Association of Arsenic with Adverse Pregnancy Outcomes/Infant Mortality: A Systematic Review and Meta-Analysis

Background Exposure to arsenic is one of the major global health problems, affecting > 300 million people worldwide, but arsenic’s effects on human reproduction are uncertain. Objectives We conducted a systematic review and meta-analysis to examine the association between arsenic and adverse pregnancy outcomes/infant mortality. Methods We searched PubMed and Ovid MEDLINE (from 1946 through July 2013) and EMBASE (from 1988 through July 2013) databases and the reference lists of reviews and relevant articles. Studies satisfying our a priori eligibility criteria were evaluated independently by two authors. Results Our systematic search yielded 888 articles; of these, 23 were included in the systematic review. Sixteen provided sufficient data for our quantitative analysis. Arsenic in groundwater (≥ 50 μg/L) was associated with increased risk of spontaneous abortion (6 studies: OR = 1.98; 95% CI: 1.27, 3.10), stillbirth (9 studies: OR = 1.77; 95% CI: 1.32, 2.36), moderate risk of neonatal mortality (5 studies: OR = 1.51; 95% CI: 1.28, 1.78), and infant mortality (7 studies: OR = 1.35; 95% CI: 1.12, 1.62). Exposure to environmental arsenic was associated with a significant reduction in birth weight (4 studies: β = –53.2 g; 95% CI: –94.9, –11.4). There was paucity of evidence for low-to-moderate arsenic dose. Conclusions Arsenic is associated with adverse pregnancy outcomes and infant mortality. The interpretation of the causal association is hampered by methodological challenges and limited number of studies on dose response. Exposure to arsenic continues to be a major global health issue, and we therefore advocate for high-quality prospective studies that include individual-level data to quantify the impact of arsenic on adverse pregnancy outcomes/infant mortality. Citation Quansah R, Armah FA, Essumang DK, Luginaah I, Clarke E, Marfoh K, Cobbina SJ, Nketiah-Amponsah E, Namujju PB, Obiri S, Dzodzomenyo M. 2015. Association of arsenic with adverse pregnancy outcomes/infant mortality: a systematic review and meta-analysis. Environ Health Perspect 123:412–421; http://dx.doi.org/10.1289/ehp.1307894

[1]  E. Guallar,et al.  Arsenic Exposure and Type 2 Diabetes: A Systematic Review of the Experimental and Epidemiologic Evidence , 2005, Environmental health perspectives.

[2]  J. A. Roberson,et al.  Some drinking-water disinfectants and contaminants, including arsenic. , 2004, IARC monographs on the evaluation of carcinogenic risks to humans.

[3]  N. Cherry,et al.  Risk of arsenic-related skin lesions in Bangladeshi villages at relatively low exposure: a report from Gonoshasthaya Kendra. , 2007, Bulletin of the World Health Organization.

[4]  A. Smith,et al.  Pregnancy outcomes, infant mortality, and arsenic in drinking water in West Bengal, India. , 2006, American journal of epidemiology.

[5]  J. Thakur,et al.  Adverse reproductive and child health outcomes among people living near highly toxic waste water drains in Punjab, India , 2009, Journal of Epidemiology & Community Health.

[6]  S. Obiri,et al.  Arsenic, Cadmium, and Mercury in Cocoyam (Xanthosoma sagititolium) and Watercocoyam (Colocasia esculenta) in Tarkwa a Mining Community , 2007, Bulletin of environmental contamination and toxicology.

[7]  E. Horvath,et al.  Arsenic exposure. , 1985, JAMA.

[8]  S. Murcott Arsenic contamination in the world : an international sourcebook 2012 , 2012 .

[9]  Sunil Kumar Occupational, Environmental and Lifestyle Factors Associated With Spontaneous Abortion , 2011, Reproductive Sciences.

[10]  Mohammed Yunus,et al.  Arsenic exposure during pregnancy and size at birth: a prospective cohort study in Bangladesh. , 2008, American journal of epidemiology.

[11]  S. Zierler,et al.  Quality of community drinking water and the occurrence of spontaneous abortion. , 1989, Archives of environmental health.

[12]  Lei Jin,et al.  Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. , 2013, Reproductive toxicology.

[13]  Michael S Kramer,et al.  The epidemiology of adverse pregnancy outcomes: an overview. , 2003, The Journal of nutrition.

[14]  R. Black,et al.  Research Priorities for the Reduction of Perinatal and Neonatal Morbidity and Mortality in Developing Country Communities , 2002, Journal of Perinatology.

[15]  J. Sen,et al.  Effect of Arsenic on the Onset of Menarcheal Age , 2007, Bulletin of Environmental Contamination and Toxicology.

