Statistical Analysis
This study was designed to detect a 5% absolute difference between
groups with 90% power and a 5% type I error rate. We assume that the
incidence of PPD was about 30% in the PE group and 15% in the control
group. Therefore, a sample size of 380 (88 in the PE group and 292 in
the control group) was needed. The MedSci Sample Size Tools (MSST,
version 5.7.15, copyright 2020 MedSci.cn) were applied for calculating.
We recruited 130 PE patients and 295 healthy women.
Variables in accordance with normal distribution were compared via an
independent t-test and presented as mean ± standard deviation.
Otherwise, variables were described as mean ± quartile and examined by
the Kruskal–Wallis test. Differences in the classified variables were
evaluated by the Chi-squared test. P < 0.05 was
considered as significant. A Multivariate logistic regression model was
used to evaluate adjusted odds ratios. Confounding factors including
age, BMI, gestational days, baby weight, delivery model, Leakage Index
Score, milk-feeding ways, and Pain Scale, which were previously reported
to be connected with PPD or unmatched between PE and normal groups. All
statistical analyses were conducted on SPSS 23.0 (SPSS Inc, Chicago,
USA).
Results
Clinical
characteristics between normal and PE mothers
A total of 130 PE patients met the inclusion and exclusion criteria. We
randomly selected 295 normal women who met the inclusion criteria during
the same period. In the PE group, 74 patients were
diagnosed
with mild PE, the others with severe PE.
Clinical
characteristics were compared between the normal and PE groups in Table
S1. The layer distribution of pre-pregnancy body mass index (BMI) was
significantly different, and PE mothers had a higher BMI than the normal
ones (P=0.005). PE patients suffered a much higher rate of
caesarean section (93.08% vs. 33.22%) and less gestational age
(260 vs. 277 days) (both P<0.001). As a result, the
birthweight of the fetuses in the PE group was inferior to the normal
one (2960 vs. 3255 g, P<0.001). In terms of feeding,
infant formula was more frequently used in PE group, no wonder the
exclusive breastfeeding rate was lower (33.08% vs. 57.63%,P<0.001). However, other clinical characteristics were not
significantly different between groups, such as BMI increase, gravidity,
parity, percentage of primipara, sex of the fetus, educational
background, annual family income, and scores of the
Leakage
Index Questionnaire and Pain Scale.
Clinical
characteristics between PPD and non-PPD groups
All participants were asked to finish EPDS, and the scores were compared
between the normal and PE groups. No differences for clinical
characteristics were found between PPD and non-PPD mothers in the normal
group (Table S2). However, in PE group, mothers who had babies with FGR
and low neonatal weight tended to develop PPD (P=0.024 andP=0.007; Table 1). Postpartum pain was another high-risk factor
for PPD in PE group (P=0.012). Unlike PE group, the scores of
pain scale showed no difference between PPD and non-PPD women in the
normal group (P=0.209).
Severe PE and FGR womenwere
inclined to develop higher EPDS scores
We tried to explore the associations between PPD and PE. The average
EPDS score in the normal group was significantly lower than the mild PE
subgroup (7.09±4.41 vs. 8.62±4.35, P=0.008; Table S3 and Figure
1). In the severe PE subgroup, the average EPDS score was even worse
(10.58±5.41), indicating most of the severe PE patients developed PPD.
Furthermore, 38 PE mothers were complicated with FGR and got the highest
EPDS scores among the subgroups (11.61±5.29, P<0.001).
Rather
than caesarean section, PE showed direct tendency on PPD development
There
was a higher caesarean section rate among PE patients than normal women
(93.08% vs.33.22%). To determine the effect of caesarean
section on PPD development, we compared the EPDS scores and PPD
incidence between C-section and
vaginal
delivery in the normal group. There was not any difference in the EPDS
score (6.74±4.42 vs. 7.27±4.41, P=0.337) and PPD incidence
(13.27% vs.15.32%, P=0.728) between the two delivery
modes (Table S4).
Interestingly,
when compared the normal and PE groups suffered from cesarean section,
it was found that both the EPDS (9.54±4.80 vs. 6.74±4.42,P<0.001) score and PPD incidence (32.23% vs.13.27%,P=0.001) were much higher among PE group than the normal group
(Table S5). It could be inferred that it was not cesarean section but PE
directly increased the risk of PPD.
