The relationship between cadmium exposure and preeclampsia: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-2966265/v1

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The relationship between cadmium exposure and preeclampsia: A systematic review and meta-analysis

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Cadmium (Cd) is a heavy metal that has been associated with several disorders in humans. Preeclampsia is a major cause of maternal mortality worldwide. Despite numerous studies on the subject, the association between Cd exposure and preeclampsia remains elusive. To better understand this relationship, we conducted a systematic review and meta-analysis of eligible studies from five databases (PubMed, Embase, Web of Science, Scopus, and CNKI) from their inception to September 10, 2022. The quality of these studies was evaluated using the Newcastle-Ottawa quality assessment scale (NOS). We calculated overall standardized mean differences (SMDs) and 95% confidence intervals (CIs) using random-effects models. Sensitivity analyses were performed to assess the robustness of our results. We also evaluated publication bias using Egger’s and Begg’s tests. Additionally, we conducted meta-regression and subgroup analyses to identify potential sources of heterogeneity among studies. Our analysis included a total of 17 studies with 10,373 participants. We found a significant association between maternal cadmium exposure and the risk of preeclampsia (SMD 0.27, 95% CI 0.09–0.44, p < 0.001). No significant publication bias was detected in either Begg’s or Egger’s tests. Meta-regression suggested that factors such as geographical location, year of publication, cadmium samples, sample size, and measurement methods did not contribute to heterogeneity between studies. Our findings suggest that maternal cadmium exposure is associated with an increased risk of preeclampsia. Further high-quality clinical studies and animal experiments are needed to better understand this association.

cadmium

heavy metal

preeclampsia

blood pressure

meta-analysis

systematic review

Cadmium (Cd) is a natural element usually exist in soil, rocks, coal and mineral fertilisers(Satarug 2018). As a heavy metal, it can co-exist with zinc, copper, and lead minerals. Cadmium is widely used in the mining and smelting of non-ferrous metals, the manufacture of fertilizers, and the burning of fossil fuels and wastes. Human exposure to Cd is primarily via taking contaminated food, especially leafy green vegetables. Spinach (0.124 mg/kg) and lettuce (0.051 mg/kg) contain the highest levels of Cd. Regular consumption of shellfish and animal organ (e.g. liver and kidney) can increase risk of cadmium exposure(Faroon, et al. 2012). According to the World Health Organization and the International Agency for Research on Cancer, Cd is the group I human carcinogen(Straif, et al. 2009). Epidemiological studies have shown that cadmium exposure via respiration or drinking contaminated water could lead to cancer of the lung(Nawrot, et al. 2006; Straif, et al. 2009), prostate(Straif, et al. 2009), kidney(Straif, et al. 2009), bladder(Kellen, et al. 2007).

Preeclampsia (PE) is a major feto-maternal threat that affects around 5% of pregnancies worldwide(Abalos, et al. 2013; Ananth, et al. 2013; Duley 2009; Wallis, et al. 2008). It is defined as either a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, or both, on two occasions at least 4 hours apart after 20 weeks of gestation in a previously normotensive woman(ACOG 2020). Apart from hypertension, preeclampsia also involves multiple systemic presentations, including reduced maternal platelets, headache, and fetal growth restriction, etc. This has caused a global concern, imposing heavy burden on public health. Despite multiple genetic, angiogenic, and immune predispositions identified in the recent decades, its etiology remains unclear(Phipps, et al. 2019).

The relationship between cadmium and preeclampsia has not been fully explored before, but we may extrapolate it from existing studies focusing on the association between Cd exposure and varieties in blood pressure (BP). Gallagher et al. was the first to systematically investigate the association between cadmium exposure and hypertension(Chowdhury, et al. 2018). In their study, a positive correlation between blood Cd and BP, along with a negative correlation between urine Cd and BP were identified. These were more prominent among females. More recent studies have explored the intrisinc role of Cd in the development of vasculopathy, eventually leading to hypertension(Aramjoo, et al. 2022; Chowdhury, et al. 2018; Jarup and Akesson 2009; Martins, et al. 2021). Possible mechanisms of cadmium-induced hypertension can be renal failure, calcium signaling disruption, oxidative stress disorder, obstruction of the renin-angiotensin system, and vascular endothelial disorder(Almenara, et al. 2020; Prozialeck, et al. 2008).

