Abstract

Background:

Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact.

Objective:

We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight.

Methods:

Within the Generation R Study, a population-based cohort in Netherlands ($n=776$), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at $<18$, 18–25, and $>25\text{\hspace{0.17em}weeks}$ of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18–25 and $>25\text{\hspace{0.17em}weeks}$ of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation.

Results:

The average EFW at 18–25 wk and $>25\mathrm{wk}$ was 369 and $\mathrm{1,626}\mathrm{g}$, respectively, and the average birth weight was $\mathrm{3,451}\mathrm{g}$. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18–25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2–Q4) had $26\mathrm{g}$ [$95\%\text{\hspace{0.17em}confidence intervals\hspace{0.17em}}\left(\text{CI}\right)\text{:}-38$, $-13$], $35\mathrm{g}$ ($95\%\text{\hspace{0.17em}CI:\hspace{0.17em}}-55$, $-15$), and $27\mathrm{g}$ ($95\%\text{\hspace{0.17em}CI:\hspace{0.17em}}-54$, 1) lower EFW compared with those in the first quartile (Q1). A similar dose–response pattern was observed at $>25\mathrm{wk}$, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1–Q2 or Q1–Q3. However, fetuses in Q4 had $91\mathrm{g}$ ($95\%\text{\hspace{0.17em}CI:\hspace{0.17em}}-258$, 76) lower birth weight in comparison with those in Q1. Results observed at 18–25 and $>25\mathrm{wk}$ were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference.

Discussion:

Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178

中文翻译：

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产前暴露于非持久性化学混合物和胎儿生长：一项基于人群的研究

摘要

背景：

产前暴露于非持久性化学物质的混合物是普遍的。大多数检查这些化学物质与胎儿生长相关的研究都仅限于单一暴露模型，而忽略了它们潜在的累积影响。

客观的：

我们旨在评估产前接触邻苯二甲酸盐、双酚和有机磷酸盐 (OP) 杀虫剂的混合物与胎儿头围、股骨长度和体重测量值之间的关联。

方法：

在 R 世代研究中，荷兰的一个基于人群的队列（$n=776$)，11 种邻苯二甲酸酯代谢物、3 种双酚和 5 种磷酸二烷基酯 (DAP) 代谢物的尿液浓度在$<18$, 18-25, 和$>25\text{\hspace{0.17em}周}$妊娠和平均。头围、股骨长度和估计胎儿体重 (EFW) 的超声测量在 18-25 岁和$>25\text{\hspace{0.17em}周}$妊娠期，头围、长度和体重的测量在分娩时进行。我们用分位数 g 计算估计了混合物中所有暴露量每四分位数增加的每个胎儿测量值的差异。

结果：

18-25 周的平均 EFW 和$>25\mathrm{周}$是 369 和$\mathrm{1,626}\mathrm{G}$, 平均出生体重为$\mathrm{3,451}\mathrm{G}$. 较高的暴露与较小的胎儿和新生儿生长参数呈非线性相关。在 18-25 周时，处于暴露的第二、第三和第四四分位数（Q2-Q4）的胎儿有$26\mathrm{G}$[$95\%\text{\hspace{0.17em}置信区间\hspace{0.17em}}\left(\text{CI}\right)\text{：}-38$,$-13$],$35\mathrm{G}$($95\%\text{\hspace{0.17em}CI：\hspace{0.17em}}-55$,$-15$）， 和$27\mathrm{G}$($95\%\text{\hspace{0.17em}CI：\hspace{0.17em}}-54$, 1) 与第一个四分位数 (Q1) 相比，EFW 较低。观察到类似的剂量反应模式$>25\mathrm{周}$，但所有效应量都较小，并且与 Q4 和 Q1 相比没有观察到关联。出生时，我们观察到 Q1-Q2 或 Q1-Q3 之间的体重没有差异。然而，第四季度的胎儿有$91\mathrm{G}$($95\%\text{\hspace{0.17em}CI：\hspace{0.17em}}-258$, 76) 与第一季度相比，出生体重较低。在 18-25 和$>25\mathrm{周}$股骨长度相似；然而，在出生时没有观察到差异。没有观察到头围的关联。

讨论：

较高的邻苯二甲酸盐、双酚和 OP 农药混合物暴露与妊娠中期较低的 EFW 相关。在妊娠晚期，这些差异相似但不太明显。在出生时，观察到的唯一关联出现在比较 Q1 和 Q4 的个体时。这一发现表明，即使是低水平的暴露也可能足以影响怀孕早期的生长，而更高的暴露水平可能对影响出生体重是必要的。联合接触非持久性化学物质可能会对胎儿生长产生不利影响，而且由于这些接触很普遍，这种影响可能是巨大的。https://doi.org/10.1289/EHP9178