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Obstetrics and gynaecology
Original research
Exposure to drinking water pollutants and non-syndromic birth defects: a systematic review and meta-analysis synthesis
  1. Eric Jauniaux1,
  2. Lydia Jeremiah1,
  3. Biba Richardson1,
  4. Ewelina Rogozińska2,3
  1. 1EGA Institute for Women Health, University College London, London, UK
  2. 2Women’s Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  3. 3The EVIE Evidence Synthesis Research Group, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, London, UK
  1. Correspondence to Professor Eric Jauniaux; e.jauniaux{at}ucl.ac.uk

Abstract

Objectives To evaluate the association between drinking water pollutants and non-syndromic birth defects.

Design Systematic review and meta-analysis synthesis.

Data sources A search of MEDLINE, EMBASE and Google Scholar was performed to review relevant citations reporting on birth defects in pregnancies exposed to water pollutants between January 1962 and April 2023.

Eligibility criteria Prospective or retrospective cohort, population studies and case–control studies that provided data on exposure to drinking water pollutants around conception or during pregnancy and non-syndromic birth defects. We included studies published in the English language after the Minamata Bay disaster to reflect on contemporary concerns about the effect of environmental pollution and obstetric outcomes.

Data extraction and synthesis Two reviewers independently read the retrieved articles for content, data extraction and analysis. The methodological quality of studies was assessed using the Newcastle-Ottawa Scale. Included studies were assessed for comparability when considered for meta-analysis.

Results 32 studies met inclusion criteria including 17 cohorts (6 389 097 participants) and 15 case–control studies (47 914 cases and 685 712 controls). The most common pollutants investigated were trihalomethanes (11 studies), arsenic (5 studies) and nitrates (4 studies). The studies varied in design with different estimates of exposure, different stages of gestation age and different durations of exposure to pollutants. 21 articles reported data on any birth defects in their population or study groups and the others on specific birth defects including congenital heart defects, neural tube defects, orofacial defects and hypospadias. An increased risk or higher incidence of overall birth defects was reported by 9 studies and for specific birth defects by 14 studies. Eight studies compared the risk or incidence of birth defects with exposure to different concentrations of the pollutants. The analysis showed an association between higher levels of trihalomethanes (TTMs) and arsenic increase in major birth defects (lower vs higher exposure (OR 0.76, 95% CI 0.65 to 0.89; p<0.001 and OR 0.56, 95% CI 0.39 to 0.82; p<0.005, respectively).

Conclusion The evidence of an association between exposure to average levels of common drinking water chemical pollutants during pregnancy and an increased risk or incidence of birth defects is uncertain. Available evidence indicates that some common chemical pollutants currently found in drinking water may have a direct teratogenic effect at high maternal exposure, however, wide variation in methodology limits the interpretation of the results. Future prospective studies using standardised protocols comparing maternal levels during all three trimesters of pregnancy and cord blood levels at birth are needed to better understand the placental transfer of water pollutants and accurately evaluate individual fetal exposure to drinking water pollutants.

PROSPERO registration number CRD42018112524.

  • Fetal medicine
  • Maternal medicine
  • Prenatal diagnosis

Data availability statement

Data are available on reasonable request. Data from the systematic review and data extraction are included in the tables.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2024-084122

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • This is the largest systematic review examining the possible association between known common drinking water pollutants, different drinking water pollutants and non-syndromic birth defects using an a priori designed protocol registered on an international register of systematic reviews.

    • The systematic review only included studies that provided secure medical records, regional or national databases with detailed descriptions of all birth defects in a defined population with detailed pathology record during the study period.

    • We included studies that were published since the Minamata Bay disaster to reflect on contemporary concerns about the effect of environmental pollution and obstetric outcomes.

    • The main limitation of this study is the many challenges in assessing prenatal exposure to specific chemical and toxics at different dosages and different gestation ages.

