Abstract
Aim: This study aimed to examine phosphoethanolamine (PEA) in postpartum women and its association with postpartum depression (PPD).
Methods: This prospective study, performed between July 2020 and August 2021 at Fukushima Medical University Hospital, included 67 women. They answered two questionnaires, the Edinburgh Postpartum Depression Scale (EPDS) and the Patient Health Questionnaire-9 (PHQ-9). EPDS is the screening tool for PPD, and the PHQ-9 scores can evaluate the degree of depressive symptom severity. Blood was collected at 5 and 40 days postpartum, and PEA levels were measured.
Results: The PEA levels of all postpartum women on day 5 were significantly lower than those on day 40. EPDS and PHQ-9 scores were significantly lower on day 40 than those on day 5 postpartum. No significant correlation was observed between the PPD-suspected (EPDS≥9) women and PEA levels, and no significant correlation was found between plasma PEA levels and PHQ-9 scores on postpartum days 5 and 40.
Conclusions: This study found that PEA levels on postpartum day 5 were lower than on postpartum day 40. It also suggested that there was no association between the degree of postpartum depression and plasma PEA concentrations.
Keywords: Edinburgh Postpartum Depression Scale, Patient Health Questionnaire, phosphoethanolamine, postpartum depression
Introduction
Phosphoethanolamine (PEA) is associated with phospholipid metabolism. Although the role of PEA in various metabolic pathways remains unclear, it could be related to the cannabinoid system. Cannabinoid is a general term for Δ9-tetrahydrocannabinol (THC, the psychoactive component of cannabis) and its analogues 1). N-Arachidonylethanolamide (anandamide) was isolated as an endogenous ligand of the cannabinoid receptor 2). Anandamide is a substance produced from phosphoanandamide by phosphatase. PEA, like anandamide, is also a substance produced when phophoanandamide is metabolized 3).
The endocannabinoid system has been associated with depression, stress-related affective disorders, and suicide 4). Kawamura et al. reported that since plasma PEA levels in patients with major depressive disorder (MDD) were lower than those in healthy controls, plasma PEA could be a potential MDD biomarker in clinical settings 5). However, there are no reports evaluating PEA levels in postpartum women and association between PEA and postpartum depression (PPD).
PPD is the most common type of postpartum psychosis, occurring in 10%-15% of postpartum mothers 6-8). Since suicide rates among pregnant and postpartum women due to psychological problems have been reported to be higher in Japan than in other countries 9), early detection and intervention for PPD are necessary for prevention. PPD has also been reported to negatively affect children’s cognitive function and emotional development 10,11). Therefore, we aimed to identify objective indicators and markers for the early detection of PPD. Although substances such as estradiol, progesterone, thyroid hormones, oxytocin, and serotonin have been reported as potential markers of PPD, they have not yet been identified as such 12).
There are no reports about changes in PEA levels during the postpartum period. For reference, anandamide, which is associated with PEA metabolism, has been reported to decrease in the second and third trimesters of pregnancy and increase before delivery 13). However, there are no reports of changes in anandamide during the postpartum period.
Therefore, the purpose of this study was to examine changes in PEA levels over time during the postpartum period, and any relationship between PEA levels and postpartum depression.
Materials and Methods
This prospective study was performed between July 2020 and August 2021 at Fukushima Medical University Hospital. This study was approved (#30149) by the ethics committee of Fukushima Medical University, which is guided by local policy, national law, and the World Medical Association Declaration of Helsinki. Informed consent was obtained from all participating patients.
Patients undergoing prenatal check-ups at our hospital were asked to participate in this study of PPD after delivery. Because there have been no previous reports about PEA levels in the postpartum period, this study included women who had a normal pregnancy and delivery process. The exclusion criteria were as follows: (1) psychiatric treatment during or before pregnancy, (2) delivery by cesarean section, (3) multiple pregnancies, (4) metabolic complications such as thyroid disease.
All participants completed two questionnaires, the Edinburgh Postpartum Depression Scale (EPDS) and the Patient Health Questionnaire-9 (PHQ-9), on postpartum days 5 and 40. EPDS is the most commonly used screening tool for PPD. The Japanese version of the EPDS has been proven to be reliable and valid in a study that defined a score ≥9 as screen-positive for PPD 14). The PHQ-9 is used as a depression-screening tool for adults in primary care, and PHQ-9 scores can evaluate the degree of depressive symptom severity 15,16). Muramatsu et al.17) demonstrated its reliability.
