Cadmium Body Burden and Gestational Diabetes Mellitus: A Prospective Study

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance that is first recognized during pregnancy (American Diabetes Association 2011). The prevalence of GDM has been steadily increasing in many countries, including China (Albrecht et al. 2010; Leng et al. 2015). GDM may lead to serious adverse maternal outcomes such as high cesarean section rate and preeclampsia and to detrimental infant outcomes such as macrosomia, infant respiratory distress syndrome, and neonatal hypoglycemia (Poel et al. 2012). GDM also increases the long-term risks of type 2 diabetes mellitus (Bellamy et al. 2009), obesity, and metabolic syndrome for both mothers and infants (Metzger 2007). It is noteworthy that pregnancy women are at high risk of glucose intolerance because of the insulin-desensitizing effects of hormonal products of the placenta (Buchanan and Xiang 2005). Some characteristics such as maternal age and high prepregnancy body mass index (BMI) (Leng et al. 2015) have been well-established as important risk factors. However, there is increasing evidence indicating that GDM might be caused by environmental chemical exposures, which has earned less attention than the traditional risk factors (Ehrlich et al. 2016; Shapiro et al. 2015).

Metals such as cadmium (Cd) and arsenic (As) have been reported to be involved in the etiology of type 2 diabetes or GDM in previous studies (Beck et al. 2017; Edwards and Ackerman 2016; Farzan et al. 2016). Cd is a toxic heavy metal that is widely used in batteries, pigments, coatings and plating, and stabilizers for plastics, among other applications (ATSDR 2012). Cd, which has a high soil-to-plant transfer rate, is easily emitted to the environment by nonferrous metal mining and refining, manufacturing and application of phosphate fertilizers, fossil fuel combustion, and waste incineration and disposal (ATSDR 2012). Cd enters the human body mainly through smoking and food ingestion, and the diet is the main source of environmental Cd exposure in nonsmokers in most parts of the world (Järup and Akesson 2009; Satarug et al. 2010). Absorbed Cd accumulates mainly in the liver and the kidney (Orłowski and Piotrowski 2003) and is primarily eliminated from the body in urine (ATSDR 2012). As is a naturally occurring element that is widely distributed in the earth’s crust, and people are exposed to As worldwide (ATSDR 2007). Simultaneous exposure to Cd and As is common in real-world exposure scenarios (Tchounwou et al. 2012). In animal studies, Cd and As have been demonstrated to have diabetogenic effects, such as damage to pancreatic $\mathrm{\beta }\text{cells}$ and impairment of insulin secretion (Edwards and Ackerman 2016; Hectors et al. 2011). A growing number of population-based studies have investigated the association between Cd body burden and type 2 diabetes in the general population. Some (Afridi et al. 2008, 2013; Haswell-Elkins et al. 2007; Kolachi et al. 2011; Li et al. 2017; Schwartz et al. 2003; Son et al. 2015; Wallia et al. 2014), but not all (Barregard et al. 2013; Liu et al. 2016; Moon 2013; Nie et al. 2016; Swaddiwudhipong et al. 2010, 2012, 2015), studies have suggested that an increased risk of diabetes is associated with higher Cd exposure. However, evidence regarding the association of Cd body burden with GDM is limited. Only two previous studies have investigated the association between Cd and GDM: A nested case–control study in China suggested that Cd residues in meconium, which were measured after delivery, were associated with GDM risk (Peng et al. 2015), but a study from Canada using Cd levels in maternal blood collected in the first trimester did not find such an association (Shapiro et al. 2015). However, the Cd concentration in blood is believed to reflect recent exposure, whereas urinary Cd more approximately reflects total body burden; the half-life of Cd is 6–38 y (ATSDR 2012). Evidence from epidemiologic studies has also suggested the association of GDM with As exposure (Ettinger et al. 2009; Farzan et al. 2016; Peng et al. 2015), even at relatively low exposure levels (Shapiro et al. 2015).

In the present study, we collected early-pregnancy urine samples from 2,026 pregnant women and examined whether an increased risk of GDM was associated with higher urinary Cd levels, which provide a better estimation of Cd body burden. We also investigated whether the association between Cd exposure and GDM was modified by fetal sex because women carrying male fetuses have been reported to have a higher risk of GDM than those carrying female fetuses (Jaskolka et al. 2015). We also examined the potential interaction between Cd and As exposure on GDM.

