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Lower Prenatal Vitamin D Status and Postpartum Depressive Symptomatology in African American Women: Preliminary Evidence for Moderation by Inflammatory Cytokines

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Vitamin D deficiency and elevated pro-inflammatory cytokines have each been associated individually with postpartum depression (PPD). African American women are at increased risk for prenatal vitamin D deficiency, inflammation, and prenatal and postpartum depressive symptoms, but biological risk factors for PPD in this population have rarely been tested. This prospective study tested whether low prenatal vitamin D status (serum 25-hydroxyvitamin D, 25[OH]D) predicted PPD symptomatology in pregnant African American women and whether high levels of prenatal inflammatory cytokines interacted with low 25(OH)D in effects on PPD symptoms. Vitamin D status was measured in the first trimester in a sample of 91 African American pregnant women who had a second trimester blood sample assayed for inflammatory markers. Depressive symptoms were assessed at a postpartum visit. An inverse association between prenatal log 25(OH)D and PPD symptomatology approached significance (β = -0.209, p = 0.058), and interleukin-6 and IL-6/IL-10 ratio significantly moderated the effect. Among women with higher levels of inflammatory markers, lower prenatal log 25(OH)D was associated with significantly higher PPD symptoms (p < 0.05). These preliminary results are intriguing because, if replicable, easy translational opportunities, such as increasing vitamin D status in pregnant women with elevated pro-inflammatory cytokines, may reduce PPD symptoms.
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ORIGINAL ARTICLE
Lower prenatal vitamin D status and postpartum depressive
symptomatology in African American women: Preliminary
evidence for moderation by inflammatory cytokines
Eynav Elgavish Accortt
1,2
&Christine Dunkel Schetter
1
&
Rosalind M. Peters
3
&Andrea E. Cassidy-Bushrow
4
Received: 5 February 2015 /Accepted: 14 September 2015
#Springer-Verlag Wien 2015
Abstract Vitamin D deficiency and elevated pro-
inflammatory cytokines have each been associated individually
with postpartum depression (PPD). African American women
are at increased risk for prenatal vitamin D deficiency, inflamma-
tion, and prenatal and postpartum depressive symptoms, but
biological risk factors for PPD in this population have rarely been
tested. This prospective study tested whether low prenatal vita-
min D status (serum 25-hydroxyvitamin D, 25[OH]D) predicted
PPD symptomatology in pregnant African American women and
whether high levels of prenatal inflammatory cytokines interacted
with low 25(OH)D in effects on PPD symptoms. Vitamin D
status was measured in the first trimester in a sample of 91
African American pregnant women who had a second trimester
blood sample assayed for inflammatory markers. Depressive
symptoms were assessed at a postpartum visit. An inverse asso-
ciation between prenatal log 25(OH)D and PPD symptomatology
approached significance (β=0.209, p=0.058), and interleukin-6
and IL-6/IL-10 ratio significantly moderated the effect. Among
women with higher levels of inflammatory markers, lower
prenatal log 25(OH)D was associated with significantly higher
PPD symptoms (p<0.05). These preliminary results are intrigu-
ing because, if replicable, easy translational opportunities, such
as increasing vitamin D status in pregnant women with elevated
pro-inflammatory cytokines, may reduce PPD symptoms.
Keywords Pregnancy .Vitamin D .25(OH)D .Cytokines .
Inflammation .Postpartum depression
Introduction
Postpartum depression is a serious mental health condition
occurring after childbirth characterized by emotional distur-
bance and behavioral changes. It is estimated that 10 to 20 %
of American women experience symptoms of magnitude and
duration to meet criteria for PPD (Centers for Disease Control
and Prevention 2008). A recent meta-analysis (Molyneaux
et al. 2014) estimated rates of diagnosed PPD to be higher
in overweight and obese pregnant women (13 vs. 10 % of
normal-weight women). Depression after childbirth portends
maternal suffering, more likelihood of parenting ineffective-
ness, and possible difficulties for the entire family (Grace et al.
2003; Paulson et al. 2006; Zelkowitz and Milet 1996).
Therefore, it is advantageous to increase our understanding
of the risk factors, etiology, and mechanisms of depression
in women following birth. Independent risk factors include
prenatal depression, high life stress, low social support, low
education, and African American race (Beck 2001; Bennett
et al. 2004). A comprehensive systematic review on post-
partum depressive symptoms and diagnosis highlighted that
most biological factors have been studied in isolation
(Yim et al. 2015). We investigated vitamin D status, inflam-
matory cytokines, and PPD symptoms together in a sample of
AfricanAmericanpregnantwomen,manyofwhomwere
overweight or obese.
*Eynav Elgavish Accortt
eynav.accortt@cshs.org
*Christine Dunkel Schetter
dunkel@psych.ucla.edu
1
Department of Psychology, University of California, 1285 Franz
Hall, Box 951563, Los Angeles, CA 90095-1563, USA
2
Department of Obstetrics and Gynecology, Cedars-Sinai Medical
Center, 8635 West 3rd Street, 160 West Tower, Los
Angeles 90048, CA, USA
3
College of Nursing, Wayne State University, Detroit, MI, USA
4
Department of Public Health Sciences, Henry Ford Hospital,
Detroit, MI, USA
Arch Womens Ment Health
DOI 10.1007/s00737-015-0585-1
Vitamin D is a unique neurosteroid hormone required for
normal brain homeostasis and development. Vitamin D
3
is
produced in the skin when exposed to the suns ultraviolet
rays and is also absorbed from various food sources, such as
oily fish (Zhang and Naughton 2010).
1
Low levels of vitamin
D have also been associated with several mental disorders
including depression (McCann and Ames 2008). According
to a recent meta-analysis of 31,424 males and females, vita-
min D was inversely associated with depression (Anglin et al.
2013); however, none of the included studies were on preg-
nancy or the postpartum. In a prospective study of 796 wom-
en, a negative association was found between prenatal vitamin
D levels at 18 weeks gestation and PPD symptoms (Robinson
et al. 2014; see also Murphy et al. 2010). Another recent
prospective study reported that lower maternal 25(OH)D3
levels in the second trimester of pregnancy were associated
with higher levels of PPD symptoms at 1 week, 6 weeks, and
6monthspostpartum(Guretal.2014). Cross-sectional studies
have also been published in support of these prospective ones
(Brandenbarg et al. 2012; Cassidy-Bushrow et al. 2012a).
Thus, the larger literature on low vitamin D levels and depres-
sion has been extended into pregnancy and postpartum. To our
knowledge, no studies have investigated the combined effects
of prenatal vitamin D status and inflammatory markers on
PPD symptoms in any ethnic group.
A complex and incompletely understood relationship be-
tween vitamin D and the immune system has been described
(Arora and Hobel 2010; Liu et al. 2006; McCann and Ames
2008). Expression of the vitamin D receptor has been detected
on a variety of immune cells including monocytes, T lympho-
cytes, dendritic cells, and macrophages (Veldman et al. 2000).
Vitamin D is beneficial, acting as an influential immune mod-
erator of both the adaptive and innate immune systems
through its ability to alter cytokine secretion (Adams and
Hewison 2008; Van Etten and Mathieu 2005), and acts as a
regulator of cell signaling pathways via its effect on toll-like
receptor expression and function (Liu et al. 2006; Thota et al.
2012; Van Etten and Mathieu 2005; Zhang et al. 2012). In
pregnancy, vitamin D regulates placental development and
function and promotes tolerance of the fetus (Arora and
Hobel 2010) and vitamin D deficiency has been associated
with neonatal and birth outcomes (Aghajafari et al. 2011,
2013; Wei et al. 2013; Theodoratou et al. 2014). Further, early
pregnancy vitamin D is inversely associated with inflamma-
tory cytokines in mid-pregnancy (Bobbitt et al. 2014). High
vitamin D status might also be a protective factor in the link
between pro-inflammatory cytokines and depression.