We obtained information from the women’s medical records regarding age, gravida, history of abortions, previous medical history, giving birth at her parent’s home, amount of bleeding during delivery, and presence of disease in the child. Blood samples were collected at 5 and 40 days after delivery. On postpartum day 5, blood was collected between 7: 00 am and 8: 00 am before breakfast during hospitalization. On postpartum day 40, blood was collected after at least 2 hours of fasting when the patient visited the outpatient clinic. Blood samples were collected in EDTA-2Na vacuum tubes.
Plasma was rapidly separated by centrifugation with swing -type centrifugal rotors (1,000 × g for 10 minutes) at room temperature. One milliliter of plasma was immediately frozen and kept at −80°C until analysis. Stored samples were transported to the Human Metabolome Technologies Inc. (HMT) laboratories in Yamagata, Japan. PEA levels were measured using a capillary electrophoresis triple-quadrupole mass spectrometer in the HMT laboratories based on methods described previously 18,19). Briefly, capillary electrophoresis-mass spectrometry (CE-MS) analysis was conducted using an Agilent CE capillary electrophoresis system equipped with an Agilent 6460 Triple Quadrupole LC/MS (liquid chromatography/mass spectroscopy) system (Agilent Technologies). The systems were controlled by Agilent G2201AA ChemStation software version B.03.01 for CE (Agilent Technologies) and connected by a fused silica capillary (50-μm ID × 80-cm total length) with commercial electrophoresis buffer (I3302-1023, HMT) as the electrolyte. The triple quadrupole LC/MS was used to detect compounds in dynamic multiple reaction monitoring mode. Peaks were extracted using MassHunter Quantitative Analysis B.04.00 (Agilent Technologies) to obtain peak information including mass-to-charge ratio, peak area, and migration time. The peak area of each metabolite was normalized to internal standards, and the PEA concentration was evaluated by standard curves with six-point calibrations using a standard compound. The normal blood PEA concentration is 2-3 μM 20). To minimize the impact of potential contamination from blood cells or hemolysis, samples with plasma PEA levels ≥3.0µM were excluded from the analysis, as these levels are considered abnormally high and may reflect analytical artifacts rather than physiological values.
We compared PEA concentrations at 5 and 40 days postpartum using the Wilcoxon signed rank-sum test. We also compared EPDS and PHQ-9 scores at 5 and 40 days postpartum using Wilcoxon’s signed rank-sum test. Furthermore, we compared PEA levels in postpartum women with an EPDS ≥9 and those with an EPDS <9 using the Mann-Whitney U test. In addition, the correlation between PEA concentration and PHQ-9 scores at 5 and 40 days postpartum was examined using Spearman’s rank sum correlation coefficient.
Kawamura et al.5) reported that PEA levels less than 1.46 μM are associated with major depressive disorder. Therefore, in this study, PHQ-9 scores were compared between groups with PEA levels more than 1.46 μM and less than 1.46 μM, using the Mann-Whitney U test.
Statistical evaluation of the data was performed using SPSS for Windows version 28 (SPSS Inc., Chicago, IL, USA).
Results
Eighty -one women were enrolled in the study, of whom 14 with PEA of ≥3µM were excluded; thus, 67 cases were analyzed. Characteristics of the participants are shown in Table 1. Plasma PEA levels were significantly lower on postpartum day 5 than on postpartum day 40 (Table 2), while EPDS and PHQ-9 scores were significantly lower on postpartum day 40 than on postpartum day 5 (Table 3). There were no significant differences in PEA levels between postpartum women with EPDS ≥9 and those with EPDS <9 (Table 4). No significant correlation was observed between the plasma PEA levels and PHQ-9 scores on postpartum day 5 or 40 (Fig. 1).
Table 1.
Characteristics of participants
| Characteristics | |
| Age, median (95% CI) | 33.0 (31.6-34.0) |
| < 35 years, n (%) | 40 (59.7%) |
| ≥ 35 years, n (%) | 27 (40.3%) |
| Primipara, n (%) | 38 (56.7%) |
| Experience of abortion, n (%) | 18 (26.9%) |
| ART, n (%) | 13 (19.4%) |
| Hospitalization during pregnancy, n (%) | 12 (17.9%) |
| Going home for a delivery, n (%) | 40 (59.7%) |
| Gestational age at delivery, median (95%CI) | 39.0 (38.7-39.3) |
| Blood loss at delivery, median (95%CI) (mL) | 319 (348.0-492.5) |
| Infant complications, n (%) | 10 (14.9%) |
| BMI - before delivery, median (95% CI) (kg/m2) | 24.7 (24.0-25.6) |
| BMI - postpartum day 40, median (95% CI) (kg/m2) | 21.2 (20.8-22.3) |
ART, assisted reproductive technologies; BMI, body mass index
95% CI, 95% confidence interval
Table 2.
