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News Author

Miriam E. Tucker

Freelance writer, Medscape

Disclosures

Miriam E. Tucker has no relevant financial relationships.

CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

Disclosures

Laurie Barclay, MD, has the following relevant financial relationships:
Formerly owned stocks in: AbbVie Inc.

Editor/Nurse Planner

Stephanie Corder, ND, RN, CHCP

Associate Director, Accreditation and Compliance, Medscape, LLC

Disclosures

Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Compliance Reviewer

Amanda Jett, PharmD, BCACP

Associate Director, Accreditation and Compliance, Medscape, LLC

Disclosures

Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

CME / CE

Can Heavy Metal Exposure Harm Reproductive Health?

Authors: News Author: Miriam E. Tucker; CME Author: Laurie Barclay, MD
CME / CE Released: 1/6/2023
Valid for credit through: 1/6/2024

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Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

Nurses - 0.25 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

Pharmacists - 0.25 Knowledge-based ACPE (0.025 CEUs)

Physician Assistant - 0.25 AAPA hour(s) of Category I credit

IPCE - 0.25 Interprofessional Continuing Education (IPCE) credit

You Are Eligible For
- Letter of Completion

Target Audience and Goal Statement

This activity is intended for obstetricians/gynecologists/women’s health clinicians, internists, family medicine/primary care clinicians, nurses, diabetologists/endocrinologists, physician assistants, pharmacists, and other members of the health care team who care for women with reproductive health concerns.

The goal of this activity is for clinicians to be better able to describe associations of blood concentrations of lead, cadmium, and mercury, alone and in a mixture, with infertility and long-term amenorrhea.

Upon completion of this activity, participants will:

Assess the associations of blood concentrations of lead, cadmium, and mercury, alone and in a mixture, with infertility and long-term amenorrhea among women of reproductive age, based on a study of such women who completed the National Health and Nutrition Examination Survey 2013 to 2018 and who had blood heavy metals data
Evaluate the clinical implications of associations of blood concentrations of lead, cadmium, and mercury, alone and in a mixture, with infertility and long-term amenorrhea among women of reproductive age, based on a study of such women who completed the National Health and Nutrition Examination Survey 2013 to 2018 and who had blood heavy metals data
Outline implications for the healthcare team

Disclosures

News Author

Miriam E. Tucker

Freelance writer, Medscape

Disclosures

Miriam E. Tucker has no relevant financial relationships.

CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

Disclosures

Laurie Barclay, MD, has the following relevant financial relationships:
Formerly owned stocks in: AbbVie Inc.

Editor/Nurse Planner

Stephanie Corder, ND, RN, CHCP

Associate Director, Accreditation and Compliance, Medscape, LLC

Disclosures

Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Compliance Reviewer

Amanda Jett, PharmD, BCACP

Associate Director, Accreditation and Compliance, Medscape, LLC

Disclosures

Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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In support of improving patient care, Medscape, LLC is jointly accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

This activity was planned by and for the healthcare team, and learners will receive 0.25 Interprofessional Continuing Education (IPCE) credit for learning and change.

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For Pharmacists

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Medscape, LLC has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 0.25 AAPA Category 1 CME credits. Approval is valid until 1/6/2024. PAs should only claim credit commensurate with the extent of their participation.

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

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This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

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Clinical Context

Infertility, or failure to achieve clinical pregnancy after 1 year of unprotected intercourse, affects up to 15% of couples worldwide. Estimated US prevalence of women with impaired fertility has increased from 4.5 million in the early 1980s to ~7.7 million by 2025.

Most women with infertility have reproductive or neuroendocrine disorders, such as premature ovarian insufficiency, oligomenorrhea or amenorrhea, anovulation, poor gamete quality, and other reproductive diseases. Mechanisms of women’s infertility may include genetic factors and exposure to reproductive toxicants, such as heavy metals increasingly released into the environment by industrial development, agricultural practices, and production and use of consumer products.