Among the 2,026 participants, 198 (9.8%) women were diagnosed with GDM. Pregnant women with GDM were older (29.9 vs. 28.5 y), had greater prepregnancy BMI (22.4 vs. $20.8{\mathrm{kg}/\mathrm{m}}^2$), and were more likely to be multiparous (18.7% vs.12.4%), than the non-GDM women. There were no significant differences between women with and without GDM in educational attainment, occupational status, passive smoking, hypertensive disorder in pregnancy, and fetal sex (Table 1). Six women were missing occupation data, and two women were missing passive smoking data. No women reported smoking or alcohol consumption during pregnancy in this study.

The geometric means (GMs) of Cd and SG-corrected Cd concentrations in maternal urine of all pregnant women were $0.59\mathrm{\mu }\mathrm{g}/\mathrm{L}$ and $0.67\mathrm{\mu }\mathrm{g}/\mathrm{L}$, respectively (Figure 1). The median value (interquartile range) of urinary Cd concentrations among all women was 0.62 (0.33–1.08) $\mathrm{\mu }\mathrm{g}/\mathrm{L}$. There was no significant difference in SG-corrected Cd concentrations between women with ($\text{GM}=0.66\mathrm{\mu }\mathrm{g}/\mathrm{L}$) and without GDM ($\text{GM}=0.73\mathrm{\mu }\mathrm{g}/\mathrm{L}$).

There was a significant increase in the risk of GDM across increasing tertiles of SG-corrected Cd in crude GEE models [crude RR: $\text{low}=1$; $\text{medium}=1.11$ (95% CI: 0.77, 1.59); $\text{high}=1.43$ (95% CI: 1.02, 2.01); $p\text{for}\text{trend}=0.02$]. After adjustment for a range of potential confounders (maternal age, maternal education, parity, prepregnancy BMI, hypertensive disorder in pregnancy, passive smoking, and fetal sex), the association between maternal Cd and GDM was slightly attenuated, but it remained borderline significant for the top tertile of Cd [adjusted RR: $\text{low}=1$; $\text{medium}=1.04$ (95% CI: 0.74, 1.44); $\text{high}=1.36$ (95% CI: 0.98, 1.90); $p\text{for}\text{trend}=0.05$] (Table 2).

Given the evidence that fetal sex is associated with risk of GDM, we explored the effect modification by fetal sex on the association between urinary Cd and GDM. Among women carrying male fetuses, the risk of GDM increased with increasing tertiles of Cd [adjusted RR for the top vs. bottom $\text{tertile}=1.86$ (95% CI: 1.14, 2.93); $p\text{-}\text{trend}=0.01$], whereas there was no association between Cd and GDM among women carrying female fetuses [adjusted RR for the top vs. bottom $\text{tertile}=0.98$ (95% CI: 0.61, 1.60); $p\text{-}\text{trend}=0.94$] (Table 2). The interaction between urinary Cd and fetal sex on the risk of GDM was significant ($p\text{for}\text{interaction}=0.03$) (Table 2).

Among women with normal prepregnancy BMI ($18.5–23.9{\mathrm{kg}/\mathrm{m}}^2$, $n=\mathrm{1,384}$), adjusted RRs increased with increasing Cd tertile, with a significant association for the top vs. bottom tertile [adjusted $\text{RR}=1.62$ (95% CI: 1.04, 2.53); $p\text{-}\text{trend}=0.03$] (Table 3). Estimates were imprecise for the high-BMI group ($n=276$) and without a consistent trend [top vs. bottom tertile adjusted $\text{RR}=1.14$ (95% CI: 0.64, 2.04); $p\text{-}\text{trend}=0.40$). The interaction between BMI and Cd was not significant ($p=0.42$).

We also investigated the association between continuous urinary Cd levels (${\text{Log}}_{10}\text{-}\mathrm{Cd}$) and PG concentrations. Among the overall study population, we found significant associations between ${\text{Log}}_{10}\text{-}\mathrm{Cd}$ and 2-h PG [$\mathrm{\beta }=0.18$ (95% CI: 0.04, 0.33)], as well as the PG z-score sum [$\mathrm{\beta }=0.37$ (95% CI: 0.09, 0.64)]. No significant associations were observed between ${\text{Log}}_{10}\text{-}\mathrm{Cd}$ and FPG or 1-h PG. Estimated associations with ${\text{Log}}_{10}\text{-}\mathrm{Cd}$ and 2-h PG or PG z-score sum were similar for women carrying male fetuses and women carrying female fetuses, although the estimates were statistically significant only for the larger subgroup of women carrying male fetuses (see Figure S1). When stratified by prepregnancy BMI, associations between ${\text{Log}}_{10}\text{-}\mathrm{Cd}$ and normal-weight women’s 2-h PG and PG z-score sum were similar for women with normal and high BMI but were statistically significant only for the larger group of normal-BMI women (see Figure S2).

