Abstract
Introduction
The aim of this study was to assess the potential role of complete blood count (CBC) inflammatory parameters in the diagnosis and management of missed abortions during early pregnancy through the analysis of their values.
Methods
The case group for our study comprised 500 instances of missed abortions at Fujian Provincial Maternal and Child Health Hospital from May 2023 to May 2024, whereas the control group consisted of 500 healthy women who did not experience delivery-related complications during this timeframe. We utilized SPSS version 25 software to conduct a retrospective analysis of factors, including age, BMI, gravidity, parity, neutrophil count, lymphocyte count, platelet count, mean platelet volume, platelet distribution width, and prothrombin time.
Results
The age and gravidity of patients in the missed abortion group were higher than those in the normal pregnancy group, with a statistically significant difference. There were no significant differences in the platelet count, mean platelet volume, platelet distribution width, neutrophil count, or prothrombin time between the two groups. But the lymphocyte count was significantly lower in the missed abortion pregnancies. The area under the ROC curve for the lymphocyte count was 0.654, indicating its diagnostic value.
Conclusion
Although the lymphocyte count can offer some predictive value in detecting missed abortion, its diagnostic accuracy is limited. Other inflammatory parameters don’t yield any predictive information regarding miscarriage retention.
Keywords
Introduction
Missed abortion, also known as delayed miscarriage, occurs when the embryo or fetus has died and remains in the uterus without being expelled naturally. It constitutes approximately 15–20% of clinically diagnosed pregnancies.1,2 Symptoms may include the disappearance of early pregnancy signs, signs of impending miscarriage, or no symptoms at all, along with a decrease in uterine size. 3 Missed abortion is a unique type of natural miscarriage with common causes, 4 including chromosomal abnormalities, anatomical issues, hormonal imbalances, infections, and autoimmune factors, among others. 5
Early-stage missed abortion can be challenging to identify because of the lack of clear symptoms, which can delay necessary treatments. Inadequate medical responses often result in the need for surgical interventions to address miscarriages, which carry risks such as intrauterine adhesions that can greatly affect a patient's fertility and even put the mother's life at risk. The causes of abortion are frequently unidentified, but there have been links between abortion and chromosomal abnormalities, ethnic background, extremely low or high body mass index (BMI), chronic medication usage, smoking and alcohol consumption, and infections.6,7 In particular, 15% of early abortions and 66% of late abortions have been linked to infection and systemic inflammation. 8
Complete blood count (CBC) parameters are considered quick and simple indicators of systemic inflammation and stress. Neutrophils and platelets are activators of inflammation, while lymphocytes are regulators. Mean platelet volume (MPV) and platelet distribution width (PDW) are markers of platelet activation 9 and have been linked to inflammatory conditions like rheumatoid arthritis, 10 cardiac conditions, 11 vertebral discopathies, 12 and malignancy. 13
Nevertheless, there has been minimal research conducted on these basic and regular blood tests and missed miscarriages. This research aimed to explore the predictive value of CBC inflammatory parameters in early pregnancy for missed abortion, with the goal of improving proactive management in the initial stages of pregnancy.
Methods
Subjects
This retrospective comparative study was conducted at Fujian Maternity and Child Health Hospital, five hundred patients who were diagnosed with “missed abortion” during early pregnancy from May 2023 to May 2024 were randomly selected as the case group, and simultaneously randomly select 500 patients who had a normal delivery without complications or adverse events during the same period at the hospital as the control group. Our study adhered to the guideline of STROBE. During the research process, we strictly define the inclusion and exclusion criteria of the research subjects to ensure the representativeness and comparability of the samples. We provide training to the data collection staff and use standardized, objective data collection forms for statistics. Special personnel are assigned to supervise the data collection and analysis process, review the research results to reduce selection bias in the data. This study was conducted in accordance with the 1975 Helsinki Declaration, as revised in 2013.
The inclusion criteria for this study included individuals over 18 years of age with a gestational age of 13 weeks and 6 days or less who were undergoing a singleton pregnancy. The relevant data for comparison were collected around the tenth week of gestation for the control group. The exclusion criteria for individuals were diabetes, hypertension, heart disease, thyroid disorders, kidney disease, a history of thrombosis, lupus, multiple pregnancies, anemia, infections, tumors, inflammatory diseases, or those taking oral anti-inflammatory and steroid medications during early pregnancy, known to cause fetal malformations or uterine abnormalities, were excluded. The control group also excluded patients with pregnancy-induced hypertension, gestational diabetes, and other internal and external complications.14,15 The study was approved by the ethics committee of Fujian Maternity and Child Health Hospital and all experiments were performed in accordance with relevant guidelines and regulations, verbal informed consent was obtained from all participants through telephone follow-up.
Sample collection
Gather two groups of related data and hematological parameters, including height, weight, age, parity, number of deliveries, neutrophil count, lymphocyte count, platelet count, MPV, PDW, and prothrombin time (PT).