[16]  Alexander van Geen,et al.  Chronic Arsenic Exposure and Blood Glutathione and Glutathione Disulfide Concentrations in Bangladeshi Adults , 2013, Environmental health perspectives.

[17]  C. Ronsmans,et al.  Measuring the need for life‐saving obstetric surgery in developing countries , 2004, BJOG : an international journal of obstetrics and gynaecology.

[18]  Y. Liao,et al.  Arsenic levels in the soil and risk of birth defects: a population-based case-control study using GIS technology. , 2011, Journal of environmental health.

[19]  Keli Zhang,et al.  Links between environmental geochemistry and rate of birth defects: Shanxi Province, China. , 2011, Science of the Total Environment.

[20]  D. Essumang Analysis and Human Health Risk Assessment of Arsenic, Cadmium, and Mercury in Manta Birostris (Manta Ray) Caught Along the Ghanaian Coastline , 2009 .

[21]  J. Higgins,et al.  Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. , 2007, International journal of epidemiology.

[22]  G. McMillan,et al.  Mortality among Children Residing near the American Smelting and Refining Company (ASARCO) Copper Smelter in Ruston, Washington , 2003, Archives of environmental health.

[23]  M. Vahter Effects of arsenic on maternal and fetal health. , 2009, Annual review of nutrition.

[24]  Xue Gu,et al.  Unusual patterns of neural tube defects in a high risk region of northern China. , 2009, Biomedical and environmental sciences : BES.

[25]  M. Vahter,et al.  Arsenic Exposure and Risk of Spontaneous Abortion, Stillbirth, and Infant Mortality , 2010, Epidemiology.

[26]  R. Kwok A review and rationale for studying the cardiovascular effects of drinking water arsenic in women of reproductive age. , 2007, Toxicology and applied pharmacology.

[27]  C. Baynes,et al.  A Hospital‐Based Case‐Control Study of Stillbirths and Environmental Exposure to Arsenic Using an Atmospheric Dispersion Model Linked to a Geographical Information System , 1998, Epidemiology.

[28]  D. Chakraborti,et al.  Murshidabad—One of the Nine Groundwater Arsenic-Affected Districts of West Bengal, India. Part II: Dermatological, Neurological, and Obstetric Findings , 2005, Clinical toxicology.

[29]  I. Hertz-Picciotto,et al.  Arsenic Exposure from Drinking Water and Birth Weight , 2003, Epidemiology.

[30]  S. Arifeen,et al.  Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh. , 2009, Toxicology letters.

[31]  M. Vahter,et al.  Pre- and Postnatal Arsenic Exposure and Body Size to 2 Years of Age: A Cohort Study in Rural Bangladesh , 2012, Environmental health perspectives.

[32]  M. Vahter Interactions between arsenic-induced toxicity and nutrition in early life. , 2007, The Journal of nutrition.

[33]  Y. Ko,et al.  Mortality for certain diseases in areas with high levels of arsenic in drinking water. , 1999, Archives of environmental health.

[34]  E. Gurzău,et al.  Spontaneous pregnancy loss in humans and exposure to arsenic in drinking water. , 2010, International journal of hygiene and environmental health.

[35]  Sharon L. Myers,et al.  Maternal drinking water arsenic exposure and perinatal outcomes in Inner Mongolia, China , 2009, Journal of Epidemiology & Community Health.

[36]  M. Vahter,et al.  Association of arsenic exposure during pregnancy with fetal loss and infant death: a cohort study in Bangladesh. , 2007, American journal of epidemiology.

[37]  Nazmul Sohel,et al.  Arsenic in Drinking Water and Adult Mortality: A Population-based Cohort Study in Rural Bangladesh , 2009, Epidemiology.

[38]  M. Hughes Biomarkers of Exposure: A Case Study with Inorganic Arsenic , 2006, Environmental health perspectives.

[39]  P. Tugwell,et al.  The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses , 2014 .

[40]  L. Say,et al.  Risk Factors for Stillbirth in Developing Countries: A Systematic Review of the Literature , 2007, Sexually transmitted diseases.

[41]  A H Smith,et al.  Lung and kidney cancer mortality associated with arsenic in drinking water in Córdoba, Argentina. , 1998, International journal of epidemiology.

[42]  M. Llanos,et al.  Fetal growth restriction is related to placental levels of cadmium, lead and arsenic but not with antioxidant activities. , 2009, Reproductive toxicology.

[43]  D. Christiani,et al.  Maternal Arsenic Exposure Associated With Low Birth Weight in Bangladesh , 2007, Journal of occupational and environmental medicine.