Numerous research studies have demonstrated a strong
positive association between inflammation and depression
(e.g., Dantzer et al. 2008;Howrenetal.2009;Milleretal.
2009), as well as an emerging body of research on the role of
stress, inflammation, and depression in perinatal health
(Christian 2012; Coussons-Read 2012). The role of vitamin
D status in this set of processes is unknown.
Inflammation is of interest in pregnancy because of the
physiological changes that occur during normal gestation. At
the uterine level, early pregnancy (implantation) and late preg-
nancy when approaching delivery are pro-inflammatory
states, whereas mid-pregnancy is an anti-inflammatory state
(Mor et al. 2011). Recent studies have longitudinally profiled
inflammatory markers throughout the perinatal period.
Interleukin-6 (IL-6), for example, increased slightly over ges-
tation in a racially diverse sample of 57 healthy pregnant
women with a significant postpartum increase (Christian and
Porter 2014). Blackmore and colleagues (2014) studied wom-
en at 4 time points in pregnancy and postpartum. They report-
ed elevations in serum pro-inflammatory markers in African
American compared to non-African American women, but
when controlling for BMI, the effect of race on IL-6 levels
was no longer significant. Furthermore, neither IL-6 nor
TNF-αwere associated with depression (Blackmore et al.
2014).
Significant associations between perinatal depression and
inflammation have been reported in several studies. For ex-
ample, depression was associated with inflammation during
pregnancy in three studies (Cassidy-Bushrow et al. 2012b;
Christian et al. 2009; Coussons-Read et al. 2007), and inflam-
mation in the postpartum period was associated with PPD in
three more studies (e.g., Boufidou et al. 2009; Corwin and
Pajer 2008;Maesetal.2000), although not in two other stud-
ies (Okun et al. 2011; Skalkidou et al. 2009). Moreover, pre-
natal depression consistently predicts PPD (Bennett et al.
2004). Nonetheless, some experts feel firm conclusions can-
not be made about the role of inflammatory processes in peri-
natal depression as yet (Osborne and Monk 2013). Firm con-
clusions are complicated by use of a broad range of tools for
mood assessment, different cutoff points, measurement of dif-
ferent cytokines, and racially and socioeconomically homog-
enous samples.
African American women appear to have among the
highest rates of prenatal and postpartum depression compared
to other racial groups in the USA (Howell et al. 2006; Orr et al.
2006; Segre et al. 2006). They are also at increased risk for
vitamin D deficiency (Nassar et al. 2011) because darker skin
limits synthesis of vitamin D and due to lower intake of sup-
plemental vitamin D (Bodnar and Simhan 2010).
Furthermore, higher levels of inflammatory markers have
been documented in African American men and women
(Deverts et al. 2010) and in both non-pregnant and pregnant
African American women in a stress reactivity study
(Christian et al. 2013). Thus, data on African American
1
Approximately 0.5 MED of UVB radiation would be absorbed after an
average of 5 to 10 min of exposure of the arms and legs to direct sunlight
depending on the time of day, season, latitude, and skin sensitivity (Zhang
and Naughton 2010).
E.E. Accortt et al.
women in pregnancy and postpartum is well suited to our
research questions.
The purpose of this study was to examine associations pro-
spectively between prenatal vitamin D status and postpartum
depressive symptomatology in a sample of African American
women. We hypothesized that in pregnant women with higher
prenatal inflammatory markers there would be a stronger
negative association of prenatal 25(OH)D, and postpartum
depressive symptoms as compared to those with lower inflam-
mation, and this association would remain after controlling for
BMI.
Methods
Participants and procedures
We analyzed prospective data obtained during pregnancy and
the postpartum from a previous study to test our study hypoth-
eses (see Cassidy-Bushrow et al. 2012a,bfor methodological
details). The study population consisted of pregnant women
who were patients in the Henry Ford Health System (HFHS),
in Detroit MI. Potential participants were identified by
accessing patient appointment lists in the electronic medical
record (EMR) of nine HFHS obstetrics and gynecology (OB/
GYN) clinics. Clinics were chosen based on the likelihood
that they would have a large number of African American
patients of varying socioeconomic status. African American
women, aged 1844 years, in the second trimester of pregnan-
cy (1328 weeks gestation based on self-reported last men-
strual period [LMP] or expected delivery date [EDD] defined
by ultrasound) were identified as potential participants.
Trained interviewers arranged to meet women at an upcoming
clinic appointment. Recruitment spanned February 2009 to
June 2010. A total of 203 women completed the prenatal
study visit. Eleven women were unable to complete the entire
prenatal study visit in person. In addition, three women with
very morbid obesity (BMI>60 kg/m
2
)wereexcluded.
For the current study on postpartum depression, we ex-
cluded two women with 1inflammatorybiomarkersex-
ceeding ±3 standard deviations from the mean for compa-
rability with a prior study (Christian et al. 2009). Following
written consent, eligible women provided self-reported de-
mographic information, and a 10-ml blood sample was ob-
tained during the second trimester research visit (13
28 weeks gestation). The final analytic sample consisted
of 91 women with a first trimester 25(OH)D measurement,
second trimester measure of inflammatory markers, and
who had a postpartum visit during which the depression
screening was completed (N=98 did not return for postpar-
tum visit). The study protocol was approved by the
Institutional Review Boards at the respective institutions.
Vitamin D status
Serum 25-OHD is considered the best measure of overall vi-
tamin D nutrition status and the most useful clinically. As part
of routine obstetrical care, vitamin D status (serum 25-OHD)
was measured during the first prenatal care visit (M=9.7±
3.7 weeks gestation). Serum samples were assayed using a
competitive chemiluminescence immunoassay platform (Rao
1999), similar to other reported methods (Ersfeld et al. 2004;
Hollis 2008). Serum 25-OHD level was used as a continuous
variable in all regression analyses.
Inflammatory biomarkers
All assays were performed in serum collected from women
during the second trimester research visit (stored at 80 °C),
which was scheduled around a pre-existing obstetrics visit
(M=21.3± 3.8 weeks gestation). Time of day for the blood
draw therefore varied, and women did not fast beforehand.
High-sensitivity C-reactive protein (hs-CRP) was measured
by enzyme immunoassay as per the manufacturersinstruc-
tions (BioCheck, Inc., Foster City, CA, USA) and concentra-
tions (mg/l) calculated from a standard curve. The limit of
detection (LOD) is 0.1 mg/l. Interleukins, IL-1β, IL-6, IL-
10, and TNF-αconcentrations (pg/ml) were assayed on a
Bio-Plex 200 System using Bio-Plex Pro Cytokine Assay
custom 4-plex kits (Bio-Rad, Hercules, CA, USA). LOD for
these cytokines are 0.6, 2.6, 0.3, and 6.0 pg/ml. Results are
reported only for inflammatory markers with <20 % of the
sample outside of the LOD (J. Carroll personal communica-
tion; Breen et al. 2011). Therefore, results for IL-6, IL-10, and
hs-CRP are reported and those for TNF-α(54 % sample be-
low LOD) and IL-1β(42 % sample below LOD) are not.