Study Synopsis and Perspective

The study covered in this summary was published in medRxiv as a preprint and has not yet been peer reviewed.^[1]

Background

Infertility in women has been attributed to both genetic factors and exposure to reproductive toxicants.
Cadmium, lead, and mercury are 3 primary heavy metals listed by the World Health Organization (WHO) as being among the top 10 toxicants of major public health concern.
Women’s reproductive health is vulnerable to environmental toxins, particularly endocrine-disrupting chemicals that interfere with the body’s normal hormone synthesis, secretion, and signaling.
Growing epidemiological and experimental evidence links heavy metals to endocrine-disrupting properties, suggesting a possible causal relationship with women’s infertility and other reproductive disorders.
Most previous studies have had small sample sizes and have focused on a single metal.

Study Design

Data were analyzed for women of reproductive age who participated in the 2013 to 2018 National Health and Nutrition Examination Survey (NHANES) and had blood heavy metals data, including 1999 patients for the comparison of ever-infertile (238 patients) versus fertile (1761 patients) patients and 297 patients for the comparison of ever-infertile (238 patients) versus pregnant (59 patients) patients.
Multiple logistic regression models were used to examine the associations.

Key Results

After full adjustment, including for demographic characteristics and lifestyle factors, there was a positive association between lead concentrations and women’s ever-infertility: As blood lead concentrations increased, women were more likely to be ever-infertile (odds ratio [OR], 1.75) versus fertile and ever-infertile (OR, 3.09) versus pregnant.
No differences were seen for cadmium and mercury concentrations.
For the analysis of ever-infertile versus pregnant patients, blood concentrations of lead in quartiles 3 and 4 were significantly associated with women’s historical infertility (OR, 3.47 and 5.26, respectively), with a dose-dependent relationship seen from quartiles 2 to 4.
No significant associations between blood concentrations of lead or mercury and women’s long-term amenorrhea were identified, but there was a negative association between blood cadmium concentrations in quartiles 2 and 3 and women’s long-term amenorrhea (OR, 0.47 and 0.31, respectively).
No significant associations were found for blood concentrations of the mixture of all 3 heavy metals and long-term amenorrhea.

Limitations

A cross-sectional study that cannot confirm causation and is prone to survival bias.
No information on conditions leading to fertility, such as endometriosis.
Self-reported reproductive health information and imprecision of definitions.
Male infertility factors were not considered.
Single blood measure of heavy metals.

Disclosures

Study funding: National Institutes of Health (NIH).
Author disclosures: NIH, one author received start-up funds from the Environmental and Occupational Health Sciences Institute at Rutgers University.

