Keywords
cesarean scar pregnancy - hemogram parameters - systemic inflammatory index
Introduction
Cesarean scar pregnancy (CSP) refers to pregnancies that occur in the scar area of
a previous cesarean section. Its incidence is increasing all over the world due to
the increasing number of cesarean sections in recent years.[1] The true incidence is unknown. According to the literature, its prevalence among
all cesarean section patients is estimated to be between 1/1800 and 1/2500. It constitutes
6.1% of all ectopic pregnancies with a history of one or more cesarean sections.[2]
[3] Increasing awareness among physicians on this issue has increased the incidence
rates. Its clinical presentation can be quite variable. Many women are asymptomatic
at presentation. Diagnosis is not always simple. Although ultrasonography is the primary
diagnostic method, magnetic resonance imaging can assist in some cases.[4] The presence of a pregnancy sac in the lower segment of the first trimester, as
well as a history of cesarean delivery, is predictive of the diagnosis. It should
be kept in mind that CSP is the precursor of the spectrum of placenta accreta (PAS).
Although the pathogenesis of CSP is unknown, it is known that the nitabuch layer does
not develop in the defective decidua, posing a risk for the spectrum of CSP and placenta
accreta.[5]
[6] The pathophysiology of CSP and PAS is known to be the same.[7]
[8] It is well understood that increased but insufficient trophoblast invasion at the
vascularized cesarean section scar causes some inflammatory responses. Recent research
has shown that the neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR),
and monocyte–lymphocyte ratio (MLR) can be used as inflammation markers. Neutrophil
(N) counts reflect active inflammation, whereas lymphocyte (L) counts regulate this
inflammation. While PLR is a thrombosis and inflammation marker, it is also a chronic
inflammation marker.[9]
The purpose of this study was to determine whether blood inflammation parameters are
effective in predicting and early diagnosing cesarean scar pregnancies, which can
be missed and cause serious morbidity and mortality when missed.
Materials and Methods
This study covers the first trimester of CSP and normal pregnancies (NP) followed
retrospectively in the Perinatology and Pregnancy Outpatient Clinic of Necmettin Erbakan
University (NEU) Meram Medical Faculty Hospital between January 2018 and October 2021.
Patients' information was obtained electronically from the NEU Meram Medical Faculty
Hospital. Approval for this study was obtained from the NEU ethics committee (decision
no: 2022/3577).
A total of 86 patients were included in the study. Demographic data and obstetric
histories of all patients were recorded. The patients were divided into two groups
CSP and NP patients. Patient numbers were matched one-to-one. The gestational week
for both groups was accepted as the first trimester (0–14 weeks). In both groups,
those with a history of hyperemesis, imminent abortion diagnosis, twin pregnancy,
a history of preeclampsia in a previous pregnancy, those with maternal systemic disease
(diabetes, renal diseases, thyroid, heart and blood diseases, chronic hypertension,
history of cancer, maternal teratogenic drug including those with autoimmune diseases)
and those who smoke and consume alcohol were excluded from the study. Cases were included
in the CSP group if its located on the anterior wall of the uterus in the isthmic
region, the uterus and cervical canal were empty, and the myometrial thickness was
absent or decreased between the bladder and gestational sac, and there was trophoblastic
vascular blood flow around the sac. Following diagnosis, dilatation and curettage
(D&C) were performed in all these cases. Only the early gestational week with the
sac and intrauterine located first-trimester ultrasonography scans with normal fetal
heartbeat were included in the NP group. For normal pregnancies, pregnant women with
a previous cesarean section history and healthy delivery were randomly included from
the electronic record system. All pregnant women had their peripheral venous complete
blood count values taken at the time of admission. Hemoglobin (H)(mg/dL), lymphocyte
(L)(103/L), neutrophil (N)(103/L), platelet (P)(103/L), and monocytes (M)(103/L) values were calculated, as well as NLR, PLR, MLR, and SII (N × P /L) ratios. Blood
samples were collected in sterile ethylenediaminetetraacetate (EDTA) tubes for measurements.
All measurements were made using the Mindray BC6200 automated blood count analyzer
(Mindray Headquarters, China).
