Vitamin D is key hormone that regulates many essential physiological functions. Vitamin D insufficiency or deficiency is a global health problem which is associated with a variety of diseases, including infectious diseases, metabolic syndrome, and critical illnesses (1). Vitamin D insufficiency or deficiency is very common in populations around the world. It has been reported that most elderly men and women in high-income countries including U.S, Canadian, and European still living in the community are vitamin D deficient (2, 3). Vitamin D deficiency is also common in low-income countries such as Middle East, India, Africa, and South America (4, 5). Children, young and middle-aged adults are at equally high risk for vitamin D deficiency and insufficiency worldwide. The incidence rates and severity of vitamin D insufficiency and deficiency are higher in infants (6–8). A reduction in vitamin D intake and absorption, decreased synthesis, and increased activated 1,25- dihydroxyvitamin D₃ (1,25(OH)2D₃) can lead to severely low levels of vitamin D.

Risk factors for vitamin D deficiency in infant include breast-feeding without vitamin D supplementation and maternal vitamin D deficiency. The infant can remain vitamin D sufficient for several weeks after birth, as long as the mother was vitamin D sufficient. However, most pregnant women are vitamin D deficient or insufficient (9, 10). Lee et al. reported that 76% of mothers and 81% of newborns had a vitamin D deficiency at birth, despite the mothers ingested about 600 IU/d of vitamin D and consumption of two glasses of milk during the period of pregnancy (11).

The vitamin D insufficiency or deficiency is often associated with severe infectious diseases, multiple organ failure, and even mortality (12, 13). Vitamin D signaling imposed a key regulator of immunity in human beings. Vitamin D, also could induce expression of antibacterial proteins which is able to support increased bacterial killing in a variety of cell types (14, 15).

We conducted this study in the Suzhou area of East China to investigate the prevalence of vitamin D insufficiency in hospitalized full-term neonates and to evaluate the factors associated with vitamin D insufficiency. and to explore the relation of vitamin D insufficiency with immunocompromise.

This study indicates that vitamin D insufficiency is associated with being born in winter. Moreover, we observed that the prevalence of vitamin D insufficiency in neonates with infectious pneumonia, sepsis, cytomegalovirus infection, and hypocalcemia was higher and the serum CD3+, CD3+, CD4+, and IgA levels were lower in neonates with vitamin D insufficiency.

In our prospective study, we found that the prevalence of vitamin D insufficiency was 28.24%, the vitamin D sufficiency was 71.76%, and there was no vitamin D deficiency in our hospital. A similar study in Boston, northeastern USA, revealed that the prevalence of serum vitamin D insufficiency (25-(OH)D3, 20–30ng/mL) in neonates with gestational age ≥37 weeks was 24.7% (17). The incidence of vitamin D insufficiency in preterm neonates was not included in this study. There are regional and lactation differences regarding neonatal serum vitamin D and associated with vitamin D deficiency during pregnancy (18). Suzhou city is located near the ocean, latitude 30°47′-32°2′ (mid-latitude region), with warm weather and adequate sunlight. The region has a flourishing economy and commerce. During pregnancy, women consciously ensure that they receive sufficient vitamin D by supplementation, which is why we found no vitamin D deficiency in hospitalized full-term neonates. Also we thought the pregnant mother in our region get enough Vitamin D supplement, further, we need to continue exploring the serum of maternal Vitamin D influence on the infants.

Our findings revealed that being born in winter was an independent risk factor for vitamin D insufficiency in full-term neonates. We all know that the major source of vitamin D for children and adults is exposure to natural sunlight (19). This widely accepted association between vitamin D insufficiency status and the season of birth was reported by Mosayebi et al. (20). They found that the majority of neonates with vitamin D insufficiency were born on cold days during the winter, and the vitamin D status was closely related to the season of birth. The correlation between vitamin D status and the season of birth has also been reported by Khuri-Bulos et al. (21) who showed that most neonates with low levels of vitamin D were born during the winter months. However, other studies did not identify a specific relationship between the season of birth and serum vitamin D levels in neonates (22). It appears that exposure to sunlight is not a critical factor for serum vitamin D status. The synthesis of vitamin D is affected by various factors such as latitude, season, air pollution, and clothing. Vitamin D is primarily synthesized by exposure of the skin to direct sunlight. Receiving breast milk, which chronically contains low levels of vitamin D and certain customs of ancient cultures that reduce direct sun exposure would contribute to the deficiency or insufficiency of vitamin D in neonates (23). Consequently, some research has shown that vitamin D was not being produced, not only in regions at latitudes of 45° or higher (such as North America and Europe), but also during special periods, including winter, which may last 6 months of the year or longer (24). Moreover, some studies revealed other factors that may affect the vitamin D status in neonates, such as mothers with restricted sun exposure inducing maternal vitamin D deficiency, preterm babies, and small for gestational age (25).

