Soluble FMS-Like Tyrosine Kinase-1: Role in placenta accreta spectrum disorder

Introduction

Placenta accreta is a serious pregnancy condition that can develop when all or part of the placenta adheres to the uterine wall.¹ As the cesarean delivery rate increases, it has been noted that placenta accreta cases are on the rise.^2,3 In 2019,at the Haji Adam Malik general hospital, Indonesia, the incidence of this complication had a sharp increase , which resulted in the increased costs of patient care. In 2016 at Adam Malik General Hospital, Medan, Indonesia, placenta accreta mortality rate was very high, as were its complications, such as bleeding, hysterectomy, and pelvic organ injuries.^2,4-9 Until recently, the diagnosis of placenta accreta spectrum depended on ultrasonography. However, the American College of Obstetricians and Gynecologists (ACOG) and the International Federation of Gynecology and Obstetrics (FIGO) have issued a new terminology for this condition called placenta accreta spectrum, and they have divided the degree of this spectrum according to the ultrasonography, and the depth of invasion at the time of surgery.^10-13 Diagnosis by ultrasonography has many weaknesses as this examination requires expertise and a good standard of ultrasonography equipment. As Indonesia is an archipelagic country, the distribution of doctors with proficient ultrasound expertise in all regions, especially in remote areas, is uneven. In several previous studies, it was reported that several biomarkers can be associated with the placenta accreta spectrum, namely soluble fms-like tyrosine kinase-1 (sFlt-1). As a protein, sFlt-1 is produced by the placenta and it has anti-angiogenetic properties.¹⁴ sFlt-1 plays a role in regulating the depth of invasion of the placenta. Previous studies have reported that there was a decrease in sFlt-1 levels in the placenta accreta spectrum.¹⁵ Therefore, we aim to investigate the use of sFlt-1 as a diagnostic biomarker for placenta accreta spectrum in the Indonesian population, as an effective replacement for the ultrasound examination.

