DEPRESSION is a major mental health problem, and there is a growing awareness of the economic burden imposed by depressive disorders.1–3 Prevalence of depression is estimated at 5% to 61% within Asian cultures, and frequently occurs in females.4 Postpartum depression (PPD) is characterized as an emotional disorder or typical depressive episode within 1 year after delivery,1,5 and at least 13% of women may experience PPD globally.6 The main symptoms of PPD include reduced interest, poor concentration, sleep deprivation, sadness, hopelessness, and anxiety.7 Besides the above changes, PPD may cause significant weight loss or weight gain, and, in some extreme cases, self-harm, suicide, or infanticide.8 Despite PPD having a significant negative impact on women, infants and as well as the family,7–9 it is still unclear how to effectively prevent PPD.

Nutritional intake of pregnant women can play an important role in mental health.10 Certain nutrients, including folate, vitamin B12, polyunsaturated fatty acids, vitamin D, and homocysteine, have been associated with PPD.11–13 Although there are numerous studies examining the relationship between nutrition and PPD, few studies have focused on folate deficiency and PPD occurrence. Folate occurs in minute quantities in natural food and is directly used in cell metabolism. Folate is involved in important biochemical processes1,14 including the folate-driven 1-carbon (1C) cycle, a fundamental metabolic hub in cells playing an important role in the synthesis of nucleotides/amino acids and epigenetic modifications.15,16 As an essential nutrient, folate cannot be synthesized by the body but is required to be consumed in the diet.17 Pregnant women have an increased folate requirement and are at risk for inadequate folate intake. A previous study has demonstrated that folate deficiency occurred in patients with depression, and patients with low folate levels may have more prominent clinical symptoms than those with normal folate levels.18 Folate deficiency may be one of the risk factors of depression. However, the relationship between prenatal folate (PF) intake and PPD is still controversial. Yan et al19 showed that PF supplementation during pregnancy could reduce the incidence of PPD, while Lewis et al11 reported that low folic acid intake, even different supplementation times, was not a risk factor for PPD. Thus, this study aims to examine whether PF supplementation is related to PPD and explore the possible risk factors of PPD, which may provide new information for effective PPD prevention.

METHODS

This investigation conformed to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of the Affiliated Hospital of Jining Medical University, Jining, Shandong, China. A hospital-based retrospective cohort study was conducted in the Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, China, from December 2018 to December 2019.

STATISTICAL ANALYSIS

Continuous variables in this study were presented as mean ± standard deviation (normal distribution). Categorical variables were analyzed with the χ2 test and expressed with number (n) and percentage (%). All analyses were performed with the statistical software packages of R (http://www.R-project.org, The R Foundation) and EmpowerStats (http://www.empowerstats.com, X&Y Solutions, Inc, Boston, Massachusetts). Binary logistic regression with single and multicategorical predictors was used to determine the possible risk factors for PPD. The data were examined at the 95% confidence level, and P < .05 was considered as statistically significant.

RESULTS Characteristics of Participants in the Study

A total of 635 participants were included in the primary experiment design. Questionnaires were used to collect basic information including age, body mass index (BMI), delivery modes, education, smoking, drinking, PF supplementation, and depressive symptoms. Information from 629 participants was analyzed in the study, while 6 were excluded: 5 were missing information about PF intake and 1 was missing delivery mode (Figure 1).

Figure 1.:

Flow diagram of included and excluded participants.

Depressive symptoms in pregnancy were assessed by the Edinburgh Postpartum Depression Scale (EPDS) at 6 weeks postpartum.20 A total of 10 items were included in the EPDS and each was scored at 4 levels according to the frequency of symptoms: “0” means “never,” “1” means “occasionally,” “2” means “often,” and “3” means “always.” A total score of 10 points or more indicated that patients had depressive symptoms. Furthermore, a higher score reflected more severe symptoms of PPD.

