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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 34  |  Issue : 1  |  Page : 25-30

A study of relationship between maternal serum vitamin D levels during pregnancy and risk of preterm births


1 Department of Paediatrics, 166 Military Hospital, Jammu, Jammu and Kashmir, India
2 Department of Obstetrics and Gynaecology, Level III Hospital, Goma, Democratic Republic of the Congo
3 Department of Psychiatry, Level III Hospital, Goma, Democratic Republic of the Congo
4 Department of Anaesthesiology and Critical Care, Level III Hospital, Goma, Democratic Republic of the Congo

Date of Submission25-Jun-2020
Date of Acceptance17-Sep-2020
Date of Web Publication16-Nov-2020

Correspondence Address:
Harpreet Singh Dhillon
Department of Psychiatry, Level III Hospital, Goma
Democratic Republic of the Congo
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_50_20

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  Abstract 


Background: Preterm birth is the leading cause of death among neonates and children under 5 years of age with long-term adverse sequelae in the survivors. Vitamin D is being increasingly researched for its protective effect against the risk for preterm births due to its role in immunomodulatory and anti-inflammatory processes. An observational study was undertaken to study the relationship between maternal serum Vitamin D levels during peripartum period and the risk for preterm birth.
Materials and Methods: This study employed a cross sectional design in a tertiary care center on 569 patients to study the relationship between maternal serum Vitamin D levels and risk of preterm births.
Results: A total of 569 samples of maternal and neonatal serum were analyzed for serum 25-hydroxyvitamin D (25[OH]D) levels. Four hundred and sixty-four (81.54%) mothers had Vitamin D sufficient (VDS) levels ≥30 ng/ml and 105 (18.45%) had Vitamin D deficient (VDD) levels <30 ng/ml. Out of the total 569 deliveries, 501 (88.04%) occurred at term (≥37 weeks' period of gestation) and 68 (11.95%) were preterm (<37 weeks' period of gestation). The incidence of preterm births was 10.77% in the VDS group as compared to 17.14% in the VDD group (P = 0.038). The mean cord blood 25(OH) D level of preterm neonates was 12.68 ng/ml (standard deviation [SD] 3.85, range 7.9–22) and term neonates was 13.63 ng/ml (SD 3.76, range 8.2–27) (P = 0.035).
Conclusion: The rate of preterm delivery was 1.59 times higher in mothers with Vitamin D deficiency. Furthermore, the mean cord blood Vitamin D levels were higher in term newborns.

Keywords: Cord blood Vitamin D, newborn, preterm, Vitamin D deficiency


How to cite this article:
Dhillon GK, Singh S, Dhillon HS, Sasidharan S. A study of relationship between maternal serum vitamin D levels during pregnancy and risk of preterm births. J Med Soc 2020;34:25-30

How to cite this URL:
Dhillon GK, Singh S, Dhillon HS, Sasidharan S. A study of relationship between maternal serum vitamin D levels during pregnancy and risk of preterm births. J Med Soc [serial online] 2020 [cited 2020 Dec 5];34:25-30. Available from: https://www.jmedsoc.org/text.asp?2020/34/1/25/300549




  Introduction Top


Preterm birth is defined by the World Health Organization (WHO) as “all births before 37 completed weeks of gestation or fewer than 259 days since the 1st day of a woman's last menstrual period.”[1] An estimated 15 million babies are born prematurely every year and preterm birth complications involving the immune system, respiratory, cardiovascular, endocrine, gastrointestinal systems as well as growth and developmental problems[2],[3] are the leading cause of death among children under 5 years of age, responsible for approximately 1 million deaths in 2015.[4] Many survivors face a lifetime of disability, including learning disabilities and visual and hearing problems. As per the WHO, India had the highest number of preterm births (3,519,100) in 2010.[5] The precise mechanism for preterm births is not yet clear, however, various proposed risk factors include infection in the fetoplacental unit, prepregnancy body mass index (BMI), ethnicity, physical activity, psychoactive substances-smoking, alcohol, other drug use, maternal socioeconomic status, and emotional distress.[6],[7],[8]