Methods

Result

Discussion

Placenta accreta is a life-threatening condition with an increasing incidence. History of cesarean section is a major risk factor for the placenta accreta spectrum. Diagnosis of this complication is currently by ultrasonography, with several recent studies reporting satisfactory results produced with this mode of diagnosis.¹⁸ However, in remote areas where there is a lack of ultrasound equipment and experienced operators, the use of biomarkers can be a solution to this challenge. Recently, studies have reported several proangiogenic and antiangiogenic markers associated with the incidence of placenta accreta spectrum.¹⁹ In this condition, there is an imbalance between proangiogenic and antiangiogenic factors, where proangiogenic factors are more dominant and have a significant increase in line with the depth of placental invasion of the uterus.¹⁵ The antiangiogenic factor that acts as a regulator is decreased so that the invasion of the placenta is uncontrolled. There are some studies that have established sFlt-1 as proangiogenic and antiangiogenic factors.¹⁵ In previous years, sFlt-1 was widely used as a predictor in cases of placenta-related disorders such as preeclampsia.²⁰ This is because in preeclampsia, implantation that occurs is usually superficial due to failure of the transformation of the spiral arteries, therefore there is usually an increase in sFlt-1 levels and decrease in placental growth factor (PLGF) level. sFlt-1 and PLGF as markers were chosen because they are specific to the placenta, although PLGF is also produced by other organs.²¹ In our study, comparison of the case group with the control group showed no significant difference in the patient characteristics, except for the history of the number of cesarean sections, the duration of the curettage and the length of the previous cesarean section (Table 1). We also found a decrease in sFlt-1 levels in the placenta accreta spectrum group compared to the control group. Increase in the degree of the spectrum was followed by a decrease in the sFlt-1 level (Table 2), as well as the FIGO score (Table 3). Based on Figure 1, we can see an increase in sFlt-1 levels in response to normal pregnancy. Serum sFlt-1 levels increased with increasing gestational age, but SFlt-1 levels in the PAS group tended to be lower than in the control group. Our results additionally showed a weak correlation between sFlt-1 with the accreta spectrum degree and FIGO score. This study is the first study to link sFlt-1 with the degree of placenta accreta spectrum based on ultrasonography and FIGO score. The concentration of sFlt-1 changes throughout the pregnancy, starting with a decrease at 8-12 weeks to 16-20 weeks, with a gradual increase at 26-30 weeks, and a rapid increase at 35-39 weeks. Hirashima et al. reported that the sFlt-1 concentration at 35-39 weeks of gestation was 2000 pg/ml.²² In this study we found lower levels of sFlt-1 (1246 pg/ml) in the control group, and even lower values were observed in the placenta accreta spectrum group (PAS 0, 1711; PAS 1, 1474; PAS 2, 1417).²² These results supports our hypothesis that sFlt-1 is decreased in the placenta accreta spectrum and therefore, it can not regulate placental invasion of the endometrium. Similarly, McMahon et al. had also reported that the lower expression of sFlt-1 in the placenta was associated with placental invasion.²³ Additionally, sFlt-1 may play a role in the regulation of cytotropoblast invasion, so that lower sFlt-1 concentration is likely to lead to deeper placental invasion (acreta/increta/percreta). Shainker et al. It has been reported that sFlt-1 expression is reduced in the placental invasion, and non-deep invasion areas of placenta accreta spectrum cases when compared with normal placentas (p = 0.003 and p = 0.001 respectively). Whereas in the placenta from the accreta spectrum cases, the invasive placenta did not show a significant difference in sFlt-1 expression.²⁴ Ostaz et al. reported that there was a decrease in oxidative stress in placenta accreta, and an invasion of the raised placenta and a high oxidative stress in preeclamsia. However, on the placenta accreta spectrum, there was a decrease in the level of oxidative stress, which is probably related to a decrease in the concentration of antio-angiogenic factor, sFlt-1.²⁵ Su et al., reported that aspirin which is usually used as a preeclamptic prophylaxis, has a suppressive effect on sFlt-1.²⁶ Therefore from these findings it can be suggested that suppression of sFlt-1 will increase placental invasion and stimulate placental angiogenesis. Although, whether giving aspirin in normal pregnancy will increase the risk of placenta accreta spectrum incidence has not yet been studied. It can be beneficial to further investigate the effects of aspirin, in order to recognise whether sFlt-1 is a single factor that plays a role in the occurrence of placenta accreta spectrum, or there are other factors involved in placental invasion, such as a history of cesarean section or curettage, which can cause damage to the nitrabuzh layer of the endometrium. This study has several limitations, such as the small sample size . Additionally, we only measured the sFlt-1 levels in the third trimester before the cesarean section was performed. Therefore, we can not report on the effects of sFlt-1 in placenta accreta in the first and second trimesters. Furthermore, we can not rule out the possibility of bias in the assessment of FIGO scores.

Figure 1. sFlt-1 level by gestational age between placentra acrreta spectrum (PAS) and control group.

Conclusions

sFlt-1 was found to be decreased in the placenta accreta spectrum, however this result requires further analysis as this correlation was not very strong. Further studies are needed to assess whether sFlt-1 can be used as a biomarker to replace ultrasonography in the diagnosis of the placenta accreta spectrum.

Data availability

Consent statement

Written informed consent for publication of the patients’ details was obtained from the patients/a guardian of the patient.

Author contributions

Sarma N Lumbanraha, role: conceptualization, funding acquisition, resources, supervision, visualization; M Rizki Yaznil, role: investigation, methodology, supervision, visualization; Andre M Siahaan, role: investigation, methodology, supervision, writing – original draft preparation; Berry E P Bancin, role: formal analysis, resources, writing – review and editing.

Acknowledgements

We would like to thanks the research institute of the University of North Sumatra for funding this research through the TALENTA 2020 program.