We also explored whether the Cd-GDM associations were different between nulliparous and multiparous women by stratified analyses. No significant associations of Cd with GDM were found in either stratum. However, the RRs for GDM appeared larger in multiparous women than in nulliparous women (see Table S1). Estimates from a model including a cross-product term for Cd and As were consistent with a synergistic effect (i.e., a stronger association than expected was observed for the combined exposures based on the observed associations with Cd only and As only), although the interaction was not significant ($p=0.09$) (see Table S2). In the sensitivity analysis that excluded women with passive smoking during pregnancy, the risk of GDM still increased across increasing tertiles of SG-corrected Cd levels, although the associations did not reach statistical significance (see Table S3).

In this study, we observed marginal associations between Cd body burden and the risk of GDM in the overall study population. Among women with male fetuses, the relative risk for those in the top versus bottom tertile of urinary Cd was 1.86 (95% CI: 1.14, 2.93). The association between higher urinary Cd and risk of GDM appeared to be limited to women with normal prepregnancy BMI, although differences between women with high versus normal BMI were not significant.

We are aware of only two published studies addressing the association of Cd exposure with GDM (Peng et al. 2015; Shapiro et al. 2015). Our study is most similar to the study from Canada in its prospective study design (Shapiro et al. 2015). Compared with their population, urinary Cd levels in our population were higher: GM in normal-glucose $\text{women}=0.2\mathrm{\mu }\mathrm{g}/\mathrm{L}$ and GM in GDM $\text{women}=0.3\mathrm{\mu }\mathrm{g}/\mathrm{L}$ (Shapiro et al. 2015) versus GM in normal-glucose $\text{women}=0.66\mathrm{\mu }\mathrm{g}/\mathrm{L}$ and GM in GDM $\text{women}=0.73\mathrm{\mu }\mathrm{g}/\mathrm{L}$ (the present study). Although Shapiro et al. (2015) did not suggest an association between blood Cd level in the first trimester and increased risk of GDM, the relationship remained borderline significant after adjustment for confounders [crude odds ratio $\left(\text{OR}\right)=2.9$ (95% CI: 1.2, 7.0); adjusted $\text{OR}=2.5$ (95% CI: 1.0, 6.4) for highest vs. lowest quartile]. In the present study, we also found a marginally significant association of Cd level with the risk of GDM after adjustment for confounders. A nested case–control study suggested that Cd residues in meconium were associated with a high risk of GDM [adjusted $\text{OR}=16.87$ (95% CI: 4.19, 67.86) for the third quartile; adjusted $\text{OR}=11.95$ (95% CI: 2.97, 48.04) for the highest quartile] (Peng et al. 2015). However, those authors assessed maternal Cd exposure by Cd in meconium, which was measured after the outcome measurement. Moreover, Cd is reported to largely accumulate in the placenta; thus, Cd levels in meconium may not be an accurate reflection of total body burden (Vilahur et al. 2015). In our study, we further examined associations of Cd levels with continuous PG concentrations. Among the three glucose measures (FPG, 1-h PG, and 2-h PG), only 2-h PG had a significant association with Cd level. However, the PG z-score sum was also significantly correlated with Cd level. We speculate that might be the case because PG z-score sum is a composite measure of PG, to some extent similar to the IADPSG criteria.

More studies have addressed associations of Cd exposure with type 2 diabetes than with GDM. Although study findings are inconsistent, most suggest that Cd exposure would increase the risk of type 2 diabetes. In an analysis of NHANES III (Third National Health and Nutrition Examination Survey, 1988–1994) data, urinary Cd levels were associated with impaired fasting glucose and diabetes in a dose-dependent manner [$\text{OR}=1.24$ (95% CI: 1.06, 1.45) for the middle versus bottom tertile; $\text{OR}=1.45$ (95% CI: 1.07, 1.97) for the top versus bottom tertile; p for trend $<0.0001$] (Schwartz et al. 2003). Another study (Wallia et al. 2014) of NHANES (2005–2010) reached the same conclusion [$\text{OR}=1.67$ (95% CI: 1.12, 2.47) for the highest quintile of Cd levels]. A recent meta-analysis also supported the positive association between Cd exposure and risk of type 2 diabetes (Li et al. 2017).

