Ureaplasma urealyticum (UU) is an opportunistic pathogenic microorganism, that attaches to epithelial cells and germ cells, and colonizes on the mucosal surface of the urogenital tract of adults or the respiratory tract of infants (1). It is a common pathogen in the reproductive tract of women of childbearing age, and the detectable rate of women in pregnancy can be as high as 82% (2). The UU infection causes reproductive tract inflammation, infertility and adverse pregnancy outcomes, such as premature rupture of membranes (PROM), chorioamnionitis and more (3, 4). Studies have reported that UU infection is closely associated with neonatal diseases, such as bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP) (5, 6), although it is controversial. Delayed detection and treatment of the infection leads to severe neonatal diseases and long-term effects, such as respiratory and nervous system sequelae (7). This study retrospectively analyzed the clinical characteristics, hemogram changes and disease outcomes of preterm infants with gestational age ≤32 weeks and weight ≤ 2000 g, with and without UU infection. We aimed to illustrate the influence of UU infection that may provide help for clinical workers.

The opportunistic pathogen UU can be divided into two biogroups, namely Ureaplasma urealyticum (UUA) and Ureaplasma parvum (UPA). The microorganism has 14 serotypes in total, among which serotypes 1, 3, 6, and 14 belong to UPA, and the other 10 serotypes are UUA. Its pathogenicity was related to different biogroups, serotypes and host factors. Perinatal UU infection is mainly transmitted vertically from mother to fetus, including intrauterine infection and intrapartum infection. The smaller the gestational age and the longer the PROM time, the greater the possibility of vertical transmission (15). A recent animal study reported that cervical epithelial damage could promote Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth (16). Moreover, Romero et al. reported that intra-amniotic infections are often the result of an ascending invasion (17). This study found that preterm infants born through vaginal delivery and those with smaller gestational age were more likely to be infected with UU. The UU infected mothers were more likely to suffer from chorioamnionitis and PROM during perinatal period. In addition to the observations in our population, mothers of UU positive neonates seemed to suffer from hypertension less frequently than mothers of not infected neonates. In our hospital, maternal samples for UU infection were not routinely detected in the department of obstetrics, so we diagnosed intrauterine UU infection with positive UU-PCR test of secreta or excreta of preterm infants after birth, which was a limitation of our study.

Currently, there is no lack of reports about UU infection and complications in preterm infants. UU infection can lead to many neonatal diseases that include the respiratory system, digestive system, nervous system and retina; however, most studies talk about BPD (18). BPD is a common complication of the respiratory system in preterm infants that has a complex etiology and pathogenesis. One of the most important principle mechanism is inflammation (19). Most studies considered UU infection as a risk factor for BPD, but the diagnostic criteria used in relevant studies was an outdated diagnostic criteria. We adopted the latest diagnostic criteria for BPD (Workshop diagnosis consensus 2018), and the results found that UU infection significantly increases the incidence of BPD in preterm infants (P = 0.02). Studies indicate that UU can induce pro-inflammatory immune responses, but may not stimulate anti-inflammatory responses in VLBW infants, that promote cytokine imbalances pushed toward a pro-inflammatory state and cause lung injury (15), thus prolonging the oxygen inhalation time and mechanical ventilation compared to the non-UU infected group (P < 0.001). Oxygen therapy and mechanical ventilation are risk factors for BPD, and this disease will lead to difficulty in the oxygen attainment of infants, further lengthening the time of oxygen inhalation and mechanical ventilation, forming a vicious circle. In this study, the level of postnatal leukocytes in the UU infection group were significantly higher than that the non-infection group (P < 0.001). The difference of postnatal procalcitonin level between the two groups was also statistically significant. But there was no significant difference in the level of IL-6 between the two groups in this study. This may be related to the short half-life of inflammatory markers that it is affected by different blood collection times.