Women usually have higher blood levels of Cd than men (median 0.41 vs 0.17 ug/L, P < 0.001), especially in reproductive age(Baecklund, et al. 1999; Fransson, et al. 2014; Vahter, et al. 2007). The difference is less obvious after menopause(Baecklund, et al. 1999). This leads to two questions: 1) whether a high level of Cd predispose women to developing preeclampsia; 2) whether women who are with higher level of Cd are more likely to develop preeclampsia. These have not been explored yet. The placenta serves as an effective barrier against Cd, with only 0.01% of Cd passed on to fetuses(Whelton, et al. 1993). Cd is hence partially concentrated in the placenta, causing potential placental and feto-maternal damage, such as fetal growth restriction (FGR), and maternal gestational diabetes mellitus (GDM)(Vidal, et al. 2015). This effect could extend to childhood, causing neurobehavioral disorders and delayed physiological development(Amegah, et al. 2021; Kippler, et al. 2012; Liu, et al. 2018b; Wang, et al. 2016; Zhu, et al. 2022).

To the best of our knowledge, we are the first to conduct a comprehensive and updated systematic review to specifically focus on the relationship between Cd exposure and PE.

The study protocol was registered with PROSPERO (No. CRD42022361291). The article was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=361291

2.1. Search strategy

Two investigators (ZX.Z. and C.L.) independently searched four international electronic databases (PubMed, Scopus, Embase and Web of Science) as well as the China National Knowledge Infrastructure (CNKI), from database inception to September 10, 2022. The search syntax applied in the databases was (Cadmium OR “heavy metal” OR “trace element”) AND (preeclampsia OR eclampsia OR pre-eclampsia OR gestosis OR “pregnancy hypertension” OR “pregnancy-induced hypertension” OR “pregnancy-associated hypertension” OR “hypertensive disorders of pregnancy” OR “pregnancy toxemia” OR “gestational hypertension” OR “HELLP syndrome*”). The detailed search strategies can be accessed in Supplementary Search Strategy. Two independent reviewers (C.L. and ZX.Z.) initially screened all articles to assessed for eligibility in accordance with the title and abstract. In addition, we searched for a list of the references and related review articles for additional articles. These include studies written in English or Chinese.

2.2. Eligibility criteria and study selection

The criteria for inclusion and exclusion of studies were established prior to the literature search. Articles were included if the following criteria were met: (1) observational studies involving maternal levels of cadmium and preeclampsia; (2) the exposure of interest should include cadmium while the outcome of interest should include preeclampsia; (3) the control should be pregnant women instead of non-pregnant women; (4) investigated the relationship between exposure to cadmium and any results mentioned in the search statement.

Articles were excluded if: (1) Studies not based on blood Cd level in maternal or placenta or urine, for instance, Cd exposure level in soil, or Cd level in maternal hair. (2) Duplicates, irrelevant studies, letters, reviews, commentaries, and conference abstracts were excluded.

Selected articles were retrieved thoroughly and further assessed for eligibility. ZX.Z. and C.L. screened the studies, and a third reviewer, YP.Y. was to resolve any discrepancies between the two.

2.3. Data extraction and quality assessment

The following information was extracted from the studies included: the first author and year of publication, location of the study, study types, number of participants, types of specimen, sample size, Cd level, average maternal age with standard deviation, sample collect time, methods of measurement and diagnostic criteria.

The quality of the eligible articles was evaluated by the Newcastle-Ottawa Scale (NOS), used to assess case-control, cohort studies. A nine-star rating system evaluated by three dimensions, such as selection, comparability, outcome ascertainment. A score between 7 and 9 indicates good quality, while 4 to 6 was considered moderate quality. Poor quality was defined if the score was ≤ 3. A modified form of NOS was used for assessing cross-sectional studies. The scores rated from 0 to 10. Studies were assessed as high quality when they had a score > 7, while studies < 3 were represented as low quality. Fair quality was defined if the score was between good and poor(Modesti, et al. 2016).

