The association between Vitamin D levels and postpartum depression: a review

According to WHO, Postpartum Depression (PPD) occurs in 10–15% of women after giving birth. Several studies assumed that vitamin D deficiency might worsen PPD symptoms. However, the association between vitamin D levels and PPD is still conflicting. This article summarizes the association between vitamin D levels and PPD. A literature search about Vitamin D levels and PPD from Scopus and PubMed databases was performed in June 2022. Eleven studies were obtained out of 30 studies. Nine out of 11 studies showed that vitamin D levels were significantly associated with PPD. However, the two others showed no significant association. The difference in the blood sample taken and how to assess depression contributes to a different result. The association is related to the role of vitamin D in mood regulation, synthesis of neurotransmitters, stimulating brain receptors, and intercellular neuronal signaling systems.


Introduction
Postpartum depression (PPD) occurs in women after giving birth with characteristics such as weakness, feelings of guilt, unable to sleep, decreased cognitive function, and feelings of suicide. Generally, postpartum depression symptoms appear 3-6 months after birth (CDC 2014). Based on statistical data from the WHO, it is estimated that around 10-15% of women worldwide experience postpartum depression. The clinical manifestations of PPD are losing interest in activities, depression for two weeks, reduced concentration, feeling guilty, and sleep disturbance (Accortt et al. 2016). PPD affects the mother and impacts the growth and development of her family, especially the baby in close contact with the mother (WHO 2012). The etiology of this disease is still not well understood. However, previous studies revealed that the role of micronutrients like vitamin D affected PPD.
Vitamin D is a fat-soluble vitamin usually found naturally in food, sunlight, and supplements. Sources of vitamin D come from food, such as fish oil, red meat, liver, egg yolks, and cow's milk (NHS Choices 2017). One-fifth of vitamin D is obtained through dietary sources, while the remaining 80% is synthesized in the skin by ultraviolet rays from 7-dehydrocholesterol (Akpınar and Karadağ 2022). The serum form of the vitamin, calcidiol, is then hydroxylated in the liver by the enzyme 25-hydroxylase (CYP2R1), and calcidiol is re-hydroxylated in the kidney and brain by the enzyme 1-hydroxylase (CYP27B1), yielding 1,25 (OH)2 cholecalciferol, also known as calcitriol (Akpınar and Karadağ 2022). This vitamin plays a role in many diseases, such as cancer, osteoporosis, cardiovascular, psychiatric, and diabetes (Fu et al. 2015). Vitamin D shows in low concentration, usually during pregnancy. Even with supplementation, only a few women are vitamin D sufficient (Fu et al. 2015).
The association between vitamin D levels and PPD is still conflicting. Several studies assumed that vitamin D deficiency might worsen PPD symptoms (Robinson et al. 2014;Abedi et al. 2018;Rouhi et al. 2018;Pillai et al. 2021;Amini et al. 2022). A systematic review in 2019, including seven articles, reported that findings from six cohort studies suggest that vitamin D deficiency is associated with the incidence of PPD. However, one study showed no association (Amini et al. 2019). In addition, the studies were between the years 2010 and 2016. Therefore, this article summarizes and updates studies on the association between vitamin D levels and PPD.

Data search
In June 2022, a literature search was conducted using the PUBMED and SCOPUS databases. "Vitamin D" and "postpartum depression" were the keywords used. The flow diagram's literature search report adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Study selection
Original research articles in English published between 2012 and 2022 are eligible for inclusion. Articles that did not discuss the relationship between vitamin D and PPD were not considered.

Article extraction
The author's name, type of study, country, number of participants, age, depression test, methods for measuring the vitamin D levels, study objective, type of sample, time for taking the samples, time for depression assessment, levels of vitamin D, depression scale score, and conclusion were extracted from the obtained articles.

Result and discussion
Fig. 1 depicts the PRISMA flow diagram of the article selection process. The initial search yielded 30 articles: five from PUBMED and twenty-five from the SCOPUS database. Following the selection process, duplicate and inaccessible files were removed until 29 articles were obtained. Following that, 18 articles were eliminated in the second round of selection. As a result, the associations between vitamin D levels and PPD were obtained from 11 studies. Table 1 shows eleven association studies between vitamin D levels and PPD. The studies were conducted in South India, Iran, Denmark, Australia, the USA, China, and Turkey, with 4,893 participants. One of the eleven studies was cross-sectional, two were case-control studies, three were randomized controlled trials, and four were cohort studies. Different methods for measuring vitamin D levels were found, such as ELISA, LCMS/MS, a competitive chemiluminescence immunoassay, reverse-phase HPLC, E601 modular analyzer, and enzyme immunoassay. The depression test was measured by Edinburgh Depression Scale (EPDS), Beck Depression Scale (BDS), The Center for Epidemiological Studies Depression (CES-D), and Beck Depression Inventory (BDI). Abbreviation: EPDS = The Edinburgh Postnatal Depression Scale; BDI = Beck Depression Inventory; CES-D = Center for Epidemiologic Studies Depression Scale; ELISA = The enzyme-linked immunosorbent assay; LCMS/MS = Liquid chromatography-mass spectrometry. Table 2 presents nine studies with a significant association between vitamin D levels and PPD. Most samples measuring vitamin D were venous blood taken during 13-28 weeks of pregnancy, 24-48 hours after birth, and 6-8 weeks after childbirth. A Depression assessment was conducted within 4-12 weeks after delivery.