The link between depression and inflammatory disorders
may be partially explained by a disruption of the immune-
regulatory balance between pro- and anti-inflammatory cyto-
kines (e.g., IL-6 and IL-10, respectively). In addition to their
absolute concentrations, the relative concentrations of pro- to
anti-inflammatory cytokines may provide a useful index of the
net inflammatory milieu and of immune dysregulation
(Dhabhar et al. 2009). After confirming that IL-6 and IL-10
were not significantly associated (r=0.1; p=0.174), we calcu-
lated the IL-6/IL-10 ratio and hypothesized that this ratio as
well as IL-6 (but not IL-10 alone) would moderate the asso-
ciation between prenatal 25(OH)D and PPD symptomatology.
Postpartum depressive symptoms
The Edinburgh Postnatal Depression Scale (EPDS; (Cox et al.
1987)) is a 10-item scale that assesses the cognitive and affec-
tive components of depressive symptomatology, while ex-
cluding somatic symptoms specific to postpartum. The
EPDS has been validated for use in pregnant and postpartum
Prenatal vitamin D and postpartum depressive symptoms
women and the sensitivity and specificity was 86 and 78 %,
respectively (Cox et al. 1987). The EPDS was administered to
assess depressive symptoms during routine postpartum visits,
which are typically scheduled 46 weeks post-delivery
(M=4.5 ± 1.8 weeks). EPDS scores were available electroni-
cally from medical records with participant consent. The
EPDS score was used as a continuous variable in all regres-
sion analyses.
Covariates
Participants reported date of birth, marital status, education,
employment status, and cigarette smoking at the second
trimester research visit. Pre-pregnancy height and weight
were self-reported, and pre-pregnancy body mass index
(BMI) calculated as weight (kg)/height (m
2
). They also re-
ported prenatal depressive symptoms using the 20-item
Center for Epidemiologic Studies Depression Scale (CES-
D; (Radloff 1977)). The prenatal CES-D score was used as
a continuous variable in all regression analyses. A history
of self-reported prior depressive illness (prior to pregnancy)
was abstracted from the OB intake form within the electron-
ic medical record. Additional medical variables (Table 1)
for descriptive purposes were abstracted from the electronic
medical record.
Statistical analysis
We used standard statistical software programs (SPSS 20.0 &
STATA 14 ) to conduct all analyses, statistical significance
was defined as p<0.05, and marginal effects were interpreted
at 0.05< p<0.10. Descriptive statistics were calculated to char-
acterize participants. Linear regression models were fitted to
estimate associations between prenatal 25(OH)D (ng/ml), in-
flammatory markers, and postpartum depressive symptoms.
Models were adjusted for demographic and medical variables
(see tables for details). To reduce non-normality in vitamin D
status, values were log transformed and are referred to as log
(25-OHD) or log vitamin D status. To examine moderation by
inflammatory markers, interaction terms were created com-
bining log vitamin D status with hs-CRP, inflammatory
markers IL-6 and IL-10 (log transformed to reduce non-nor-
mality), as well as the calculated IL-6/IL-10 ratio.
Results
Demographic characteristics
Women in the current study (N=91, Table 1)wereonaverage
26 years old (SD=5.9). The majority of women were unmar-
ried (75 %), currently employed (63 %), and approximately
half had a high school diploma (58 %). Few had a history of
depression (7 %), history of hypertension (9 %), or history of
preterm birth (9 %). A total of 6 of the 91 women delivered
babies before 37 weeks of gestation (7 % preterm birth). Many
women were overweight (N=24, BMI 2530) or obese
(N=34, BMI> 30); average BMI was 29.2 (SD = 8.2). The
majority did not smoke during this pregnancy (98 %).
We compared the 91 women in the analytic sample to the
85 women with 2nd trimester vitamin D and inflammation
data but no postpartum EPDS score. There were no significant
differences in any of the key variables: maternal age, 2nd
Tabl e 1 Descriptive characteristics for sample
Total s amp le ( N=91)
Demographic variables
Maternal age (years) 26± 6
Married 23 (25 %)
High school diploma 53 (58 %)
Currently employed 57 (63 %)
Annual income ($)
a
$36,623±34,609
Medical variables
History of chronic hypertension 4 (4 %)
History of preterm birth 8 (9 %)
Preterm birth in this pregnancy
b
6(7 %)
Low birth weight in this pregnancy
b
7(8 %)
Nulliparous
c
43 (47 %)
Smoking in this pregnancy 2 (2 %)
Pre-pregnancy BMI (kg/m
2
)29±8
Psychological variables
Prenatal CES-D 16.1±11
History of depression 6 (7 %)
EPDS 5.20±4.95
Vitamin D variables
Vitamin D season:
AprilDecember 55 (60 %)
JanuaryMarch 36 (40 %)
Vitamin D status ng/ml 13.2±9.4
Vit ami n D 20 ng/ml
d
77 (85 %)
Inflammatory cytokines
IL-6 (pg/ml)
e
4.0± 2.1
IL-10 (pg/ml) 2.0± 0.5
IL-6/IL-10 2.1 ±1.1
hs-CRP (pg/ml) 4.6±3.0
Data are N(%) or mean ±standard deviation
EPDS Edinburgh Postnatal Depression Scale, CES-D Center for Epide-
miologic Studies Depression Scale
a
Income data for 79 women
b
Birth outcomes for 90 women
c
Defined as no previous pregnancy lasting at least 6 months
d
Inadequate or deficient vitamin D (Institute of Medicine 2011)
e
18 women with inflammatory biomarker IL-6 <LOD (19.8 % were set to
the mid-point between 0 and LOD (Alper et al. 2010)
E.E. Accortt et al.
trimester CESD score, rate of preterm birth or levels of 25-
OHD, hs-CRP, IL-6, or IL-10 (all p>0.05).
Sample characteristics on vitamin D status
Sixty percent had their vitamin D status measured during
AprilDecember whereas 40 % had vitamin D levels mea-
sured during JanuaryMarch. The average level of 25(OH)D
in the sample was 13.2 ng/ml (SD= 9.4), and 85 % (N=77)
met criteria for vitamin D inadequacy or deficiency (vitamin
D20 ng/ml) by the standard cutoff (Ross et al. 2011).
Furthermore, 97 % (N=88) did not meet the level suggested
for pregnant or lactating women (vitamin D 30 ng/ml) by the
Endocrine Societys Clinical Practice Guideline (Holick et al.
2011). An authoritative source on recommended serum levels
of vitamin D for African Americans, or specifically pregnant
African Americans, does not exist. Therefore, we examined
two additional vitamin D cutoffs (risks for cardiovascular dis-
ease and all-cause mortality) to be conservative.
2
Vitamin D status and PPD symptoms
The mean EPDS score was 5.20 (SD=4.95). Twelve percent
of this sample had EPDS scores 12 indicating probable PPD,
a rate comparable to rates in other reports (Centers for Disease
Control and Prevention 2008), and EPDS scores were signif-
icantly higher in overweight and obese women (mean =5.98,
SD=5.17) as compared to normal-weight women (mean=
3.82, SD=4.28, p< 0.05), as reported in a recent meta-
analysis (Molyneaux et al. 2014), although rates were still in
the low range of the EPDS in both groups. The entire de-
pressed subgroup (11 of 11) was below the most lenient cutoff
for low vitamin D status (30 ng/ml), although the rate was
not statistically significant from the non-depressed subsample
in which 96 % (77 of 80) were vitamin D deficient.
Sample characteristics on inflammatory markers
Levels of prenatal inflammatory biomarkers (Table 1)were
higher than those reported in other studies (Coussons-Read
et al. 2007; Madan et al. 2009; Vassiliadis et al. 1998), poten-
tially due to differing assay modalities or racial composition of
the samples.
