Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on pregnancy and birth outcomes: A systematic review of experimental studies on non-human mammals

Abstract

Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on pregnancy and birth outcomes: A systematic review of experimental studies on non-human mammals My note: This paper (SR4: Adverse reproductive outcomes (animal and in vitro studies)), the first of ten systematic reviews commissioned by the World Health Organization (WHO) was published online in a forthcoming special issue, "WHO assessment of health effects of exposure to radiofrequency electromagnetic fields: systematic reviews," of the journal Environment International. These reviews will form the basis of a forthcoming WHO publication: Environmental Health Criteria (EHC) Monograph on Radio Frequency (RF) Fields and Health Risks. For more information about the monograph see bit.ly. Cordelli E, Ardoino L, Benassi B, Consales C, Eleuteri P, Marino C, Sciortino M, Villani P, Brinkworth MH, Chen G, McNamee JP, Wood AW, Belackova L, Verbeek J, Pacchierotti F. Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on pregnancy and birth outcomes: A systematic review of experimental studies on non- human mammals, Environment International, 2023, doi: 10.1016/j.envint.2023.108178. Abstract Background The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Within the project, 6 topics have been prioritized by an expert group, which include reproductive health outcomes. Objectives According to the protocol published in 2021, a systematic review and meta-analyses on the adverse effects of RF-EMF exposure during pregnancy in offspring of experimental animals were conducted. Methods Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 8 or 17, 2022. Based on predefined selection criteria, the obtained references were screened by two independent reviewers. Studies were included if they met the following criteria: 1) original, sham controlled experimental study on non-human mammals exposed in utero, published in peer- reviewed journals, 2) the experimental RF-EMF exposure was within the frequency range 100 kHz-300 GHz, 3) the effects of RF-EMF exposure on fecundity (litter size, embryonic/fetal losses), on the offspring health at birth (decrease of weight or length, congenital malformations, changes of sex ratio) or on delayed effects (neurocognitive alterations, female infertility or early-onset cancer) were studied. Study characteristics and outcome data were extracted by two reviewers. Risk of bias (RoB) was assessed using the Office of Health Assessment and Translation (OHAT) guidelines. Study results were pooled in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses, after exclusion of studies that were rated at “high concern” for RoB. Subgroup analyses were conducted for species, Specific Absorption Rate (SAR) and temperature increase. The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results Eighty-eight papers could be included in this review. Effects on fecundity. The meta-analysis of studies on litter size, conducted at a whole-body average SAR of 4.92 W/kg, did not show an effect of RF-EMF exposure (MD 0.05; 95% CI -0.21 to 0.30). The meta-analysis of studies on resorbed and dead fetuses, conducted at a whole-body average SAR of 20.26 W/kg, showed a significant increase of the incidence in RF-EMF exposed animals (OR 1.84; 95% CI 1.27 to 2.66). The results were similar in the dose-response analysis. Effects on the offspring health at birth. The meta-analysis of studies on fetal weight, conducted at a whole-body average SAR of 9.83 W/kg, showed a small decrease in RF-EMF exposed animals (SMD 0.31; 95% CI 0.15 to 0.48). The meta-analysis of studies on fetal length, conducted at a whole-body average SAR of 4.55 W/kg, showed a moderate decrease in length at birth (SMD 0.45; 95% CI 0.07 to 0.83). The meta-analysis of studies on the percentage of fetuses with malformations, conducted at a whole-body average SAR of 6.75 W/kg, showed a moderate increase in RF-EMF exposed animals (SMD -0.45; 95% CI -0.68 to -0.23). The meta-analysis of studies on the incidence of litters with malformed fetuses, conducted at a whole-body average SAR of 16.63 W/kg, showed a statistically significant detrimental RF-EMF effect (OR 3.22; 95% CI 1.9 to 5.46). The results were similar in the dose-response analyses. Delayed effects on the offspring health. RF-EMF exposure was not associated with detrimental effects on brain weight (SMD 0.10, 95% CI -0.09 to 0.29) and on learning and memory functions (SMD -0.54, 95% CI -1.24 to 0.17). RF-EMF exposure was associated with a large detrimental effect on motor activity functions (SMD 0.79, 95% CI 0.21 to 1.38) and a moderate detrimental effect on motor and sensory functions (SMD -0.66, 95% CI - 1.18 to -0.14). RF-EMF exposure was not associated with a decrease of the size of litters conceived by F2 female offspring (SMD 0.08, 95% CI -0.39 to 0.55). Notably, meta-analyses of neurobehavioural effects were based on few studies, which suffered of lack of independent replication deriving from only few laboratories. Discussion There was high certainty in the evidence for a lack of association of RF-EMF exposure with litter size. We attributed a moderate certainty to the evidence of a small detrimental effect on fetal weight. We also attributed a moderate certainty to the evidence of a lack of delayed effects on the offspring brain weight. For most of the other endpoints assessed by the meta-analyses detrimental RF-EMF effects were shown, however the evidence was