As shown in Table 1, 540 (85.85%) took PF regularly until the sixth week postpartum (PF) and 89 (14.15%) never took PF during the whole gestational period (non-PF). The BMI, education, smoking status, and drinking status were not different between the 2 groups. Maternal age in the non-PF group was significantly higher than that in the PF group (non-PF: 30.48 ± 2.40 vs PF: 28.44 ± 3.69, P < .001). The rate of caesarean section was 70.79% in the non-PF group and 57.96% in PF group. Among the participants with PPD, 37 were found in the non-PF group (41.57%) and 251 occurred in the PF group (46.48%).

Table 1. - Characteristics of Participants in the Studya Characteristics Non-PF PF P Value n 89 (14.15%) 540 (85.85%) Age, y 30.48 ± 2.40 28.44 ± 3.69 <.001b BMI, kg/m2 27.31 ± 3.09 28.39 ± 3.95 .14 Delivery modes .022c Vaginal delivery 26 (29.21%) 227 (42.04%) Cesarean section 63 (70.79%) 313 (57.96%) Education .304 Below high school 26 (29.21%) 189 (35.00%) High school 22 (24.72%) 97 (17.96%) Undergraduate 35 (39.32%) 230 (42.59%) Postgraduate 6 (6.74%) 24 (4.44%) Smoking 1 (1.12%) 8 (1.48%) Drinking 2 (2.25%) 8 (1.48%) PPD .389 No 52 (58.43%) 289 (53.52%) Yes 37 (41.57%) 251 (46.48%)

Abbreviations: BMI, body mass index; non-PF, without prenatal folate; PF, prenatal folate; PPD, postpartum depression.

aContinuous variables expressed as mean ± SD or n (percentage).

bP < .001.

cP < .05.

Univariate analysis of different variables for PPD

The scores of each item (A) and total scores (B) in all participants are shown in Figure 2. Univariate linear regression analysis was performed to determine the relationship between characteristics and PPD. As shown in Table 2, age (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.64–0.73) and BMI (OR = 1.09, 95% CI: 1.04–1.13) were significantly associated with the onset of PPD, respectively (P < .001). However, delivery mode, education, and smoking or drinking status, regardless of PF, were not significantly associated with the occurrence of PPD (P > .05).

Figure 2.:

EPDS scores in non-PPD and PPD. EPDS indicates Edinburgh Postpartum Depression Scale; non-PPD, nonpostpartum depression, PPD, postpartum depression.

Table 2. - Univariate Analysis of Different Variables for PPDa Characteristics Statistics OR (95% CI) P Value Age, y 29.86 ± 4.98 0.68 (0.64–0.73) <.001b BMI 28.24 ± 3.86 1.09 (1.04–1.13) <.001b Delivery modes Cesarean 376 (59.78%) 1.0 Vaginal 253 (40.22%) .9755 Education Below high school 215 (34.18%) 1.0 High school 119 (18.92%) .9784 Undergraduate 265 (42.13%) .9756 Postgraduate 30 (4.77%) .9774 Smoking 9 (1.43%) .9741 Drinking 10 (1.59%) .9727 PF No 89 (14.15%) 1.0 Yes 540 (85.85%) 1.22 (0.78–1.92) .3896

Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; PF, prenatal folate; PPD, postpartum depression.

aContinuous variables expressed as mean ± SD or n (percentage).

bP < .001.

Multivariate piecewise linear regression analysis

The relationship of PF supplementation and PPD was further evaluated using multivariate logistic regression analysis. The OR and 95% CIs are listed in Table 3. In the nonadjusted model, the multivariate logistic regression analysis showed that PF was not associated with PPD (OR = 1.22, 95% CI: 0.78–1.92, P = .3896). In adjusted model I (adjusted for age) or adjusted model II (adjusted for age, BMI, and delivery mode), prenatal PF intake remained not associated with PPD (P > .05). Thus, PF supplementation was not associated with a decreased risk of PPD.