3
Associations of 25(OH)D and inflammatory markers
with PPD symptoms
We first examined the association between demographic and
medical variables with postpartum depressive symptoms to
determine whether these should be included in the model as
potential confounders. The significant associations between
history of depression
4
, BMI, and low education with postpar-
tum depressive symptoms were the basis for inclusion of these
three variables in analyses. Additional theoretically derived
confounding variables included maternal age, marital status,
prenatal depressive symptoms (CES-D), and season of vita-
min D measurement. Regression analyses were then conduct-
ed to examine whether vitamin D status and inflammatory
marker levels were associated with depressive symptoms.
Tables 2and 3display results from regression analyses.
Tab le 2shows that log 25(OH)D was not significantly associ-
ated with postpartum depressive symptomatology in unadjusted
regression analyses (β=0.145, p=0.172). When adjusted for
covariates, the effect was marginally significant (β=0.209,
p=0.058); higher log 25(OH)D was associated marginally with
lower EPDS symptoms. None of the individual inflammatory
markers were significantly associated with EPDS scores; how-
ever, as shown in Table 3, IL-6 and the IL-6/1 L-10 ratio both
significantly moderated the association between prenatal
25(OH)D levels and PPD symptoms. Figures 1and 2depict
moderation results. The unstandardized simple slope for wom-
en 1 SD above the mean of IL-6 was significant, such that in
women with higher levels of IL-6, lower prenatal 25(OH)D
levels were associated with higher levels of postpartum depres-
sive symptoms. The unstandardized simple slope for women 1
SD above the mean of the IL-6/IL-10 ratio was also significant,
such that in women with greater levels of IL-6/IL-10 ratio,
lower prenatal vitamin D levels were associated with higher
levels of PPD symptoms. A test of moderation by IL-10 alone
was marginally significant (p=0.09), and there was no evidence
that hs-CRP moderated the association (p=0.12). Finally, these
findings persisted when controlling for prenatal depressive
symptoms, using a standardized though different screener mea-
sured in second trimester (CES-D, Radloff 1977)andwhen
controlling for preterm birth (results not shown).
Discussion
Findings from this study suggest that higher levels of
25(OH)D in early pregnancy in African American women
2
The other vitamin cutoffs we considered were vitamin D 15 ng/ml for
risk of cardiovascular disease (Wang et al. 2008) and vitamin D 10 ng/ml
used for risk for all-cause mortality (Dobnig et al. 2008). Analyses
showed that 69 % of our sample (63 women) met the cardiovascular risk
cutoff, and 48 % (44 women) were at risk of all-cause mortality.
3
A table displaying the Spearman correlation coefficients among the
main study variables, including vitamin D status and each inflammatory
marker can be provided by the authors.
4
History of depression was abstracted from the electronic medical record.
We do not know if any women sought out psychological or complemen-
tary treatments for depression nor how long ago a previous episode oc-
curred. One woman in our study reported taking antidepressants (Zoloft)
during her postpartum visit, and removing her from analyses did not
change our results.
Prenatal vitamin D and postpartum depressive symptoms
may contribute to lower postpartum depressive symptoms,
though the association of vitamin D status and EPDS scores
was only marginally significant (p=0.058). Moreover, when
pregnant African American women were lower in 25(OH)D
and higher in pro-inflammatory cytokine levels (specifically
IL-6, IL-6/IL-10 ratio) in adjusted models, they reported more
postpartum depressive symptoms. Although two recent inves-
tigations reported an association between prenatal vitamin D
status and PPD symptoms similar to ours, neither study
assessed prenatal depression; thus, depression symptoms
may have predated the measurement of 25(OH)D (Gur et al.
2014; Robinson et al. 2014). In contrast, our study found
evidence for a possible inverse association between
25(OH)D and PPD symptoms controlling for prenatal depres-
sive symptoms and also for history of depression.
Previous research has shown that vitamin D appears to
downregulate the Th1 or cellular immunity pathway and stim-
ulate the Th2 or humoral immunity pathway (McCann and
Ames 2008). Vitamin D also regulates placental development
and function and promotes tolerance of the fetus, likely by
enhancing anti-bacterial and anti-inflammatory responses in
both the maternal and fetal components of the placenta
(Arora and Hobel 2010). These regulatory shifts are accom-
plished in part by decreasing the production of pro-
inflammatory cytokines and by increasing the production of
anti-inflammatory cytokines (McCann and Ames 2008).
Tab l e 2 Linear regression model testing the main effects of log-
transformed vitamin D status and cytokines on EPDS
Variable Unadjusted Adjusted
βpβp
Log 25(OH)D 0.145 0.172 0.209 0.058
Log IL-6 0.084 0.430 0.142 0.180
Log IL-10 0.004 0.971 0.094 0.349
Log IL-6/IL-10 ratio 0.089 0.401 0.100 0.354
Log hs-CRP 0.174 0.099 0.147 0.209
Dependent variable: Edinburgh Postnatal Depression Scale (EPDS)
score, N=91. Each independent variable in the BUnadjusted^column
was run separately. Each variable in the BAdjusted^column was run
separately with the following covariates: maternal age, education (high
school diploma), marital status, history of depression, season of vitamin
D measurement, and pre-pregnancy BMI. Results pertaining to covariates
were obtained but were omitted from this table. Only two covariates were
consistently statistically significantly associated with EPDS; Beducation^
was negatively associated, and Bhistory of depression^was positively
associated with EPDS in each analysis. Also, Bbeing married^was pos-
itively associated with EPDS in the Log Vitamin D analysis
Tabl e 3 Linear regression models testing the interactive effects of log-
transformed vitamin D and cytokines on EPDS
Vari a b l e βp
a. Log 25(OH)D 0.123 0.271
Log IL-6 0.062 0.559
Log 25(OH)D X Log IL-6 0.232 0.025
b. Log 25(OH)D 0.208 0.057
Log IL-10 0.061 0.535
Log 25(OH)D X Log IL-10 0.166 0.093
c. Log 25(OH)D 0.257 0.233
Log IL-6/IL-10 Ratio 0.065 0.580
Log 25(OH)D X Log IL-6/IL-10 ratio 0.531 0.016
d. Log 25(OH)D 0.182 0.097
Log hs-CRP 0.155 0.178
Log 25(OH)D X Log hs-CRP 0.152 0.118
Statistically significant pvalues are shown in italics
Models Bad^were adjusted for maternal age, education (high school
diploma), marital status, history of depression, season of vitamin D mea-
surement, and pre-pregnancy BMI. Results pertaining to covariates were
obtained but were omitted from this table. Only two covariates were
consistently statistically associated with EPDS in all above models;
Beducation^was negatively associated, and Bhistory of depression^was
positively associated with EPDS. In models a, c, and d, Bbeing married^
was also positively associated with EPDS
-5 0 5 10 15
Postpartum Depressive Symptoms
(EPDS)
-.7 -.5 -.3 -.1 .1 .3 .5 .7 .9
Log Vitamin D (Centered)
1 SD below mean
Mean IL-6
1 SD above mean
Log IL-6 (Centered)
Interaction Results
Fig. 1 Interleukin-6 (IL-6) significantly moderates the relationship be-
tween log 25(OH)D and EPDS
-10 -5 0 5 10 15
Postpartum Depressive Symptoms
(EPDS)
-.7 -.5 -.3 -.1 .1 .3 .5 .7 .9
Log Vitamin D (Centered)
1 SD below mean
Mean IL-6/IL-10 Ratio
1 SD above mean
Log IL-6/IL-10 Ratio (Centered)
Interaction Results
Fig. 2 The ratio of interleukin-6 (IL-6) to interleukin-10 (IL-10)
significantly moderates the relationship between log 25(OH)D and EPDS
E.E. Accortt et al.