attributed a low or very low certainty. The body of evidence had limitations that did not allow an assessment of whether RF-EMF may affect pregnancy outcomes at exposure levels below those eliciting a well- known adverse heating impact. In conclusion, in utero RF-EMF exposure does not have a detrimental effect on fecundity and likely affects offspring health at birth, based on the meta-analysis of studies in experimental mammals on litter size and fetal weight, respectively. Regarding possible delayed effects of in utero exposure, RF-EMF probably does not affect offspring brain weight and may not decrease female offspring fertility; on the other hand, RF-EMF may have a detrimental impact on neurobehavioural functions, varying in magnitude for different endpoints, but these last findings are very uncertain. Further research is needed on the effects at birth and delayed effects with sample sizes adequate for detecting a small effect. Future studies should use standardized endpoints for testing prenatal developmental toxicity and developmental neurotoxicity (OECD TG 414 and 426), improve the description of the exposure system design and exposure conditions, conduct appropriate dosimetry characterization, blind endpoint analysis and include several exposure levels to better enable the assessment of a dose response relationship. Study selection Figure 2 shows the flow diagram from the initially retrieved references to the finally included papers, as per the PRISMA 2020 template (Page et al., 2021). After exclusion of duplicate records and of papers deemed not eligible based on title/abstract, a total of 236 papers remained for full-text assessment; we could not retrieve 11 papers and were unable to translate 10 papers. Of the remaining 215 papers, we excluded 127 after reading the full text. Therefore, the systematic review is based on a total of 88 papers. Implications for policy and research This systematic review of animal studies shows that RF-EMF exposure does not affect fecundity and likely has only a small effect on fetal weight decrease. However, some studies retrieved by the literature search that showed a detrimental effect on the incidence of dead/resorbed fetuses or the increase of malformations at high exposure levels, largely exceeding the current human exposure limits, cannot be discounted. These studies confirm what is known about the harmful effect of heating on fetuses, but they leave largely uncertain the possibility of RF-EMF effects at lower exposure levels, closer to relevant human exposure levels. Currently, it remains difficult to determine the exposure levels at which RF-EMF can start to affect fecundity or offspring health at birth. The whole body average SAR values in the included experiments are well above the recommended human exposure limit values for the general public set by international bodies (ICNIRP 2020). Actual SAR values experienced by the public in the general environment are below, and in most cases, well below, the recommended human exposure limit values. The dose effect meta-analyses contributed to support the results of the meta-analysis but were not supposed to define the shape of the dose-effect relationship or find a minimum exposure level at which a clear effect could be discerned. For two endpoints planned in the protocol, namely ano-genital distance at birth and early-onset cancer no studies were retrieved. Ano-genital distance is a well-known developmental biomarker associated with impairment of the reproductive system and exposure to environmental carcinogens during pregnancy have been linked with development of childhood cancer (Botsivali and Kyrtopoulos, 2019). Hopefully, future research will shed light on the impact of RF-EMF exposure on these outcomes. As a whole, the possible impact of in utero RF-EMF exposure remains uncertain due to the severe limitations of some of the studies. In particular, during the systematic review, we identified several methodological limitations in the studies that should be overcome in future studies to improve the quality of the research. Blinding during experiment performance and outcome assessment should always be applied to minimize bias. More adherence to OECD Test Guideline 414 “Prenatal Developmental Toxicity study” and 426 “Developmental Neurotoxicity Study” is recommended together with a more standardized approach for reporting results. A large proportion of included studies was rated at either “some” or “high concern” for RoB for exposure characterisation or temperature rise assessment and some others had to be excluded from the systematic review because they did not reach a minimum quality standard for these aspects. We would recommend that future studies bear the reasons for exclusion or RoB concerns in mind in study design and implementation. There are several papers in the research literature with recommendations on how exposure characterisation concerns can be mitigated, for example Kuster and Schönborn (2000). Finally, studies investigating not just a single level but several exposure levels, spanning from low levels comparable to human exposure to higher levels where mild hyperthermic effects could be expected, should be conducted under the same experimental conditions. In spite of the large number of studies collected, our systematic review could only partly answer the PECO question and did not provide conclusions certain enough to inform decisions at a regulatory level, but it can be considered a solid starting point to direct future research on this topic. Open access paper: sciencedirect.com