    • The studies included in our systematic review had varied study designs, including differences in timing and duration of exposures to a drinking water pollutant before and during pregnancy, different methodologies to evaluate the concentration of each pollutant component, and different ranges and regulatory limits for an individual pollutant level between countries, limiting the extend of the meta-analysis and interpretation of our results.

    Introduction

    Unlike other commodities, water is paramount for human survival and only 0.4% of the water on earth is fresh water readily available for consumption.1 Industrial methods, such as fossil fuel extraction, chemical waste treatment and agricultural processes, have threatened freshwater ecosystems for decades.2 More recently, climate change has been shown to have a disproportionate effect on pregnant women’s health, directly through exposure to toxic chemicals and vectorborne diseases and indirectly by influencing food and water security.3 4 These effects are further exacerbated in low-resourced countries (LRCs) where prenatal and maternity healthcare is limited. Warmer temperatures also increase the environmental distribution and toxicity of chemical pollutants including air pollutants, persistent organic pollutants, such as some organochlorine pesticides and other classes of pesticides.5 The effects of water pollution on aquatic biota and ecosystems, and in particular, on fish reproduction and survival in lakes and rivers further compromise the food chain in LRCs.6

    Unlike air pollution, in which only a small handful of parameters need tracking, thousands of water quality parameters have been identified by organisations such as the WHO.7 The range of pollutants found in drinking water is ever-increasing and now includes pharmaceutical by-products such as hormones, painkillers and antibiotics,8 personal care products9 and drugs of abuse.10 Chemical contaminants and disinfection by-products (DBP) found in drinking water have been associated with adverse pregnancy outcomes including fetal growth restriction, premature delivery and stillbirth.11 The environmental disaster of Minamata Bay in the late 1950s,12 where children whose mothers had eaten excessive amounts of fish and shellfish contaminated by methylmercury during pregnancy had neurological defects from early in life, was pivotal in highlighting the relationship between maternal exposure to water pollution and the developmental anomalies. However, this event has been largely forgotten and eclipsed by pharmaceutical drug disasters (thalidomide, diethylstilbestrol). There are currently limited data on chemical water pollution and the risks of birth defects.13

    The pathogenesis of congenital anomalies in humans and other mammals is multifactorial, caused by complex interactions between genes and environment during the organogenesis phase of fetal development.14 Water pollutants can have a preconceptional mutagenic and postconceptional teratogenic action, periconceptional endocrine disruption and epigenetic effects. The objective of this study was to systematically review the literature to evaluate the possible association between pollutants found in drinking water and different non-syndromic birth defects.

    Methods

    Data sources and search strategy

    This systematic review was guided by a prospectively developed protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO number CRD42018112524). We searched MEDLINE, EMBASE and Google Scholar with a search strategy including the following MeSH (Medical Subject Headings) terms: “drinking water“ OR “water pollution“ OR “water toxicant“ OR “water pollutant“ OR “pesticides” OR “fertilisers” OR “microplastics” OR “lead” OR “mercury” AND “birth defects” OR “congenital malformations” OR “fetal anomalies”. The database was searched from January 1958 to April 2023. Additional studies were identified from reference lists of full-text articles for relevant citations, expert reviews and editorials. The study is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis.15 The search was limited to human studies and articles published in English (online supplemental appendix 1).

    Selection criteria and data extraction

    Two reviewers (LJ and BR) independently assessed identified titles and abstracts against the eligibility criteria. The study had to meet the following criteria to be included in the review: (1) observational study (population, cohort or case control) that investigates the association between non-syndromic birth defects and exposure to one or more drinking water pollutants around the time of conception and/or during pregnancy; (2) study had to report outcomes with appropriate estimates of women who were or became pregnant during the study and newborns born during the study period. We excluded letters, editorials, case reports and duplications of previously published data from the same centres or with an indication of overlapping in the methodology (online supplemental appendix 1). As we aimed to evaluate the incidence of non-syndromic birth defects according to drinking water pollutants in observational studies, we also excluded case–control studies including syndromic birth defects or using syndromic birth defects as controls, studies that did not report on contemporary measurements of a specific pollutant from the area under investigation and studies that did not describe the timing of exposure before or during pregnancy.