Subclinical infections[6],[9],[10] are implicated for almost 50% of spontaneous preterm births. Vitamin D is being increasingly researched for its protective effect against the risk for preterm births due to its role in immunomodulatory and anti-inflammatory processes.[11],[12],[13] Vitamin D induces expression of cathelicidin in the urogenital epithelium, which is a very potent antimicrobial peptide.[14],[15] In addition to production of cathelicidin, Vitamin D also enhances intracellular killing of microorganisms through hydrogen peroxide induced oxidative damage especially in the macrophages.[16],[17] It is also believed to be involved in cell-mediated immunity by regulating the inflammatory cytokines such as interleukin (IL)-1, 6 and tumor necrosis factor.[18],[19],[20] Vitamin D also regulates the calcium concentration across the myometrial cell membranes thus influencing its contractility and preventing onset of preterm labor.[21],[22] Thus, Vitamin D is believed to play a very important role in maintaining the normal length of pregnancy period by modifying the anti-inflammatory and antimicrobial activity within the fetoplacental unit. Although there is ambiguity in the optimal serum concentration of Vitamin D, levels above 30 ng/mL (75 nmol/L) is considered sufficient; 21–29 ng/mL (51–74 nmol/L) insufficient and below 20 ng/mL (50 nmol/L) is considered deficient.[23],[24] The recommended levels for special groups such as pregnancy are higher than 30 ng/mL.[25] However, Vitamin D deficiency is a major global public health issue with around 1 billion people worldwide having Vitamin D deficiency with very high prevalence in south Asian women especially during pregnancy.[26],[27],[28] Low maternal Vitamin D levels in pregnancy may be associated with an increased risk of preeclampsia, gestational diabetes mellitus (GDM), preterm birth, and small for gestational age (SGA).[29],[30] The available research on the levels of Vitamin D and risk of preterm births provide inconclusive results. A multiethnic study by Hollis and Wagner[31] compared the gestational ages of the neonates in 350 pregnant women receiving Vitamin D supplements and controls. This study did not find any significant relationship between maternal Vitamin D levels and preterm births. A study by Hossain et al.[32] showed inverse relationship between maternal Vitamin D level and period of gestation, i.e., high maternal Vitamin D levels were associated with preterm birth. Perez-Ferre et al.[33] studied 266 pregnant mothers and found maternal Vitamin D deficiency increased the risk of premature delivery with odds ratio (OR) of 3.31 (95% confidence interval [CI] 1.52–7.19). Morley et al.[34] found a positive association between maternal 25-hydroxyvitamin D (25[OH]D) at 28–32 weeks and gestation length. Thus, in view of inconsistent results linking maternal Vitamin D and risk of preterm births in the available literature, this study was undertaken to expand our existing knowledge in the subject.


  Materials and Methods Top


Study design

This was an observational study.

Sample population

The study group included healthy pregnant women and their newborns. The tertiary care hospital caters for families from across the country with all subjects belonging to the upper middle socioeconomic status (Kuppuswamy scale). Majority of the women were literate and none of them suffered from malnutrition or indulged in cultural practices such as purdah and hijab which would have affected the synthesis of Vitamin D. The institutional ethics committee approved the study protocol and informed consent was obtained from subjects.

Inclusion criteria

  1. Healthy pregnant women without any comorbidities and their newborn.


Exclusion criteria

  1. Pregnancy losses, spontaneous abortion, and still birth were excluded
  2. Twin/triplet were excluded because of their high risk of PTB, LBW, LSCS[35]
  3. Known history or evidence of rheumatoid arthritis, thyroid, parathyroid, adrenal diseases, hepatic, or renal failure
  4. Metabolic bone disease
  5. Type 1 diabetes and malabsorption diseases.


Methodology

A total of 569 pregnant women were recruited into the study group after applying inclusion and exclusion criterion. The primary objective of this project was to assess the Vitamin D status in maternal serum and to study its relationship, if any, with preterm delivery. A comparison of cord blood Vitamin D levels in preterm versus term neonates was also studied. The analysis of the data was done using the Statistical software IBM SPSS statistics 20.0 (IBM Corporation, Armonk, NY, USA). The statistical analysis was done using Student's t-test. P value < 0.05 was taken as statistically significant. The 25(OH) D levels more than 30 ng/ml were taken as sufficient and <30 ng/ml was taken as deficient as per US Endocrine Society Classification.[23]


  Results Top


A total of 569 samples were collected for the study from the maternal serum and neonatal cord blood during peripartum period. There were 252 (44.2%) males and 317 (55.7%) female newborns. Out of the total 569 deliveries, 501 (88.04%) occurred at term (≥37 weeks' period of gestation) and 68 (11.95%) were preterm (<37 weeks' period of gestation).