Much higher screening of PPD in PE mothers than the normal
ones
We compared the rate of positive screening of PPD in each subgroup
(Table 2). Totally 83 people were screened positive for PPD, while the
remaining 342 were negative. The incidence of PPD was 14.58% in the
normal group, whereas the rate was much higher among PE mothers. About
30.77% of women in the PE group met the diagnostic criterion for PPD.
Furthermore, the incidences of PPD dramatically increased with the
severity of PE and its complications. For instance, the incidences of
PPD in the mild PE and severe PE subgroups were 27.03% and 36.96%
respectively, which were significantly higher than the normal mothers
(14.58%, P=0.014 & P=0.002).
We
also tried to explore the associations between PE complications and PPD
development. In the PE+ FGR subgroup, the incidence of PPD was the
highest among all the subgroups (44.74%). Thirty new-borns were
extremely weak and had to be sent to the neonatal intensive care unit
(NICU). Obviously, when the babies were sent to NICU, their mothers
tended to develop PPD. PPD incidence among these mothers increased
dramatically (36.66%), which was extremely high. Preterm, one of the
common complications in PE, occurred in almost half of PE mothers (61 of
130). PPD occurrence was 32.79% in the PE + preterm subgroup.
Independent risk factors for PPD
Then multiple logistic regression was performed to evaluate the
independent risk factors for PPD. With PPD as the dependent variable,
PE, severe PE, FGR, NICU admission were regarded as independent
variables individually, while age, BMI, gestational days, baby weight,
delivery model, Leakage Index Score, milk-feeding ways and Pain Scale
analysed as confounding factors. Women with mild PE demonstrated 2-fold
higher odds of PPD (AOR=2.117, 95% CI: 1.001-4.479; Table 3).
Furthermore, severe PE, FGR, and NICU admission all increased nearly
3-fold risk for PPD positive screening. These findings indicate that the
severity and complications of PE will increase the risk of PPD (as shown
on Figure S2).
Besides PE, postpartum pain was another independent risk factor for PPD
(AOR=1.509, 95%CI: 1.078-2.114). The effect of breastfeeding on PPD has
not been clearly indicated before, but in our study, exclusive
breastfeeding seemed not to positively affect the mood of the mothers
(AOR=0.752,
95%CI:
0.445-1.270). Pelvic floor muscle recovery has always been a concern
among new mothers and can dramatically influence their moods. After
evaluating pelvic floor function, we found the dysfunction of pelvic
floor muscles had no negative effect on PPD (AOR=1.137, 95%CI:
0.952-1.358). Moreover, we observed there were no correlations between
the caesarean section and PPD (AOR=1.177, 95%CI: 0.620-2.232).
Discussion
Among the general population, hypertension has already been proved to be
an independent risk factor for depressive
disorder.24Hypertension increased 1.12-fold of developing depression among 6,237
old Chinese adults.25For pregnant women, few studies were exploring the connection between PE
and PPD. To our knowledge, this is the first retrospective cohort study
to clarify the associations of the severity and complications of PE with
PPD in Chinese population. The number of cases (425) in our trial is the
largest among the existing relevant studies.
As reported, PPD occurred in 20.5% PE patients in Tanzanian and in
about 21% PE mothers in
Greek.1,26In our study, the percentage of a positive screening for PPD in PE group
was even higher (30.77%). Besides PE, its complications could also
increase the risk of PPD. Similar to our findings, Hoedjes M. et al.
discovered that the prevalence of PPD was 23% in mild PE patients and
44% in severe PE.27These studies suggest PE affects PPD strongly.
For PE mothers, besides
unfavourable experience of hypertension, other conditions such as
additional costs, concerns of the new-borns with complications also
increase mothers’ psychological
burden.28,29The outcomes of infants play an important role in PPD development among
severe PE patients. 27This conclusion was confirmed in our study, especially for
growth-restricted babies. A study reported the prevalence of PPD among
FGR family was 48.2%, which was similar to our result
(44.74%).28 38% of
mothers experienced significant depressive symptoms when their babies
were sent to NICU.30These studies mentioned that baby conditions and financial problems
maybe two of the most risk factors of PPD. In our clinical trial,
mothers were asked ‘what most upsets you?’ The majority of mothers told
us that they were bothered most by the poor outcomes of their babies and
NICU admission. In our study, 30 neonates were admitted to NICU.
Notably, the incidence of PPD among these mothers was very high
(36.6%). Many randomized controlled trials have implicated that
insufficient contact with babies will increase the odds of
PPD.31-33 Therefore,
clinical healthcare workers should provide psychological supplies to
mothers with NICU babies. The financial problem was the second problem:
seven of them received lower annual income (less than 80 k RMB per
year), they felt huge burden on children hospital expenses.