    Two reviewers (LJ and BR) independently assessed the content of the full text for content, and subsequently extracted relevant data. The extracted data were checked again by two researchers (EJ and ER) and any discrepancies were resolved between the reviewers through discussion. Data from eligible studies were entered into an Excel spreadsheet including the first author of the study, year of publication, country of origin, study characteristics (study design, sample size, recruitment setting and pollutant(s) investigated), methodology and outcomes of interest.

    Quality assessment

    The quality of eligible studies was independently assessed by LJ and EJ using the Newcastle-Ottawa Quality Assessment Scale.16 Each type of study was evaluated on three domains: selection of study groups, comparability of groups and ascertainment of exposure (for case control) or outcome (for cohort). Each positive criterion scores 1 point, except comparability, which scores up to 2 points. A score of 7–9 was considered low, 4–6 moderate and 0–3 high risk of bias.

    Data synthesis

    Included studies were assessed for comparability when considered for meta-analysis. Studies that only reported adjusted measures of association that is, risk ratio, OR or log OR, were not included in the meta-analysis. Due to a low number of available studies per type of pollutant, we used a fixed effect model to pool data where possible. Between-study heterogeneity was assessed using I2 statistic. Analyses were conducted by using Review Manager (V.5.4.1).

    Patient and public involvement

    None.

    Results

    Search results

    The search identified 292 potential citations. From these, 170 were excluded after reviewing the title and abstract. Following full-text reading, 32 articles were included in the final analysis (6 389 097 participants in the cohort studies and 47 914 cases with a birth defect or exposed to one or more drinking water pollutants and 685 712 controls). The process of selection of the articles is summarised in figure 1.

    Figure 1
    Figure 1

    Flow diagram for study selection.

    Characteristics of studies included in the systematic review

    The included 32 studies17–48 were conducted in 12 different countries over a period of 72 years and published between 1984 and 2022 (table 1).

    View this table:
    Table 1

    Characteristics of included studies

    Only seven of the studies were published before the year 2000.17–23 15 studies had a case–control design,17–19 26 27 32 33 35 37–40 43 45 the others were cohort studies. The 15 case–control studies compared cases presenting with a non-syndromic birth defect at delivery with normal controls17 18 26 27 33 35 37–40 42 43 45 or cases exposed to one or more drinking water pollutants with non-exposed controls.19 32 All case–control studies, except one,17 used unequal numbers of cases and controls with one study comparing 20 151 cases with a birth defect with 668 381 normal controls.37 All studies, except one,47 were retrospective. 11 studies analysed data following maternal exposure to trihalomethanes (THMs)23 25 26 29–31 36 43 45 in drinking water, five studies reported on arsenic,28 38 41 42 46 four on nitrates,17 35 44 48 three on trichloroethane,19 21 22 two on atrazine,39 40 one on tetrachloroethylene (PCE), one on dibromochloropropane and one on lead.24 Four studies investigated more than one different drinking water pollutants.18 27 33 37

    19 studies used the data on one or more chemicals provided by the local water providers matched with individual home addresses,17 18 20–22 25–27 30–33 37 39 40 42–45 three from a national water provider database46–48 and one from a national water provider database and from local water measurements (table 2).41

