Journal of Clinical Neonatology

: 2022  |  Volume : 11  |  Issue : 3  |  Page : 165--171

Cordblood vitamin A levels and intraventricular hemorrhage outcomes in preterm infants

Emmanuel Augustine Ogbe1, Emmanuel Ademola Anigilaje2, Eyinade Kudirat Olateju3, Uduak Mayen Offiong4, Usman Abiola Sanni5, Kaareem Iwunmole Airede3,  
1 Department of Paediatrics, R-JOLAD Hospital Nigeria Limited, Lagos, Nigeria
2 Department of Paediatrics, Nephrology Division, University of Abuja Teaching Hospital, Abuja, Nigeria
3 Department of Paediatrics, Neonatology Division, University of Abuja Teaching Hospital, Abuja, Nigeria
4 Department of Paediatrics, Neurology Division, University of Abuja Teaching Hospital, Abuja, Nigeria
5 Department of Paediatrics, Federal Medical Centre, Birnin Kebbi, Nigeria

Correspondence Address:
Emmanuel Augustine Ogbe
Department of Paediatrics, R-JOLAD Hospital Nigeria Limited, Gbagada, Lagos


Background and Aims: Intraventricular hemorrhage (IVH) is a major complication of preterm birth and large haemorrhages may yield significant future disability. Although multifactorial, prematurity and low birth weight are the most important risk factors for IVH. Furthermore, being “born too soon” affects the accretion of Vitamin A (VA) which is essential for normal brain development. We sought out to estimate VA nutrient levels among preterm newborn infants at birth and establish any relationship with IVH occurrence and grade severity. Methods: Ninety infants were recruited over a 6-month period. VA levels were determined by the enzyme-linked immunosorbent assay using cord blood and IVH was assessed by transcranial ultrasound scan done on the 7th day of life. Data analysis was by the Statistical Package for the Social Sciences IBM (SPSS) version 21. P < 0.05 was considered statistically significant. Results: The infants' median interquartile ranges for gestational age, birth weight, and cord blood VA levels were 32 weeks (4.25 weeks), 1580 g (650 g), and 0.31 μmol/L (0.19 μmol/L), respectively. The prevalence of VA deficiency, low VA, and sufficient VA was 67.8%, 25.5%, and 6.7%, respectively. IVH was found in 8 (9.20%) infants, with incidence rates of 5.70%, 2.30%, and 1.10% for Grades I, II, and III, respectively. Although statistically insignificant, the occurrence of IVH was only among infants with abnormal VA status at birth (P = 0.65). Conclusions: Despite low median cord blood VA level of preterm infants in this study, there is no impact on IVH occurrence or grade severity. Further study with larger sample size is warranted.

How to cite this article:
Ogbe EA, Anigilaje EA, Olateju EK, Offiong UM, Sanni UA, Airede KI. Cordblood vitamin A levels and intraventricular hemorrhage outcomes in preterm infants.J Clin Neonatol 2022;11:165-171

How to cite this URL:
Ogbe EA, Anigilaje EA, Olateju EK, Offiong UM, Sanni UA, Airede KI. Cordblood vitamin A levels and intraventricular hemorrhage outcomes in preterm infants. J Clin Neonatol [serial online] 2022 [cited 2022 Oct 1 ];11:165-171
Available from:

Full Text


Intraventricular hemorrhage (IVH) is the most common intracranial bleed in newborn and preterm infants in particular. It can be associated with severe complications including posthemorrhagic ventricular dilatation and periventricular hemorrhagic infarctions. The hemorrhage originates from the germinal matrix with an immature capillary bed where vascularization is intense and active cell proliferation is high. The role of Vitamin A (VA) in cell proliferation is well known and low levels have been demonstrated severally among preterm infants.[1],[2],[3]

Cranial ultrasound scan (CUS) is the gold standard for the diagnosis of IVH. It is a safe procedure and can be done by bedside. Approximately half of IVHs occur in the first 6 h of life, and hemorrhage rarely occurs after the 5th day of life (DOL) thus, if present, could be reliably detected by CUS done on the day 7th of life.[4]

Treatment of IVH is nonspecific, thus a lot lies on prevention. Proven and effective preventive modalities include prevention of preterm labor, antenatal corticosteroids, active neonatal resuscitation, slow administration of intravenous therapy, correction of acid − base state, and appropriate nutrition.

VA is essential for life with significant role in the development of the vascular endothelium. Given the low levels expected in preterm infants due to poor feto-maternal nutrient accretion as a result of being “born too soon,” the possibility of relationships if any, with IVH incidence needs to be investigated. Furthermore, the potential role for VA supplementation (VAS) as a survival strategy in neonate and the lack of sufficient data on its benefits deserves this study; to examine VA status of preterm infants at birth and evaluate the relationship if any with the incidence or severity of IVH.