2.4. Sub-group analysis and meta-regression

Sub-group analysis and meta-regression were performed to assess whether geographic locations, sample types (blood, urine, placenta), or measurements influenced the correlations. We divided all studies into five groups based on the original location of the study population: Asian studies were all from China. Studies from the USA were allocated to American. African studies consisted of reports from the Democratic Republic of Congo and South Africa. Middle-East studies covered reports from Iran and Turkey. European studies contained reports from France and the Republic of Serbia.

2.5. Statistical analysis

We calculated the results and performed data analysis via Review Manager 5.1 (The Nordic Cochrane Center, Copenhagen, Denmark) and Stata version 16.0 (StataCorp, College Station, TX, USA). The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to summarize maternal exposure levels of cadmium. Heterogeneity was tested by I² (I² ≥ 50% indicates high heterogeneity). The forest plot was used to visualize the overall results, with the random-effect model (REM) being adopted for calculation as the heterogeneity was considered significant. A sensitivity analysis was performed, removing each study once to assess whether anyone study influenced the overall results. Publication bias was visualized via funnel plot and verified by Begg’s and Egger’s tests.

3.1. Study selection

692 articles identified via searching five databases (PubMed, Scopus, Embase, Web of Science, and CNKI). After examining all the references from full-text articles, eight additional studies were identified. Of the 700 studies, 246 were deleted due to duplication. 454 literatures were further screened, and 422 were excluded after preliminarily browsing the title and abstract. There were 32 records being evaluted in the full-text assessment. 15 of them were removed for reasons: Six studies were excluded for not reporting cadmium samples(Akinloye, et al. 2010; Hamdan, et al. 2020; Harrington, et al. 2016; Kahn and Trasande 2018; Rduch, et al. 2022; Zhang, et al. 2022). Four that reported amniotic fluid or nail samples were not included in our study(Dawson, et al. 1999; Ebrahim and Ashtarinezhad 2015; Soobramoney, et al. 2019; Suliburska, et al. 2016). One article was excluded for overlapped the study population with another article which was included(Zhang, et al. 2016a). One was conference paper(Liu, et al. 2019a). Two studies that reported incomplete or absent data, such as no integral data for normal pregnancy and PE(Osorio-Yañez, et al. 2016; Padula, et al. 2021). One article failed to make it into the finalist as it mainly focused on the relationship between Cd exposure and obstetric outcomes during pregnancy without preeclampsia(Kovalchuk, et al. 2013). The remaining 17 reports were included in systematic review and meta-analysis(Bommarito, et al. 2019; Elongi Moyene, et al. 2016; Kolusari, et al. 2008; Kosanovic, et al. 2002; Laine, et al. 2015; Li, et al. 2022; Liu, et al. 2018a; Liu, et al. 2019b; Maduray, et al. 2017; Musa Obadia, et al. 2018; Ovayolu, et al. 2021; Vigeh, et al. 2006; Wang, et al. 2018; Wang, et al. 2008; Wang, et al. 2020; Yazbeck, et al. 2009; Zhang, et al. 2018). Details of the study selection process can be illustrated in Fig. 1.

3.2. Characteristics of included studies

The 17 articles from 9 countries spanning over two decades. The size of the population between different studies was contrastingly different, ranging from 46 (minimum) to 5429 (maximum). Differences were also observed in varied types of samples (blood, urine, placenta) and methods of measurement, such as inductively coupled plasma optical emission spectrometry (ICP-OES), inductively coupled plasma mass spectrometry (ICP-MS), and atomic absorption spectrometry (AAS). Despite these differences, most studies adopted ACOG’s diagnostic criteria of preeclampsia. More detailed information can be seen in Supplementary Table 1.

3.3. Results of the systematic review

The 17 studies were further divided into case-control and cohort studies, and assessed by NOS and modified NOS. None of the studies was evaluated as fair or poor quality. The specific score is accessible in Supplementary Tables 2, 3.