    View this table:
    Table 2

    Methodology and main outcomes of included studies

    The remaining studies used data on chemical exposure obtained directly from measurements in local drinking water distribution system19 23 34–36 or from individual household including from common and private wells.24 28 38 In one study, the authors obtained data on the concentrations of arsenic in maternal blood38 and in another, lead level was measured in maternal hair.34 In 10 studies, the authors also obtained data from individual household consumption via interviews and/or questionnaires.17 21 22 27 28 34 35 42 43 45 In one of these studies, the authors also collected data from work-exposure to the pollutant.27 The timing of exposure to the pollutants was the first trimester of pregnancy in eight studies.17 21 22 31 33 35 38 47 The other studies used the timing of exposure ranging from 12 months before conception to the time of birth (table 2). 21 articles reported data on any birth defects in their population or study groups17 19 20 22 23 26–37 41 44 47 48 and the others on specific birth defects including congenital heart defects (CHDs),18 21 40 46 neural tube defects (NTDs),24 26 38 orofacial defects (OFDs)42 43 and hypospadias.39 45 An increased risk or higher incidence of overall birth defects was reported by nine studies17 19 23 28 29 32 33 36 41 and for specific birth defects by 14 studies.18 21 25 27 29–31 35 37 41 44 46–48 The remaining studies found no association between one or more pollutants and one or more birth defects. In one study, the authors26 adjusted their results for published nitrate levels from the same study groups.

    Assessment of study quality

    The studies were rated based on selection, comparability and outcome ascertainment. Overall, 5 studies had a low risk of bias and 18 studies had moderate risk of bias (online supplemental figure 1).

    Data synthesis

    The detailed outcomes of cohort studies according to overall birth defects and individual organ systems for THM (n=7), arsenic (n=3) and nitrates (n=2) are presented in online supplemental table 1. The risk or incidence of birth defects to the corresponding drinking water pollutants was categorised according to the average water level,23 different concentrations25 28–30 36 46 47 or below or above the limit of a National Environment Agency.41 44 48 Out of the eight studies comparing the risk or incidence of birth defects with exposure to different concentrations of the pollutants, five used three categories (low–medium–high)29–31 36 47 and three used four or more different concentration ranges.25 28 46 In those studies using >3 level ranges, the authors compared the highest with the lowest levels or levels below the detection level of the assay. All authors, except one,29 adjusted their analysis for standard potential confounders including maternal age, body mass index, fetal gender and parity. In addition, nine authors included socioeconomic background and/or education status,23 25 28 31 41 44 46–48 four included maternal smoking25 44 47 48 and two maternal gestational diabetes.30 47

    Figure 2 presents the association between exposure to THMs and arsenic during pregnancy and the incidence of major birth defects, at low and high exposures. Both pollutants were associated with a lower risk of major birth defects at lower exposures compared with higher exposure (OR 0.76, 95% CI 0.65 to 0.89 and OR 0.56, 95% CI 0.39 to 0.82, respectively).

    Figure 2
    Figure 2

    Pooled estimated and forest plots for total trihalomethanes and arsenic at lower and higher exposure during pregnancy and major birth defects.

    Discussion

    Main findings

    The detailed data analysis of the 32 studies included in this systematic review shows that 21 studies reported an association between a panel of 17 different pollutants in drinking water distributed by local water companies and an increased risk or incidence of overall non-syndromic birth defects and/or specific birth defect (table 1). We found evidence of an association between maternal exposure levels to TTMs and arsenic and an increase in major birth defects at high exposures.

    Comparison with previous studies

    Birth defects occur in approximately 1 in 33 newborns in the USA and are estimated to affect around 8 million babies worldwide each year.49 Non-syndromic or isolated birth defects account for up to 75% of all birth defect cases and the most prevalent malformations, that is, CHDs, NTDs, OFDs and limb defects.50 The aetiopathology of individual birth defects remains unknown in 70% of the cases.51 A relatively small proportion of birth defects can be attributed, at least in part, to specific environmental causes such as congenital viral or parasitic infections and the use of pharmaceuticals (eg, valproic acid) or recreational drugs (eg, cocaine) in early pregnancy. However, the majority of birth defects are considered the result of multiple environmental factors acting together with an individual’s genetic susceptibility.14 This can also explain the wide variation in the incidence of overall or specific birth defects following exposure to the same water pollutant such as trichloroethane, THMs or arsenic (table 2). Similar heterogeneity in outcome data has been found for the association between congenital anomalies and maternal exposure to a variety of air pollutants during pregnancy.52 53

    Globally, there are currently over 350 000 chemicals and mixtures of chemicals registered for production and use in the manufacturing industry, agriculture, food packaging, cosmetics and production industries among others.54 A large number of these chemicals have been registered only in LRCs and there are at least 900 pesticide, biocide and cosmetic active ingredients that are not covered by chemical inventories.54 The impact of many of these chemicals and unintentionally produced chemicals such as unreacted intermediates, by-products and degradation products on human health as well as on their releases, persistence, mobility in soil and rivers, and environmental fate are still unknown.