Study Highlights

Using NHANES 2013 to 2018, 1999 women were identified for analysis of infertility (238 ever-infertile; 1761 fertile) and 1,919 for analysis of long-term amenorrhea.
Percentages of women who exceeded typical or normal levels of blood heavy metals were 18.5% for lead, 0.05% for cadmium, and 0.9% for mercury.
Blood concentrations of lead and heavy metal mixtures were significantly higher in ever-infertile women than pregnant women, but concentrations of cadmium and mercury were similar.
Ever-infertility was not associated with recent long-term amenorrhea.
After multiple logistic regression analysis fully adjusted for demographic and lifestyle factors, there was a significant and dose-dependent positive association between blood lead concentrations and women’s historical infertility, a negative association between cadmium and long-term amenorrhea, and no associations between mercury and heavy metal mixture and women’s infertility or long-term amenorrhea.
As blood lead concentrations increased, women were more likely to be ever-infertile than fertile (OR, 1.75) or pregnant (OR, 3.09).
For analysis of ever-infertile vs pregnant, lead blood concentrations in quartiles 3 and 4 were significantly associated with women’s historical infertility (OR, 3.47 and 5.26, respectively), with a dose-dependent relationship from quartiles 2 to 4.
Blood cadmium concentrations in quartiles 2 and 3 were negatively associated with long-term amenorrhea (OR, 0.47 and 0.31, respectively).
Blood concentrations of lead, mercury, or the mixture of all 3 heavy metals was not significantly associated with long-term amenorrhea.
The investigators concluded that significant percentages of women had blood heavy metal levels exceeding typical or normal levels, that blood concentrations of single lead and heavy metal mixtures were associated with increased historical infertility, and that exposure to heavy metals had differential associations with women’s infertility and long-term amenorrhea.
Female reproductive health is vulnerable to environmental toxins, particularly heavy metals and other endocrine-disrupting chemicals interfering with normal hormone synthesis, secretion, and signaling.
Overall, the risk for heavy metal exposure to women’s reproductive health and fertility mandates prevention and reduction of heavy metal exposure, which is an urgent, unmet need.
Genetic factors and reproductive toxicant exposure may both contribute to female infertility.
WHO’s top-10 list of toxicants of major public health concern includes cadmium, lead, and mercury.
As animal studies found that cadmium may adversely affect female reproduction, the finding that cadmium was protective against long-term amenorrhea was unanticipated.
This may suggest that women with normal menstruation, and thus more upregulated metal transporters in the gastrointestinal tract than amenorrheic women, tend to have higher cadmium blood levels.
Future research is needed to evaluate associations among cadmium levels, dietary patterns, iron levels, and amenorrhea.
Experimental research suggests that lead may affect female fertility via various mechanisms, including menstrual cycle disruption, altered hormone levels, and impaired fetal development.
In mouse models, lead accumulates in the ovary and disrupts folliculogenesis, reduces ovarian reserve, and increases follicle atresia, all of which may contribute to lead-induced historical infertility.
Evidence is insufficient to draw meaningful conclusions about how mercury affects female reproductive outcomes, highlighting the need for additional research.
The lack of association between ever-infertility and recent long-term amenorrhea suggests that recent menstrual cycle status does not reflect fertility history and that amenorrhea is only one of many complex factors contributing to fertility success.
The mechanism underlying amenorrhea remains poorly understood, but may involve both genetic and environmental factors.
Study limitations include that it was a cross-sectional study precluding causal inferences; potential survival bias; lack of data on endometriosis, other conditions impairing fertility, and male infertility factors; reliance on self-report for reproductive health information; imprecise definitions; and reliance on a single blood measure of heavy metals.

Clinical Implications

Exposure to heavy metals had differential associations with women’s infertility and long-term amenorrhea.
Overall, the risk for heavy metal exposure to women’s reproductive health and fertility mandates prevention and reduction of heavy metal exposure, which is an urgent, unmet need.
Implications for the Health Care Team: Members of the healthcare team should educate women of childbearing age about the risks posed by exposure to heavy metals, including cadmium, lead and mercury.

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Disclaimer

The educational activity presented above may involve simulated, case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient, whether living or deceased, is intended or should be inferred. The material presented here does not necessarily reflect the views of Medscape, LLC, or any individuals or commercial entities that support companies that support educational programming on medscape.org. These materials may include discussion of therapeutic products that have not been approved by the US Food and Drug Administration, off-label uses of approved products, or data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. Readers should verify all information and data before treating patients or employing any therapies described in this or any educational activity. A qualified healthcare professional should be consulted before using any therapeutic product discussed herein.

Faculty and Disclosures

News Author

Miriam E. Tucker

CME Author

Laurie Barclay, MD

Editor/Nurse Planner

Stephanie Corder, ND, RN, CHCP

Compliance Reviewer

Amanda Jett, PharmD, BCACP

CME / CE

Can Heavy Metal Exposure Harm Reproductive Health?

Credits Available

You Are Eligible For

Target Audience and Goal Statement

Disclosures

News Author

Miriam E. Tucker

CME Author

Laurie Barclay, MD

Editor/Nurse Planner

Stephanie Corder, ND, RN, CHCP

Compliance Reviewer

Amanda Jett, PharmD, BCACP

Accreditation Statements

For Physicians

For Nurses

For Pharmacists

For Physician Assistants

Instructions for Participation and Credit

Can Heavy Metal Exposure Harm Reproductive Health?

Clinical Context

Study Synopsis and Perspective

Study Highlights

Clinical Implications