Association between circulating concentrations of vitamin D and risk of antenatal, postnatal depression: a meta-analysisABSTRACT
Background: Previous studies showed consistent results for associations between circulating concentrations of vitamin D and risk of antenatal, postnatal depression.
Methods: Articles published in English before November 2020 were searched in databases as follows: PubMed, EMBASE, Web of Science, Medline, Google Scholar and Cochrane. These articles explored associations between circulating concentrations of vitamin D and risk of antenatal, postnatal depression.The present meta-analysis was conducted using STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) extracted from included studies were computed using a random effects model or a fixed effects model according to heterogeneities between included studies. Q test and I2 were used to explore heterogeneities between included studies.
Results: 7 cohort studies (including 1567 depression cases and 5254 controls) and 3 case-control studies (including 995 depression cases and 1265 controls) were included in the present study. The study showed that low circulating levels of 25-hydroxy (OH) vitamin D is significantly associated with a higher risk of antenatal and postnatal depression (OR = 1.02, 95% CI 1.01 to 1.04, I2 = 90.7%, p < 0.001).
Conclusion: Our results have shown that the low level of vitamin D may be an adverse factor of antenatal and postnatal depression.
Keywords:
antenatal depression; meta-analysis; postnatal depression; vitamin D; 25-hydroxyvitamin D
Introductions
Depression is the most common mental illness over the world and leads to the decrease of life quality and the deterioration of clinical outcomes, such as suffering, family disruption, disability, and suicide1,2. Pregnancy is a process together with a variety of complicated emotional, psychological and biological changes. These changes such as multiple hormonal changes have been considered as contributing factors of depression3. Depression during pregnancy is frequently reported as a severe psychopathological disorder with the risk of suicide and infanticide. In addition, depression during pregnancy is associated with a train of adverse obstetric and neonatal complications, including preterm delivery, preeclampsia, emergent operative delivery, and negative consequences on child neurodevelopment4,5. According to recent investigations, the prevalence of depression was 11.9% during the perinatal period6,7. Approximately one in four and one in five women experience a major depressive episode during the antenatal and postnatal period, respectively6,7.
Vitamin D has been recognized as an essential fat-soluble vitamin for bone health and calcium homeostasis. Recent studies have proved that it is related to non-skeletal health, including immunity, cancer, renal disease, and neurological dysfunction8. Vitamin D is mainly endogenously produced by skin under the exposure of ultraviolet sunlight, with a small proportion ingesting from food sources9. Similarly, vitamin D deficiency has been a global public health problem in all age groups, affecting more than one billion children and adults10,11.
The available reviews have illustrated the relationship between vitamin D deficiency and depression12,13. Several studies also have demonstrated the association between vitamin D deficiency and antenatal, postnatal depression14,15. Some studies showed a significant association between circulating concentrations of vitamin D and risk of antenatal, postnatal depression16,17, whereas some studies showed that no significant association was detected between circulating concentrations of vitamin D and risk of antenatal, postnatal depression18,19. Therefore, we conducted the meta-analysis to evaluate available evidence regarding the association between circulating concentrations of vitamin D and risk of antenatal, postnatal depression. In addition, the study aimed to provide more reliable guidelines for clinical decision.
Methods
The study was made based on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guideline20.
Search strategy
Two independent reviewers (Dan Lin and Mian Pan) used search terms as follows: (‘vitamin D’ OR ‘vitamin D3’ OR ‘cholecalciferol’ OR ‘25(OH)D’ OR ‘25-hydroxyvitamin D’) AND (‘perinatal’ OR ‘antenatal’ OR ‘postnatal’ OR ‘peripartum’ OR ‘antepartum’ OR ‘postpartum’ OR ‘pregnancy’ OR ‘periparturient’ OR ‘puerperium’ OR ‘maternal’ OR ‘puerperal’ OR) AND (‘depression’). Articles published in English before November 2020 were searched in databases as follows: PubMed, EMBASE, Web of Science, Medline, Google Scholar and Cochrane.
Selection criteria
Two independent reviewers (Dan Lin and Mian Pan) read the titles, abstracts and full texts to include studies according to selection criteria. Inclusion criteria were showed as follows: 1) Included studies explored the association between circulating concentrations of vitamin D and risk of antenatal, postnatal depression; 2) Included studies should be cohort and case-control studies. We excluded studies according to the following criteria: 1) secondary processing articles (meta-analyses and reviews); 2) case reports; 3) Studies did not provide sufficient information to obtain odds ratios (ORs) and 95% confidence intervals (CI) regarding association between circulating concentrations of vitamin D and antenatal, postnatal depression.
Data extraction
Two independent reviewers (Dan Lin and Mian Pan) independently used an Excel file to abstract data as follows: Author, publication year, study type, study location, sample size, mean age of included participants, subgroups, time and method of depression diagnosis, depression cases, adjusted variables and results.