    Implications for clinical practice

    The most used chemicals that have been investigated in observational studies, as shown in the present systematic review, are THMs, arsenic and nitrates (online supplemental table 1).

    THMs are drinking water DBP that form when chlorine reacts with the organic matter in water31 and include mainly chloroform, bromodichloromethane, dibromochloromethane and bromoform. Chlorination of drinking water has been essential in eliminating waterborne infectious diseases in the Western world.55 THMs have been linked to small for gestational age (SGA) fetuses56 57 and may have carcinogenic effects58 but the evidence for both outcomes remains limited. A systematic review and meta-analysis of articles published up to December 2008 found an increased in overall birth defects (OR 1.17; 95% CI 1.02, 1.34) and in particular for ventricular septal defects (OR 1.58; 95% CI 1.21 to 2.07) associated for high versus low exposure to water chlorination during pregnancy, however, this meta-analysis was based on only three studies.57 The results of the present meta-analysis suggest an exposure level–response relationship (figure 2). A recent prospective large cohort study of 623 468 newborns has reported a decreased risk of CHDs after TTMs exposure during pregnancy,47 highlighting the heterogeneity of currently available data.

    In Europe and North America, arsenic level in drinking water is regulated by national and international environment agencies and the WHO recommends concentration of arsenic of <10 µg/L.58 In many low-income and middle-income countries in Asia and South America, in part due to mining activities and the use of arsenic-based pesticides, arsenic levels in drinking water often exceed >300 µg/L and have been associated with mass poisoning.59 Chronic arsenic exposure has been associated with an increased risk of developing type 2 diabetes, cardiovascular diseases and cancer.60 Similar relationships exist with other heavy metals such as lead, mercury and cadmium. The most recent article identified in our systematic review was a retrospective case–control study of data collected in the USA between 2003 and 2008 (table 1) which, reported no association between birth defects and arsenic, cadmium or lead.37 However, like for TTMs exposure, the present data suggest an exposure level–response relationship for the overall risk of major birth defects (figure 2).

    Nitrate and nitrite ions are widespread in the environment and are found naturally in plants and water.2 However, their increasing use in inorganic fertiliser and as additives in processed food has led to a global increase in nitrate levels in water resources. High levels have been associated with abnormal pregnancy outcomes, thyroid disease, risk of specific cancers, that is, colorectal, breast and bladder cancer.61 A recent systematic review and meta-analysis of articles published up to November 2022 on the association between nitrate in drinking water and adverse reproductive outcomes found an increased risk of preterm birth risk of NTDs based on the data of three cohort and two case–control studies, respectively.62 Two large recent Scandinavian cohort studies, published after the above systematic review, reported an increased risk of SGA for a median exposure <25 mg/L but not for an exposure >25 mg/L.48 63 No increased risk of overall birth defects was also reported, however, the authors observed a higher incidence of eye defects.48 Together, this highlights the inconsistency in the data available on nitrates exposure and pregnancy outcomes.