Maternal serum Vitamin D levels

Maternal Vitamin D levels are described in [Table 1]. The mean serum Vitamin D level of the mothers was 35.63 ng/ml (standard deviation [SD] = 6.18, range 9.2–49). Out of the total 569 mothers enrolled in this study, 464 (81.54%) had sufficient Vitamin D (VDS) levels (≥30 ng/ml) and 105 (18.45%) had Vitamin D deficiency (VDD) levels (<30 ng/ml).
Table 1: Maternal Vitamin D levels

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Maternal Vitamin D and preterm births

[Table 2] describes the incidence of preterm births (<37 weeks' period of gestation) in Vitamin D sufficient (VDS) and Vitamin D deficient (VDD) mothers. Out of 464 VDS mothers, 50 (10.77%) delivered before term and 414 (89.22%) delivered at term. Out of 105 VDD mothers, 18 (17.14%) delivered before term and 87 (82.85%) delivered at term. The incidence of preterm births was 10.77% in the sufficient group as compared to 17.14% in the VDD group. The rate of preterm delivery was 1.59 times higher in mothers with Vitamin D deficiency. On comparison of the two values using Student's t-test, the P value was found to be statistically significant.
Table 2: Rate of preterm versus term neonates in Vitamin D sufficient and Vitamin D deficiency mothers

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Preterm births and neonatal Vitamin D levels

[Table 3] describes the cord blood Vitamin D levels in preterm and term neonates. All the neonates were deficient in cord blood Vitamin D (<30 ng/ml). The mean cord blood 25(OH)D level of preterm neonates was 12.68 ng/ml (SD 3.85, range 7.9–22) and term neonates was 13.63 ng/ml (SD 3.76, range 8.2–27). The difference in values was statistically significant (P = 0.035).
Table 3: Cord blood vitamin D levels in preterm and term neonates

Click here to view



  Discussion Top


This study attempted to evaluate the relationship between the maternal vitamin D levels and its outcome in the form of risk of preterm delivery. Out of the total of 569 deliveries, 501 (88.04%) occurred at term (≥37 weeks' period of gestation) and 68 (11.95%) were preterm (<37 weeks' period of gestation). The incidence of preterm births has been reported to range from 5% to 7% of live births in developed countries, but are estimated to be substantially higher in developing countries.[36] Beck et al.[37] estimated that 9.6% of all births worldwide in 2005 were preterm and approximately (85%) of these preterm births were concentrated in Africa and Asia. The findings in these studies are close to figures in the current study (11.95% preterm births).

Maternal Vitamin D levels are described in [Table 1]. Out of the total 569 mothers enrolled in this study, 464 (81.54%) had VDS levels (≥30 ng/ml) and 105 (18.45%) had VDD levels (<30 ng/ml). There is a wide range of the prevalence of Vitamin D deficiency in the Indian subcontinent extending from 50% to 90%[38],[39],[40] which is not in consonance with the current study population (18.45% Vitamin D deficiency). This could be attributed to the study sample in current study being from upper middle socioeconomic status without any malnutrition or indulgence in cultural practices such as purdah and hijab and also had free access to a tertiary care center; thus, more likely to be taking a balanced diet and nutritional supplements.

[Table 2] describes the incidence of preterm births (<37 weeks' period of gestation) in the VDS (≥30 ng/ml) group as compared to VDD (<30 ng/ml) group. The incidence of preterm births was 10.77% in the sufficient group as compared to 17.14% in the VDD group (P = 0.038). The rate of preterm delivery was 1.59 times higher in mothers with Vitamin D deficiency and the difference was statistically significant. Perez-Ferre et al.[33] studied 266 pregnant mothers for Vitamin D levels between 24 and 28 weeks of gestation with a cut-off of <50 nmol/L (20 ng/ml) to represent Vitamin D deficiency. Maternal Vitamin D deficiency increased the risk of premature delivery with OR of 3.31 (95% CI 1.52–7.19). A systematic review and meta-analysis consisting of 24 studies reported the association between maternal blood Vitamin D levels and adverse pregnancy outcomes including preterm birth, preeclampsia, and GDM.[29] The results revealed that women with circulating Vitamin D level <20 ng/mL (50 nmol/L) in pregnancy had an increased risk of preterm births (OR 1.58 [1.08–2.31]), preeclampsia (OR 2.09 [95% CIs 1.50–2.90]) and GDM (OR 1.38 [1.12–1.70]). The cut off levels for Vitamin D deficiency in both the above studies was taken at 20 ng/mL (50 nmol/L) in contrast to the current study (Vitamin D deficiency <30 ng/ml) despite which the results were similar and statistically significant (P = 0.038). This indicates that even Vitamin D levels between 20 and 30 ng/ml are associated with increased risk of preterm births.

