Correlation of Prenatal Vitamin D Deficiency and Neonatal Urinary Tract Infection

 Urinary tract infection (UTI) is a common infection during pregnancy and different age groups of children, including the neonatal period. It comprises 1/3 of bacterial infections in newborn infants, with a prevalence of 0.1-1% in term and 4-25% in preterm neonates. UTI occurs more commonly in male neonates (M/F: 2-6/1) for the higher incidence of structural abnormalities (1, 2). Urinary tract anomaly is found in about 20-50% of infants with UTI. UTI rarely occur during the first 3 days of life, and urine culture is not routinely recommended for the evaluation of early onset sepsis (3). Appropriate serum vitamin D level is important for the prevention of multiple infections during pregnancy, including UTI. Maternal serum vitamin D has a negative correlation with UTI (4, 5). The role of maternal vitamin D deficiency during pregnancy as a risk factor of neonatal UTI remains controversial.
This review study was performed to evaluate the correlation between maternal vitamin D deficiency during pregnancy and neonatal UTI for the early diagnosis and prevention of its complications.

Relevant articles from PubMed, Google Scholar, ISI web of knowledge and scopus databases were evaluated in this review article to investigate the correlation between reduced maternal vitamin D and neonatal UTI up to 2022. Diagnosis of UTI was made in neonates with clinical manifestations of fever, vomiting, poor feeding, jaundice, failure to thrive, weight loss, diarrhea, irritability, lethargy, apnea, bradycardia, or abdominal distention associated with urine white blood cells more than 5/hpf, and positive urine culture (any growth of a single pathogen in suprapubic urine aspiration, or more than 104 CFU/ml of a single pathogen from urine obtained by urethral catheterization, or more than 105/ml of urine bag sample), if possible. However, urinalysis has low specificity and sensitivity for diagnosis of UTI in neonates, and does not consider as a part of evaluation. Vitamin D measurement has been defined by the Institute of Medicine (IOM) as; severe vitamin D deficiency (less than 12 ng/mL), deficiency (12-20 ng/ml), vitamin D insufficiency (20-30 ng/mL), vitamin D sufficiency (more than 30 ng/mL), and more than 50 ng/ml as the cause for concern.

Maternal UTI is a common infection during pregnancy with several adverse maternal and perinatal complications such as pre-eclampsia, chrorioamnionitis, growth and developmental delay, low birth weight (prematurity, intrauterine growth retardation) and perinatal death (2, 6). Maternal UTI might contribute to the increased incidence of UTI during the neonatal period (1, 2, 7, 8). In Bilgin et al study on 230 neonates, maternal UTI was non-significantly associated with intrauterine growth retardation, preterm labor and low birth weight. However, neonatal UTI was significantly higher in neonates with maternal UTI, compared to the control group, which suggested maternal UTI as a risk factor of the neonatal UTI (2).  A significant correlation was found between prenatal maternal and neonatal UTI in Micle et al study, in which neonatal UTI was reported in about 30% of prenatal maternal UTI vs 6.8% without infection (6). Emamghorashi et al showed a significant relationship between maternal prenatal UTI and neonatal infection; in which 30% of neonates with UTI vs 6.8% without UTI had mothers with a history of UTI. They suggested a possible benefit of evaluating neonates with a history of maternal UTI during pregnancy (7). In Khalesi et al study, about 15% of neonates had a positive maternal history of UTI (4.4%, 6.1%, and 4.4% during the 1(st), 2(nd), and 3(rd) trimesters of pregnancy, respectively). Totally, maternal UTI increased 6 fold higher risk of neonatal UTI. They emphasized on more attention for the assessment and management of UTI among neonates for reducing the related complications (8). UTI has different presentations during the neonatal period. It usually remains asymptomatic in the majority of newborns, or presents with nonspecific symptoms such as failure to thrive or prolonged hyperbilirubinemia. However, other manifestations of a severe illnesses such as poor feeding, abdominal distension, vomiting, tachypnea, gastrointestinal manifestations, fever, irritability, lethargy, and cyanosis might be reported.Therefore, regular monitoring of at risk neonates is recommended for asymptomatic or nonspecific clinical manifestations (2,3,8).  Vitamin D is an important hormone during pregnancy, which is provided from dietary sources and skin synthesis by sunlight exposure (8). Previous studies have shown essential role of vitamin D in regulation of both innate and adaptive immune responses by increasing motility and phagocytic activity of neutrophils, producing antimicrobial peptides, regulating cytokine production, inhibiting inflammatory process and lowering the severity of infectious and autoimmune disorders. Vitamin D, is known to have an effect on urothelium, with immunomodulatory capacity against bacterial infection (5, 6, 9, 10). Increasing vitamin D level during pregnancy modulates the innate immune system for a protective response in infectious disorders. Vitamin D deficiency has been considered as the risk factor of UTI, especially in females. Maintenance of normal vitamin D level might reduce the occurance of UTI (4, 9, 10).  Some studies showed the importance of sufficient vitamin D level for the prevention of UTI by inhibiting the production of inflammatory factors such as IL-6 and TNF-@, and producting defensive antibacterial urinary tract peptides such as Cathelicidin and β-defensines. Cathelicidin is secreted by the immune cells and epithelial surfaces of multicellular organisms. It has a protective role against infection by increasing cytokine production, stimulating macrophage proliferation and up regulating macrophage vitamin-D receptor. β- defensin expresses on the epithelial cell surface, which attracts and increases white blood cells during kidney infection. Vitamin D deficiency increases the risk of UTI by decreased production of these substances (5, 10). Maternal vitamin D level has a negative correlation with the incidence of UTI, and the risk of UTI increases in pregnancy with low serum vitamin D level, which shows the etiologic correlation between serum vitamin D and potential risk of UTI (9, 10). In Yang et al study on 238 infants, serum 25(OH) D levels were significantly lower in cases with UTI (29.09 ± 9.56 ng/mL) than controls (38.59 ± 12.41 ng/mL). Infants with acute pyelonephritis had lower serum 25(OH) D than those with lower UTI. They showed that serum 25(OH) D <20 ng/mL was positively related to an increased odds of UTI, and vitamin D supplementation was associated with a lower risk of UTI (9). In a meta-analysis of 9 studies included 580 patients with UTI, vitamin D insufficiency was significantly associated with the increasing incidence of UTI, especially in childhood. A significant etiologic correlation was found between serum vitamin D level and increased risk of UTI (10). In a case-control study on 187 participants (97 pregnants with a symptomatic UTI and 90 matched healthy pregnant), mothers with serum vitamin D less than 10-20 ng/ml have a higher incidence of UTI during pregnancy than women with serum vitamin D more than 30 ng/ml in Haghdoost et al study. Pregnant women with acute pyelonephritis had significantly lower serum vitamin D level than those with acute cystitis (5). Vitamin D deficiency has been reported in breast fed infants secondary to low maternal sun exposure and insufficient vitamin D intake (9). Increasing serum vitamin D level by supplemental products during pregnancy increases the protective response of urinary tract system and prevents of further infections. Therefore, regular monitoring of newborns at risk of UTI is recommended during the neonatal period (2, 5, 9).

Multiple studies showed the protective effect of sufficient serum vitamin D level for the prevention of UTI. Based on the increased incidence of maternal UTI in cases with low serum vitamin D level, and correlation between maternal and neonatal UTI supplementation and maintenance of normal maternal vitamin D level is recommended for the prevention of neonatal UTI in all mothers during pregnancy.