In this retrospective cohort study of Chinese women, we investigated the association of UA and UN with adverse pregnancy outcomes. High UA levels in the second trimester were not significantly associated with adverse pregnancy outcomes, but with an increased risk of PROM and SGA in the third trimester was observed. We also found that mothers with elevated UN had a higher risk of SGA, whether they were in the second or third trimester of pregnancy. Moreover, we found for the first time that pregnant women with concurrently elevated UA and UN concentrations had a higher risk of giving birth to SGA infants.
After entering the fetal circulation, high levels of UA affect fetal development by causing placental inflammation and dysfunction. In vitro studies have suggested that UA can induce inflammatory pathways in vitro, with activation of p38 MAPK, NF–κB, and AP-1 and an increased expression of COX-2 and MCP-1 . Elevated of UA levels can also inhibit placental amino acid uptake, trophoblast invasion and the incorporation of trophoblast into endothelial monolayers, leading to placental hypoperfusion [26–28]. Additionally, during late gestation, UA crystals activate the nod-like receptor protein_3 (NLRP3) inflammatory pathwayvia an IL-1–dependent pathway, causing placental interface inflammation and affecting fetal development [29, 30]. Numerous population–level studies have also investigated the association between UA and adverse maternal and infant outcomes, although their conclusions have been inconsistent. In a retrospective analysis of 212 women in Pittsburgh, Laughon et al. attested that hyperuricemia in the second trimester (18–21 weeks of gestation) was associated with lower birthweight in normotensive women. A prospective multicentric cohort study of 404 Iranian normotensive pregnant women indicated that maternal hyperuricemia in the third trimester (28–42 weeks of gestation) was independently associated with PTB (OR, 3.17; 95% CI, 2.1–4.79) and SGA (OR, 1.28; 95% CI, 1.04–2.57) . Similar findings were also found in two studies: a case-control study carried out in 120 Japanese women in the third trimester with normal blood pressure by Akahori et al.  and a retrospective cohort study carried out in 1,880 Australian women by TL-A Hawkins et al. . In contrast, in a prospective study that included 1,541 subjects, Laughon et al. indicated that elevated UA levels in the first trimester (less than 15 weeks of gestation) were not associated with PTB and SGA. In the present study, we extended these findings to a relatively large cohort of Chinese pregnant women and observed that women in the fourth quartile of UA levels during the third trimester of pregnancy exhibit a 48% and 99% higher risk of PROM and SGA, respectively. During a normal pregnancy, the UA concentration changes dynamically. UA concentration is significantly reduced at 8 weeks of gestation, and these reduced levels remain stable until approximately 24 weeks of gestation, after which maternal UA levels increase rapidly to pre-pregnancy levels. Heterogeneity in the results reported in previous studies may be due to variations in study design, sample size, the timing of biomarker evaluation, diagnostic criteria, or other confounding factors.
UN, which is generally recognized to be a biomarker of kidney function, is associated with pregnancy-induced hypertension such as preeclampsia. Previous experimental studies, both in vitro and in vivo, have indicated that urea-induced ROS stimulates activation of endothelial pro-inflammatory pathways by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular advanced glycation end products (AGEs) . Simultaneously, reactive oxygen species induced by urea also directly inactivated the antiatherosclerosis enzyme PGI2 synthase and also caused endoplasmic reticulum (ER) stress. It is well established that the elevated blood UN level is an independent risk factor for adverse fetal pregnancy outcomes in pregnant women undergoing hemodialysis. Multiple case reports have shown that blood UN levels in pregnant women undergoing hemodialysis were negatively correlated with fetal birth weight and gestational age [17–20]. We initially explored the relationship between UN and adverse pregnancy outcomes in normal pregnant women, and observed that women in the fourth quartile of UN levels exhibited 118% and 129% higher risk of SGA during the second and third trimester of pregnancy, respectively. More animal studies and population epidemiological evidence are needed to elucidate the relationship between the UN and maternal and infant pregnancy outcomes.
To the best of our knowledge, this study is the first to assess the relationship between the combined association of UA and UN concentrations with the risk of developing adverse pregnancy outcomes. An interesting finding from our study was that women with higher levels of both UA and UN levels exhibited a 151% higher risk of SGA during the second trimester of pregnancy. Another striking finding was that women with both UA and UN levels in the second or third quartile had a 98% higher risk of developing SGA during the third trimester and in the fourth quartile had a 131% higher risk of developing SGA during the third trimester. These results highlighted the importance of paying attention to UA and UN concentrations across the whole duration of pregnancy. However, further longitudinal studies with larger sample sizes are needed to validate our findings.
Although our study comprehensively examined the relationship between maternal renal function indicators and the risk of adverse pregnancy outcomes using two parameters in a relatively large sample size, some limitations still exist. Firstly, the analytic cohort was from China, which may limit the generalizability of the study results. Secondly, although we accounted for known confounders, some unmeasured or unknown residual confounders remained (either unmeasured or unknown). Finally, the small size of the subgroup of women aged > 35 years and with a BMI of >24 kg/m2 limited the statistical power. However, the chosen biochemical parameters of UA and UN to assess maternal renal function are simple, inexpensive, and readily available tests, and thus should be additionally evaluated.