Expunerea perinatală la metale grele și consecințele la naștere

1. Introduction

Millions of people around the world are affected by contamination of air and water by toxic metals which are of environmental and human health concern. Food contamination with heavy metals is another concern for both human and animal health. Metals among the other environmental pollutants may also occur naturally and remain in the environment. The exposure to heavy metals has harmful effects on human health, affecting different body organs. The simultaneous exposure to two or more metals may have cumulative effects⁽¹⁾.

It is important to recognize that the fetal exposure to heavy metals, in communities around the world, continue beyond birth, and postnatal exposures are also associated with adverse health effects⁽²⁾. Lead (Pb), mercury (Hg) and arsenic (As) head the list, followed by aluminum (Al), cadmium (Cd), chromium (Cr), nickel (Ni), titanium (Ti) and others, whose presence is not essential to the human body. As a result, exposure to high concentrations is likely to be adversely associated with health outcomes. Since toxic metals are known to cross the placenta and blood-brain barrier and deposit in fetal tissues, children are likely to be susceptible to metal exposure early, starting from the time of gestation. For this reason, maternal metal concentration is frequently used as a proxy for that of a fetus when studying health outcomes⁽³⁾.

Heavy metals enter the human body through primarily ingestion and inhalation. Lead is the most studied metal and is teratogenic prenatally as well as toxic postnatally. The maternal exposure most often occurs through ingestion of dust from lead-based paints or water contaminated by lead pipes. Lead is readily transported across the placenta and can lead to epigenetic changes in the fetus. Maternal and cord blood lead levels have been associated with lower birth weight, shorter birth length, and smaller head circumference⁽⁴⁾. Mercury, which enters the environment through sources such as coal-fired power plants, can enter the body through ingestion of food grown in contaminated soil, or fish that bioaccumulate mercury due to water pollution. Mercury and other heavy metals, such as cadmium and arsenic, have been related to reduced birth weight in the case of exposure of pregnant women⁽⁵⁾.

2. Research method

The aim of this research was to perform a literature review regarding perinatal exposure to heavy metals, in particularly to lead and mercury, and birth outcomes. 

We conducted a non-systematic analysis in PubMed with the following keywords: “lead” AND (OR) “mercury” AND (OR) “perinatal exposure” AND (OR) “birth outcomes”, with publication dates from the 1^st of January 2016 to the 30^th of October 2021 for the first search, and “lead” AND (OR) “mercury” AND (OR) “perinatal exposure” AND (OR) “birth outcomes” with publication dates between the 1^st of January 2020 and the 30^th of October 2021 for the second search.

The objective of the first search was to assess the scientific interest in topic. The second search had the following steps: introduction of words and limits in PubMed with first step exclusion criteria for articles that did not refer to lead and mercury. The second step exclusion criteria refer to the population in whom the search was performed: perinatal exposure and birth outcomes.

3. Results and discussion

Interest in the topic of perinatal exposure to heavy metals and their effects on birth outcomes and childhood health has constantly increased in the last five years. We found a total number of 687 articles related to this subject between the 1^st of January 2016 and the 30^th of October 2021. In the last five years, the interest has constantly increased, with a peak of 143 in 2020. During the period for which we performed the non-systematic analysis (from the 1^st of January 2020 to the 30^th of October 2021), 44 articles were found, of which 18 were considered of interest for our topic, being summarized in Table 1.

Main findings of the selected studies

A study conducted by Zajac et al. suggests that pregnant women living near lead hotspots in low- and middle-income countries may have blood lead levels that put their fetus at risk for adverse neurodevelopmental and other health impacts, which in turn can have quality of life and economic impacts. This underscores the need for increased investment in the remediation of lead-contaminated sites⁽⁶⁾.

In a study investigating prenatal metal mixtures and birth weight for gestational age in a predominately lower-income Hispanic pregnancy cohort in Los Angeles, authors findings suggest that, in this understudied population, Hg may reduce fetal growth – an inverse linear association was estimated for Hg⁽⁷⁾.