This is a prospective cross-sectional study of 90 preterm infants at the University of Abuja Teaching Hospital (UATH) Gwagwalada, Abuja, North-Central Nigeria, conducted over a 6 months period from December 2018 to May 2019.

The study was approved by the health research ethics committee of the UATH Gwagwalada. An informed consent was obtained from patient's parents.

Ninety infants of <37 weeks gestational age (GA) were enrolled into the study.

Inclusion criteria

Prematurity with GA <37 weeks delivered at UATHAbsence of congenital malformations and central nervous system (CNS) disorderNo need for vigorous resuscitationAPGAR score at 5 min ≥7, andSPO2 >90%.

Exclusion criteria

Presence of congenital malformations and CNS disordersAPGAR at 5 min <7 thereby requiring resuscitationSPO2 <90%Neonate who needed vigorous resuscitation in the first 3 days of lifeBabies whose parents did not consent to the study.

Sampling technique

Upon delivery of the placenta, 3 ml of cord blood was collected into plasma bottles from the maternal end of the cord using disposable sterile syringe and needles from the umbilical vein and transferred into ethylenediaminetetraacetic acid (EDTA) tube. Where free flow of blood through the cord was available, the sample was collected from the free flow into the EDTA tube.

All procedures were carried out in the darkroom to avoid photodegradation of VA. The blood sample was protected from light by wrapping in alminium foil to avoid photodegradation of VA and transported immediately in ice park to the side lab and centrifuged at 1000 rpm for 10 min and the separated plasma was transferred into clear tubes, tightly capped and stored in the freezer at −20°C until analysis. Dim light only was used at all possible exposure times. The plasma was stored for a maximum of 6 months from the time of separation to assay of VA.

Plasma VA was assayed by the enzyme-linked immunosorbent assay (ELISA) at the Clinical Chemistry Department of UATH with human VA ELISA kit by Bioassay Technology Laboratory® Shanghai China using an Automatic ELISA Plate Analyser:Redwell touch by Unitron Biomedical® Bengahiru. Human ELISA VA kit has been widely used for the measurement of retinol in plasma.

VA levels were measured in μg/ml and converted to μmol/L to reflect adequacy and deficiency standards established by WHO.[5] The conversion factor used was 286 μg retinol is equivalent to 1 μmol retinol.[6] In this study, VA deficiency (VAD) was defined as plasma VA <0.35 μmol/L. VA values of 0.35 μmol/L–0.7 μmol/L were regarded as low cord blood VA, while values >0.7 μmol/L were termed as sufficient VA.

The diagnosis of IVH was done by a CUS. The CUS was performed using a Philips® HD5 ultrasound system with a probe for neonatal transcranial assessment located in the scanning room attached to the newborn unit.

The scan was performed by 7th DOL. Where hemorrhage was detected in sonographic findings, grading was done using Volpe's creteria and the severity was evaluated. Hemorrhagic Grades I and II were determined as moderate hemorrhage and III and IV as severe hemorrhage.

Data collection and analysis

All completed questionnaires were cross-checked for accuracy and entered into an Excel spreadsheet. Data analysis was done using the Statistical Package for the Social Sciences IBM, SPSS® Statistics version 21, Chikago, U.S.A. Data on GA, birth weight, cord blood VA, and hemoglobin concentration were skewed and thus summarized using medians and interquartile ranges (IQR). Percentages were computed for dichotomous variables. Chi-square test or Fisher exact test were used to compare the proportion of infants' clinical outcomes with cord blood VA status. The Kruskal–Wallis test was used to compare median within groups due to the violations of the normality assumption of “cord blood VA status.” For all quantitative variables, P < 0.05 were also considered as significant.


The baseline characteristics of the 90 preterm infants included in the study are shown in [Table 1]. The majority of the infants (53; 58.9%) were delivered through cesarean section. There were fifty male infants (55.60%). Of the enrolled babies for the study, 6 (6.70%) were of upper socio-economic class, 29 (32.20%) were of middle socio-economic class and 55 (61.10%) were of low socio-economic class. The median (IQR) GA and birth weight of the infants were 32 weeks (4.25 weeks) and 1580 g (650 g), respectively. Most of the infants (85; 94.40%) were appropriate for GA. There was a wide range of VA in cord blood from 0.09 μmol to 2.32 μmol/L, with the median (IQR) being 0.31 μmol/L (0.19 μmol/L). IVH was found in 8 (8.90%) infants. The severity included 5 with Grade I, 2 with Grade II and one with Grade III.{Table 1}

Baseline characteristics of study infants

The baseline characteristics of the study neonates including gender, GA, mode of delivery, and social class are shown in [Table 1].