3.4. Results of meta-analysis

The meta-analysis of the 17 reports included a total of 10,373 participants. The number of healthy pregnant controls was much more compared to the case group. There were 1,403 preeclamptic women, and more than six-fold more as non-preeclamptic pregnant women(1,403 Vs. 8,970). The overall results showed that maternal cadmium exposure in preeclamptic women was significantly higher than that of healthy pregnant control (SMD 0.27, 95% CI 0.09–0.44); (I² = 82.6%; p = 0.000), see Fig. 2. The funnel plot showed insignificant publication bias, as shown in Fig. 3. Publication bias were evaluated quantitatively by Begg’s test and Egger’s test (z = 2.06, p = 0.039; t = 1.86, p = 0.082; see Supplementary Fig. 2). The leave-one-out sensitivity analysis showed that Moyene et al. and Zhang et al. reported inverse contributions to the combined results (Supplementary Fig. 3)(Elongi Moyene, et al. 2016; Zhang, et al. 2018).

3.5. Results of meta-regression

Meta-regression was performed because of significant heterogeneity between studies. Different year of publication, geographical locations, different types of samples of cadmium, sample size, and measurement methods were further tested to look for potential causes of heterogeneity. However, it turned out that none of them was the major contributor (p-value of sample type: 0.766; p-value of location: 0.465; P-value of measurements: 0.685; p-value of year: 0.609; p-value of sample size: 0.145). Detailed information can be seen in Supplementary Fig. 4.

In the systematic review and meta-analysis, we recruited 17 studies involving 10,373 pregnant women to confirm the positive association between Cd exposure and preeclampsia. We also observed that sample selection bias, measurements, study designs may contribute the heterogeneity between studies. The meta-analysis found that maternal cadmium exposure in preeclamptic women was significantly higher than that of healthy pregnant controls. Generally, blood Cd usually reflects recent Cd exposure, while urine Cd levels generally reflects long-term Cd exposure(Adams and Newcomb 2014; Faroon, et al. 2012).

The link between Cd and hypertensive disorders was first proposed by Henry. In his animal study in 1965, a hypertensive animal models were successfully replicated through injection to pregnant rats with a water solution of Cd(Schroeder and Buckman 1967). The pregnant rats developed some forms of typical clinical manifestations, such as hypertension, albuminuria and FGR during pregnancy. Autopsy histopathological report revealed endothelial cells swelling, thickening of the media of the renal vessel walls, and protein tubes formation in the renal tubules. The impaired placental angiogenesis were the typical changes in human with PE(Wang, et al. 2014; Zhang, et al. 2016a). Cd can change the placental structure, thereby affecting the function of placental transfer, predisposing pregnant women to PE(Zhang, et al. 2019).

Cadmium can also expresse a potent estrogen-like activity in vivo, stimulating the growth of myometrium(Byrne, et al. 2009; Knazicka, et al. 2015). In animal models, the exposure to Cd can increase uterine weight and induced the expression of hormone-regulating genes expression even after oophrectomy(Johnson, et al. 2003). Cadmium enhances Lipopolysaccharide (LPS) and interleukin 4 (IL-4) mediated activation. The activation-induced cytosine deaminase (AID) expresses in B cells via the estrogen receptor(Pauklin 2016; Zhang, et al. 2016a). It can up-regulate the angiotensin II type 1-receptor-agonistic autoantibodies (AT1-AAs), inducing hypertension(Modesti, et al. 2016; Zhang, et al. 2016a). Cadmium-mediated complement C5a receptor activates C5, which further activates AT1R leading to increased blood pressure(Zhang, et al. 2016a). In vitro studies have shown that cadmium up-regulates gene expression in transforming growth factor-β (TGF-β) pathway and IL-8(Adebambo, et al. 2018; Brooks, et al. 2016; Hu, et al. 2018), thereby inhibiting the migration of placental trophoblast cells(Brooks and Fry 2017). Reduced migration of trophoblast cells are arguably one of the mechanisms of the development of preeclampsia(Burton, et al. 2019; Kadyrov, et al. 2006). Cd induces IL-6 production in trophoblast cells through a reactive oxygen species (ROS) dependent activation of the extracellular signal-regulated kinases (ERK)1/2 to and increased ERK1/2, c-Jun N-terminal kinases (JNK), and c-Jun phosphorylation(Hu, et al. 2018), it then stimulate B cell production of AT1R(Paniagua, et al. 2019; Zhang, et al. 2019), contributing to the endothelial dysfunction and eventually hypertension in pregnancy. Furthermore, normal pregnant rats with long-term injection of IL-6 showed significant increase in arterial pressure(Gadonski, et al. 2006). Previous studies have identified that cadmium exposure decreased the expression of vascular endothelial growth factor (VEGF) and placental growth factor (PLGF)(Bommarito, et al. 2019; Li, et al. 2022), which activate systemic maternal endothelia leading to vascular injury and hypertension(Burton, et al. 2019; Chappell, et al. 2021). In vivo studies have suggested that cadmium may induce preeclampsia by impairing the immune function(Zhang, et al. 2016a), increasing oxidative DNA damage in the placenta(Zhang, et al. 2016b) and damaging the kidneys(Jacobo-Estrada, et al. 2017). However, Sutoo and Akiyama found contradictory fact in rats(Sutoo and Akiyama 2000). They observed that the exposure to Cd increases dopamine through calmodulin, which in turn lowers blood pressure(Sutoo and Akiyama 2000). Whether cadmium raises blood pressure remains controversial.