Baldewsingh et al., in an article about prenatal mercury exposure in pregnant women from Suriname, found out the fact that most women living in the interior of Suriname had hair mercury levels well above the international accepted action levels. While Hg exposure in pregnant women is of significant concern, it was found that low Hg exposure was associated with low birth weight, suggesting the protective effects of the high consumption of fish containing beneficial nutrients that counteract Hg exposure⁽⁸⁾.

A scoping review about prenatal environmental metal exposure and preterm birth (PTB) in studies between 2000 to 2019 documented a higher incidence of PTB with lead and cadmium exposures. The findings for mercury and arsenic exposures were inconclusive. Metal-induced oxidative stress in the placenta, epigenetic modification, inflammation and endocrine disruptions are the most common pathways through which heavy metals and metalloids affect placental functions, leading to preterm birth⁽⁹⁾.

A systematic review on mercury and prenatal growth concluded that, from the numerous cross-sectional and prospective studies of mercury and fetal growth, many show no strong evidence of an effect, but a significant minority report inverse associations with birth weight, particularly studies of populations with the highest mean mercury concentrations. Gaps remain in understanding the interpretation of different mercury biomarkers and the possible interaction effects⁽¹⁰⁾.

Findings from an article by Ashrap et al. regarding the association with birth outcomes between maternal blood metal and metalloid concentrations in Northern Puerto Rico suggest that low-level prenatal Pb exposure, as well as elevated Mn and Zn exposure may adversely affect birth outcomes. These findings provide further support for the need to reduce Pb exposure as much as possible among pregnant women. Also, mercury was associated with a higher risk of preterm birth at the later window of pregnancy⁽¹¹⁾.

An article by Gajewska et al. suggested that BLL (blood lead level) had an independent and significant association with PE (preeclampsia), while there were no differences in the BLL between the healthy pregnant women and healthy non-pregnant women groups. Furthermore, both the SBP (systolic blood pressure) and DBP (diastolic blood pressure) values were positively associated with BLL. This study indicates that preeclamptic women tend to present with a significantly higher BLL compared to healthy pregnant women⁽¹²⁾.

A study in Suriname about the influence of prenatal exposure to mercury on birth outcomes suggests that, while mercury was not significantly associated with birth weight and low Apgar score, it may affect preterm birth. Mercury exposure was significantly associated with preterm birth in the overall study cohort⁽¹³⁾.

Findings From the UmMuKi Bratislava-Vienna Study, about how gene variants determine placental transfer of perfluoroalkyl substances (PFAS), mercury and lead, and birth outcomes, indicate that fetal exposures to toxic substances and endocrine disrupters can adversely affect lifetime health. In agreement with other European studies, the results show the need to minimize the perinatal exposures. Especially exposures to PFAS and Pb should be investigated at more regular intervals⁽¹⁴⁾.

A review about exposure to toxic metals and per- and polyfluoroalkyl substances (PFAS) and the risk of preeclampsia and preterm birth in the United States suggests that exposure to organic and inorganic toxicants may be significantly associated with the development of preterm birth and preeclampsia. There is a significant heterogeneity among studies of environmental exposures during pregnancy. Many studies found relatively low levels of toxic exposures, reducing the ability to make conclusions regarding dose-dependent effects. Furthermore, the lack of standardization in the definition of “high” or “abnormal” toxicant levels limits the ability to compare results across cohorts⁽¹⁵⁾.

Vaiserman et al. summarize epidemiological findings, indicating that prenatal toxic metal exposure can induce epigenetic dysregulation, thereby potentially affecting adult health outcomes. The present-day environmental conditions, exposure to man-made environmental pollutants, such as heavy metals, including lead, chromium, cadmium, arsenic and mercury, is undoubtedly a factor significantly influencing genetically determined pathways of epigenetic regulation and thereby causing various pathological outcomes. Exposure to heavy metals in utero can be especially hazardous. This is because an organism is most sensitive to stressful events throughout prenatal and early postnatal periods. Moreover, developmentally induced epigenetic modifications can persist long even after a transient environmental signal has disappeared, thereby enhancing the risk for future disorders, sometimes even in subsequent generations (due to the mechanism of transgenerational epigenetic inheritance)⁽¹⁶⁾.

