With the increasing rate of cesarean delivery, there is a growing concern about many clinical problems, such as uterine rupture, placenta praevia, placental implantation, cesarean scar pregnancy (CSP), infertility, and intra-abdominal visceral adhesions after cesarean delivery. CSP is a special type of ectopic pregnancy because the gestational sac is implanted in the uterine scar or diverticulum of the previous cesarean delivery. CSP has become a “new disease” that has received unprecedented attention, and the number of relevant academic articles published in China and abroad continues to increase. The type of articles has also changed from early case reports to more recent series of studies with increasing numbers of cases. In the historical context of high Cesarean section rate in China, the morbidity of CSP may be particularly serious, therefore, it is more urgent for scholars to continue to study and summarize in depth, and to develop a professional standard that meets the characteristics of China, in order to improve the level of diagnosis and treatment of CSP and the quality of perinatal health care work. The focus of this article is not on placental implantation in the second half of pregnancy, but on the problems related to CSP and placental implantation in early and middle pregnancy, in order to enhance clinical workers’ understanding of this serious obstetric comorbidity. It is important to understand this serious obstetric comorbidity so that it can be recognized and managed appropriately in the clinical setting as early as possible.
I. CSP is an early lesion of placental implantation
The number of abnormal placental implantation (adherent placenta, implanted placenta, penetrating placenta) has increased significantly with the increase in the number of women of childbearing age with a history of cesarean delivery. In this paper, we use the term “placental implantation” to represent the three types of abnormal placental implantation mentioned above. Data from the United States show that placental implantation was rare in 1930-1950, with an incidence of 1 in 30,000 births; in 1950-1960, the incidence was 1 in 19,000 births; in the 1980s, it rose to 1 in 7,000 births; and in 1994-2002, the incidence rose to 1 in 7,000 births. -2002, the incidence rose to 1/2,500-1/2,000 births; after 2010, it was estimated to reach 1/333 births [1-3]. It has been suggested that the increased incidence of CSP is closely related to the increased rate of cesarean delivery.
In addition, for CSP and placental implantation, which are both distant complications of cesarean delivery, the incidence of both is increasing with the increase in the cesarean delivery rate, so a close association between placental implantation and CSP is also presumed [4]. Placental implantation and CSP have a common pathological basis. Both are trophoblastic cells that implant in the uterine scar and invade the myometrium. The risk of placental implantation is significantly higher in patients with multiple cesarean deliveries. High-resolution ultrasonography shows the presence of chorionic trophoblasts deep in the diverticulum of the uterine scar at a very early stage of CSP. The placental villi cross the meconium of the Nitabuch layer and enter the uterine scar. It has also been shown that the placenta is attached to the uterine scar and the local hypoxic stress environment stimulates further invasion of the cytotrophoblast deeper into the myometrium. Trophoblasts have a higher affinity for the extracellular matrix than endometrial cells, a phenomenon that could explain why macrophages tend to prefer exposed scar tissue covered with no cellular components [5]. The formation of uterine scar diverticula after cesarean section should have a predisposing effect on the development of CSP. This explanation is clinically consistent with the fact that the location of placental implantation mostly occurs in the uterine scar after surgery; the higher the number of cesarean deliveries, the greater the chance of CSP and placental implantation. Of course, there are other aspects to the development of placental implantation, but the common feature is the increased ability of trophoblast cells to invade the surface of the uterine cavity where the mela is absent; curettage, cesarean section, manual removal of the placenta, uterine cavity infection and history of uterine surgery may lead to local mela loss and induce abnormal placental implantation.
Timor-Tritsch et al [5] reported the pregnancy outcome of 10 patients diagnosed with CSP in early pregnancy, resulting in the eventual hysterectomy of all 10 patients, all of whom had pathologically confirmed penetrating placental implantation and shared common pathological features with CSP. The authors used the term “early placental implantation” to describe this condition secondary to CSP, distinguishing it from placental implantation that is usually found in late pregnancy. Further, it has been suggested that CSP is the precursor lesion to placental implantation, which ultimately leads to placental implantation [6]. There is a continuum of disease from CSP to placental implantation; usually, the former is limited to early pregnancy, while the latter is directed to middle and late pregnancy. The pathological mechanisms are the same in both, despite the differences in clinical presentation. However, to date, there is no clear definition of the two worldwide, and there is a lack of uniform criteria in clinical use and publication of articles.
II. Clinical characteristics of early placental implantation secondary to CSP
Early placental implantation secondary to CSP results in two serious consequences, namely spontaneous uterine rupture and hemorrhage due to placental implantation into the uterine incision of cesarean delivery.
More importantly, unlike normal placental implantation, this type of early placental implantation secondary to CSP is symptomatic in early and early mid-trimester and even leads to life-threatening clinical consequences. In one case, the hysterectomy was performed at 20 weeks of gestation due to sudden massive vaginal bleeding; the hysterectomy was performed in all patients, and in two cases, a balloon was placed in the internal iliac artery to assist in compression to stop the bleeding, but despite this, the bleeding was still massive.