Meta-analysis
The present meta-analysis was conducted using STATA 12.0 software. ORs and 95% CIs extracted from included studies were computed using a random effects model or a fixed effects model according to heterogeneities between included studies. Q test and I2 were used to explore heterogeneities between included studies. With high heterogeneity (p value for Q test ≤ 0.05 and I2 ≥ 50%), a random effects model was used to compute all the ORs and 95% CIs; Inversely, with low heterogeneity (p value for Q test > 0.05 and I2 < 50%), a fixed effects model was used to compute all the ORs and 95% CIs. Subgroup studies (for different types of studies, different ethnic groups, antenatal or postnatal depression) were conducted to explore source of the heterogeneity. In addition, sensitivity analysis was performed to assess the stabilization of the meta-analysis. Moreover, we used Begg’s test, Egger’s test and funnel plot to assess publication bias.
Results
Study characteristics
Supplementary Figure 1 showed the process of including studies. Supplementary Table 1 showed data extracted from included studies. Finally, 7 cohort studies1,16–18,21–23 (including 1567 depression cases and 5254 controls) and 3 case-control studies14,15,19 (including 995 depression cases and 1265 controls) were included in the present study.
Forest plot regarding associations between circulating levels of 25-hydroxy (OH) vitamin D and risk of antenatal and postnatal depression.
Results of meta-analysis
The study showed that low circulating levels of 25-hydroxy (OH) vitamin D is significantly associated with a higher risk of antenatal and postnatal depression (OR = 1.02, 95% CI 1.01 to 1.04, I2 = 90.7%, p < 0.001, Figure 1). Subgroup studies showed that low circulating levels of 25(OH) vitamin D is significantly associated with a higher risk of antenatal and postnatal depression in both cohort and case-control studies (cohort studies: OR = 1.02, 95% CI 1.01 to 1.04; case-control studies: OR = 1.94, 95% CI 1.40 to 2.70; figure 2). In addition, subgroup study showed a significantly negative association between circulating levels of 25(OH) vitamin D and the risk of antenatal, postnatal depression in both Caucasian and Asian populations (Caucasian: OR = 1.02, 95% CI 1.01 to 1.04; Asian: OR = 2.93, 95% CI 2.14 to 4.01; Figure 3). Subgroup study also showed that low circulating levels of 25(OH) vitamin D is significantly associated with a higher risk of both antenatal and postnatal depression (antenatal depression: OR = 1.02, 95% CI 1.01 to 1.04; Asian: OR = 2.64, 95% CI 2.07 to 3.35; Figure 4). The present sensitivity analysis indicated that no changes in the direction of effect happened when any study was excluded from the meta-analysis (Supplementary figure 2). Begg’s test, Egger’s test and funnel plots showed a significant risk of publication bias (Begg’s test: p = 0.721; Egger’s test: p < 0.001; supplementary figure 3).
Subgroup studies regarding associations between circulating levels of 25-hydroxy (OH) vitamin D and risk of antenatal and postnatal depression in different types of studies.
Subgroup studies regarding associations between circulating levels of 25-hydroxy (OH) vitamin D and risk of antenatal and postnatal depression in different ethnic groups.
Subgroup studies regarding associations between circulating levels of 25-hydroxy (OH) vitamin D and risk of antenatal and postnatal depression.
Discussion
Our meta-analysis included 3 case-control studies and 7 cohort studies investigating the relationship between vitamin D deficiency and perinatal depression. Our results showed that there were strong associations between vitamin D deficiency and risk of antenatal and postnatal depression (OR = 1.02, 95% CI 1.01 to 1.04). And subgroup analysis also showed that compared with antenatal depression, there was a more significant positive association between vitamin D deficiency and postnatal depression (antenatal depression: OR = 1.02, 95% CI 1.01 to 1.04; postnatal depression: OR = 2.64, 95% CI 2.07 to 3.35). Our results were in line with a previous article published in 201824. However, we just compared the different effects of high and low levels of serum 25-hydroxy (OH) vitamin D on the onset of depressive symptoms, and did not determine the accurate cut-off value of vitamin D deficiency.
The potential mechanism of high risk of perinatal depression in pregnant women with vitamin D deficiency are still unclear. A study published in 2018 showed that serum 25-hydroxy (OH) vitamin D levels were positively associated with peripheral grey matter volume. In addition, the dysmaturation of grey matter may partly explain the abnormalities of neural development25. One of the main functions of vitamin D is contributing to the calcium homeostasis. The vitamin D deficiency may lead to persistent increase in calcium, resulting in the onset of depression26,27. Another important function of vitamin D is regulating the synthesis of serotonin. In addition, depression is associated with the reduction of serotonin28,29. The hypothalamic-pituitary-gonadal (HPG) axis participate in the regulation of female reproductive cycle and sex hormone levels. Following a sudden estrogen drop after delivery, the reduction of maternal calcium deposits can affect gonadotropin-releasing hormone (GnRH), which played a role in fertility cycle and postpartum depression30. Several clinical studies have also demonstrated that vitamin D supplement can reduce depressive symptoms31.