Kima et al. studied birth outcomes associated with ma­ter­nal exposure to metals from electronic waste re­cy­cling in Guiyu, China, and revealed the fact that mothers from Guiyu had higher concentrations of Pb, Cd and Cr, while smaller head circumference and BMI were observed in the Guiyu neonates compared to neonates from the control group. The mixtures model suggested a cumulative impact of the studied metals on head circumference and BMI, but not with birth weight⁽²⁾.

A case-control study about associations between prenatal exposure to cadmium and lead with neural tube defect (NTD) risks that are modified by single nucleotide polymorphisms of fetal MTHFR and SOD2 shows that higher concentrations of Cd, but not Pb, in umbilical cord tissue were associated with a higher risk for NTDs⁽¹⁷⁾.

Research conducted in Suriname regarding association of mercury exposure and maternal sociodemogra­phic on birth outcomes of indigenous and tribal women reveals that indigenous participants had higher odds of adverse birth outcomes compared with tribal participants, independent of their parity and Hg exposure during pregnancy. Ethnic background, maternal age and Hg exposure during pregnancy were independent predictors of preterm birth, which is in line with other studies⁽⁸⁾.

Novo et al., in a review about cellular and molecular mechanisms mediating methylmercury neurotoxicity and neuroinflammation, concluded that oxidative stress, cytokine release, mitochondrial dysfunction, glutamate and Ca²⁺ dyshomeostasis, and ultimately cell death are significant consequences of brain cells exposure to MeHg, but additional research is needed to continue clarifying the precise short-term effects of MeHg on brain cells, as well as the long-term consequences for human health⁽¹⁹⁾.

A study conducted in Norway, regarding the environmental risk factors about maternal seafood intake during pregnancy, prenatal mercury exposure and child Body Mass Index trajectories up to 8 years, showed that within a population with moderate seafood consumption and low mercury exposure, the maternal seafood consumption in pregnancy was associated with child growth trajectories, and the direction of the association varied by seafood type and level of prenatal mercury exposure. Prenatal mercury exposure was negatively associated with child growth. Their findings on maternal seafood intake are likely non-causal⁽²⁰⁾.

Another study about neonatal Pb exposure and capillary blood leukocyte DNA methylation identified associations between DNA methylation and Pb at 32CpG sites, with the majority being inversely associated with Pb concentrations. Their pathway analysis suggested that low-level Pb exposure was related to development and neurological function⁽²¹⁾.

The results of a research conducted by Farzan et al. suggest that early childhood, rather than the prenatal period, may be a critical window of exposure for Hg to influence blood pressure. The study conclusions suggest that this relationship may be modified by sex and birth weight, but further investigation is needed⁽²²⁾.

Adverse health effects of mercury exposure in pregnancy

Mercury is abundant in the earth’s crust and is mobilized into the environment through human industrial activity and natural events such as volcanic activity. Organic mercury is the most toxic form that can readily cross the placental barrier. It can be found as ethylmercury which is present in medical preparations and can passively diffuse the placental barrier, while methylmercury may be present in fish and seafood and can actively cross the barrier via amino acid carriers. On the other hand, inorganic mercury exists in the dental fillings, but also in the atmosphere where it is transferred via the different industrial occupations⁽²³⁾.

Mercury health hazards are catastrophic in the case of perinatal exposure because of two reasons. First, adverse effects of mercury do not imply only the fetus (fetotoxicity), but it can also go on throwing its malinfluences up to the age of 14 years old, as documented by neurophysiological tests, suggesting irreversibility on many occasions⁽²⁴⁾.

All forms of mercury are toxic to the fetus, but methylmercury most readily crosses the placenta to the fetus, where deposition within the developing fetal brain can occur. In the brain, methylmercury causes focal necrosis of neurons and destruction of glial cells and is toxic to the cerebral and cerebellar cortex⁽²⁵⁾. Even when asymptomatic, maternal exposure can lead to spontaneous abortion or retardation⁽²⁶⁾.