Participants’ plasma PEA levels
| Postpartum day 5 | Postpartum day 40 | p-valuea | |
| PEA (μM) | 0.930 (0.895-1.050) | 1.280 (1.275-1.450) | <0.001 |
aWilcoxon signed-rank test was used, with statistical significance defined as p < 0.05.
PEA, phosphoethanolamine
Table 3.
EPDS and PHQ-9 scores of participants
| Postpartum day 5 | Postpartum day 40 | p-valuea | |
| EPDS | 2.00 (2.38-4.12) | 2.00 (1.89-3.31) | 0.028 |
| PHQ-9 | 2.00 (1.94-3.68) | 1.00 (1.12-2.25) | 0.003 |
aWilcoxon signed-rank test was used, with statistical significance defined as p < 0.05.
EPDS, Edinburgh Postpartum Depression Scale; PHQ-9, Patient Health Questionnaire-9
Table 4.
Comparison of PEA levels with EPDS 8/9 points as classification thresholds
| EPDS ≥9 | EPDS <9 | p-valueb | |
| Postpartum day 5 | (n=6) 0.805 (0.476-1.505) |
(n=61) 0.930 (0.893-1.048) |
0.614 |
| Postpartum day 40 | (n=3) 1.000 (0.934-1.339) |
(n=64) 1.285 (1.282-1.464) |
0.187 |
bMann-Whitney U test was used, with statistical significance defined as p < 0.05.
PEA, phosphoethanolamine; EPDS, Edinburgh Postpartum Depression Scale
Fig 1.
Correlation between serum PEA and PHQ-9.
Spearman’s rank sum correlation coefficient was used, and statistical significance was defined as p < 0.05.
(a) postpartum day 5
(b) postpartum day 40
PEA, phosphoethanolamine; PHQ-9, Patient Health Questionnaire-9.
In addition, the PHQ-9 scores were compared in the two groups with PEA levels ≥1.46 and <1.46 µM. The results showed no significant differences between the two groups at either postpartum day 5 or 40 (Table 5).
Table 5.
Comparison of PHQ-9 scores with a threshold PEA of 1.46 μM
| (a) Postpartum day 5 | |||
| PEA<1.46 μM (n=63) | PEA≥1.46 μM (n=4) | p-valuec | |
| PHQ-9 score | 2.00 (1.91-3.74) | 2.00 (-1.71-6.71) | 0.969 |
|
(b) Postpartum day 40 | |||
| PEA<1.46 μM (n=44) | PEA≥1.46 μM (n=23) | p-valuec | |
| PHQ-9 score | 1.00 (0.83-2.21) | 1.00 (0.97-3.03) | 0.408 |
cMann–Whitney U test was used, with statistical significance defined as p < 0.05.
PEA, phosphoethanolamine; PHQ-9, Patient Health Questionnaire-9
These results were similar in the analysis of all 81 patients enrolled in the study.
Discussion
In this study, we found that PEA levels were low on postpartum day 5 and increased on postpartum day 40. On the other hand, the degree of depression (per EPDS and PHQ-9 scores) of the mothers was found to be lower at 40 days postpartum compared to 5 days postpartum. However, there was no significant association between PPD-suspected women and PEA levels, and there was no significant association between plasma PEA levels and the degree of postpartum depression.
Changes in PEA during the postpartum period
We found that PEA levels on postpartum day 5 were lower than on postpartum day 40. To our knowledge, there have been no reports examining changes in plasma PEA levels over time during the postpartum period. In this study, we did not measure PEA levels during pregnancy. Therefore, it is unclear whether (i) plasma PEA levels decrease from pregnancy to the early postpartum period from the non-pregnant status and returns to the non-pregnant status shortly after birth, or (ii) plasma PEA levels decline in the early postpartum period due to physiological changes such as lactation after delivery.
