with higher arsenic exposure. Specifically, the odds of nausea/vomiting and abdominal cramping were significantly higher among participants in the third quartile and fourth quartile. This is noteworthy because the mean arsenic concentration in the third quartile was 12 μg As/L (range, 2.1-31 μg As/L). Not only is this concentrations of arsenic commonly observed in potable groundwater, this water would be considered safe to drink in Bangladesh because it is below the current recommended level of 50 μg As/L. It is plausible that women whose tubewell met the current recommendations in Bangladesh would be less likely to consider their drinking water to be problematic and subsequently this group may be less inclined to exaggerate symptomology relating to the arsenic levels in their water source compared to participants whose drinking water did not meet the Government’s recommendations.

Nausea/vomiting and abdominal cramping are common ailments in pregnancy and will range in severity [23,24]. While these symptoms tend to resolve during pregnancy and are frequently considered an expected aspect of pregnancy, nausea/vomiting during pregnancy are linked with maternal distress and contribute to maternal morbidity [25-29]. In Sri Lanka, nausea/vomiting have been shown to be the leading cause of lost household productivity among pregnant women [9]. Nausea/vomiting is also highly correlated with maternal anxiety, maternal depression, and contribute to a reduction in maternal quality of life [27,30,31]. Data from studies that examined the relationship between nausea/vomiting and infant birthweight are inconsistent with some studies showing no relationship with birthweight and some reporting that severe nausea/vomiting was associated with decreased birthweight [32,33].

Our finding that arsenic exposure is related to nausea/vomiting during pregnancy increases our understanding of the etiology of this pregnancy-related condition. Studies in other populations also report that nausea/vomiting during pregnancy is more common in younger women, primigravidas, and obese women although these associations were not observed in our population [22]. Researchers have also reported that nausea during pregnancy is related to human chorionic gonadotropin levels, and the absence of these symptoms in early pregnancy may be sign of poor implantation or miscarriage [34]. However, our study includes measures of nausea/vomiting through the second and third trimester which is not likely to represent implantation, an early event in pregnancy. Also, we observed a consistent association between higher levels of arsenic exposure and nausea/vomiting among only those pregnancies that resulted in live birth.

While others have reported that nausea is common in individuals who experienced acute arsenic poisoning [35-37] this study contributes new evidence that chronic arsenic exposure at relatively moderate concentrations are associated with increased risk of nausea [38]. We observe, however, that relatively modest arsenic concentrations in drinking water were associated with increased odds of nausea/vomiting and abdominal cramping during pregnancy. Our study has many strengths including the ascertainment of arsenic exposure early in pregnancy from personal drinking water samples, confirmed singleton pregnancies, and the ability to control for many confounders including second-hand smoke exposure, sanitary conditions, medication usage, and others. Furthermore, our findings remained consistent when we accounted for the potential effect of parity and medication usage. The potential for bias for self-reported maternal symptoms is limited because the prospective analyses yielded very similar results to cross-sectional analyses conducted at the time of enrollment using all available data (Additional file 1: Supplemental Tables S1 and S2). Also, participants were asked three times throughout their pregnancy to report any symptoms. Additionally, participants did not know the concentration of arsenic in their drinking water prior to enrolling in the study. It is possible, however, that participants had previously tested their water for arsenic and this knowledge may have resulted in differential report of maternal symptoms. However, the higher odds of nausea/vomiting were observed at arsenic concentrations below the current Bangladesh drinking water recommendations and subsequently the well would be considered an acceptable source of potable water.

We observed a positive exposure-response relationship between arsenic concentrations in drinking water and self-reported nausea/vomiting and abdominal cramping during pregnancy in a prospective cohort of pregnant women recruited in Bangladesh. These data provide additional evidence that arsenic-contaminated drinking water at moderate concentrations adversely affects maternal and reproductive health. Continued efforts to reduce arsenic exposure in Bangladesh are warranted particularly for women of reproductive age.

BMI: Body mass index; CI: Confidence intervals; GM: Geometric mean; GSD: Geometric standard deviation; LOD: Limit of detection; OR: Odds ratio; WGS: Weeks gestational age; Q: Quartile.

The authors declare they have no competing interests.

MLK conceived the hypothesis, supervised data collection and analysis, and developed the manuscript. CBD supervised data entry and contributed to data analysis and manuscript preparation. MM contributed clinical interpretation and manuscript preparation. ER supervised data entry including quality control and contributed to manuscript preparation. ND was responsible for database management. MG supervised field activities and data collection. QQ also supervised data collection and clinical operations in Bangladesh, and contributed to manuscript preparation. MR also supervised field activities and clinical operations in Bangladesh. DCC is the principal investigator of the cohort and contributed to manuscript preparation. All authors contributed equally to the research described in this manuscript. All authors read and approved the final manuscript.