Additionally, cytokine signals from the periphery can be trans-
mitted to the brain via the circumventricular organs, unique
areas of the brain outside the blood-brain barrier (BBB), or
vagal afferents (Buller 2001;Maier2003), potentially leading
to changes in maternal neurotransmission and later depressive
symptomatology. Since inflammatory markers were collected
in the second trimester and may be mechanisms linking first
trimester vitamin D status to PPD symptomatology, we ran an
exploratory analysis on possible mediation by each inflamma-
tory marker of the association between 25(OH)D and PPD
symptoms. None of these analyses were statistically signifi-
cant. We recommend testing this in future studies with larger
samples. We also did not find strong evidence for direct effects
of inflammatory markers on postpartum depressive symptoms
although we note that reviews of this literature show mixed
results (Osborne and Monk 2013). It is possible that higher
levels of cytokines and lower levels of 25(OH)D increase risk
for later depressive symptoms in pregnant women only when
acting synergistically. Whether this is unique to African
American women, we do not know. We also did not find
evidence of significant moderation by hs-CRP, a marker of
low-grade inflammation. Consistent with our results, a recent
study in a non-pregnant sample found an association between
depression and CRP in Caucasian but not African American
women (Amyre et al. 2011).
Levels of prenatal inflammatory markers were higher here
than those reported in other studies (Coussons-Read et al.
2007; Madan et al. 2009; Vassiliadis et al. 1998), perhaps
because the sample was all African American women.
Differences in assay modality (differing LOD) may also have
led to some differences between our study and others. Our
findings, however, were similar to those of Christian et al.
(2009) whose sample was 57 % African American
(Christian et al. 2009). Two recent studies focused on levels
of cytokines across pregnancy in racially diverse samples, and
one attributed differences in levels of cytokines to high BMI,
not race (Blackmore et al. 2014; Christian and Porter 2014).
Notably, our findings remained significant even after control-
ling for BMI.
We suspect that null results in past studies of vitamin D
status and depression in non-pregnant (e.g., Bertone-Johnson
2009) and pregnant (Nielsen et al. 2013)samplesmaybedue
to low levels of inflammatory markers. Our preliminary find-
ings suggest that the effects of low 25(OH)D on PPD symp-
toms may be potentiated only in the presence of inflammation.
Whether inflammation moderates the relationship between
low 25(OH)D and depression in non-pregnant samples is
therefore worth testing.
Strengths, limitations, and future directions
Compared to prior research, this prospective study utilized a
relatively large sample which permitted us to test interactions
of study variables. In addition, women in our sample were
studied both in pregnancy and postpartum, and having medi-
cal and psychosocial data enabled us to control for many
relevant confounders. The sample was also solely African
Americans who are at higher risk of inflammation and low
vitamin D status. Finally, vitamin D measures that were ob-
tained as part of HFHS clinical care were assayed with a
competitive chemiluminescence immunoassay platform, con-
sistent with other large clinical laboratories. Importantly,
HFHS participates in the Vitamin D External Quality
Assessment Scheme, as recommended by experts in the field
(e.g., Hollis 2008).
Limitations of this secondary data analysis include some
missing data on depressive symptoms 6 weeks postpartum
because a portion of women either did not return for their
routine postpartum visits or their clinician did not record
the EPDS result. Future research would benefit from
assessing depressive symptoms repeatedly rather than only
once in the first 6 weeks at their obstetrics postpartum
follow-up visit, e.g., at 12 weeks. Additionally, the percent-
age of women with elevated postpartum depression scores
in our sample is consistent with other reports of low income
African American women (Dolbier et al. 2013). Further,
participants dropped from analyses due to lack of EPDS
scores were of similar age and 25(OH)D levels and had
comparable prenatal CES-D scores to those included.
Thus, underestimates of depressive symptoms due to attri-
tion seem less probable.
Finally, 74 % of women in this sample reported use of a
vitamin D supplement (50,000 IU/week of vitamin D
2
)which
might have raised mean levels in the sample and also may
have favorably affected levels of inflammatory markers.
However, serum levels of 25(OH)D were measured between
9 and 13 weeks gestation with supplementation prescribed
thereafter in only a portion of women.
5
Inflammatory markers
were measured later between 1328 weeks of gestation, and
they are normally lower at this point during pregnancy and
higher in early and late pregnancy. However, if a short-term
benefit of vitamin D supplementation occurred, it would most
likely have attenuated the association we detected with in-
flammatory markers and PPD symptoms. In a small subset
of women in the sample (n=38 of 203), we measured the same
inflammatory cytokines again in the 3rd trimester. There were
high paired sample correlations among the cytokines from the
2nd to 3rd trimester: IL-6 (r=0.57; p<0.001), IL-10 (r=0.53;
p=0.001). This suggests that our results were not necessarily
influenced by large trimester-specific changes in these
cytokines.
5
IU refers to international units, which equal 25 ng. Vitamin D supple-
ments were prescribed to 87 % of the women with 74 % reporting use of
the supplement at a prenatal care visit. Most vitamin D supplements
prescribed were 50,000 IU, taken once weekly.
Prenatal vitamin D and postpartum depressive symptoms
In addition to obtaining concurrent measures of 25(OH)D,
inflammatory markers, and depressive symptoms throughout
pregnancy and postpartum, it would be ideal to track adher-
ence of vitamin D use and determine whether levels of
25(OH)D influence the trajectory of depression during preg-
nancy and from pregnancy to postpartum. Future research
would also benefit from collecting dietary intake data and
sun exposure information from participants. We studied four
inflammatory markers/marker combinations, thus our findings
may be subject to multiple testing issues. Because exploratory
studies such as this rarely correct for multiple comparisons
and Bonferroni correction is considered conservative
(Gelman et al. 2012), it is not necessarily appropriate to hold
the findings to that standard; nonetheless, our significant mod-
eration results were very close to significance when tested by
Bonferroni criteria.
6
While these results are preliminary and
do not establish causation, they are novel and particularly
important given the prevalence of low 25(OH)D in this pop-
ulation of African American women. We hope that they may
spark interest in further research on this topic including ran-
domized controlled studies. Furthermore, this study does not
involve confirmed cases of PPD and future research can in-
clude diagnostic interviews.
An important clinical implication is to determine if in-
creased prenatal vitamin D supplementation can reduce PPD
symptoms using a randomized controlled trial.
Supplementation is particularly relevant for overweight and
obese pregnant women, as they are more likely to have insuf-
ficient 25(OH)D levels (Bodnar et al. 2007) and higher rates
of PPD (Molyneaux et al. 2014). Arguably, supplementation
might also be recommended only for those women with high
levels of inflammatory cytokines in pregnancy and those with
clinically significant depression. Indeed, two recent systemat-
ic reviews of vitamin D supplementation on depressive symp-
toms in the non-pregnant state suggested no overall effect on
depressive symptoms. In one review, the evidence suggested
that supplementation might be effective in reducing depres-
sive symptoms in individuals with clinically significant pre-
existing depression (Shaffer et al. 2014). The other, a meta-
analysis, separated randomized control trials into those with
and without methodological flaws and concluded that studies
without flaws demonstrated a statistically significant improve-
ment in depression with vitamin D supplements (Spedding
2014). Vitamin D supplementation is a cost-effective and safe
intervention during pregnancy (Hollis et al. 2011)thatmay
reduce prenatal and postpartum symptoms of depression and
benefit the mothers health and that of the developing fetus
(Kalra et al. 2012; Morales et al. 2012). A recent randomized,
double-blind, placebo-controlled clinical trial of vitamin D
supplementation in 48 pregnant women resulted in significant
decreases in serum hs-CRP, fasting plasma glucose, systolic
blood pressure, and diastolic blood pressure compared with
placebo (Asemi et al. 2013). However, depressive symptoms
were not measured in this study. Randomized controlled trials
of prenatal vitamin D supplementation to reduce postpartum
depression, especially in overweight women with high levels
of prenatal inflammation, may be merited.