[44]  Wayne Smith,et al.  Chronic Arsenic Exposure and Adverse Pregnancy Outcomes in Bangladesh , 2005, Epidemiology.

[45]  Mohammad Sohel Rahman,et al.  An eight-year study report on arsenic contamination in groundwater and health effects in Eruani village, Bangladesh and an approach for its mitigation. , 2006, Journal of health, population, and nutrition.

[46]  E. T. Snow,et al.  Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. , 1998, Mutation research.

[47]  J. Higgins Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration , 2011 .

[48]  G. Ozolins,et al.  WHO guidelines for drinking-water quality. , 1984, WHO chronicle.

[49]  J. Sen,et al.  Arsenic Exposure through Drinking Water and its Effect on Pregnancy Outcome in Bengali Women , 2008, Arhiv za higijenu rada i toksikologiju.

[50]  M. Vahter,et al.  Exposure to inorganic arsenic metabolites during early human development. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[51]  D. Chakraborti,et al.  Arsenic groundwater contamination and its health effects in the state of Uttar Pradesh (UP) in upper and middle Ganga plain, India: a severe danger. , 2006, The Science of the total environment.

[52]  M. Vahter,et al.  Intra-individual variation in the metabolism of inorganic arsenic , 2002, International archives of occupational and environmental health.

[53]  T. Yoshimura,et al.  The Prevalence of Subjective Symptoms after Exposure to Arsenic in Drinking Water in Inner Mongolia, China , 2003, Journal of epidemiology.

[54]  U. Högberg,et al.  Perinatal outcome among the offspring of employees and people living around a Swedish smelter. , 1995, Scandinavian journal of work, environment & health.

[55]  D. Brooks,et al.  Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[56]  A. K. Chakraborti,et al.  Arsenic groundwater contamination in Middle Ganga Plain, Bihar, India: a future danger? , 2003, Environmental health perspectives.

[57]  P. Shah,et al.  KNOWLEDGE SYNTHESIS GROUP ON DETERMINANTS OF PRETERM/LBW BIRTHS. AIR POLLUTION AND BIRTH OUTCOMES: A SYSTEMATIC REVIEW , 2011 .

[58]  X. Le,et al.  Increased Mortality Associated with Well-Water Arsenic Exposure in Inner Mongolia, China , 2009, International journal of environmental research and public health.

[59]  C. Marsit,et al.  Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study , 2013, Environmental Health.

[60]  Eliseo Guallar,et al.  Arsenic Exposure and Hypertension: A Systematic Review , 2011, Environmental health perspectives.

[61]  R. Ghosh Child mortality in India: a complex situation , 2012, World Journal of Pediatrics.

[62]  I Hertz-Picciotto,et al.  Chronic arsenic exposure and risk of infant mortality in two areas of Chile. , 2000, Environmental health perspectives.

[63]  Craig Steinmaus,et al.  Case-control study of bladder cancer and drinking water arsenic in the western United States. , 2003, American journal of epidemiology.

[64]  D. Stinchcomb,et al.  Maternal exposure to arsenic, cadmium, lead, and mercury and neural tube defects in offspring. , 2006, Environmental research.

[65]  F. Kitamura,et al.  Prenatal Exposure to Arsenic and Its Effects on Fetal Development in the General Population of Dalian , 2012, Biological Trace Element Research.

[66]  M S Kramer,et al.  Determinants of low birth weight: methodological assessment and meta-analysis. , 1987, Bulletin of the World Health Organization.

[67]  N. Cherry,et al.  Manganese, Arsenic, and Infant Mortality in Bangladesh: An Ecological Analysis , 2010, Archives of environmental & occupational health.

[68]  D G Altman,et al.  The scandal of poor medical research , 1994, BMJ.

[69]  M. Vahter,et al.  Effect of Arsenic Exposure during Pregnancy on Infant Development at 7 Months in Rural Matlab, Bangladesh , 2008, Environmental health perspectives.

[70]  Á. Bereczky,et al.  Epidemiological studies on human subjects exposed to arsenic in drinking water in Southeast Hungary , 2006, Archives of Toxicology.

[71]  N. Paneth,et al.  Fetal death during labor: an epidemiologic indicator of level of obstetric care. , 1985, American journal of obstetrics and gynecology.

[72]  L. Barraj,et al.  Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis. , 2008, Regulatory toxicology and pharmacology : RTP.

[73]  F. Armah,et al.  Cancer and Non-Cancer Risk Assessment from Exposure to Arsenic, Copper, and Cadmium in Borehole, Tap, and Surface Water in the Obuasi Municipality, Ghana , 2010 .

[74]  M. Bottai,et al.  Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. , 2011, International journal of epidemiology.