When VAD status was analyzed in relation to sociodemographic characteristics (social class, gender, birth weight, and GA) of these neonates and certain maternal characteristics, the relationship was null (P > 0.05), as shown in [Table 2].{Table 2}

Cord blood Vitamin A status of study neonates

The proportion of neonates having different plasma retinol is shown in [Figure 1]. Sixty-one neonates (67.80%) reached the criterion for VAD while 23 (25.50%) had low levels. Only six neonates (6.70%) had sufficient VA levels. There was a trend of increasing cord VA levels with increasing GA. Furthermore, the median (IQR) cord levels of VA were found to be lower among the small for GA (SGA) neonates as shown in [Table 3]. However, associations did not reach statistical significance (P > 0.05).{Figure 1}{Table 3}

Intraventricular hemorrhage

Brain sonography done on the 7th DOL showed that 82 (91.11%) neonates had no hemorrhage while IVH was found in 8 (8.88%) neonates. The severity included 5 with Grade I, 2 with Grade II and 1 with Grade III, giving an incidence of 5.56%, 2.20%, and 1.10%, respectively. Although the only case of major IVH was in an infant with VAD, there was no difference in the incidence or severity of IVH between the infants who were VA deficient at birth and those who were not (P = 0.648), as shown in [Table 4].{Table 4}

Other clinical characteristics of the 90 studied infants were analyzed across cord blood VA status as summarized in [Table 4]. Antenatal corticosteroid was received by 75 (83.3%) mothers who presented with imminent preterm birth before the second stage of labor, in line with the Obstetrics Departmental protocol. The occurrence of VAD, VA insufficiency, and VA sufficiency at birth did not depend on the antenatal use of corticosteroids by the mothers (P > 0.05). Although severe respiratory distress syndrome (RDS), neonatal clinical infection, and bacterial sepsis, were common among the VAD and VA insufficient groups; this was not statistically significant (P > 0.05).

Neonatal clinical infection (probable sepsis) occurred in 39 (43.0%) infants, 13 (33.33%) of whom was blood culture-proven. All the infants with culture-proven sepsis also had abnormal VA level (VAD or low VA). The microorganisms isolated in these 13 infants included Staphylococcus aureus (5, 38.50%), coagulase-negative Staphylococcus (5, 38.50%), Group A beta-hemolytic Streptococcus (1, 7.70%), Escherichia coli (1, 7.70%), and Klebsiella spp. (1, 7.70%).

The clinical characteristics of the neonate in relation to VA status at birth is shown in [Table 5].{Table 5}


In our study, VA level in preterm infants at birth is low. Furthermore, VA level at birth is independent of maternal antenatal steroid, social status, or educational level. In addition, the incidences of IVH and other adverse clinical events including SGA, sepiapterin reductase deficiency SRD, sepsis, and mortality were found to be insignificantly more among infants with VAD and/or VA insufficiency.

Furthermore, a median retinol level of 0.31 μmol/L was found among the preterm infants in our study. This value is slightly lower than 0.35 μmol/L reported among British[7] preterm infants. Notably, the median GA of 32 weeks in the present study is similar to the median GA of 31 weeks in the British study.[7] Possible explanation for the observed difference may be related to the small sample size of the British study which was carried out among 26 preterm infants, compared to 90 preterm infants in the present study. It may also be a reflection of better nutritional status of the British infants. The low median VA level in our study cannot also be linked to degradation that occurs with dehydration during the storage of samples as the work of Drammeh et al.[8] had earlier shown that plasma carotenoids and retinoids were stable for up to 15 months when stored at a temperature of <−20°C. In the present study, samples were stored in small, tight-stoppered tubes and at a temperature of <−20°C for not more than 6 months.

We observed a wide range of VA values in cord blood plasma ranging from 0.09 μmol/L to 2.32 μmol/L. This observation is consistent with the findings of Adhikari et al.[9] where plasma VA level was also noted to be in a wide range from 0.2 μmol/L to 0.9 μmol/L among the preterm infants. A similar observation was also made by Radhika et al.[10] in India.

A high prevalence of 67.8% was seen for VAD in this study. When compared to similar studies were VAD among preterm infants was defined as plasma VA level <0.35 μmol/L, the finding of 67.8% in this study was lower than the 75% reported by Fares et al.[11] in Tunisia but much higher than the respective 48.5%, 48%, and 35% among Egyptian,[12] British,[7] and American[13] preterm infants. The difference in the prevalence of VAD in this study and those of others[7],[12],[13] may be explained by differences in the nutritional status of the mother-infant pairs.