Conclusion
These findings provide the first evidence that low prenatal
25(OH)D and high prenatal inflammation together might pre-
dict future postpartum depressive symptomatology in African
American women. We know of no other studies that investi-
gated inflammatory moderation of the relationship between
25(OH)D levels and later depressive symptomatology in
non-pregnant women or men. These results may therefore
elucidate inflammatory moderators linking vitamin D status
to depressive symptoms, not only in pregnant African
American women, but potentially in other subgroups of the
population. Future research on the synergistic relationship of
25(OH)D and inflammation on depression is worthwhile.
Understanding how vitamin D alters the immune system
may shed new light on the emerging links between inflamma-
tion and depression.
Acknowledgments R.M.P. and A.C.B. conducted the study. E.E.A.
developed the research questions for secondary analyses, analyzed the
data, and wrote the article. C.D.S, A.C.B., and R.M.P. assisted in writing.
All authors contributed to the study design, interpretation of data, and
approved the final manuscript. The authors have no financial gain related
to the outcome of this research, and there are no potential conflicts of
interest. This project was supported by funding from the Institute for
Population Sciences, Health Assessment, Administration, Services, and
Economics (INPHAASE) to A.C.B. and R.M.P. and National Institutes of
Mental Health (T32MHI5750) postdoctoral fellowship to E.E.A. We
thank the participants in this study for contributing to this research and
increasing our knowledge about the experiences of African American
pregnant women. We acknowledge the support of the research team
members, Dayna Johnson, Project Manager, HenryFord Hospital Depart-
ment of Public Health Sciences and Christine Wells, Ph.D., Statistician,
UCLA Statistical Consulting Group. We also thank Judith E. Carroll,
Ph.D. of the UCLA Semel Institute for Neuroscience and Human Behav-
ior and the Dunkel Schetter lab for consultation in this work.
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Prenatal vitamin D and postpartum depressive symptoms
... There are few studies examining the complex relationship of vitamin D, depression and inflammation [25][26][27][28]. Accortt et al. reported that in African American women (n = 91) the association between postpartum depressive symptoms and prenatal 25(OH)D levels were significantly moderated by interleukin 6 (IL-6) and the ratio of IL-6/IL-10 [26]. ...
... There are few studies examining the complex relationship of vitamin D, depression and inflammation [25][26][27][28]. Accortt et al. reported that in African American women (n = 91) the association between postpartum depressive symptoms and prenatal 25(OH)D levels were significantly moderated by interleukin 6 (IL-6) and the ratio of IL-6/IL-10 [26]. Still, individual inflammatory markers were not associated with Edinburgh Postnatal Depression Scale scores and prenatal 25(OH)D levels were only marginally associated with postnatal depressive symptoms [26]. ...
... Accortt et al. reported that in African American women (n = 91) the association between postpartum depressive symptoms and prenatal 25(OH)D levels were significantly moderated by interleukin 6 (IL-6) and the ratio of IL-6/IL-10 [26]. Still, individual inflammatory markers were not associated with Edinburgh Postnatal Depression Scale scores and prenatal 25(OH)D levels were only marginally associated with postnatal depressive symptoms [26]. Moreover, higher levels of postpartum depressive symptoms were related with lower prenatal serum 25(OH)D levels in women with increased levels of IL-6 and greater IL-6/IL-10 ratios. ...
Article
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Depression and vitamin D deficiency are major public health problems. The existing literature indicates the complex relationship between depression and vitamin D. The purpose of this study was to examine whether this relationship is moderated or mediated by inflammation. A community sample (n = 7162) from the LIFE-Adult-Study was investigated, for whom depressive symptoms were assessed via the German version of CES-D scale and serum 25-hydroxyvitamin D (25(OH)D) levels and inflammatory markers (IL-6 and CRP levels, WBC count) were quantified. Mediation analyses were performed using Hayes’ PROCESS macro and regression analyses were conducted to test moderation effects. There was a significant negative correlation between CES-D and 25(OH)D, and positive associations between inflammatory markers and CES-D scores. Only WBC partially mediated the association between 25(OH)D levels and depressive symptoms both in a simple mediation model (ab: −0.0042) and a model including covariates (ab: −0.0011). None of the inflammatory markers showed a moderation effect on the association between 25(OH)D levels and depressive symptoms. This present work highlighted the complex relationship between vitamin D, depressive symptoms and inflammation. Future studies are needed to examine the effect of vitamin D supplementation on inflammation and depressive symptomatology for causality assessment.
... Our search identified a total of 2810 manuscripts, of which there were 21 eligible articles (see Figure 1 for flow); two RCTs [29,30]; and 18 observational studies [29,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], including one trial that also reported associations between depression and vitamin D status at trial entry [29] and two cohorts that reported results across multiple publications [42,43,47,48]. One potentially eligible case-control study was excluded, as it was reported as a dissertation from 2013 and had not been peer reviewed [50]. ...
... Our search identified a total of 2810 manuscripts, of which there were 21 eligible articles (see Figure 1 for flow); two RCTs [29,30]; and 18 observational studies [29,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], including one trial that also reported associations between depression and vitamin D status at trial entry [29] and two cohorts that reported results across multiple publications [42,43,47,48]. One potentially eligible case-control study was excluded, as it was reported as a dissertation from 2013 and had not been peer reviewed [50]. ...
... Our search identified a total of 2810 manuscripts, of which there were 21 elig ticles (see Figure 1 for flow); two RCTs [29,30]; and 18 observational studies [29 including one trial that also reported associations between depression and vitami tus at trial entry [29] and two cohorts that reported results across multiple publ [42,43,47,48]. One potentially eligible case-control study was excluded, as it was r as a dissertation from 2013 and had not been peer reviewed [50]. ...
Article
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Depression is a common mood disorder associated with childbirth and is hypothesized to be affected by low vitamin D. This systematic review identified two randomized controlled trials (RCT) of vitamin D supplementation for the treatment or prevention of depressive symptoms in the perinatal period, as well as 18 observational studies of vitamin D exposure and depression in the antenatal and postnatal periods. Both RCTs claimed an improvement in depressive symptoms in the vitamin D group, although the sample sizes were too small to draw firm conclusions. The case-control and cohort studies had mixed findings and were limited by study quality. There were inconsistent results within the few studies with a more robust methodology or within samples restricted to women likely to have depression. The current evidence is inconclusive due to the poor quality and heterogeneity of studies, likely contributing to the contradictory findings. Given there are already numerous RCTs of prenatal vitamin D supplementation, we recommend adding an appropriate measure of depression in the perinatal period to assist in resolving the uncertainty.
... In one study, higher levels of the inflammatory marker IL-6 were documented in Black women during pregnancy and postpartum (95), although this same study showed neither IL-6 nor TNF-α were associated with depressive symptoms. Other work by Accortt et al. (101) examined pregnant African American women, investigating vitamin D and immune factors during pregnancy as mediators of postpartum depressive symptomology. Their results show that when lower in vitamin D and higher in pro-inflammatory cytokine levels, specifically IL-6 and the relative expression of IL-6 compared to IL-10, self-reported symptoms of PPD were higher. ...
... Examining the relative balance or the ratio of both proinflammatory and anti-inflammatory factors has gained traction in the literature beyond the single study by Accortt et al. (101) described above. For example, Corwin et al. (102) examined blood cytokine levels during late gestation (third trimester), and again postpartum on days 7 and 14, as well as 1, 2, 3, and 6 months following delivery. ...