[75]  K. Nachman,et al.  Public health responses to arsenic in rice and other foods. , 2013, JAMA internal medicine.

[76]  J. Zhang,et al.  What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. , 1998, JAMA.

[77]  H. Stenlund,et al.  Occupational and environmental risks of spontaneous abortions around a smelter. , 2002, American journal of industrial medicine.

[78]  Xiaoying Zheng,et al.  Effect of Exposure to Trace Elements in the Soil on the Prevalence of Neural Tube Defects in a High-risk Area of China* , 2022 .

[79]  A H Smith,et al.  Arsenic in Drinking Water and Bladder Cancer: Environmental Carcinogenesis , 2000, Cancer investigation.

[80]  J. Yoshinaga,et al.  Maternal exposure to low-level heavy metals during pregnancy and birth size , 2010, Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering.

[81]  C. Ferreccio,et al.  Arsenic exposure and its impact on health in Chile. , 2006, Journal of health, population, and nutrition.

[82]  A. Sharrett,et al.  Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence. , 2005, American journal of epidemiology.

[83]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[84]  O. Landgren,et al.  Environmental pollution and delivery outcome in southern Sweden: a study with central registries , 1996, Acta paediatrica.

[85]  R. Walvekar,et al.  Chronic arsenic poisoning: a global health issue – a report of multiple primary cancers , 2007, Journal of cutaneous pathology.

[86]  P. Shah,et al.  Pregnancy and neonatal outcomes of aboriginal women: a systematic review and meta-analysis. , 2011, Women's health issues : official publication of the Jacobs Institute of Women's Health.

[87]  M. S. Patel,et al.  An introduction to meta-analysis. , 1989, Health Policy.

[88]  M. Bottai,et al.  Maternal Cadmium Exposure during Pregnancy and Size at Birth: A Prospective Cohort Study , 2011, Environmental health perspectives.

[89]  U. Högberg,et al.  Congenital malformations in the vicinity of a smelter in Northern Sweden, 1973-1990. , 1996, Paediatric and perinatal epidemiology.

[90]  F. Song,et al.  Evaluating non-randomised intervention studies. , 2003, Health technology assessment.

[91]  B. Howard,et al.  Association Between Exposure to Low to Moderate Arsenic Levels and Incident Cardiovascular Disease , 2013, Annals of Internal Medicine.

[92]  Division on Earth Review of Epa's Integrated Risk Information System (Iris) Process , 2014 .

[93]  J. Jaakkola,et al.  Occupational exposures and adverse pregnancy outcomes among nurses: a systematic review and meta-analysis. , 2010, Journal of women's health.

[94]  A. Smith,et al.  Health effects of arsenic and chromium in drinking water: recent human findings. , 2009, Annual review of public health.

[95]  D. Chakraborti,et al.  Arsenic contamination of groundwater and its health impact on residents in a village in West Bengal, India. , 2005, Bulletin of the World Health Organization.

[96]  S. A. Ahmad,et al.  Arsenic in drinking water and pregnancy outcomes. , 2001, Environmental health perspectives.

[97]  Chun-Yuh Yang,et al.  Arsenic in drinking water and adverse pregnancy outcome in an arseniasis-endemic area in northeastern Taiwan. , 2003, Environmental research.

[98]  E. Mcclure,et al.  Stillbirth in developing countries , 2006, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[99]  I. Hertz-Picciotto,et al.  Association Between Arsenic Exposure From Drinking Water and Anemia During Pregnancy , 2006, Journal of occupational and environmental medicine.

[100]  Michael F Hughes,et al.  Arsenic toxicity and potential mechanisms of action. , 2002, Toxicology letters.

[101]  M. Vahter,et al.  Arsenic Exposure in Pregnancy Increases the Risk of Lower Respiratory Tract Infection and Diarrhea during Infancy in Bangladesh , 2010, Environmental health perspectives.

[102]  M. Zaworotko,et al.  Uptake, distribution, and metabolism of trivalent arsenic in the pregnant mouse. , 1988, Journal of toxicology and environmental health.

[103]  Amitava Mukherjee,et al.  Arsenic contamination in groundwater: a global perspective with emphasis on the Asian scenario. , 2006, Journal of health, population, and nutrition.

[104]  S G Selevan,et al.  Identifying critical windows of exposure for children's health. , 2000, Environmental health perspectives.

[105]  Rebecca M. Turner,et al.  The Impact of Study Size on Meta-analyses: Examination of Underpowered Studies in Cochrane Reviews , 2013, PloS one.

[106]  N. Cherry,et al.  Stillbirth in rural Bangladesh: arsenic exposure and other etiological factors: a report from Gonoshasthaya Kendra. , 2008, Bulletin of the World Health Organization.