Anandamide, which is associated with PEA metabolism, has been reported to change with the menstrual cycle and correlate with FSH, LH, and E2 21). In addition, anandamide has been reported to decrease in the second and third trimesters of pregnancy and increase before delivery 13). Therefore, plasma PEA levels in the postpartum period may have also decreased due to changes in female hormones associated with pregnancy and delivery. Further studies, including plasma PEA levels during pregnancy, are warranted.
PEA and postpartum depression
Ethanolamine is a precursor of PEA, and its levels in the cerebrospinal fluid are lower in MDD patients 22). Kawamura et al.5) reported that the plasma PEA level could be a potential MDD biomarker in clinical settings. In this study, however, there was no association between plasma PEA levels and the degree of depression.
In our study, the PHQ-9 scores of postpartum women were a median of 2.00 (1.94-3.68) on day 5 postpartum and a median of 1.00 (1.12-2.25) on day 40 postpartum (Table 3). PHQ-9 scores of 10 or more are reported to indicate risk of depression. However, in our study, the number of women with PHQ-9 scores of 10 or more were only 2 at postpartum day 5 and 1 at postpartum day 40. Therefore, it is possible that no significant association between PEA levels and PPD was found in this study because of the large number of mildly depressed and healthy women in this study compared to the number of patients with major depressive disorder in previous studies 5-8).
Kawamura et al.5) reported a threshold PEA of 1.46 μM, with lower PEA levels associated with major depressive disorder. In our study, 91.0% (61/67) of patients at postpartum day 5, and 64.2% (43/67) at postpartum day 40 had PEA levels less than 1.46 µM, regardless of a PHQ-9 score less than 10. The results showed many cases with PEA <1.46 µM during the postpartum period, despite the lack of depressive symptoms. Therefore, our findings suggest that threshold values for plasma PEA levels in previous studies may not be applicable to the postpartum period.
This study appears to be the first report of changes of PEA levels during the postpartum period in healthy women who had a vaginal delivery without obstetric complications. The results suggested that PEA levels may not be associated with a risk of depression during the postpartum period. However, this study has several limitations. First, both the number of participants and the number of women at high risk for depression were small. A history of postpartum depressive episodes and prenatal depression have been described as risk factors for PPD 23-25). In this study, mothers with a history of mental illness, including depression, were excluded. Therefore, the proportion of postpartum mothers with high risk of depression may have been underestimated. The second limitation is the timing of the blood sampling. In this study, PEA levels were measured during the postpartum period, not during pregnancy. Therefore, changes in PEA during pregnancy are unknown. We would like to do additional studies investigating changes in PEA in mothers during pregnancies with and without complications. The third limitation is the possibility of including psychiatric disorders other than major depression and PPD. Several women who have experienced PPD have been reported with bipolar disorder 26). The women with treatment-resistant PPD have undiagnosed bipolar disorder 26,27). In this study, we did not assess the manic state of postpartum women. No screening tools exist for bipolar disorder before or after birth 27). Post-traumatic stress disorder following childbirth (PTSD-FC) is a psychiatric disorder possibly occurring during the postpartum period. Past traumatic experiences, such as sexual trauma or childhood abuse, and delivery by emergency cesarean section have been reported as risk factors for PTSD-FC 28). In the present study, we excluded women with a known history of previous psychiatric disorders, such as bipolar disorder or PPD. Women with past traumatic experiences, which are risk factors for postpartum PTSD, and women who had emergency cesarean sections were excluded. In addition, at approximately 6 months postpartum, we made telephone calls and asked whether the mothers were experiencing any mental health problems and whether they had visited the hospital for mental illness after delivery, and no patient reported any problems. The association between PEA and psychiatric disorders other than major depressive disorder is unclear, so future studies are needed.
In conclusion, this study found that PEA levels on postpartum day 5 were lower than on postpartum day 40. It also found no association between the degree of postpartum depression and plasma PEA concentrations.
Acknowledgments
The authors are grateful to Dr. Masanori Jinbo (Fukushima Medical Center for Children and Women, Fukushima Medical University), Dr. Shun Yasuda, Dr. Toma Fukuda, and Dr. Hideki Miura (Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine) for facilitating patient enrollment. We thank Dr. Yoshiaki Ohashi and Mr. Kazunori Sasaki (Human Metabolome Technologies, Inc.) for measuring the PEA levels. We also thank all the participants of the study.
Disclosure Statement
The authors declare no conflict of interests for this article.
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