Statistical analysis
Data analysis was performed using SPSS 25.0 software. Levene's test was used to examine the equality of variances, chi-square test was employed for comparing categorical variables between groups, and independent t-tests were conducted for comparing continuous variables between groups. Continuous variables were described using mean ± standard deviation (SD) or median (minimum: maximum) values. A p-value <0.05 was considered statistically significant for differences.
Results
A comparison was made between 500 patients with missed abortion and 500 women with normal pregnancy and delivery. There was no statistically significant difference in BMI and parity between the two groups (p > 0.05) (Table 1). However, the patients with missed abortion were older and had higher parity compared to the normal pregnancy group, with statistically significant differences between the two groups (p < 0.05) (Table 1).
Demographic parameters of the groups.
The patients with missed abortion had higher platelet count and prolonged PT compared to the normal pregnancy group. MPV, PDW and neutrophil count were lower in the missed abortion group compared to the normal pregnancy group, but these differences were not statistically significant (p > 0.05) (Table 2). The lymphocyte count was lower in the missed abortion group compared to the normal pregnancy group, with a statistically significant difference (p < 0.05).
Complete blood count inflammatory parameters of the groups.
To further assess the diagnostic value of lymphocyte count in missed miscarriage, a ROC curve was constructed. The area under the curve (AUC) for lymphocyte count was determined to be 0.654 (95% CI: 0.620–0.688), and the specificity and sensitivity was 48.2% and 70.4%, respectively (Figure 1), suggests that lymphocyte count has predictive value for missed miscarriage, although the diagnostic efficacy is modest (0.5 < AUC<0.7).
ROC curve analysis for lymphocyte count in predicting missed abortion. The AUC for lymphocyte count was determined to be 0.654 (95% CI: 0.620–0.688), and the specificity and sensitivity was 0.482 and 0.704, respectively.
Discussion
Missed abortion is a common issue among women of reproductive age, with 8–20% of early pregnancies resulting in this complication. 2 The outcome of missed miscarriage and the complications of curettage surgery can bring immense physical pain to patients, even leading to various negative psychological reactions such as anxiety and depression. 16 Therefore, predicting the occurrence of the disease early and providing appropriate intervention measures is currently a hot topic in the industry.
Our research suggests that age and parity are correlated with missed abortion, with the age of the missed abortion group being significantly higher than the normal pregnancy group. Moghadam et al. pointed out that as age increases, not only does ovarian reserve decrease, but also follicle quality decreases, particularly in the form of an increased rate of chromosomal aneuploidy in follicles. Therefore, chromosomal abnormalities in trophoblasts may be a major cause of missed abortion. 17 Xue H et al. also indicated that advanced maternal age may lead to oocyte degeneration, increased rates of chromosomal abnormalities, and consequently an increased risk of fetal death. These are all potential reasons for the correlation between age and missed abortion.18,19 These factors could serve as potential explanations for the association between age and abortion retention. The number of pregnancies in the missed abortion group is higher than the normal pregnancy group, possibly due to the fact that patients with missed abortion who have a desire for fertility often experience recurrent miscarriages, even unexplained recurrent miscarriages, and therefore these patients may need to have multiple pregnancies to achieve a live birth.
Inflammation plays a crucial role in the placental dysfunction and pregnancy complications at the maternal-fetal interface, essential for the successful pregnancy and childbirth in women. 20 Throughout pregnancy, the maternal immune system shows different levels of inflammation. 21 Moderate inflammation in the early stages of pregnancy is beneficial for embryo implantation. Subsequently, a local shedding membrane needs to establish an anti-inflammatory and immune-tolerant microenvironment to ensure the survival and growth of the embryo. Excessive inflammatory responses are associated with miscarriage or other pregnancy complications such as preeclampsia or preterm birth.