Statistical Analysis
In the descriptive statistics of continuous variables, mean, standard deviation, median,
minimum, and maximum values are given in the definition of categorical variables,
frequency (n) and percentage (percent) values are given. The normality assumptions of the variables
were tested using skewness and kurtosis coefficients, the Kolmogorov–Smirnov test,
and the histogram.
The Mann–Whitney U test was performed to compare the non-normally distributed continuous variables between
the two groups, and when the normality assumption was met, an independent samples
t-test was completed. The variables predicting scar status were determined using logistic
regression analysis, and the sensitivity and specificity values were calculated using
receiver operating characteristics (ROC) analysis. In all analyses, the IBM SPSS.25
program was used, and p < 0.05 was accepted as the level of significance.
Results
A total of 86 patients, with 44 (51.2%) in the control group and 42 (48.8%) in the
scar group, were included in the study. [Table 1] shows a comparison of the patients included in the study based on obstetric and
hematological parameters. As shown in [Table 1], the mean age of the patients in the scar group (p < 0.001), gravida value (p < 0.001), parity value (p < 0.001), number of surviving children (p < 0.001), number of abortions (p < 0.001), cs number (p < 0.001), dc value (p = 0.013), monocyte value (p = 0.039) and mono/lymph value (p = 0.035) were significantly higher than the control group ([Table 2]). The gestational week of the patients in the scar group (p = 0.021) was found to be significantly lower than the control group.
Table 1
Obstetric parameters of study and control groups
|
Parameters
|
n
|
Mean ± SD
|
Median (Min–Max)
|
p-Value
|
|
Age* < 0.001
|
|
control
|
44
|
26.70 ± 5.20
|
27.00 (18.00–38.00)
|
|
|
Scar
|
42
|
35.31 ± 5.23
|
34.00 (24.00–49.00)
|
|
|
Gravida**
|
|
control
|
44
|
2.45 ± 1.11
|
2.50 (1.00–5.00)
|
<.001
|
|
Scar
|
42
|
3.93 ± 1.50
|
4.00 (2.00–8.00)
|
|
Parity**
|
|
control
|
44
|
1.07 ± 0.85
|
1.00 (0.00–3.00)
|
<.001
|
|
Scar
|
42
|
2.07 ± 0.75
|
2.00 (1.00–4.00)
|
|
Abortion**
|
|
Control
|
44
|
.07 ± 0.33
|
0.00 (0.00–2.00)
|
<.001
|
|
Scar
|
42
|
.83 ± 1.10
|
0.50 (0.00–4.00)
|
|
Cesarean**
|
|
Control
|
44
|
.52 ± 0.76
|
0.00 (0.00–2.00)
|
<.001
|
|
Scar
|
42
|
2.02 ± 0.68
|
2.00 (1.00–3.00)
|
|
D&C**
|
|
Control
|
44
|
.30 ± 0.51
|
0.00 (0.00–2.00)
|
.013
|
|
Scar
|
42
|
.76 ± 0.96
|
0.50 (0.00–4.00)
|
|
Gestational age**
|
|
Control
|
44
|
7.50 ± 1.17
|
8.00 (5.00–10.00)
|
.021
|
|
Scar
|
42
|
6.86 ± 1.69
|
7.00 (4.00–11.00)
|
Abbreviation: D&C, dilatation curettage.
* Independent t-test; **Mann–Whitney U test.
