Reproductive and developmental toxicity of formaldehyde: a systematic review

Abstract

Formaldehyde, the recently classified carcinogen and ubiquitous environmental contaminant, has long been suspected of causing adverse reproductive and developmental effects, but previous reviews were inconclusive, due in part, to limitations in the design of many of the human population studies. In the current review, we systematically evaluated evidence of an association between formaldehyde exposure and adverse reproductive and developmental effects, in human populations and in vivo animal studies, in the peer-reviewed literature. The mostly retrospective human studies provided evidence of an association of maternal exposure with adverse reproductive and developmental effects. Further assessment of this association by meta-analysis revealed an increased risk of spontaneous abortion (1.76, 95% CI 1.20-2.59, p=0.002) and of all adverse pregnancy outcomes combined (1.54, 95% CI 1.27-1.88, p<0.001), in formaldehyde-exposed women, although differential recall, selection bias, or confounding cannot be ruled out. Evaluation of the animal studies including all routes of exposure, doses and dosing regimens studied, suggested positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mechanisms underlying formaldehyde-induced reproductive and developmental toxicities, including chromosome and DNA damage (genotoxicity), oxidative stress, altered level and/or function of enzymes, hormones and proteins, apoptosis, toxicogenomic and epigenomic effects (such as DNA methylation), were identified. To clarify these associations, well-designed molecular epidemiologic studies, that include quantitative exposure assessment and diminish confounding factors, should examine both reproductive and developmental outcomes associated with exposure in males and females. Together with mechanistic and animal studies, this will allow us to better understand the systemic effect of formaldehyde exposure.

Figure 1. Flow diagram of study selection process

This figure depicts the logic of the study selection process, the results of which are included for review in this paper.

Figure 2. Forest plot for studies of spontaneous abortion (SAB) and all reproductive outcomes combined

These Forest plots show that ORs equal to or above 1.01 were found in (A) 5 of the 7 (71%) studies in the SAB analysis, and (B) 9 of the 12 (75%) studies in the all outcomes analysis. Most of the confidence intervals in the all outcomes analysis were well above 1, indicating higher significance. *ORs in (A) were calculated from SAB dat a reported in Axelsson et al. (1984), Hemminki et al. (1982), and Saurel-Cubizzoles et al. (1994), and recalculated from the data provided in Hemminki et al. (1985) as described in the footnote to Table 1. ORs in (B) were calculated from data on congenital malformations reported in Ericson et al. (1984), and from data on SAB and congenital malformations combined in Hemminki et al. (1985) as these outcomes were based on separate controls.

Figure 2. Forest plot for studies of spontaneous abortion (SAB) and all reproductive outcomes combined

These Forest plots show that ORs equal to or above 1.01 were found in (A) 5 of the 7 (71%) studies in the SAB analysis, and (B) 9 of the 12 (75%) studies in the all outcomes analysis. Most of the confidence intervals in the all outcomes analysis were well above 1, indicating higher significance. *ORs in (A) were calculated from SAB dat a reported in Axelsson et al. (1984), Hemminki et al. (1982), and Saurel-Cubizzoles et al. (1994), and recalculated from the data provided in Hemminki et al. (1985) as described in the footnote to Table 1. ORs in (B) were calculated from data on congenital malformations reported in Ericson et al. (1984), and from data on SAB and congenital malformations combined in Hemminki et al. (1985) as these outcomes were based on separate controls.

Figure 3. Funnel plot of studies of spontaneous abortion (SAB) and all reproductive outcomes combined

Publication bias is not apparent in the analysis of (A) SAB and (B) all outcomes.

Figure 3. Funnel plot of studies of spontaneous abortion (SAB) and all reproductive outcomes combined

Publication bias is not apparent in the analysis of (A) SAB and (B) all outcomes.