Due to being the most cost-effective and widely used test, full blood cell count serves as a common marker for systemic inflammation, patients would greatly appreciate if meaningful predictive information could be extracted from CBC analysis. There is growing interest among scholars worldwide in investigating the correlation between complete blood cell count inflammatory parameters and missed abortion. Studies were observed between these CBC indices and miscarriage, and with recurrent pregnancy loss, suggesting their utility as markers for risk assessment of spontaneous miscarriage. Ismail Biyik et al. conducted a statistical comparison of the complete blood cell parameters of 40 cases of retained pregnancy and 40 cases of normal term deliveries. The results revealed that the PDW, neutrophil‒lymphocyte ratio (NLR), and platelet‒lymphocyte ratio (PLR) values of the retained pregnancy group were significantly different from those of the normal pregnancy group, whereas the MPV value was not significantly different. 22 On the other hand, Dan Liu et al. statistically compared the complete blood cell parameters of 200 cases of retained pregnancy and 200 cases of normal term deliveries. The results revealed no significant differences in white blood cells, red blood cells, platelets, red cell distribution width-standard deviation, PDW, neutrophil count, lymphocyte count, NLR, or PLR between the two groups. Nevertheless, there was a statistically significant difference in MPV between the missed abortion group and the control group, with the former showing a lower value. 23 The contrasting conclusions of the two researchers indicate a clear difference. Owing to the limited sample sizes of both studies and the embryos of the control group were alive at the time of termination of pregnancy, but the subsequent pregnancy was unknown, which may cause bias in the data, the statistical results and credibility are limited. Therefore, our research aims to increase the statistical sample size and tightly screened control group to achieve more dependable outcomes. We included 500 missed abortion patients and 500 normal pregnancy delivery patients and analyzed their complete blood cell inflammatory parameters. The results revealed that there was no statistically significant difference in the MPV, PDW, PT, platelet count, or neutrophil count between the two groups, whereas the lymphocyte count was significantly different. The three research findings showed both similarities and differences. By constructing the ROC curve, this study revealed that the AUC for the lymphocyte count was 0.654, suggesting that its predictive value is limited. Lymphocytes are crucial cells in the body's immune response function, being a type of cell line with immune recognition capabilities, may play an essential role in the pathophysiology of pregnancy loss. Studies were reported that increased lymphocyte count in missed abortion may be the reflection of an increased maternal systemic response due to placentation disorder and trophoblast injury in the early stages of pregnancy.24,25 We think that our study may be another clue that increased inflammatory responses are operative in missed abortion. The results of this study align closely with those of Humadi EH et al. 26 and in contrast to some other findings. 27 The variability in findings may reflect a possible inflammatory response. That is why the current study preferred the use of markers like NLR. This is also a task we will expand on in the future. Detailed and elaborative studies are needed to speculate that this inflammatory response may be an indirect sign of defective placentation in missed abortion.
On the other hand, missed abortion can be attributed to a variety of factors, such as chromosomal abnormalities, endocrine imbalances, infections, immune system issues, environmental influences, abnormal placental implantation, irregular development of villous blood vessels, environmental factors, and male-related factors. Studies have shown that patients with missed miscarriage generally exhibit deficiencies and insufficiencies in luteal function, as well as immune function abnormalities and cervical (or uterine) infections. 28 Some studies have shown that elevated levels of Hcy (a byproduct of methionine metabolism) and exposure to heavy metals can both result in cytotoxicity and embryotoxicity, inhibiting embryo development and causing embryo arrest, ultimately contributing to the occurrence of missed miscarriages.29,30 Zeng et al.'s most recent study has also revealed that ferroptosis involving multiple genes is related to the occurrence of early missed abortion. 31 In addition, about 50% of the reasons for missed miscarriage are still unknown.28,32 Therefore, this study did not include other factors for multivariate analysis, and predicting missed abortion solely through blood parameters is insufficient. Factors such as chromosomes, immunity, infections, and environmental factors should also be considered. Although this study had the largest sample size compared to other relevant studies, sample size analysis was not conducted. Considering the high incidence of missed abortion, it could also be possible that the lymphocyte count values may reflect a common mechanism for a subgroup of women with a miscarriage potentially with an immunologic component. We cannot exclude, however, that due to the small sample size this observation may be due to a random effect, despite the significance of the statistical tests. Future work could involve increasing sample size through more scientific methods or power analysis to enhance the validity of results. Additionally, this study had a retrospective design and utilized data from a single center, limiting the ability to calculate population-based rates. Finally, the systemic immune and inflammatory response involves not only CBC parameters such as lymphocytes and neutrophils count, previous studies have shown that serum inflammatory cytokines interleukin 2 (IL-2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) also increase in patients with missed abortion,33,34 suggesting that missed abortion is a process involving multiple factors. Given the complex etiology of missed abortion, further research is needed to explore the correlation between various hematological parameters and missed abortion.
Conclusion
Our research revealed that the platelet count, MPV, PDW, neutrophil count, and prothrombin time did not offer strong prognostic value in cases of missed abortion. However, the lymphocyte count has some significance, although its predictive capacity is limited. Due to the intricacies involved in the development of missed miscarriage, it is necessary to conduct more large-scale, multicenter, and systematic prospective studies with standardized methodologies. Furthermore, a deeper investigation into the pathogenesis of missed miscarriage could involve studying such as ferroptosis and relevant genes in more detail in the future.
Footnotes
Abbreviations
Author contributions
Lingna Huang wrote the main manuscript text. Xiumei Xiong contributed to study concept and design. Lingna, Jiaran Wang, Lebin Yan, and Jingjing Wang collected the data. Jiaran Wang, Lebin Yan, and Jingjing performed the statistical analysis. All authors reviewed the manuscript.
Availability of data and materials
The dataset used and analyzed during the current study is provided within the supplementary information files.
Consent for publication
Verbal informed consent for publication was obtained from all participants through telephone follow-up.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Fujian Provincial Natural Science Foundation of China (2022J011038).
Ethics approval and consent to participate
This retrospective comparative study was conducted at Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University. The study was approved by the ethics committee of Fujian Maternity and Child Health Hospital, the approval number is: 2022KYLLRD01036.
