In our several years of neonatal practice, we have seen many cases of late preterm or near-term neonates admitted for tachypnea who were fully recovered in a few hours. The initial tests, blood gas, radiography, and blood culture of these infants were all normal. Despite the good prognosis, separation of the mother and neonate in the first few hours imposes significant stress on the mother and deprives them of the benefits of indispensable mother-infant contact [1]. It would also be a nonessential burden on the medical and nursing staff. This condition is common in elective cesarean cases and in non-academic centers. We have used the term non-specific respiratory distress syndrome (NRDS) to describe this condition. Undoubtedly, the major cause of this problem is a disorder in the respiratory system in the transition from intrauterine to extrauterine life. The most important likely predisposing factors for NRDS are elective cesarean delivery and premature births.

During pregnancy, the fetal lung secretes fluid into the alveolar space through the chloride transport-driven liquid secretion mechanism. Na-K-2Cl channel inhibitors block this secretion. This fluid plays an important role in developing the lungs, providing a framework for preventing airway collapse and promoting them growth [2].

The fetus faces a challenge at birth because the fluid is emptied out of the airways quickly (secreted throughout the pregnancy) with an initial warning (labor) or even without any warning (elective cesarean delivery). A significant component of this process is the lung epithelium, which switches placental to pulmonary gas exchange. Effective gas exchange requires clearing the airways of fluid and increases pulmonary blood circulation to match ventilation and perfusion [3]. Any disturbance in the above process can lead to respiratory problems in the infant. If this respiratory problem lasts for more than 12 h but improves within 24 h to 48 h, transient tachypnea of the newborn (TTN) is suggested [4]. However, this condition often improves within 12 h, which we called non-specific respiratory distress syndrome (NRDS). One way to mitigate this condition is to allow normal labor. Nevertheless, despite the countless benefits of normal labor, elective cesarean delivery is still very frequent. Therefore, before birth, the fetal lung must be well prepared for extrauterine life. Some studies have suggested the role of vitamin D in type-II pneumocyte cell maturation, fibroblast proliferation, surfactant synthesis, and alveolarization; therefore, vitamin D deficiency may be a risk factor for respiratory problems [5, 6]. Premature birth increases the risk of vitamin D deficiency in the infant due to insufficient opportunity for vitamin D to pass from mother to fetus. In this respect, the prevalence of vitamin D deficiency in premature infants has varied in different parts of the world. For instance, vitamin D deficiency has been reported in 64%, 83%, and 82% of preterm infants in the United States, India, and Iran, respectively [7]. Numerous studies have been done on the relationship between vitamin D deficiency and respiratory diseases such as bronchopulmonary dysplasia (BPD), TTN, and respiratory distress syndrome (RDS), and vitamin D deficiency has been considered among the influential factors in the occurrence of these diseases in infants [6, 8, 9, 10, 11]. We hypothesize that vitamin D deficiency may also play a role in NRDS. Therefore, the present research aimed to assess the relationship between non-specific respiratory distress at birth and maternal intramuscular 25-hydroxy vitamin D intake.

In this study, 14 of 169 mothers were excluded from the study, and the remaining 154 mothers were randomly equally divided into the intervention and control groups. Of 77 newborns in each group, 40 infants in the control group and 31 infants in the intervention group were eventually excluded from the study for different reasons as mentioned in Fig. 1. Finally, 37 infants in the control group and 46 infants in the intervention group were included in the study.

In the control group, 51.4% were boys and 48.6% girls, and in the intervention group, 53.3% were boys and 46.7% were girls. The results showed no statistically significant difference between the two groups in terms of gender (p = 0.673) and type of delivery (cesarean section and normal vaginal delivery) (p = 0.299). However, in both groups, the rate of cesarean delivery was higher. The mean duration between vitamin D injection and delivery was overall 23.68 $\pm$ 9.78 h in intervention group.

The mean weight of neonates in the control and intervention groups was 2017.64 $\pm$ 651.11 g and 2624.56 $\pm$ 639.70 g, respectively, and the difference between the two groups was significant. The mean gestational age was 34.81 $\pm$ 1.88 weeks in the control and 35.60 $\pm$ 1.87 weeks in the intervention group, with no significant difference.

The mean level of 25-hydroxy vitamin D of mothers in the control and intervention groups was both less than 30 ng/mL, and there was no significant difference between the two groups. However, there was a significant difference between the two groups in terms of infant’s weight, 1-minute and 5-minute Apgar score, and maternal age. The details are provided in Table 1. Comparing two groups of neonates without respiratory distress and neonates with non-specific respiratory distress in terms of gestational age, weight, parity, maternal age, and serum levels of vitamin D in neonates and mothers showed no significant difference between the two groups.

On the mothers’ side, a significant difference was observed between the two groups of mothers who received 25-hydroxy vitamin D and the control group, in terms of non-specific respiratory distress incidence in infants and improvement within less than 12 h. The results also indicated that maternal intake of 25-hydroxy vitamin D significantly reduced the incidence of non-specific respiratory distress in the infants (Table 2).

Our results showed that injecting 50,000 units of 25-hydroxy vitamin D to a mother at risk of preterm delivery can reduce the transient respiratory problems of the infant. This result indicates the significance of vitamin D in accelerating the maturation of the lungs of newborns. Moreover, we may conclude that vitamin D enhances the development of the cardiorespiratory system and the successful transition from fetal to neonatal life during the delivery process. In the present study, for the first time, we investigated the effect of vitamin D on non-specific neonatal respiratory problems. We hope this study is a prelude to new efforts on reducing the respiratory problems of preterm infants. To the best of our knowledge, there is no similar study in the literature.