Studies with a significant association between vitamin D levels and PPD
A cross-sectional study in South India that measured serum 25(OH)D levels in women with and without PPD discovered that low serum 25(OH)D levels are associated with depression in women six weeks after delivery (Pillai et al. 2021). A case-control study of reproductive-aged Iranian women who had a venous blood sample taken 6-8 weeks after childbirth discovered an association between low vitamin D levels and PPD. (Abedi et al. 2018).
Vitamin D supplementation had positive effects on PPD symptoms and serum concentrations of 25[OH]D, according to two randomized controlled trials by Amini et al. (2022) and Rouhi et al. (2018), which examined the effects of vitamin D supplementation in PPD (Amini et al. 2022). Furthermore, in the intervention group, vitamin D reduced depression and fatigue (P < 0.001) (Rouhi et al. 2018).
Five cohort studies conducted in the USA, China, Turkey, and Australia revealed that low vitamin D levels during pregnancy and childbirth were associated with PPD. In the United States, Accortt et al. reported that low prenatal 25(OH)D and high prenatal inflammation may predict future postpartum depressive symptomatology in African American women, and Vitamin D deficiency, as measured by the Vitamin D Metabolite Ratio (VMR), is associated with an increased risk of PPD (Accortt et al. 2016(Accortt et al. , 2021.  Table 3 shows two studies in that found no link between vitamin D levels and PPD. In a case-control study from Denmark, Nielsen et al. found no overall association between vitamin D status during pregnancy and PPD risk (Nielsen et al. 2013). However, in this study, no depression scale score was reported. The depression assessment was obtained from women who took anti-depressant within one year after delivery. A study in Australia also found no association between cord blood 25(OH)D concentration at delivery and PPD six weeks or six months later (Gould et al. 2015). The difference in the blood sample taken and how to assess depression contributes to a different result.

Association between Vitamin D levels and PPD
Our study revealed that most studies (9 out of 11) of Vitamin D levels were associated with PPD. A theory suggests  that vitamin D plays an important role in mood regulation. Mood regulation and the incidence of depression are closely related to neurotransmitters. The association of low vitamin D levels with depression is related to hypothalamic function and neurotransmitter production (Ellsworth-Bowers and Corwin 2012). Neurotransmitters involved in the process of depression are mainly dopamine and norepinephrine. The synthesis of dopamine and norepinephrine is influenced by the role of the essential enzyme Tyrosine Hydroxylase in their gene expression, which is influenced by vitamin D (Khan et al. 2022). Vitamin D stimulates receptors in the limbic system, cortex, and cerebellum, which are associated with emotion and behavior regulation. Vitamin D also promotes the release of neurotrophins, which play an important role in neuronal development regulation (Khan et al. 2022). Vitamin D can prevent depression associated with dysfunction of the intracellular neuronal signaling system. A hypothesis explained that increased neuronal Ca 2+ levels significantly determine the onset of depression. Vitamin D works to maintain Ca 2+ homeostasis. As a result, the increase in Ca 2+ caused by vitamin D deficiency influences the onset of depression (Berridge 2017). Vitamin D deficiency has been proposed to contribute to brain development and function in humans based on animal studies (Pet and Brouwer-Brolsma 2016). Increased expression of region-specific vitamin D receptors (VDR) in brain regions known to play an important role in mood regulation (such as the prefrontal and cingulate cortices) is thought to be effective in slowing the progression of depression (Berridge 2017;Menon et al. 2020). It has been established that people with abnormalities in this hippocampus structure experience chronic depression because it regulates memory, emotional processes in other brain regions, and limbic structure atrophy. Following the identification of VDR in the hippocampus, the activity of vitamin D in this structure was investigated, and it was discovered that vitamin D is a powerful modulator of the expression of neurotrophic agents such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT)-3. Vitamin D can boost the ex-pression of neurotrophic factors, which are required for the viability, development, and migration of neurons that demonstrate their biological roles by interacting with cognate tropomyosin-related kinase (Trk) receptors (Akpınar and Karadağ 2022). It is underlined that neurogenesis and neurons that release neurotransmitters play crucial roles in depression and that vitamin D is crucial for supporting the health of neurons (Geng et al. 2019).

Conclusion
Most studies found a significant association between vitamin D levels and PPD. The association is related to the role of vitamin D in mood regulation, influencing the synthesis of neurotransmitters, stimulating receptors in the brain, and being involved in the intercellular neuronal signaling system.

Funding
Universitas Padjadjaran Indonesia supports this work. To investigate the relationship between 25(OH)D at birth and the risk of PPD six weeks and six months later in a large cohort of Australian women.

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There was no association found between cord blood 25(OH)D concentration at delivery and PPD six weeks or six months later.