Table 3. - Relationship Between PF Supplements and PPD in Different Models Using Multivariate Linear Regressiona Exposure PF Nonadjusted Adjusted I Adjusted II OR (95% CI) 1.22 (0.78–1.92) 0.00 (0.00, Inf) 0.00 (0.00, Inf) P Value .3896 .9898 .9418

Abbreviations: CI, confidence interval; PF, prenatal folate; OR, odds ratio; PPD, postpartum depression.

aNonadjusted model adjusted for: none. Adjusted model I adjusted for: age. Adjusted model II adjusted for: age, body mass index, and delivery modes.

The relationship between maternal age and PPD was further analyzed based on curve fitting. As shown in Figure 3, when maternal age was greater than 26 years, there was a significant and positive relationship between maternal age and total EPDS scores (β = −0.61, 95% CI: 0.57–0.65; P < .001).

Figure 3.:

The relationship between maternal ages and EPDS total scores in by smooth curve fitting (A) and threshold effect analysis (B).

DISCUSSION

In this retrospective case-control study, the association between prenatal PF supplements and PPD was investigated and a significant association between PF supplementation and PPD risk was not observed. However, maternal age may be a risk factor for PPD, specifically age greater than 26 years.

PPD is a serious psychiatric disorder that is caused by physiological, psychological, and social factors.21 The prevalence of PPD is up to 30% in Chinese women according to a previous cross-sectional survey.9 Besides affecting maternal health,22,23 it has adverse effects on infant behavioral, emotional, and cognitive development.24–28 Thus, some researchers indicate that antenatal depression can result in fetal reprogramming.29–31 Importantly, pregestational maternal depression is one of the greatest risk factors for developing PPD.32 This underlines the importance of early identification and timely prevention of maternal PPD.

Many animal models were used to explore the risk factors of PPD and have achieved remarkable findings.33–35 Currently, psychosocial and psychological interventions, somatic therapies, and pharmacological treatment are the main prevention and treatment measures for PPD.36 Medications used for PPD include tricyclic antidepressants, monoamine oxidase antidepressants, and selective 5-hydroxytryptophan (5-HT) reuptake inhibitors.36 However, due to the adverse reactions for both mothers and infants, drug treatment may not be the best choice for PPD.

Folate, as water-soluble vitamin B, has been reported to be associated with depression.37 A previous study has identified that lower PF intake may be associated with depression due to a disruption of neurotransmitter synthesis.1 During pregnancy, the demand for folic acid is increased to meet the needs of fetal growth and development. Therefore, obstetric experts have suggested that PF should be supplemented to reduce the risk of fetal neural tube defects.38 However, the relationship between PF supplementation during pregnancy and PPD is controversial. Some studies have indicated that PF supplementation during pregnancy has been identified as a protective factor for PPD,11,39 while other studies have not established an effective association between PF supplementation and PPD.10,40 Consistent with a study conducted by Cho et al,41 our study demonstrated that PF supplements did not decrease the onset of PPD. However, the present study indicates that maternal age, especially age greater than 26 years, may be a risk factor for the development of depression, identifying a higher PPD risk with increased age.

There are various methods of folic acid supplementation including folic acid tablets as well as multivitamins and prenatal vitamins, which include folic acid. These variations could allow for additional stratification of data, which may then show a relationship between PF supplementation and PPD. For example, there may be notable differences found in those without PF supplementation compared with those who consume a multivitamin or those who consume a multivitamin plus PF supplementation.

There are limitations in our study. First, the observed results in the cross-sectional study cannot identify a direct relationship between PF intake and PPD. Second, all study subjects are from China, which minimizes the confounding effects of ethnic background but reduces the ability to generalize the findings. Third, the sample size of the non-PF group was small likely due to improvement in health care awareness and financial levels leading to most women being likely to consume PF during the perinatal period. Fourth, dosing/frequency of PF supplementation is hard to confirm in each participant. In addition, the diverse diet in different families or regions is another factor affecting the actual PF intake.

CONCLUSION

In this study, the protective effect of PF against PPD was found to be marginal. However, age and BMI were identified as significant risk factors for PPD. Further studies are needed to better define the modifiable and nonmodifiable risk factors for PPD.

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