However, several articles on animals have suggested the role of vitamin D in fetal lung maturity [3, 9]. A systematic review conducted in 2015 concluded that vitamin D stimulates fetal lung maturation in animals. These data support the hypothesis that vitamin D deficiency is a risk factor, as well as modifiable RDS and BPD [5]. Our results are consistent with those of this article in terms of improved lung function and faster adaptation to the extra-uterine environment owing to vitamin D. This vitamin may also help to transform fetal lungs into neonates’ by protecting the integrity of the pulmonary epithelial barrier in the premature or near-term infants. Lack of vitamin D receptors in the pulmonary epithelial barrier leads to acute lung injury caused by lipopolysaccharides. Vitamin D treatment reduces lipopolysaccharide-induced lung damage and maintains the alveolar barrier function. Thus, vitamin D treatment has been suggested as a potential treatment strategy in acute lung injury and RDS [12].

Hansdottir et al. [13] reported that the effects of vitamin D are very broad, including increased secretion of cathelicidin antimicrobial peptide, decreased chemokine production, inhibition of dendritic cell activation, and altered T-cell activation. All these cases effectively reduce inflammation and lung damage and are more important in preterm and near-term infants who are more prone to inflammatory conditions and lung damage. Numerous studies have indicated vitamin D deficiency as a risk factor for respiratory problems, such as RDS and TTN, in preterm infants [2, 6].

A successful transition from fetal to neonatal life at delivery requires a series of extensive physiological changes in the cardiorespiratory system, leading to an adjustment in the gas exchange pathway from the placenta to the lungs. Replacement of intra-alveolar fluid with air, initiation of regular respiration, and increased pulmonary blood circulation are the most critical respiratory changes at birth. In this regard, normal and term labor are two fundamental factors that facilitate this important process. Numerous mechanisms are involved in alveolar fluid clearance, including the delivery process, initial respiration, and thoracic pressure. Secretion of chloride during pregnancy is vital in lung growth and development. In late pregnancy, the lung epithelium changes from the active secretion of chloride and fluid into the airways to the active absorption of sodium and fluid in response to the increased concentrations of catecholamines and other hormones. Increased oxygen pressure at birth increases sodium transfer and expression of the epithelial sodium channel gene and causes a high absorption of alveolar fluid [3, 14].

Early effective breaths cause high transpulmonary pressures. The mean esophageal pressure is estimated to be –52 cm H${}_2$O during inhalation and 71 cm H${}_2$O during exhalation in the term infants. Increased pulmonary blood circulation occurs due to increased systemic vascular resistance and decreased pulmonary vascular resistance [14]. In a study, 49%, 78%, and 100% of infants over 35 weeks had complete airway clearance at 2, 4, and 24 h postpartum, respectively [15]. Prematurity and vitamin D deficiency may be two predisposing factors that delay this process, leading to respiratory distress in the early hours of life in preterm and near-term infants, although it lasts less than 12 h and all laboratory and radiological evaluations are normal. This phenomenon, which occurs probably due to the prolongation of the transition phase from the fetal stage to the neonatal, was called “non-specific respiratory distress”. Expression of vitamin D receptors in the lungs in late pregnancy in animals highlights the role of vitamin D in alveolar maturation [5]. Further, vitamin D may be involved in postpartum lung growth and alveolarization, but the evidence is limited in this regard. Premature infants have lower levels of 25-hydroxy vitamin D at birth and are at greater risk than term infants for postpartum vitamin-D deficiency. This problem, which is due to intestinal failure and comorbidities, theoretically puts them at risk for acute and chronic lung diseases [16].

According to our results, 25-hydroxy vitamin D injection into the mother improved the 1-minute and 5-minute Apgar scores in infants. Vitamin D affects the airways through several mechanisms, including increased resistance and airway smooth muscle mass, pulmonary parenchyma density, and alveolar septa [17]. Its effects on surfactant production have also been supported in human studies [18]. All of these can be considered effective factors in improving the neonatal Apgar score. A significant correlation was observed in another study between vitamin D levels and the 1-minute and 5-minute Apgar scores [6]. In a study, maternal vitamin D intake improved the 1-minute and 5-minute Apgar scores in the neonates [19]. However, Amegah et al. [20] reported that the relationship between vitamin D and Apgar score is contradictory.

Nevertheless, strongly attributing the incidence of these disorders in infants to vitamin D deficiency needs more research on the role of vitamin D in neonatal respiratory diseases. More research should also be done on the pathophysiology and cause of NRDS to prevent the occurrence.

The most significant limitation of the present study was the lack of measurement of vitamin D level before the administration. The second main limitation was that we did not control the injection time interval until delivery, which can explain the lack of difference in the serum vitamin D levels in infants of the two groups.

The results of the present study showed that a single injection of 25 hydroxyvitamin D to mothers with labor symptoms after the 31st week of pregnancy reduces transient respiratory problems in their infants. Therefore, proper vitamin D supplementation during pregnancy may reduce the respiratory problems of the neonates, although more studies are still required.

All methods were performed in accordance with the relevant guidelines and regulations.

All data generated or analyzed during this study are included in this published article.

HB and NP participated in the design of the study. Statistical analyses were conducted by AD and MRS. All authors contributed to the interpretation of the results. NP and MHAN contributed to the drafting of the manuscript. All authors also contributed to the critical revision of the manuscript for important intellectual content, approved the final version, and are accountable for the integrity of its content.

This study was approved by the Ethics Committee of the Mashhad University of Medical Science (Ethics code: IR.MUMS.MEDICAL.REC.1399.613). The researchers obtained informed consent from the participating patients. The study was registered in the Iranian Clinical Trial Registration Center (IRCT20110807007244N7).

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

This work was supported by Mashhad University of Medical Sciences (grant number of 990699).

The authors declare no conflict of interest.