Associations of maternal urinary nitrophenol concentrations with adverse birth outcomes and neurodevelopment delay at 4 years of age: The Japan environment and children's study

Maternal urinary nitrophenol concentrations are reportedly associated with preterm birth and foetal/offspring development delay, but the evidence is still inconclusive. We investigated the association between maternal urinary concentrations of 4-nitrophenol (4NP) and 3-methyl-4-nitrophenol (3M4NP) and adverse birth outcomes, as well as offspring neurodevelopment delay, defined using the Ages and Stages Questionnaires at 4 years of age, stratified by offspring sex. A total of 3650 non-hypertensive mothers with singleton births were enrolled from the Japan Environment and Children's Study. High 4NP (≥0.41 μg/L) and 3M4NP (≥0.29 μg/L) were defined as ≥ lowest concentration minimum reporting level. Four groups were created using these dichotomized 4NP and 3M4NP concentrations: 'both low', 'either high/low', and 'both high'. Multivariable logistic regression models were used to estimate the adjusted odds ratios (aOR) and population attributable fraction (PAF). For 4NP and 3M4NP, 68.4% and 19.0% of participants had 'high' urinary concentrations, respectively. Compared to 'both low', the overall analysis showed no significant associations between 'both high' and any of the outcomes. However, the stratified analysis showed that the aOR (95% confidence interval [CI]) and PAF (95% CI) for 'both high' regarding preterm birth (<37 weeks' gestation) were 2.7 (1.3, 5.7) and 16.3% (2.5%, 28.1%), respectively, in male offspring. Among female offspring, the aOR and PAF for the 'both high' regarding small-for-gestational-age (SGA)-defined as weight-for-gestational age <10 percentile based on the Japanese neonatal anthropometric charts-were 1.7 (1.0, 2.8) and 10.6% (-0.2%, 20.2%), respectively. Urinary 4NP and 3M4NP concentrations showed no association with low birth weight (<2500 g) and neurodevelopment delay. In conclusion, offspring sex-specific associations of maternal urinary nitrophenols with preterm birth and SGA were observed. Even slight elevations in their levels may explain a certain proportion of preterm birth and SGA. The exposure source, expressed by urinary nitrophenols, should be identified.