There were still some limitations in our study. First, the classification criteria of vitamin D is different in all included studies. We just compared the effects of highest and lowest levels of vitamin D on depression. Second, Begg’s test, Egger’s test and funnel plots showed a significant risk of publication bias, which may suggest that our results have been exaggerated. This may be because of lack of unpublished studies.
Conclusions
Our results have shown that the low level of vitamin D may be an adverse factor of antenatal and postnatal depression. However, whether pregnant women with vitamin D deficiency need extra supplement should be treated with caution. There remains a need for more randomized controlled trials and empirical studies to evaluate the role of vitamin D in the antenatal and postnatal depression.
References
-
1 Cunha Figueiredo AC, Trujillo J, Freitas-Vilela AA, et al. Association between plasma concentrations of vitamin D metabolites and depressive symptoms throughout pregnancy in a prospective cohort of Brazilian women. J Psychiatr Res. 2017;95:1-8. doi:10.1016/j.jpsychires.2017.07.009
» https://doi.org/10.1016/j.jpsychires.2017.07.009 -
2 Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci. 2003;58(3):249-265. doi:10.1093/gerona/58.3.m249
» https://doi.org/10.1093/gerona/58.3.m249 -
3 Hammen C. Risk Factors for Depression: An Autobiographical Review. Annu Rev Clin Psychol. 2018;14:1-28. doi:10.1146/annurev-clinpsy-050817-084811
» https://doi.org/10.1146/annurev-clinpsy-050817-084811 -
4 Vivenzio V, Nardi B, Bellantuono C. Depression in pregnancy: focus on the safety of antidepressant drugs. Recenti Prog Med. 2018;109(9):432-442. doi:10.1701/2990.29929
» https://doi.org/10.1701/2990.29929 -
5 Schaffir J. Consequences of Antepartum Depression. Clin Obstet Gynecol. 2018;61(3):533-543. doi:10.1097/GRF.0000000000000374
» https://doi.org/10.1097/GRF.0000000000000374 -
6 Woody CA, Ferrari AJ, Siskind DJ, Whiteford HA, Harris MG. A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J Affect Disord. 2017;219:86-92. doi:10.1016/j.jad.2017.05.003.
» https://doi.org/10.1016/j.jad.2017.05.003 -
7 Gelaye B, Rondon MB, Araya R, Williams MA. Epidemiology of maternal depression, risk factors, and child outcomes in low-income and middle-income countries. Lancet Psychiatry. 2016;3(10):973-982. doi:10.1016/S2215-0366(16)30284-X
» https://doi.org/10.1016/S2215-0366(16)30284-X -
8 Trehan N, Afonso L, Levine DL, Levy PD. Vitamin D Deficiency, Supplementation, and Cardiovascular Health. Crit Pathw Cardiol. 2017;16(3):109-118. doi:10.1097/HPC.0000000000000122
» https://doi.org/10.1097/HPC.0000000000000122 -
9 Gois PHF, Ferreira D, Olenski S, Seguro AC. Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?. Nutrients. 2017;9(7):651. doi:10.3390/nu9070651
» https://doi.org/10.3390/nu9070651 -
10 Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem?. J Steroid Biochem Mol Biol. 2014;144 Pt A:138-145. doi:10.1016/j.jsbmb.2013.11.003
» https://doi.org/10.1016/j.jsbmb.2013.11.003 -
11 Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017;18(2):153-165. doi:10.1007/s11154-017-9424-1
» https://doi.org/10.1007/s11154-017-9424-1 -
12 Gu Y, Zhu Z, Luan X, He J. Vitamin D status and its association with season, depression in stroke. Neurosci Lett. 2019;690:99-105. doi:10.1016/j.neulet.2018.09.046
» https://doi.org/10.1016/j.neulet.2018.09.046 -
13 Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107. doi:10.1192/bjp.bp.111.106666
» https://doi.org/10.1192/bjp.bp.111.106666 -
14 Abedi P, Bovayri M, Fakhri A, Jahanfar S. The Relationship Between Vitamin D and Postpartum Depression in Reproductive-Aged Iranian Women. J Med Life. 2018;11(4):286-292. doi:10.25122/jml-2018-0038
» https://doi.org/10.25122/jml-2018-0038 -
