Congenital anomalies associated with ambient temperature variability during fetal organogenesis period of pregnancy: Evidence from 4.78 million births

Backgrounds: Evidence for the effects of temperature variability on risk of congenital anomalies is lacking. We aimed to examine the association of temperature variability during fetal organogenesis period (weeks 3-8 post-conception) with major congenital anomalies. Methods: A retrospective cohort study comprising 4,787,356 singleton live-births and stillbirths in China was performed. We defined two temperature variability indices within gestational week i: the standard deviation (SD) of daily temperature (TVSDi) and the maximum day-to-day temperature difference OW. At 6-week long timescales, we computed the SD of daily temperature (TVSD3-8) and the average value of TVDi (TVD3-8). We matched two temperature variability indices, pollutant exposure levels over entire exposure window and data of each mother-infant pairs. An extended generalized estimating equation log-binomial regression model was constructed to explore their associations after adjusting for individual characters, temperature extremes and air pollutants. Stratified and sensitivity analyses were also performed. Results: 59,571 neonates were registered as major congenital anomalies besides genetic and chromosomal anomalies. At weekly levels, the highest risk estimates of two temperature variability indices occurred at the 5th week for most anomaly groups. All TVSD5, TVD5, and maximum weekly TVSD and TVD were significantly associated with all anomaly groups: with the increment of 1 degrees C, the estimated risk ratio (RR) and corresponding 95% confidence interval (CI) ranges from 1.03 (1.01-1.05) to 1.19 (1.08-1.31). At 6-week scales, TVSD3-8 and TVD3-8 were associated with most anomaly subgroups. Overall, the strongest associations were estimated for isolated defects among morphology subgroups and cardiac defects among type subgroups. Conclusions: Exposure to temperature variability during fetal organogenesis period of pregnancy is associated with increased risk of major congenital defects. Our findings provide a research foundation for public health policies, and further mechanism investigation. (C) 2021 Published by Elsevier B.V.