In addition, we also found a statistically significant difference between postnatal platelet level of preterm infants with and without UU infection (P = 0.002). However, no relevant previous reports were reported to support these findings. Platelets play an important role in physiological and pathological process, including coagulation, thrombosis, inflammatory reaction, and maintain the integrity of vascular endothelium cell. Studies report that platelets can be used as an indicator of infection and as a guide for diagnosis and evaluation of treatment effect. Most children with sepsis have reduced platelet level (20). This study showed no difference in mean platelet volume between the two groups (P = 0.633); however, the platelet level in infants with UU infection were still higher than those without infection. The mechanism may be related to platelet activation caused by inflammation, which remains to be explored and confirmed.

This study analyzed the diagnostic ability of postnatal leukocyte level on UU infection, and the resulting area under the curve AUC was = 0.658, indicating its poor diagnostic efficiency. For the changes in postnatal hemogram of the infected infants over time, and whether there is a linear correlation with UU infection, or whether the values and changes can be used as diagnostic indicator for infection still needs to be confirmed with a larger sample size.

ROP is a potentially blinding disorder seen in premature infants where there is abnormal blood vessels growth in the retina. There are few reports about UU infection and ROP at present. Ozdemir et al. reported that one of the independent risk factors for severe ROP in premature infants is UU infection, and it can increase the release of vascular endothelial growth factor, which is not conducive to the growth and development of vessels in the fundus (21). MBDP is also one of the common complications that has an increased risk among those with smaller gestational age and lower birth weight (22). Current common risk factors for MBDP include nutritional deficiencies (calcium, phosphorus, vitamin D), maternal or gestational factors, mechanical factors, endocrine changes, use of certain drugs that antagonize bone metabolism, and chronic diseases (intestinal malabsorption, renal or liver insufficiency, and collagen or metabolic diseases) (23). This study shows that UU infection also increases the risk of MBDP. However, there have been no previous studies reporting the association between UU infection and MBDP, and its mechanism remains to be explored.

Some studies presented that intrauterine UU infection can promote the development of fetal lungs. The infection could be a protective factor of neonatal respiratory distress syndrome; however there was no significant statistical difference seen in the incidence of RDS between the two groups in this study (24). Similarly, there was no statistical difference in the incidence of ICH, WMI, NEC, PDA, sepsis and other diseases between the two groups. Inflammation mediated by UU infection leads to an increase in white blood cells count and inflammatory factors such as IL-8 and IL-6 in newborn blood (25).

At present, the main clinical treatment drugs are macrolides, tetracycline and chloramphenicol. Macrolides, which mainly include erythromycin, azithromycin and clarithromycin, are the most commonly used drugs for UU infection that are widely studied. Among the drugs mentioned, some scholars reported that azithromycin can improve the clearance rate of UU in infected infants, and inhibit the pulmonary inflammatory response. Its efficacy is stronger than erythromycin, reducing the morbidity and mortality of BPD. However, there is still no standard for the initial timing, optimal dose, course of treatment, and safety of azithromycin application (26). But several azithromycin therapy for chronic lung disease of prematurity (AZTEC) studies are ongoing (27). In addition, Motomura et al. found that the use of clarithromycin could reduce adverse pregnancy and neonatal outcomes induced by Ureaplasma parvum (28).

In conclusion, UU infection can increase the duration of oxygen inhalation and mechanical ventilation of preterm infants under 2000 g and 32 weeks, increase level of leukocytes and platelets after birth, and increase the incidence of BPD, ROP and MBDP. However, the infection, has no effect on the incidence of NEC, ICH, WMI and other diseases in preterm infants. Furthermore, delivery mode, PROM and leukocyte level after delivery were independent risk factors for UU infection. Therefore, high-risk neonates should undergo early screening of UU through a comprehensive analysis of clinical manifestations and laboratory results. This shall aid the clinician in obtaining an immediate diagnosis and providing definitive treatment to reduce complications and poor prognosis among preterm infants. However, multiple-center studies with larger scale should be done to support our conclusion.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Ethics Committee of Shengjing Hospital affiliated to China Medical University (2021PS674K). Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

JF conceived the review and revised the manuscript. TS performed the search, collected the data, and took charge of writing the original manuscript. Both authors contributed to the article and approved the submitted version.

This research received a grant from the funding of Key R&D Guidance Plan Projects in Liaoning Province (2020JH1/10300001).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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