There were two previous systematic reviews that reported the correlation between Cd exposure and preeclampsia. Pollack et al. study included only three studies. Two of the investigations were cross-sectional. One did not adjust for potential confounders, while the other one only reported term preeclampsia in pregnancy outcome(Pollack, et al. 2014). The limited number of articles may give biased perspective. Meanwhile, Stone et al. study in 2021 was very comprehensively designed and written, including inorganic toxicants (arsenic, cadmium, mercury, lead)(Stone, et al. 2021). Nevertheless, there was a significant mistake with regard to the accuracy of the data. We have found that the review extracted results from Dawson et al. study by mistake(Dawson, et al. 1999). The sample type should be amniotic fluid instead of maternal red blood cells, and the total numbers of participants were also wrong (should be 130 instead of 29). The inaccurate data extraction may compromise the reliability of the overall result aggregated in this meta-analysis.

By comparison, there are several strengths in our report. First, this is the first meta-analysis to pool blood, urine and placental Cd comprehensively together to explore the association between Cd and preeclampsia. Second, our meta-analysis has included all the recent available studies to maximally avoid selection bias. We also included articles written in Chinese as there are many articles focusing on this topic. This is because the environmental contamination of heavy metals is a hot research topic in China currently. This helps complete evidence for this research. Third, we conducted sub-group analyses and meta-regression to further explore the association and determine the source of heterogeneity between studies.

However, we also noted some limitations in our study. The studies that met the inclusion criteria were still limited compared to other heavy metal studies(Zhong, et al. 2022), this confined us from exploring deeper. Furthermore, some studies reported the correlation between Cd and preeclampsia but did not report their data completely, and hence we could not pool them together for further analysis(Kovalchuk, et al. 2013; Osorio-Yañez, et al. 2016).

In summary, our meta-analysis provides quantitative evidence that Cd exposure is positively associated with preeclampsia in pregnancy. Large cohort studies, animal studies are needed to further clarify the role of cadmium in the pathogenesis of PE.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Materials, further inquiries can be directed to the corresponding author.

Supplementary materials

The following supporting information can be accessible upon request.

Funding:This work was supported by the Zhejiang Provincial Project for Medical and Health Science [2022503241].

Competing Interests:The authors have no relevant financial or non-financial interests to disclose.

Author Contributionsn: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Chu Li, Zixing Zhong and Yunping Yang. The first draft of the manuscript was written by Chu Li and Zixing Zhong reviewed and edited the manuscriptall.Qianqian Wang and Yanmei Zheng commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments:This work was supported by the Zhejiang Provincial Project for Medical and Health Science [2022503241].

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The relationship between cadmium exposure and preeclampsia: A systematic review and meta-analysis

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Abstract

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1.Introduction

2. Methods

2.1. Search strategy

2.2. Eligibility criteria and study selection

2.3. Data extraction and quality assessment

2.4. Sub-group analysis and meta-regression

2.5. Statistical analysis

3. Results

3.1. Study selection

3.2. Characteristics of included studies

3.3. Results of the systematic review

3.4. Results of meta-analysis

3.5. Results of meta-regression

4. Discussion

5. Conclusion

Declarations

References

Supplementary Files

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