Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth: Systematic-review of the human and animal evidence

Abstract

Background: Adverse effects of prenatal stress or environmental chemical exposures on fetal growth are well described, yet their combined effect remains unclear.

Objectives: To conduct a systematic review on the combined impact and interaction of prenatal exposure to stress and chemicals on developmental outcomes.

Methods: We used the first three steps of the Navigation Guide systematic review. We wrote a protocol, performed a robust literature search to identify relevant animal and human studies and extracted data on developmental outcomes. For the most common outcome (fetal growth), we evaluated risk of bias, calculated effect sizes for main effects of individual and combined exposures, and performed a random effects meta-analysis of those studies reporting on odds of low birthweight (LBW) by smoking and socioeconomic status (SES).

Results: We identified 17 human- and 22 animal-studies of combined chemical and stress exposures and fetal growth. Human studies tended to have a lower risk of bias across nine domains. Generally, we found stronger effects for chemicals than stress, and these exposures were associated with reduced fetal growth in the low-stress group and the association was often greater in high stress groups, with limited evidence of effect modification. We found smoking associated with significantly increased odds of LBW, with a greater effect for high stress (low SES; OR 4.75 (2.46-9.16)) compared to low stress (high SES; OR 1.95 (95% CI 1.53-2.48)). Animal studies generally had a high risk of bias with no significant combined effect or effect modification.

Conclusions: We found that despite concern for the combined effects of environmental chemicals and stress, this is still an under-studied topic, though limited available human studies indicate chemical exposures exert stronger effects than stress, and this effect is generally larger in the presence of stress.

Fig 1. Prisma flow diagram.

A flow diagram of the progression from the literature search to inclusion in the systematic review (n = 69 studies) and quantitative analysis (n = 39).

Fig 2. The number of studies reporting on each outcome category.

The vertical gray bar represents the cut-off for the number of human studies required to take the outcome forward to a quantitative analysis.

Fig 3. Risk of bias assessment.

A heat-map of the risk of bias for human and non-human studies on growth outcomes and combined chemical and psychosocial stress.

Fig 4. Impact of stress and chemicals on fetal development.

The impact in humans of stress alone (green squares), chemicals in low stress (blue triangles) versus high stress (red diamonds) on birth weight (A) and odds of low birth weight (C) and their interaction (B and D respectively). Horizontal error bars represent 95% confidence intervals. Asterisks’ and letters denote the same population measured for more than one chemical or stress exposure.

Fig 5. Impact of stress and chemicals on birth weight.

(A) and (C) Birth weight effects in humans of chemicals in low stress (blue triangles) versus high stress (red diamonds) groups; and (B) and (D) the interaction between stress and chemicals on relative reduction in birth weight. Horizontal error bars represent 95% confidence intervals. Asterisks’ represent the same population measured for more than one chemical or stress exposure.

Fig 6. Meta-analysis of the effect of the low SES and smoking in high and low SES groups on odds of low birth weight (LBW) in humans.

(A) The effects of low SES alone (high stress; green squares) or smoking in high SES (low stress; blue triangles) and low SES groups (high stress; red diamond) are shown for each of four studies and their pooled random-effects estimate at the bottom of the figure; horizontal error bars represent 95% CI, symbol sizes represents the log of the precision of the estimate (i.e. weight in the meta-analysis). (B) the random-effects pooled interaction effect between low and high SES in smokers and non-smokers. Vertical error bars represent 95% CI and the horizontal grey bar represent the line of no effect.

Fig 7. The effect of prenatal aluminum and restraint stress in rats and mice.

The impact of stress alone (green squares), chemicals in low stress (blue triangles) versus high stress (red diamonds) on postnatal weight at various times of assessment in rats (A) and mice (B) and their interaction (C and D respectively). Horizontal error bars represent 95% confidence intervals; the vertical grey bar represents the line of no effects. Letters denote the same stress control group used for multiple doses at the same time point. Figure legend is the same as Fig 4. Abbreviation: IP, intraperitoneal.