In this prospective nested case-control study, we identified for the first timethat a high maternal plasma Mn level in the third trimester was positively associated with an increased risk of SPB, especially in normal-weight women and non-PROM women. Moreover, there is a dose-dependent relationship in the non-PROM population. The higher the level of plasma Mn in the third trimester, the higher risk of SPB.
Blood Mn concentration is an effective and representative biomarker of Mn exposure. The average blood Mn concentration range was quite inconsistent across different regions, from 10 to 22.5ng/ml [3, 8, 11-18]. In this study, plasma Mn concentrations both in the first and third trimester were significantly lower than that reported by the China Nutrition and Health Survey 2010-2012 of pregnant women (2.4ng/ml, 95%CI: first trimester 1.1-9.2ng/ml;third trimester 1.4-7.7ng/ml)[19]. However, plasma Mn concentrations in the third trimester observed in this study were similar to Mn levels in the first trimester reported in Shanxi and Anhui cohort study in China [6, 7, 20]. Due to the development of the coal mining industry, the environmental exposure risk of Mn is remarkablyhigher in Anhui and Shanxi provinces than in Beijing. Otherwise, our observed plasma Mn concentration in the third trimester was higher than that reported in the Indonesian cohort study (premature birth group: 1.09ng/ml; term birth group: 1.0ng/ml) [20]. Our results in the third trimester were similar to that reported in the Pakistan cohort study (1.38ng/ml) [21]. The results may be affected by the participants' character, sampling time, region, eating habits, laboratory testing methods, and environmental exposure. In addition, we found that there was a cumulative effect of blood Mn levels during pregnancy, which was consistent with the research results in Taiwan, China [22], Wuhan [14], Anhui [13, 20] and Costa Rica[13]. It may be related to the average growth and development of the fetus and the increased demand for the balance of the redox system during pregnancy.
As part of metalloenzymes or their activators, Mn participates in maintaining the balance of the redox system in some critical physiological processes. An abnormal concentration of Mn may lead to premature birth by inducing an imbalance of the redox system in the body[23]. Stratified by BMI grade, the difference in Mn concentration between the two groups was significant only in the normal weight population.The reason may be that overweight or thin is a risk factor for premature birth and would modify the effect of Mn on SPB. Researchers should fully evaluate these confounders when doing further research. All the above suggested that plasma Mn level in the third trimester may be a risk factor for SPB, and the effect is significant in specific populations.
Several previous studies have reported that excessive Mn concentration was associated with higher preterm birth risk. Most studies didn’t strictly distinguish SPB from iatrogenic preterm birth, and most sampling time was at delivery. Only one study conducted in a Shanxi cohort study estimated the relationship between serum Mn level and SPB in the first and second trimesters. But their serum samples in the first and second trimesters were from different populations. They reported a positive risk association between serum Mn levels and SPB in a positive dose-dependent manner in the first trimester, not the second trimester [6]. However, we found that a high concentration of plasma Mn (3rdtertile) in the third trimester of pregnancy, not the first trimester, was a risk factor for SPB. The serum Mn concentration in the first trimester of pregnant women in Shanxi was close to that in the third trimester in our study. Therefore, it may further indicate that a high concentration of Mn is a risk factor for SPB, and it may have nothing to do with the pregnancy stage. In contrast, other previous studies didn’t find an association between Mn concentration and preterm birth risk. Those inconsistent results may be related to population, study design, sample type, sampling time, and preterm birth type. Our study proved that Mn concentration in pregnancy increase with gestational age in a dynamic motoring manner in pregnancy. However, most previous studies collect serum samples at delivery, whether preterm birth (<37 weeks= or term birth (≥37 weeks), resulting in different sampling times in the two groups. In our study, sampling time was similar in the SPB and term birth groups. Therefore, our results may be more representative of clarifying the relationship between high maternal Mn concentration and SPB risk.
Considering that vaginal GBS infection may impact SPB, we performed a sensitivity analysis after excluding these people. The results showed that relationship between Mn concentration and SPB risk was still significant. It further confirmed the results above that high Mn concentration is a risk factor for SPB.
Advantages and limitations
There are some advantages to our study. First, we are the first to use a repeated measurement design to clarify the dynamic changes of plasma Mn during pregnancy in the related studies. Second, iatrogenic preterm birth would confuse the study results with a specific reason for preterm birth. In this study, only SPB cases were selected for analysis and were strictly distinguished from iatrogenic preterm birth. Third, the sampling time was similar in the two groups, which could reduce the effect of the gestational week on element concentration. Fourth, this nested case-control study relied on a prospective cohort study conducted in Beijing. The same exposure backgrounds helped to reduce the region confounding. Also, we can get accurate information needed in the survey and minimize recall bias.
Still, several limitations should be considered when explaining our results. First, there was no information on diet and nutrient supplementation, and we couldn’t evaluate pregnant women’s dietary Mn exposure level and its relationship with plasma Mn concentration. Second, when the stratified analysis was carried out according to specific factors, some subgroups’ relatively small sample size may affect the power to determine the association between Mn level and SPB.Third, in this study, all cases were late-preterm (labor week≥34 weeks), close to full-term. The pathological condition related to SPB may be too little to observe a meaningful difference between the two groups. It would be helpful to include early preterm women in further studies to clarify the relationship between plasma Mn levels and SPB.