Table 2
Blood parameters of study and control groups
|
Parameters
|
n
|
Mean ± SD
|
Median (Min–Max)
|
p-Value
|
|
Platelet*
|
|
Control
|
44
|
273.36 ± 56.21
|
269.00 (156.00–459.00)
|
0.734
|
|
Scar
|
42
|
277.76 ± 63.40
|
273.50 (154.00–388.00)
|
|
Neutrophil*
|
|
Control
|
44
|
6.36 ± 1.83
|
6.50 (3.50–10.88)
|
0.183
|
|
Scar
|
42
|
6.93 ± 2.15
|
6.75 (2.89–12.91)
|
|
Lymphocyte**
|
|
Control
|
44
|
2.12 ± 0.66
|
2.15 (1.25–4.06)
|
0.622
|
|
Scar
|
42
|
2.05 ± 0.69
|
2.08 (0.49–3.74)
|
|
Monocyte**
|
|
Control
|
44
|
.48 ± 0.17
|
0.41 (0.28–1.06)
|
0.039
|
|
Scar
|
42
|
.55 ± 0.24
|
0.51 (0.28–1.80)
|
|
Hemoglobin**
|
|
Control
|
44
|
12.83 ± 1.25
|
12.80 (9.20–15.20)
|
0.836
|
|
Scar
|
42
|
12.67 ± 1.50
|
12.80 (8.20–15.90)
|
|
Neutrophil/lymphocyte**
|
|
Control
|
44
|
3.20 ± 1.20
|
2.78 (1.59–6.03)
|
0.207
|
|
Scar
|
42
|
4.02 ± 2.71
|
3.25 (1.15–14.04)
|
|
Platelet/lymphocyte**
|
|
Control
|
44
|
131.88 ± 37.56
|
128.70 (20.69–206.92)
|
0.342
|
|
Scar
|
42
|
153.41 ± 71.21
|
139.44 (64.29–422.22)
|
|
Monocyte/lymphocyte**
|
|
Control
|
44
|
.24 ± 0.10
|
.21 (0.13 - 0.60)
|
0.035
|
|
Scar
|
42
|
.35 ± 0.50
|
.26 (0.11–3.33)
|
|
Neutrophil x platelet/lymphocyte**
|
|
Control
|
44
|
834.46 ± 341.96
|
752.65 (161.40–1643.77)
|
0.099
|
|
Scar
|
42
|
1093.37 ± 649.09
|
898.78 (185.79–2921.61)
|
* Independent t-test; **Mann–Whitney U test.
To examine the parameters that predict scar condition, a logistic regression analysis
was performed. The gestational week was added as a covariate variable to the first
step, and monocyte and mono/lymph parameters, which showed significant differences
between groups, were added to the second and final steps. As shown in [Table 3], while the gestational week covariantly predicted scar status significantly (p = 0.03), the monocyte and mono/lymph parameters did not significantly predict the
scar status (p > 0.05).
Table 3
Parameters predicting scar condition
|
B
|
SE
|
Wald
|
Exp (B)
|
p-Value
|
%95 CI
|
|
Lower
|
Upper
|
|
Gestational age
|
−0.335
|
0.162
|
4.261
|
0.716
|
0.039
|
0.521
|
0.983
|
|
Monocyte
|
1.398
|
1.676
|
0.696
|
4.045
|
0.404
|
0.152
|
107.952
|
|
Monocyte/lymphocyte
|
2.197
|
2.483
|
0.783
|
8.995
|
0.376
|
0.069
|
1.167.291
|
ROC analysis was used to calculate the diagnostic value by calculating the AUC (area
under the ROC curve). AUC = 0.629 (SE = 0.061) for the M value. The optimal M value
cut-off value was found to be > 0.40, the sensitivity value was 78.57, and the specificity
value was 50.00. AUC = 0.632 (SE = 0.061) for the MLR value. The optimal MLR cut-off
value was found to be > 0.232, the sensitivity value was 61.90, and the specificity
value was 63.64. ROC curves of M and MLR values are shown in [Fig. 1] and [Fig. 2], respectively.
Fig. 1 Receiver operating characteristic curves monocyte for the diagnosis of scar pregnancy.
Fig. 2 Receiver operating characteristic curves monocyte to lymphocyte ratio (MLR) for the
diagnosis of scar pregnancy.
Discussion
The purpose of this study was to compare the inflammatory parameters of patients with
scar pregnancy to those with normal pregnancy using blood inflammation markers, which
have predictive value in many obstetric conditions and gynecological cancers. Although
the N, P, and SII rates in scar pregnancies were high, they were not statistically
significant. M and MLR were found to be significantly higher. When the gestational
age was taken into account, it was discovered that these parameters had no predictive
value. This demonstrated that while ultrasonography remains the gold standard in the
diagnosis of CSP, blood parameters that are quick, inexpensive, and available everywhere
do not aid in the diagnosis.