Mercury may be a threat to the developing fetus be­cause both elemental and organic forms of mercury can cross the placenta during gestation, where it may accumulate in a far higher dose-to-weight ratio than is possible in an adult⁽¹⁰⁾. An inverse linear association was estimated for Hg in relation with fetal growth, which may be reduced by this toxic metal⁽⁷⁾. Mercury may also affect preterm birth, but the study’s results are inconclusive^(9,11,13,15).

Adverse health effects of lead exposure in pregnancy

For centuries, exposure to high concentrations of lead has been known to pose health hazards. Lead exposure is a concern for pregnant women and young children in low- and middle-income countries. Although most countries have banned leaded gasoline and population average blood lead levels (BLLs) are declining, lead levels at “toxic hotspots” – areas of unusually high contamination – may pose risks to local populations. Hotspots include both legacy and active sites where activities such as used lead acid battery recycling, lead mining and smelting, and electronics (e-waste) recycling have been conducted without stringent environmental protections^(27,28).

Lead exposure during pregnancy can impact both the mother and fetus. In utero and early life lead exposure is linked to adverse neurodevelopmental outcomes, including alterations in cognitive functioning and a reduction in intelligence quotient (IQ) points, even at low levels of exposure. Lead exposure during pregnancy is also a risk factor for reproductive health outcomes such as gestational hypertension, preeclampsia, preterm birth including abortion, and reduced fetal growth⁽⁴⁾. Also, in mothers with higher concentrations of Pb, inverse associations were observed between blood Pb concentrations and head circumference and Ponderal Index of newborns⁽²⁾.

The recommendations of US Centers for Disease Control regarding the frequency of maternal blood lead follow-up testing during pregnancy in females exposed to lead are presented in Table 2⁽²⁹⁾.

Observational studies suggest that prenatal lead exposure, even with maternal blood lead levels below 10 µg/dL, is inversely related to the fetal growth and neurodevelopment independent of the effects of postnatal exposure, though the exact mechanism by which low-level lead exposure, whether incurred prenatally or postnatally, might adversely affect the child development remains uncertain⁽³⁰⁾.

Lead may adversely impact the sexual maturation in the developing female and may reduce fertility, but the scientific evidence is limited. Lead exposure has been associated with an increased risk for gestational hypertension, but the magnitude of the effect, the exposure level at which the risk begins to increase, and whether the risk is more associated with acute or cumulative exposure remain uncertain^(31,32).

No safe blood lead level (BLL) in children exists, and even low levels may cause harm. CDC has not identified an allowable exposure concentration for lead, a level of concern or unsafe level of exposure for either mother or fetus. Instead, CDC is applying public health principles of prevention to intervene when prudent⁽³²⁾.

Recently (in October 2021), CDC has updated the blood lead reference value (BLRV) to 3.5 µg/dL, which provides an opportunity for additional progress in addressing long-standing disparities in lead exposure and BLLs in children⁽³³⁾.

In Table 3, there are presented recommendations regarding breastfeeding or use of reconstituted infant formula in the case of mother exposure to lead.

4. Conclusions

Lead and mercury are naturally occurring elements, ubiquitous in the environment, and are well-known environmental pollutants due to their toxicity, persistence in the environment, and bio-accumulative nature. Humans are exposed to toxic metals through a variety of routes including ingestion, inhalation and absorption through the skin.

Even though some inconsistencies exist in the findings across studies, there is overwhelming evidence that perinatal exposure to heavy metals – particularly to lead and mercury – is associated with a higher incidence of adverse birth outcomes.

Additional studies are needed to examine the extent of the perinatal exposure to these metals and their association with adverse birth outcomes. Studies are also needed to further delineate the mechanisms through which metal exposures lead to adverse birth outcomes.

Developing sustainable technologies to remove contamination, together with improved understanding of environmental and other factors that contribute to adverse birth outcomes, will have a direct impact on public health.

Conflicts of interests: The authors declare no conflict of interests.