Low serum vitamin D levels in neonates are associated with rickets, bronchopulmonary dysplasia (BPD), respiratory tract infections, and other diseases (26–28). A previous study revealed that neonates with vitamin D deficiency or insufficiency are at greater risk of developing serious infection and sepsis, and lower serum vitamin D levels in pregnant mothers are closely linked with increased risk of sepsis in neonates (29). A study also showed that 25 hydroxy vitamin D level of children in the NRDS group was significantly lower than that of the non-NRDS group (SMD = −0.51, 95%CI: −0.63 to −0.39, p ≤ 0.05). Suggests that vitamin D deficiency is very likely to be a high-risk factor of NRDS, and reasonable vitamin D supplementation during pregnancy and after birth is of great significance (30). In other related fields, a study in Taipei revealed that the prevalence of vitamin D deficiency was 59%, and only 10% of critically ill patients had a vitamin D level >30 ng/mL. They also found that most critically ill patients had a median vitamin D level <20 ng/mL during their stay at the intensive care units (31).

In our study, the serum CD3⁺, CD3⁺CD4⁺, and IgA levels in neonates with vitamin D insufficiency were lower. Vitamin D has other functions as well, including modulating activated B and T lymphocytes, insulin, and thyroid-stimulating hormone secretion (32). Vitamin D potentially influences human immunity, including the induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation. Infants with rickets are at risk of developing diseases unrelated to calcium homeostasis, including immune disorders, and a study showed that immune production of 25-(OH)D is regulated by factors that are not linked to calcium homeostasis. Local synthesis of 25-(OH)D and its downstream signaling are integral components of innate immune responses to microbes (33). Another study reported that locally produced 25-(OH)D activated the transcription of certain signaling pathways and genes related to innate immunity. In laboratory studies, the gene encoding CD14, the co-receptor of the pattern recognition receptor toll-like receptor-4, is strongly induced by 25-(OH)D (34). Clinical and epidemiological studies have reported that the immune protection induced by vitamin D could protect the body from some viruses, including hepatitis viruses, human immunodeficiency virus, and viral respiratory pathogens (35).

In our analysis, several limitations were noted. We did not identify whether suboptimal maternal vitamin D status directly contributed to the neonates. Further, our study did not include data on prenatal vitamin D supplementation and maternal 25(OH)D levels and therefore, did not facilitate better risk prediction regarding suboptimal vitamin D status.

Vitamin D is key hormone that plays an important role in human health. Vitamin D insufficiency or deficiency is a global health problem which is associated with a variety of diseases. Results from this study suggest the prevalence of vitamin D insufficiency in neonates is high, and birth in winter was a risk factor for vitamin D insufficiency in hospitalized full-term neonates. Neonates with infectious pneumonia, sepsis, cytomegalovirus infection, and hypocalcemia exhibited a high risk of vitamin D insufficiency. The serum CD3⁺, CD3⁺CD4⁺, and IgA levels in neonates with vitamin D insufficiency were lower. We believe that suppling and remain the neonates Vitamin D sufficiency will improve initiatives for optimizing neonate care.

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

The studies involving human participants were reviewed and approved by Ethics Committee of the Children's Hospital of Soochow University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

HW and YD participated in the study design and manuscript writing. ZW and HG collected clinical data collection and conducted data analysis. XuZ and XiZ supervised the design and execution of the study, performed the final data analysis, and contributed to the writing of the manuscript. All authors read and approved the final manuscript.

This study was financially supported by the National Natural Science Foundation of China (No. 81971423, 81771626), Jiangsu Key Talent Program of Maternal and Child Health (No. FRC201731), Jiangsu Provincial Social Development Key General Project (No. BE2020658), and Jiangsu Provincial Health and Family Planning Commission Medical Research Project (No. ZD2021013).

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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