The use of Doppler with abdominal and vaginal ultrasonography (USG) is still the gold
standard for CSP diagnosis. Typical scar pregnancy findings may not always be seen
on USG, which may lead to misdiagnosis or delay in diagnosis in CSP, which is the
precursor of placental invasion anomalies (PAS). The diagnosis of scar pregnancies
is easier between the 5th and 7th gestational weeks than between the 11 and 14th gestational
weeks.[10] In one examination of the CSP case series, the mean gestational age at diagnosis
was 7.5 ± 2.5 weeks.[11] The diagnosis may be missed in the following weeks of pregnancy because the gestational
sac and fetus will grow toward the upper fundus. In this case, close attention should
be paid to the placental tissue that remains in the incision line and the vascularization
that surrounds it. Differentiating CSP from unavoidable miscarriages and cervical
pregnancies is not always simple. Delays in diagnosis can result in uterine rupture
and bleeding, which can result in serious maternal morbidity and mortality.[11]
[12] In a series of 751 CSP cases, 107 (13.6%) underwent hysterectomy because they could
not be misdiagnosed or diagnosed, and as a result, these patients lost their fertility.[13] Another study found that 17 (15.4%) of 111 CSP cases were misdiagnosed as an incomplete
abortion or cervical pregnancy.[11] Cali et al reported that the lower segment located sac image, which they detected
in the first 11 weeks and is the most important finding of CSP in the first trimester,
is also a very important finding for PAS in the subsequent weeks.[10] A few CSP cases were followed up on as expectant, and their hysterectomy rates ranged
from 50 to 100%, even though PAS was found in almost all of them.[14] This situation necessitates that the physicians involved gain more experience in
the diagnosis of CSP.
Recent research on obstetric and gynecological cancers has demonstrated that inflammatory
indices obtained in peripheral blood using L, N, M, and P parameters can be an indicator
of local and systemic inflammatory response. When these parameters were examined in
preeclampsia patients, it was discovered that they could be used to monitor the disease's
severity and prognosis. It has been demonstrated that M is elevated in preeclampsia
cases and is a good indicator of chronic inflammation, and MLR is a prognostic factor
reflecting poor outcomes and body condition.[15] Syncytiotrophoblast microparticles released by the placenta effectively activate
neutrophils and stimulate neutrophil formation. It is well known that neutrophils
serve as a vital link between syncytiotrophoblasts and vascular endothelial cells
and that an increase in N in preeclampsia patients triggers a systemic inflammatory
response.[16]
[17] In third-trimester studies of PAS cases with the same pathophysiology as CSP, NLR
was significantly higher than in normal pregnant women, N and PLR ratios were higher,
and L ratios were the same.[18]
[19]
[20] In the study conducted by Eskicioglu et al, which compared ectopic and normal pregnancies,
N and M values were found to be high, but only M values were found to be statistically
significant. PDW (platelet distribution width) is assumed to be low in ectopic pregnancies,
M ratios are high, and monocytes may play a role in the pathophysiology of tubal ectopic
pregnancies.[21] This result is consistent with the results we found in scar pregnancies, which are
considered ectopic pregnancies. Kan et al discovered that NLR and PLR levels were
significantly higher in ruptured ectopic pregnancies.[9] In our case series, although L ratios were low and N and P were high, they were
not statistically significant. Even though M and MLR values were significantly higher,
they were insufficient to establish a cut-off. Perhaps the fact that we did not perform
an early D&C due to the risk of complicating pregnancies influenced these results.
According to studies, the L ratio is low, and the PLR and NLR are significantly higher
in pregnant women with hyperemesis compared with the control group, and these markers
can help in the diagnosis.[22]
The limitations of our study include the early detection of scar pregnancies, the
early termination of pregnancy, the failure to analyze detailed inflammatory cytokine
responses, and the fact that it is retrospective. To examine detailed cytokine response,
we believe that laboratory studies and large patient populations are required.
Conclusion
As a result, while systemic inflammatory markers may aid in the diagnosis, they are
not predictive. Ultrasonography is an indispensable diagnostic method in the diagnosis
of CSP. To avoid fatal complications, public awareness should be raised.