15 Pillai RR, Premkumar NR, Kattimani S, et al. Reduced Maternal Serum Total, Free and Bioavailable Vitamin D Levels and its Association with the Risk for Postpartum Depressive Symptoms. Arch Med Res. 2021;52(1):84-92. doi:10.1016/j.arcmed.2020.10.003
» https://doi.org/10.1016/j.arcmed.2020.10.003 -
16 Brandenbarg J, Vrijkotte TG, Goedhart G, van Eijsden M. Maternal early-pregnancy vitamin D status is associated with maternal depressive symptoms in the Amsterdam Born Children and Their Development cohort. Psychosom Med. 2012;74(7):751-757. doi:10.1097/PSY.0b013e3182639fdb
» https://doi.org/10.1097/PSY.0b013e3182639fdb -
17 Cassidy-Bushrow AE, Peters RM, Johnson DA, Li J, Rao DS. Vitamin D nutritional status and antenatal depressive symptoms in African American women. J Womens Health (Larchmt). 2012;21(11):1189-1195. doi:10.1089/jwh.2012.3528
» https://doi.org/10.1089/jwh.2012.3528 -
18 Gould JF, Anderson AJ, Yelland LN, et al. Association of cord blood vitamin D at delivery with postpartum depression in Australian women. Aust N Z J Obstet Gynaecol. 2015;55(5):446-452. doi:10.1111/ajo.12344
» https://doi.org/10.1111/ajo.12344 -
19 Nielsen NO, Strøm M, Boyd HA, et al. Vitamin D status during pregnancy and the risk of subsequent postpartum depression: a case-control study. PLoS One. 2013;8(11):e80686. doi:10.1371/journal.pone.0080686
» https://doi.org/10.1371/journal.pone.0080686 -
20 Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097
» https://doi.org/10.1371/journal.pmed.1000097 -
21 Fu CW, Liu JT, Tu WJ, Yang JQ, Cao Y. Association between serum 25-hydroxyvitamin D levels measured 24 hours after delivery and postpartum depression. BJOG. 2015;122(12):1688-1694. doi:10.1111/1471-0528.13111
» https://doi.org/10.1111/1471-0528.13111 -
22 Gur EB, Gokduman A, Turan GA, et al. Mid-pregnancy vitamin D levels and postpartum depression. Eur J Obstet Gynecol Reprod Biol. 2014;179:110-116. doi:10.1016/j.ejogrb.2014.05.017
» https://doi.org/10.1016/j.ejogrb.2014.05.017 -
23 Robinson M, Whitehouse AJ, Newnham JP, et al. Low maternal serum vitamin D during pregnancy and the risk for postpartum depression symptoms. Arch Womens Ment Health. 2014;17(3):213-219. doi:10.1007/s00737-014-0422-y
» https://doi.org/10.1007/s00737-014-0422-y -
24 Wang J, Liu N, Sun W, Chen D, Zhao J, Zhang W. Association between vitamin D deficiency and antepartum and postpartum depression: a systematic review and meta-analysis of longitudinal studies. Arch Gynecol Obstet. 2018;298(6):1045-1059. doi:10.1007/s00404-018-4902-6
» https://doi.org/10.1007/s00404-018-4902-6 -
25 Berg AO, Jørgensen KN, Nerhus M, et al. Vitamin D levels, brain volume, and genetic architecture in patients with psychosis. PLoS One. 2018;13(8):e0200250. doi:10.1371/journal.pone.0200250
» https://doi.org/10.1371/journal.pone.0200250 -
26 Berridge MJ. Vitamin D: a custodian of cell signalling stability in health and disease. Biochem Soc Trans. 2015;43(3):349-358. doi:10.1042/BST20140279
» https://doi.org/10.1042/BST20140279 -
27 Berridge MJ. Vitamin D and Depression: Cellular and Regulatory Mechanisms. Pharmacol Rev. 2017;69(2):80-92. doi:10.1124/pr.116.013227
» https://doi.org/10.1124/pr.116.013227 -
28 Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014;28(6):2398-2413. doi:10.1096/fj.13-246546
» https://doi.org/10.1096/fj.13-246546 -
29 Dell'Osso L, Carmassi C, Mucci F, Marazziti D. Depression, Serotonin and Tryptophan. Curr Pharm Des. 2016;22(8):949-954. doi:10.2174/1381612822666151214104826
» https://doi.org/10.2174/1381612822666151214104826 -
30 Amini S, Jafarirad S, Amani R. Postpartum depression and vitamin D: A systematic review. Crit Rev Food Sci Nutr. 2019;59(9):1514-1520. doi:10.1080/10408398.2017.1423276
» https://doi.org/10.1080/10408398.2017.1423276 -
31 Casseb GAS, Kaster MP, Rodrigues ALS. Potential Role of Vitamin D for the Management of Depression and Anxiety. CNS Drugs. 2019;33(7):619-637. doi:10.1007/s40263-019-00640-4
» https://doi.org/10.1007/s40263-019-00640-4