Potential mechanisms for associations between Cd and GDM are not clear. Cd is reported to induce pancreatic $\mathrm{\beta }\text{-}\text{cell}$ death via increased reactive oxygen species (Chang et al. 2013). Notably, $\mathrm{\beta }\text{cells}$ normally increase their insulin secretion to compensate for insulin resistance during pregnancy (Buchanan and Xiang 2005). $\mathrm{\beta }\text{cells}$ undergo hyperplasia, resulting in increases in both insulin secretion and insulin sensitivity in early pregnancy, followed by progressive insulin resistance. In addition, we found evidence of effect modification on the association between Cd and GDM by fetal sex, and the association was more evident and stronger among women carrying male fetuses. To the best of our knowledge, no other study has explored effect modification on the Cd-GDM association by fetal sex. Women carrying male fetuses have been reported to have lower $\mathrm{\beta }\text{-}\text{cell}$ function and higher risk of GDM than women carrying female fetuses (Jaskolka et al. 2015; Retnakaran et al. 2015), and it has been proposed that this phenomenon might be explained by differences in the influence of male versus female fetuses on placental secretion of hormones or proteins involved in $\mathrm{\beta }\text{-}\text{cell}$ compensation (Retnakaran et al. 2015). Given the potential damage to $\mathrm{\beta }\text{cells}$ by Cd, we cautiously speculate that pancreatic $\mathrm{\beta }\text{cells}$ of women carrying male fetuses might be more vulnerable to Cd exposure. Future studies are needed to clarify the influence of fetal sex on the Cd-GDM relationship, as well as the underlying mechanisms.

Evidence of effect modification by prepregnancy BMI was inconclusive, in part because of the relatively small number of women with high prepregnancy BMI. However, associations between urinary Cd and GDM appeared to be limited to normal-weight women, perhaps as a consequence of the higher baseline risk of GDM in obese women compared with normal weight women, which might negate or obscure a smaller effect of Cd exposure (Li et al. 2014). However, potential differences in the association of Cd with GDM between normal- and high-BMI women need to be confirmed in a larger study population. We also performed sensitivity analyses that excluded women who were exposed to passive smoke during pregnancy. The risk of GDM still increased across increasing Cd tertiles, although the observed associations were weakened and became nonsignificant, which might be due to the reduced sample size; another reason for the weakening of the association might be that the women without passive smoking who remained in the analysis had relatively low Cd exposure. Finally, we found preliminary evidence of a synergistic effect of Cd and As on the risk of GDM. In vitro, Cd (Chang et al. 2013; El Muayed et al. 2012) and As (Lu et al. 2011; Yang et al. 2012) have both been shown to cause oxidative stress, impaired glucose-stimulated insulin release, and pancreatic $\mathrm{\beta }\text{-}\text{cell}$ death, which could lead to diabetes (Edwards and Ackerman 2016). However, although a synergistic effect of As and Cd is plausible, future studies are needed to confirm our findings.

Our study has several strengths. First, this prospective cohort study enabled us to assess Cd exposure during early pregnancy, before the onset of GDM, which helped us to avoid the potential bias caused by misclassification of Cd exposure. Second, urinary Cd provides a better reflection of the Cd body burden than blood Cd. We excluded women with type 2 diabetes, which may lead to diabetes-related changes in renal function, thereby increasing urinary excretion of Cd. Third, the interviews, medical record abstraction, and urinary total As concentration provided extensive data on potential confounders. Nevertheless, our study has some limitations. First, we did not account for the impact of micronutrient (i.e., iron, zinc and calcium) intake because participants’ nutritional levels were not registered. Second, the interviews were conducted at delivery, which was after the diagnosis of GDM, which may have led to measurement error in the confounders. Third, although we excluded pregnant women with a family history of diabetes from the study population, the information on family history of diabetes was self-reported and may not have been completely accurate. Finally, some unmeasured or unknown coexposure may contribute to the risk of GDM, although we did control urinary total As.

Our findings suggest that Cd body burden may be a potential risk factor for GDM and that the association may be modified by fetal sex. However, additional studies are needed to confirm these findings in other study populations.

We thank all the participants in the study and all collaborators in the study hospital.

This work was supported by the National Natural Science Foundation of China (21437002, 81372959, 81402649, and 91643207), the National Key Research and Development Plan (2016YFC0206203 and 2016YFC0206700), and the Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology (HUST) (2016YXZD043).

Supplemental Material is available online (https://doi.org/10.1289/EHP2716).

The authors declare they have no actual or potential competing financial interests.

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