Both antenatal and postnatal steroid is believed to significantly increase the plasma concentration of retinol in preterm infants.[14] Antenatal steroid, for instance, is suggested to be responsible for the higher plasma values of VA measured soon after birth[14] However, in the present study, no significant difference in the plasma VA level was observed among infants whose mothers received or did not receive antenatal steroids. This observation corroborates the findings of Chen et al.[15] who reported that neither antenatal nor postnatal steroids had a significant influence on newborn retinol at birth or within the first 48 h of life. A likely explanation for the observation in this study is that newborn preterm infants have comparatively insufficient liver stores of retinol, such that, there is insufficient retinol to be released into the blood stream.[1]

Although not statistically significant, improvement in markers of socioeconomic status noted in this study was associated with improvement in plasma concentrations of VA. The nutritional status of a population can depend to a great extent on its socioeconomic status.[16] On the contrary, an earlier study in a Nigerian urban setting showed no association between socioeconomic characteristics like occupation and household size with plasma retinol concentrations; however, education was found to have a positive impact.[17] While our study did not find an effect of maternal education or socioeconomic status on infants' plasma levels of VA, the infants of mothers who had better education and social class did have higher plasma VA level. A possible explanation for this is that increased income and education allow for greater flexibility in food choices.[2] Furthermore, employed mothers may be more likely to be urban residents and have access to a wider range of VA enriched food products, which eventually may impact on their infants' nutritional status.[2]

Brain sonography was done on day 7th after birth to detect IVH. The incidence of IVH was higher among infants with abnormal VA status at birth. There was no occurrence of IVH among infants with normal VA status at birth, giving the thought of a protective effect of VA on IVH, but the decrease was not statistically significant. Our study also did not find any difference in grade severity among the neonates. These findings are consistent with other findings reported by other studies. The study of Tyson et al.[18] among 807 preterm newborns showed that infants VA sufficiency status was associated with nonsignificant trends toward reduced risks of intracranial hemorrhage (relative risk, 0.93), and periventricular leukomalacia (relative risk, 0.74). Similarly, Hustead et al.[19] in a study of 75 infants revealed a nonsignificant rise in incidence of IVH in infants with VAD. Another study of 134 newborns with <1500 g birth weight showed that VA status did not significantly affect incidence of IVH among the infants.[20] just as Mactier and Weaver[1] did not find any significant difference among preterm infants with better VA status. Also, meta-analysis of neonatal VAS have failed to demonstrate improved IVH outcomes among preterm infant, suggesting a role for factors other than VA.[21]

In our study, sepsis was evaluated in neonates by clinical assessment and blood culture. Positive blood culture and clinical sepsis were more prevalent in infants with abnormal VA status at birth, yet the difference was not considerable. However, it suggests that VA can decrease risk of sepsis in newborns. A systematic review reported that using VA in neonates could increase risk of sepsis.[20] Another study on 50 neonates who received intramuscular VA showed that VA has no effect on sepsis.[22] In this study, SRD was less prevalent in infants who were VA sufficient at birth suggesting that VA might help decrease the risk for SRD yet this decrease in risk was not statistically significant. A systematic review on the effects of VA showed that VA insignificantly reduced the incidence and severity of SRD in infants diagnosed with RDS. However, a study on 914 premature neonates showed that using VA could increase the risk for both sepsis and RDS.[20]

Mortality in our study was higher in the infants with subnormal VA status at birth yet insignificantly. In a study on 149 newborns with lower than 1000 g birth weight showed that using intramuscular VA can decrease mortality rate.[14] However, Edmond et al.[23] reported no effect of VA on mortality.


One of the limitations of this study was related to the sample size which was too small to be generalizable to whole community. Another limitation was the small number of extreme preterm infants which may be responsible for the low incidence of IVH. To evaluate the effects of VA on the incidence of IVH, mortality and morbidity in neonates, further studies are needed to investigate the factors that potentially affect the results.