Article
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The postpartum period is a time associated with high rates of depression and anxiety as well as greater risk for psychosis in some women. A growing number of studies point to aberrations in immune system function as contributing to postpartum mental illness. Here we review evidence from both clinical and animal models suggesting an immune component to postpartum depression, postpartum anxiety, and postpartum psychosis. Thus far, clinical data primarily highlights changes in peripheral cytokine signaling in disease etiology, while animal models have begun to provide insight into the immune environment of the maternal brain and how central inflammation may also be contributing to postpartum mental illnesses. Further research investigating peripheral and central immune function, along with neural and endocrine interactions, will be important in successfully developing novel prevention and treatment strategies for these serious disorders that impact a large portion of new mothers.
... Several cohort studies suggest low levels of the circulating form of vitamin D, that is, 25-hydroxyvitamin D (25-[OH]-D), in patients with PPD [196,197]. The interdependence of vitamin D with calcium is widely known, and it is intuited that it plays an important role in the matter in question, since calcium stimulates signaling for the activation of gonadotropin, which in turn will lead to an increase in luteinizing and follicle-stimulating hormone which, as a consequence, increases the production of estradiol (E2). ...
Article
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Major depressive disorder (MDD) is an incapacitating condition characterized by loss of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising prevalence, it is considered a public health issue that affects economic productivity and heavily increases health costs alone or as a comorbidity for other pandemic non-communicable diseases (such as obesity, cardiovascular disease, diabetes, inflammatory bowel diseases, etc.). What is even more noteworthy is the double number of women suffering from MDD compared to men. In fact, this sex-related ratio has been contemplated since men and women have different sexual hormone oscillations, where women meet significant changes depending on the age range and moment of life (menstruation, premenstruation, pregnancy, postpartum, menopause…), which seem to be associated with susceptibility to depressive symptoms. For instance, a decreased estrogen level promotes decreased activation of serotonin transporters. Nevertheless, sexual hormones are not the only triggers that alter neurotransmission of monoamines and other neuropeptides. Actually, different dietary habits and/or nutritional requirements for specific moments of life severely affect MDD pathophysiology in women. In this context, the present review aims to descriptively collect information regarding the role of malnutrition in MDD onset and course, focusing on female patient and especially macro- and micronutrient deficiencies (amino acids, ω3 polyunsaturated fatty acids (ω3 PUFAs), folate, vitamin B12, vitamin D, minerals…), besides providing evidence for future nutritional intervention programs with a sex-gender perspective that hopefully improves mental health and quality of life in women.
... A cross-sectional study (194) found that higher dietary vitamin D intake was significantly associated with a lower prevalence of depressive symptoms during pregnancy. A recent prospective study found an association between lower prenatal log 25(OH)D and significantly more severe PPD symptoms, among women with higher levels of inflammatory markers (195). In a controlled study, Fu et al. (196) found an association between lower serum 25(OH)D levels measured 24 h after delivery and PPD. ...
Article
Full-text available
Postpartum depression (PPD) is a serious health issue that can affect about 15% of the female population within after giving birth. It often conveys significant negative consequences to the offsprings. The symptoms and risk factors are somewhat similar to those found in non-postpartum depression. The main difference resides in the fact that PPD is triggered by postpartum specific factors, including especially biological changes in the hormone levels. Patients are usually diagnosed using a questionnaire onsite or in a clinic. Treatment of PPD often involves psychotherapy and antidepressant medications. In recent years, there have been more researches on the identification of biological markers for PPD. In this review, we will focus on the current research status of PPD, with an emphasis on the recent progress made on the identification of PPD biomarkers.
... This has been noted in elderly populations, who have reduced skin synthesis of Vitamin D3 due to a reduction in 7-dehydrocholesterol [80]. Vitamin D has been implicated across different kinds of depression, including with perinatal onset, seasonal pattern or bipolar depression [87][88][89]. ...
Article
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Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.
Article
Background and objectives High prevalence of suboptimal vitamin-D levels is observed in pregnant Australian women. Postpartum depression (PPD) is the most prevalent mood disorder associated with childbirth and it is suggested low vitamin-D is associated with depression. There is minimal research investigating antenatal screening of vitamin-D. Additionally, there is conflicting research on the link between vitamin-D levels during pregnancy and developing PPD. Aims were to investigate antenatal screening of vitamin-D and prevalence of suboptimal vitamin-D levels among pregnant women in rural Australia, and to explore the link between low levels of vitamin-D and PPD. Methods A retrospective observational study was conducted at a rural general practice Australia. The percentage of women screened and the levels of vitamin-D at time of screening was profiled. Additionally, the association between antenatal vitamin- D levels, risk factors for PPD and developing PPD were assessed. Results 57.1% of women were screened during the antenatal period for vitamin-D. 66.3% had serum vitamin-D below optimal levels (23.9% deficient; 42.4% suboptimal). Women with PPD had significantly lower levels of vitamin-D antenatally (p < 0.01) compared to women without PPD. PPD was significantly negatively correlated with antenatal vitamin D levels (p < 0.01). Conclusion Doctors screened over half of women for vitamin-D in the antenatal period and the majority of pregnant women had below optimal levels of vitamin D. Low vitamin-D levels during pregnancy is associated with developing PPD. Future research should investigate effects vitamin-D supplementation may have on reducing incidence of PPD and other adverse pregnancy outcomes associated with low antenatal levels of vitamin-D.
Article
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The maternal immune response is essential for successful pregnancy, promoting immune tolerance to the fetus while maintaining innate and adaptive immunity. Uncontrolled, increased proinflammatory responses are a contributing factor to the pathogenesis of preeclampsia. The Th1/Th2 cytokine shift theory, characterised by bias production of Th2 anti-inflammatory cytokine midgestation, was frequently used to reflect the maternal immune response in pregnancy. This theory is simplistic as it is based on limited information and does not consider the role of other T cell subsets, Th17 and Tregs. A range of maternal peripheral cytokines have been measured in pregnancy cohorts, albeit the changes in individual cytokine concentrations across gestation is not well summarised. Using available data, this review was aimed at summarising changes in individual maternal serum cytokine concentrations throughout healthy pregnancy and evaluating their association with preeclampsia. We report that TNF-α increases as pregnancy progresses, IL-8 decreases in the second trimester, and IL-4 concentrations remain consistent throughout gestation. Lower second trimester IL-10 concentrations may be an early predictor for developing preeclampsia. Proinflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-8, and IL-6) are significantly elevated in preeclampsia. More research is required to determine the usefulness of using cytokines, particularly IL-10, as early biomarkers of pregnancy health.
Article
Objective The association between 25-hydroxyvitamin D (25(OH)D) and maternal depression (MD) is deemed to be inconclusive. The current analysis aimed to quantify the relationship between 25(OH)D serum concentrations, the main indicator of vitamin D nutritional status, and MD. Design Dose–response meta-analysis. Setting A systematic search in PubMed, Embase and Web of Science from inception to June 2019. Participants Relevant observational studies reporting risk estimates and 95 % CI of random effects for 25(OH)D concentration on MD were identified. Results Twelve observational studies with thirteen independent reports involving 10 317 pregnant women were included. Compared with the lowest category of 25(OH)D, the pooled OR for the highest category of MD was 0·49 (95 % CI 0·35, 0·63); a high heterogeneity was observed ( P = 0·001, I ² = 82·1 %). A non-linear association between 25(OH)D and MD was found ( P for non-linearity = 0·001); the dose–response analysis indicated that the lowest pooled OR was at blood 25(OH)D concentrations of 90–110 nmol/l. Subgroup analyses suggested a stronger association between 25(OH)D and MD in summer time (OR 0·25, 95 % CI 0·08, 0·43) than in other seasons (OR 0·68, 95 % CI 0·52, 0·83) ( P for interaction = 0·008). A visual inspection of funnel plot and Begg’s and Egger’s tests did not indicate any evidence of publication bias. Conclusions Low circulating 25(OH)D is associated with MD, and our analysis suggests that they influence each other. Further randomised controlled trials would be needed to determine the direction of causation.