    The teratogenic effects of any chemicals are the consequence of an insult between from day 31 after the last menstrual period in a 28-day cycle to 71 days from the last period and thus depend on the ability of the corresponding molecule to cross the placental barrier during that period.51 60 The use of laboratory animal models such as rodents to study placental transfer of water pollutants is limited due to species differences in placental biological functions, transporters, molecular kinetics and metabolism. The transfer of heavy metals by the human placenta has been extensively studied following the 1958 Minamata disaster.12 64 These studies found that methylmercury easily crosses the placental barrier compared with lead, arsenic and cadmium.65–67 Yet, methylmercury is not regarded as a teratogen in the conventional sense as it did not cause structural congenital birth defects.12 Furthermore, this contamination did not occur via drinking water but was the consequence of the maternal diet which included mainly fish and shellfish contaminated by methylmercury from the effluent of a plastic plant in Minamata Bay. There are very few studies that investigate the placental transfer of other drinking water pollutants such as THMs or nitrates.68 69 In only 1 of the 32 studies included in the present review did the authors present data on maternal serum levels of arsenic.38 Future prospective studies comparing maternal levels during all three trimesters of pregnancy and cord blood levels at birth are needed to better understand the placental transfer of water pollutants and accurately evaluate individual fetal exposure to drinking water pollutants. New statistical methodologies70 71 should be considered when examining the link between water pollutants and health outcomes in general and perinatal outcomes in particular.

    Strengths and limitations

    This is the largest systematic review examining the possible association between the different drinking water pollutants reported in the international literature and non-syndromic birth defects. We performed a broad search for all known common drinking water pollutants and all the studies included in our systematic review provided secure medical records, regional or national databases with detailed descriptions of all birth defects in a defined population with detailed pathology records when required.

    The main limitation of this study is the many challenges in assessing prenatal exposure to environmental pollutants in general and the many contaminants in water that can be found in different concentrations in water samples at any one time in particular.72 The studies included in our systematic review had varied designs including differences in timing and duration of exposures to a drinking water pollutant before and during pregnancy. The authors also used different methodologies in the evaluation of the concentration of the different pollutant components and different ranges for individual pollutant levels with different regulatory limits in different countries. Another limitation of this kind of study is a possible over-reliance on database studies that focus on correlations rather than causal links.72 12 of the cohort studies20 21 23–25 29–31 44 46–48 and 1 of the case–control study37 included in our systematic review used large population-level registers. These large databases are unable to provide data for confounding factors associated with birth defects such as individual work-related exposure to high levels of different water and air pollutants and other environmental toxins, folic acid supplementation before and during pregnancy,73 incidence of uncontrolled type 1 diabetes and the use of pharmaceutical medications and drug abuse. Only two studies provided data on individual maternal serum or urine pollutant measurements during pregnancy.34 38 In addition, all studies except one were conducted retrospectively, which limits the use of a standard meta-analysis to compare the data of most studies currently published in the international literature.74

    Conclusions

    Evaluation of any links between birth defects and environmental exposures is likely to be limited due to constraints of quality and availability of data for exposure to a single water pollutant. Overall, the potential teratogenic effects of a specific chemical molecule have specific and narrow critical periods of susceptibility that may span only days, and considerably depend on exposure doses and placental transfer mechanisms. Animal models have been the gold standard to obtain teratogenic data, but interspecies differences have limited the suitability of those models. The evidence of an association between exposure to average levels of common drinking water chemical pollutants during pregnancy and an increased risk or incidence of birth defects is sparse and often contradictory. There is only evidence that any of the current common chemical water pollutants have a direct teratogenic effect on the developing human fetus at higher maternal exposure levels, such as, in case of professional exposure. These findings may help to advise patients about the risk of birth defects following exposure to common drinking water pollutants during pregnancy and to design further prospective studies using standardised research protocol.

    Data availability statement

    Data are available on reasonable request. Data from the systematic review and data extraction are included in the tables.

    Ethics statements

    Patient consent for publication

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    Supplementary materials

    Footnotes

    • Contributors All authors contributed to the study conception and design. EJ, LJ and BR draft the study protocol. ER reviewed the protocol. LJ and BR screened the abstract and performed data abstraction. LJ and EJ performed the methodological quality assessment. ER carried out the statistical analysis and contributed to data interpretation of the findings. EJ wrote the first draft of the manuscript. All authors contributed input for the final manuscript and accepted the responsibility for the overall content of this manuscript. EJ is the guarantor for the study.

    • Funding No funding was obtained for this study

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.