In a case–control study by Baker et al.,[41] a decrease of 0.7 weeks in gestational duration was seen in women with Vitamin D levels <12 ng/ml during 28–32 weeks, but no relation with maternal blood levels during third trimester was reported. The results were similar to the current study but Vitamin D concentration was determined in the beginning of third trimester in contrast to the current study (perinatal period). De-Regil et al.[42] in a systematic review from the Cochrane database studied neonatal outcome data from three trials involving 477 women and suggested that Vitamin D supplementation during pregnancy reduces the risk of preterm births compared to no intervention or placebo (8.9% vs. 15.5%; relative risk 0.36; 95% CI 0.14–0.93). However, an interesting finding in this review was that when Vitamin D and calcium were combined, the risk of preterm births increased. Hence, these results need to be interpreted with caution. The results corroborate with current study, however, the current study did not take Vitamin D supplementation during pregnancy into account.

Various other studies have shown that both maternal and neonatal 25(OH) D concentrations do not have any association with the risk of preterm births. Thorp et al.[43] in a nested case control study to determine whether Vitamin D status is associated with recurrent preterm births found that serum 25(OH) D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48–3.70 for lowest vs. highest quartiles). However, this study population unlike the current study had marked racial disparity in Vitamin D deficiency. 27% of the total cohort in this study was deficient in Vitamin D but 52% of these were African American women. In addition, the subgroup analysis for recurrent preterm births was done only in African American women. In a randomized controlled trial by Yu et al.,[44] 179 pregnant women were given Vitamin D supplementation either as a one-time oral dose of 200,000 IU or as a daily dose of 800 IU from 27 weeks' gestation until they delivered. Subjects in the control group did not receive any supplementation. This study again, did not find any significant difference in gestational age at delivery despite supplemental group subjects having higher Vitamin D levels. Scholl and Chen[45] in an observational study, reported no relationship with low Vitamin D intake <5 mcg/day with gestational age. In an RCT by Hollis et al.,[46] Vitamin D supplementation with 50-100 mcg/day did not alter gestational duration compared with Vitamin D supplementation of 10 mcg/day.

A prospective study conducted by Hossain et al.[32] Included 75 mothers along with their newborns. Maternal Vitamin D levels for sufficiency were taken as 30 ng/mL (75 nmol/L) similar to current study. Hossain et al. found higher maternal and cord blood Vitamin D status to be associated with shorter gestational periods (r = 0.33, P = 0.003). This finding is in contrast to current as well as most other studies which could be explained by relatively small sample size (75 vs. 569 in the current study).

The possible reasons for the contrasting results in the relation between Vitamin D and period of gestation may be due to several variables such as pre-pregnancy BMI, arbitrary cut off values for Vitamin D, smoking status (including secondhand smoke), socioeconomic status, physical activity (prepregnancy as well as during pregnancy), ethnicity, geographical location, season of birth, and emotional distress.[47] However, the potential role of Vitamin D cannot be undermined in mitigating risk for preterm births given its important role in immunomodulation, inflammatory response, and calcium metabolism in uterine myometrium cells.

The strength of this study is that a large sample size (569) with relatively uniform population in terms of socioeconomic status with unrestricted access to free tertiary medical care was studied. Secondly, sampling for Vitamin D was done during the peripartum period when levels of Vitamin D are not falsely high as compared to first and second trimester.[48] The limitation of the study was that despite a strict exclusion criterion being applied, all the possible confounding factors (e.g., subclinical infections) affecting the period of gestation could not be removed.


  Conclusion Top


Preterm birth is the leading cause of mortality and morbidity in neonates and children under 5 years of age with a multitude of possible etiologies for the same. The rate of preterm delivery was1.59 times higher in mothers with Vitamin D deficiency and the difference was statistically significant. However, due to inconclusive results from related studies, further research on the subject is warranted.

Acknowledgments

The authors would like to thank all the subjects who consented to participate in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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