AI evidence extraction

Main findings

This WHO-commissioned systematic review included 88 sham-controlled experimental studies of in utero RF-EMF exposure (100 kHz–300 GHz) in non-human mammals and conducted random-effects and dose-response meta-analyses after excluding studies rated “high concern” for risk of bias. Meta-analyses reported no effect on litter size, but reported increased resorbed/dead fetuses and increased malformations at higher whole-body average SARs, along with small-to-moderate decreases in fetal weight and length. For delayed outcomes, no association was reported for brain weight or learning/memory, while some neurobehavioral endpoints (motor activity; motor/sensory functions) showed detrimental associations but were based on few studies with limited independent replication and were judged very uncertain.

Outcomes measured

• Litter size
• Resorbed and dead fetuses (embryonic/fetal losses)
• Fetal weight
• Fetal length
• Congenital malformations (percentage of fetuses with malformations; incidence of litters with malformed fetuses)
• Offspring brain weight
• Learning and memory functions
• Motor activity functions
• Motor and sensory functions
• F2 female offspring fertility (litter size conceived by F2 female offspring)
• Ano-genital distance at birth (no studies found)
• Early-onset cancer (no studies found)

Limitations

• Many included studies had risk-of-bias concerns, particularly for exposure characterization and temperature rise assessment.
• Evidence for several endpoints was rated low or very low certainty using GRADE.
• Neurobehavioral meta-analyses were based on few studies with lack of independent replication from only a few laboratories.
• The evidence did not allow assessment of effects at exposure levels below those eliciting well-known adverse heating impacts.
• Dose-response meta-analyses were not intended to define the dose-response shape or identify a minimum effect level.
• No studies were retrieved for ano-genital distance at birth or early-onset cancer.

Suggested hubs

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  Abstract states the review was commissioned within a WHO project and discusses ICNIRP 2020 exposure limits.

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        "Meta-analyses reported a small decrease in fetal weight and a moderate decrease in fetal length at birth at the studied SARs.",
        "Delayed outcomes showed no association for offspring brain weight and learning/memory, while some motor-related neurobehavioral endpoints showed detrimental associations.",
        "The authors emphasized that many observed detrimental effects occurred at exposure levels exceeding current general-public limits and may reflect heating-related impacts.",
        "For most endpoints beyond litter size (and some others), certainty was low/very low due to methodological limitations and risk-of-bias concerns."
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        "facebook": "A WHO-commissioned systematic review in Environment International analyzed 88 sham-controlled animal studies of in utero RF-EMF exposure (100 kHz–300 GHz). It reported no effect on litter size, a small decrease in fetal weight, and mixed findings for other outcomes, with many effects observed at high SARs where heating may play a role. doi:10.1016/j.envint.2023.108178",
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