Our results showed that there was a significant positive correlation between exposure to PM2.5, PM10, O3 in the second month of pregnancy and the risk of CL/P. Among them, PM10 was associated with an increased risk of CL/P. This is consistent with the results of Rao A et al 's previous meta-analysis that O3 increases the risk of OFCs [33].
In 2016, the results of the global death factor survey showed that air pollutants were the sixth leading cause of death, and 7.5% of global deaths were attributed to ambient air pollution. The countries with higher deaths included China and India[34]. PM can be emitted directly from sources such as construction sites, roads, fields, chimneys, or formed by complex reactions of chemicals such as sulfur dioxide and nitrogen oxides. PM consists of hundreds of different chemicals[35]. Relevant studies have found that particulate pollutants can freely pass through the placenta and accumulate on the side of the fetus by comparing the levels of particulate pollutants on both sides of the placenta under different exposure levels of particulate pollutants[36]. PM may exert its adverse effects by directly acting as a pro-oxidant or free radical generator for lipids and proteins, promoting oxidative stress and inducing inflammatory responses[37, 38].
Ozone (O3) is a photochemical environmental pollutant affected by climate. It is easy to form when the temperature fluctuates greatly[39]. Studies have shown that high concentrations of ozone pollution can lead to adverse health effects and increase the morbidity and mortality of respiratory and cardiovascular systems[40–43]. This is consistent with our results that there is a significant positive correlation between exposure to PM2.5, PM10, O3 and the risk of OFCs during the critical period of pregnancy.
There are many reasons for the occurrence of OFCs, including genetics, environment and their combined effects. The combination of genetics and environment is called “epigenetics”[44]. Related studies have shown that low-income families, pesticide exposure history, smoking during pregnancy, gestational diabetes, and heavy metal exposure history such as Pb(lead), Cd (cadmium), and Sr(strontium) are all high-risk risks of OFCs. The reasonable supplement of vitamin, potassium and calcium during pregnancy is a protective factor to reduce the occurrence of OFCs [45–48]. However, due to the limitation of the number of studies included in this paper and the difference in the quality of the literature, Hansen CA et al only adjusted the age of pregnancy and lacked the adjustment of many related confounding factors, which would lead to deviations in the results[26].
Whether the address change during pregnancy will affect the accuracy of the results, many scientists have studied it. Two cohort studies conducted in the United States showed that the address registered by the mother at birth could well replace the residential address during pregnancy, and a high level of consistency was observed, which was not statistically significant for the difference in pollutant exposure[49, 50]. But a cohort study in China 's Gansu province found that people who moved were less likely to have adverse birth outcomes than those who did not[51]. A mate analysis of environmental exposure and residential mobility during pregnancy, using incomplete residential information to estimate environmental exposure, may be misclassified. However, most of the movements are short-distance, so limited residential data can be used to estimate environmental exposure during pregnancy[52].
Our study has several advantages. First, we conducted a systematic review and meta-analysis. Compared with individual studies, the evidence level of systematic reviews and meta-analysis is relatively high. Second, we divided OFCs into CL, CP, CL/P and analyzed them with air pollutants respectively. Finally, among the 11 articles we included, 10 studies were low risk of bias and only 1 study was high risk of bias. After adjusting for them, we found that the heterogeneity was lower than before.
There are some limitations in our research. First of all, we study the high heterogeneity between some literatures, which is related to the limited number of literatures, different geographical locations, different exposure methods, and large research time span. Secondly, there may be differences in the diagnosis of diseases in different studies. There are no trained nurses to inquire about prenatal exposure factors, and professional doctors use relevant scales to classify and evaluate diseases[53, 54]. Third, in the included literature, there is not enough information for dose response assessment, and we have not been able to assess whether there is a linear relationship between pollutant exposure concentration and the occurrence of OFCs. Fourthly, different studies have different exposure assessment methods. Marshall EG et al, Hansen CA et al and Liu FH et al used air quality monitoring stations to monitor the exposure assigned by individuals within a specified radius around, which may lead to measurement errors in exposure concentration, which may cause errors in risk assessment and result deviations[25, 26, 30]. Finally, the exposure points of the literature we included all selected the pregnancy address, without considering the possibility of mobility during pregnancy.