Article
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Postpartum depression (PPD) adversely affects the health and well being of many new mothers, their infants, and their families. A comprehensive understanding of biopsychosocial precursors to PPD is needed to solidify the current evidence base for best practices in translation. We conducted a systematic review of research published from 2000 through 2013 on biological and psychosocial factors associated with PPD and postpartum depressive symptoms. Two hundred fourteen publications based on 199 investigations of 151,651 women in the first postpartum year met inclusion criteria. The biological and psychosocial literatures are largely distinct, and few studies provide integrative analyses. The strongest PPD risk predictors among biological processes are hypothalamic-pituitary-adrenal dysregulation, inflammatory processes, and genetic vulnerabilities. Among psychosocial factors, the strongest predictors are severe life events, some forms of chronic strain, relationship quality, and support from partner and mother. Fully integrated biopsychosocial investigations with large samples are needed to advance our knowledge of PPD etiology.
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Efficacy of Vitamin D supplements in depression is controversial, awaiting further literature analysis. Biological flaws in primary studies is a possible reason meta-analyses of Vitamin D have failed to demonstrate efficacy. This systematic review and meta-analysis of Vitamin D and depression compared studies with and without biological flaws. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was undertaken through four databases for randomized controlled trials (RCTs). Studies were critically appraised for methodological quality and biological flaws, in relation to the hypothesis and study design. Meta-analyses were performed for studies according to the presence of biological flaws. The 15 RCTs identified provide a more comprehensive evidence-base than previous systematic reviews; methodological quality of studies was generally good and methodology was diverse. A meta-analysis of all studies without flaws demonstrated a statistically significant improvement in depression with Vitamin D supplements (+0.78 CI +0.24, +1.27). Studies with biological flaws were mainly inconclusive, with the meta-analysis demonstrating a statistically significant worsening in depression by taking Vitamin D supplements (-1.1 CI -0.7, -1.5). Vitamin D supplementation (≥800 I.U. daily) was somewhat favorable in the management of depression in studies that demonstrate a change in vitamin levels, and the effect size was comparable to that of anti-depressant medication.
Article
Vitamin D is essential for the health of both mother and fetus during pregnancy. In the nonpregnant state, vitamin D demonstrates anti-inflammatory effects, but little is known about this relationship during pregnancy. African-American women are at a higher risk of vitamin D deficiency and for altered inflammatory responses during pregnancy. Therefore, we investigated the association of early pregnancy vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D (25-OHD), with second-trimester inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, IL-10, IL-1β and TNF-α) in 178 pregnant African-American women. Mean serum 25-OHD was 13.4±8.4ng/ml, and most women (n=147, 82.6%) had inadequate or deficient levels of 25-OHD (<20ng/ml). Both serum 25-OHD and some inflammatory cytokines (IL-1β and TNF-α) demonstrated significant seasonal variation. In univariate models, log transformed 25-OHD was significantly and inversely associated with log transformed IL-1β (p=0.002) and log transformed IL-6 (p=0.032). After adjusting for covariates, including seasonality, only the inverse association with IL-1β remained statistically significant (p=0.027). Early pregnancy vitamin D nutrition is associated with some inflammatory biomarkers in mid-pregnancy. Additional studies are needed to determine if low vitamin D nutrition is associated with birth outcomes via an inflammatory-mediated pathway. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Article
Objectives Postpartum depression (PPD) is a common disorder that affects 10–15% of postpartum women, and it can have negative effects on both the mother and newborn. Recent studies have suggested that low levels of vitamin D are associated with poor mood and depression. The aim of this prospective study was to evaluate a possible association between PPD and serum levels of 25-hydroxy vitamin D3 (25(OH)D3), a reliable measurement of vitamin D, during mid-pregnancy. Study design The source population consisted of all pregnant women between 24 and 28 gestational weeks from June 2012 to October 2012 at Bornova Health Research and Application Hospital, Sifa University. In order to better evaluate a possible effect between vitamin D levels and PPD, individuals with characteristics that put them at risk for developing PPD were excluded from the study. Serum 25(OH)D3 levels were evaluated mid-pregnancy in the study group. Serum 25(OH)D3 concentrations ≤20 ng/mL (50 nmol/L) were classified as a mild deficiency and those ≤10 ng/mL (25 nmol/L) were classified as a severe deficiency. Pregnant subjects having complications during birth or with the newborn after delivery were excluded from the study. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess maternal PPD 1 week, 6 weeks, and 6 months after delivery. A Pearson correlation was used to measure the strength of the associations between the EPDS scores and vitamin D levels analyzed during the three time periods. A logistic regression analysis was used to determine the independent effects of vitamin D on PPD. Results Six hundred and eighty-seven pregnant women were included in this study. After excluding women due to PPD risk factors (in two stages), 179 pregnant women were screened for vitamin D levels during mid-pregnancy and in the 6th month postpartum. Eleven percent of our study group had severe vitamin D deficiency and 40.3% had mild vitamin D deficiency. The frequency of PPD was 21.6% at the 1st week, 23.2% at 6th week, and 23.7% at the 6th month. There was a significant relationship between low 25(OH)D3 levels in mid-pregnancy and high EPDS scores, which is indicative of PPD for all three follow-up periods (p = 0.003, p = 0.004 and p < 0.001, respectively). In addition, there was a significant negative correlation between vitamin D levels and EDPS at all three time points (r = −0.2, −0.2, −0.3, respectively). Conclusions Vitamin D deficiency in mid-pregnancy may be a factor affecting the development of PPD. More extensive studies are required to be carried out on this subject.
Article
To evaluate the prevalence and risk of antenatal and postpartum mental disorders among obese and overweight women. Seven databases (including MEDLINE and ClinicalTrials.gov) were searched from inception to January 7, 2013, in addition to citation tracking, hand searches, and expert recommendations. Studies were eligible if antenatal or postpartum mental disorders were assessed with diagnostic or screening tools among women who were obese or overweight at the start of pregnancy. Of the 4,687 screened articles, 62 met the inclusion criteria for the review. The selected studies included a total of 540,373 women. Unadjusted odds ratios were pooled using random-effects meta-analysis for antenatal depression (n=29), postpartum depression (n=16), and antenatal anxiety (n=10). Obese and overweight women had significantly higher odds of elevated depression symptoms than normal-weight women and higher median prevalence estimates. This was found both during pregnancy (obese odds ratio [OR] 1.43, 95% confidence interval [CI] 1.27-1.61, overweight OR 1.19, 95% CI 1.09-1.31, median prevalence: obese 33.0%, overweight 28.6%, normal-weight 22.6%) and postpartum (obese OR 1.30, 95% CI 1.20-1.42, overweight OR 1.09, 95% CI 1.05-1.13, median prevalence: obese 13.0%, overweight 11.8%, normal-weight 9.9%). Obese women also had higher odds of antenatal anxiety (OR 1.41, 95% CI 1.10-1.80). The few studies identified for postpartum anxiety (n=3), eating disorders (n=2), or serious mental illness (n=2) also suggested increased risk among obese women. Health care providers should be aware that women who are obese when they become pregnant are more likely to experience elevated antenatal and postpartum depression symptoms than normal-weight women, with intermediate risks for overweight women.