It should be mentioned that the observed low VA in preterm neonates was not significantly accompanied with IVH incidence, but the rate of IVH occurrence was less in neonates with sufficient VA at birth. In addition, despite the fact that findings in the current study were not significant, mortality and sepsis rates, as well as SRD incidence were more in infants with subnormal VA status at birth.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Mactier H, Weaver LT. Vitamin A and preterm infants: What we know, what we don't know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 2005;90:F103-8.
2Hanson C, Lyden E, Anderson-Bery A, Nicholas K, Rezac A, Delari S, et al. Status of retinoids and carotenoids and associations with clinical outcomes in maternal-infant pairs in Nigeria. Nutrients 2018;10:1286-90.
3Maziya-Dixon BB, Akinyele IO, Sanusi RA, Oguntona TE, Nokoe SK, Harris EW. Vitamin A deficiency is prevalent in children less than 5 y of age in Nigeria. J Nutr 2006;136:2255-61.
4Özek E, Kersin SG. Intraventricular hemorrhage in preterm babies. Turk Pediatri Ars 2020;55:215-21.
5Lu Z, O'Dell D, Srinivasan B, Rey E, Wang R, Vemulapati S, et al. Rapid diagnostic testing platform for iron and vitamin A deficiency. Proc Natl Acad Sci U S A 2017;114:13513-8.
6International Vitamin A Consultative Group. Conversion factor For Vitamin A and Carotenoids: Cancum, Mexico: International Vitamin A Consultative Group; 2016.
7Chan V, Greenough A, Cheeseman P, Gamsu HR. Vitamin A levels at birth of high risk preterm infants. J Perinat Med 1993;21:147-51.
8Drammeh BS, Schleicher RL, Pfeiffer CM, Jain RB, Zhang M, Nguyen PH. Effects of delayed sample processing and freezing on serum concentrations of selected nutritional indicators. Clin Chem 2008;54:1883-91.
9Adhikari KM, Somani BL, Kalra S, Mathai SS, Arora MM. Umbilical cord blood plasma vitamin A levels in low birth weight (LBW) babies. Med J Armed Forces India 2011;67:142-6.
10Radhika MS, Bhaskaram P, Balakrishna N, Ramalakshmi BA, Devi S, Kumar BS. Effects of vitamin A deficiency during pregnancy on maternal and child health. BJOG 2002;109:689-93.
11Fares S, Sethom MM, Khouaja-Mokrani C, Jabnoun S, Feki M, Kaabachi N. Vitamin A, E, and D deficiencies in Tunisian very low birth weight neonates: Prevalence and risk factors. Pediatr Neonatol 2014;55:196-201.
12Hamdy AM, Abdel Aleem MM, El-Shazly AA. Maternal Vitamin A deficiency during pregnancy and its relation with maternal and neonatal hemoglobin concentrations among poor Egyptian families. ISRN Pediatr 2013;2013:652148.
13Rugolo LM, Trindade CE, Methorn MM, Khouaja-Mokrani C, Jabnoun S, Feki M, et al. Selenium and Vitamin A and E in the nutrition of very low-birth weight preterm infants. J Neonatal Biol 2013;2:1-7.
14Bennasir H, Sridhar S, Abdel-Razek T. Vitamin A from physiology to disease prevention. Int J Pharm Sci Rev Res 2010;1:68-73.
15Chen HJ, Hsu CH, Chiang BL. Serum retinol levels and neonatal outcomes in preterm infants. J Formos Med Assoc 2017;116:626-33.
16Danneskiold-Samsøe N, Fisker AB, Jørgensen MJ, Ravn H, Andersen A, Balde ID, et al. Determinants of vitamin a deficiency in children between 6 months and 2 years of age in Guinea-Bissau. BMC Public Health 2013;13:172.
17Williams O, Parker R. Vitamin A content of southeastern Nigerian vegetable dishes, their consumption parttern and contribution to vitamin a requirement of pregnant women in Calabar Urban, Nigeria. Park J Nutr 2009;8:1000-4.
18Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, et al. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 1999;340:1962-8.
19Hustead VA, Gutcher GR, Anderson SA, Zachman RD. Relationship of vitamin A (retinol) status to lung disease in the preterm infant. J Pediatr 1984;105:610-5.
20Uberos J, Miras-Baldo M, Jerez-Calero A, Narbona-López E. Effectiveness of vitamin A in the prevention of complications of prematurity. Pediatr Neonatol 2014;55:358-62.
21Inder TE, Graham PJ, Winterbourn CC, Austin NC, Darlow BA. Plasma vitamin A levels in the very low birthweight infant Relationship to respiratory outcome. Early Hum Dev 1998;52:155-68.
22Ding Y, Chen Z, Lu Y. Vitamin A supplementation prevents the bronchopulmonary dysplasia in premature infants: A systematic review and meta-analysis. Medicine (Baltimore) 2021;100:e23101.
23Edmond KM, Newton S, Shannon C, O'Leary M, Hurt L, Thomas G, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): A randomised, double-blind, placebo-controlled trial. Lancet 2015;385:1315-23.