Whether the cesarean section will increase the risk of PPD is still
controversial. In China, some healthy pregnant women would like to
choose cesarean section due to social-psychological factors. In this
research, mothers with PE preferred to have a
cesarean
section to avoid possible adverse outcomes. This can explain why the
rate of operative delivery in China among PE patients is so high.
First of all, to figure out the effect of cesarean section for PPD, we
compared delivery models among normal women. Patel et al. demonstrated
that operative delivery would not increase the incidence of PPD in
14,633 women.34 A
meta-analysis in 2017 also reported that elective cesarean section would
not significantly exacerbate the odds of PPD (AOR: 1.15, 95%CI:
0.92-1.43).35 In our
study, there was not any difference in the EPDS score and PPD incidence
between the two delivery models among normal pregnant populations.
However, in PE group, we found that both EPDS score and PPD incidence
were much higher in mothers suffered from operation. It could be
inferred that PE directly increased the risk of PPD rather than cesarean
section. Then we applied subgroup analysis to find the reason. In PE+
FGR subgroup, the incidence of PPD was the highest among all the
subgroups. Obviously, mothers tended to showing anxiety when babies were
sent to NICU. Another common complication is preterm. Almost half of PE
mothers occurred preterm. As expected, mothers in the PE+preterm group
experienced higher psychological distress than others. Weigl et al.
pointed new mothers of preterm infants exhibited higher scores of
depression, anxiety and stress than parents of term infants. Preterm
mothers showed lower levels of estradiol, progesterone, and prolactin,
as well as a heightened post-awakening cortisol response compared to
term mothers36. These
results are consistent with our finding.
Postpartum pain, urinary incontinence, and feeding methods were also
evaluated in the regression model. Postpartum pain was an independent
risk factor for PPD, increasing the odds by 1.5-fold.
A
few trials showed that untreated pain is associated with a risk of
PPD.37,38The usage of painkillers can help decrease the incidence of PPD in some
cases.39,40Our study implied postpartum pain as another risk factor of PPD in the
PE group. This was probably because PE mothers suffered more postpartum
pain from the operation. Therefore, it is reasonable to use painkillers
for PE mothers during the postnatal period.
Hullfish Kl. et al has demonstrated a correlation between
urinary
incontinence and PPD41,
but Doering AD. et al showed no such connection42. In our study, there
was no significant result about urinary incontinence in PPD development.
Nonetheless, more authoritative urinary incontinence scales need to be
tested in the future. Non-breast-feeding was regarded as a risk factor
for PPD in many
cases.43,44But in our study, exclusive breastfeeding did not help decrease the
incidence of PPD.
Although the connection between PE and PPD is still unclear, some
mechanisms, such as clinical symptoms, inflammation, and genetic
changes, have been used as hypotheses for the reason between PE and PPD.
The pathogenesis for PE, a placenta disease, can be explained by the
“two-stage theory”.45At the first stage, vascular remodeling disorders of uterine spiral
arterioles caused by multiple factors result in “superficial placental
implantation” and ultimately cause insufficient placental perfusion and
impairment of placental function. In the second stage, the ischemic
placenta will experience oxidative stress and release inflammatory
factors, such as IL-6, leading to systemic endothelial dysfunction.
Therefore, PE patients often have excessive inflammatory factors in
blood circulation.46-49For example, abnormally elevated C-reactive protein (CRP) and tumour
necrosis factor (TNF)-α are detected in the serum of PE mothers,
resulting in vascular remodelling dysfunction of the
placenta.50Consistently, like PE, inflammatory biomarkers also take part in PPD
development.51 Studies
confirm that increased IL-6 and TNF-α levels during the perinatal period
can intensify the risk of
PPD.52-54 Based on
these studies, we speculate that inflammatory cytokines are released by
the dysfunctional placenta in PE mothers, finally leading to the
development of
PPD.50,55,56Our further research will pay more attention to these inflammatory
cytokines.
We must admit that there are some limitations in our study. As a
retrospective study, it suffered from bias and case limitations.
Firstly, patients were recruited from 2 hospitals and the local bias may
be relatively reduced, but there is still a need for a study involving
multiple centres. Secondly, it was hard to control operation rate in PE
group, although this delivery mode was not found to be a risk factor in
our regression model. In future, we would like to initiate larger
randomized controlled trials and more in-depth mechanistic studies.