Almost all bleeding originated from adhesions of the neovascularization to the intrapelvic organs. Hemorrhage occurring during placental abruption is more frequent, but spontaneous uterine rupture occurs in a few cases.
Timor-Tritsch and Monteagudo [4] summarized 47 cases reported in the literature in which placental implantation occurred during early and middle pregnancy, 15 of which had spontaneous uterine rupture with intra-abdominal bleeding requiring open exploration, uterine artery embolization, or even hysterectomy; the mean gestational week of uterine rupture was 18.1 weeks. It has been suggested that uterine rupture occurring in early pregnancy almost invariably arises from the invasion of trophoblast cells into the uterine scar [6]. It can be speculated that the already thin uterine scar myometrium is made weaker by continued invasion of trophoblast cells, which may be the main cause of spontaneous uterine rupture in late early or early midtrimester. Of course spontaneous rupture may also occur in a non-scarred uterus with placental implantation, but the risk of uterine rupture is higher with placental implantation in the scar.
The serious consequences of early placental implantation described above necessitate a change in the protocol for the diagnosis of obstetric complications. Early and reliable diagnosis of placental implantation, knowledge of the medical history, and the knowledge that most of the placenta is implanted in the location of the previous cesarean uterine scar, have led to an earlier focus on placental implantation in early or early midtrimester.
III. Diagnosis of early placental implantation secondary to CSP
Diagnosis of early placental implantation and CSP is difficult and may be misdiagnosed as lower uterine segment pregnancy, cervical pregnancy or miscarriage. However, it has been suggested that implantation of the gestational sac at the uterine scar may be the earliest clinical evidence of placental implantation that can be detected by ultrasound.
Timor-Tritsch et al [5] reported the diagnostic imaging criteria for early pregnancy (5 weeks + 4 to 9 weeks + 2) in 10 patients with early placental implantation secondary to CSP as.
(1) the uterine cavity was empty; (2) the placenta or gestational sac was located in or on the uterine incisional scar defect; (3) for gestational sacs <8 weeks of gestation, a triangle formed completely embedded in the diverticulum formed by the uterine scar, while it was round or oval at >8 weeks of gestation; (4) the muscular layer between the gestational sac and the bladder became thin (1-3 mm) or even disappeared; (5) the cervical canal was closed or empty; (6) the fetal bud and yolk sac, with or without fetal heart; (7) positive pregnancy test with abundant blood flow in or on the uterine scar. These 10 patients showed typical signs of placental implantation on ultrasonography in mid to late pregnancy.
Ballas et al [7] performed a retrospective analysis of early pregnancy ultrasound features in patients with pathologically diagnosed placental implantation in mid and late pregnancy and suggested the following high-risk features: placenta praevia, absence of echogenicity in the placental region, and abnormal myometrial boundaries, which are signs that should alert for placental implantation if present in early pregnancy; low gestational sac position is also often seen with it.Stirnemann et al [8] performed a prospective In a prospective study, the ultrasound characteristics of pregnant women with a history of cesarean delivery were analyzed from 11 to 14 weeks of gestation to determine whether they were at high risk for placental implantation based on the relationship between the uterine scar and the trophoblast, which was determined to be high risk if the uterine scar was exposed in the uterine cavity and located above the lowest point of the gestational sac, if the gestational sac occupied the superior portion of the cervical canal, and if there was a low lying placenta overlying it; if the uterine scar was protected and wrapped in the cervical canal and the trophoblast did not The ultrasound characteristics of placental implantation in patients with mid- to late-term pregnancy are: post-placental blood sinus (Doppler ultrasound showing an area of irregular vascular flow behind the placenta), absence of clear boundaries behind the placenta, thinning of the muscular layer covered by the placenta, interruption of the bladder boundary, protrusion of the placenta into the bladder, and Doppler showing abundant blood flow [9-10]. The incidence of placental implantation in high-risk patients under this criterion ranges from 9% to 44%. MRI can also assist in the detection of placental implantation, but the accuracy and sensitivity of these tests remain unknown [11-12]. A significant proportion of placental implantations are not detected until termination of pregnancy, and the diagnosis of placental implantation can be a clinical diagnosis during cesarean section or a pathological diagnosis after hysterectomy, more likely to be accompanied by serious complications [13-15].
IV. Does CSP in early pregnancy inevitably develop into placental implantation?
The natural course of CSP remains unclear as few of the patients diagnosed with CSP at an early stage are treated expectantly.Timor-Tritsch et al [5] provided histological evidence that CSP progresses to placental implantation in mid-trimester, thus suggesting that CSP is an early lesion of placental implantation. However, the outcomes of CSP reported in the literature are likely to be biased, as only cases with serious clinical consequences are reported, while other cases with a good prognosis are not represented.
According to Vial et al [16], there are two types of CSP, one in which the gestational sac is implanted in the uterine scar of the previous cesarean delivery but grows subsequently towards the cervical canal or the uterine cavity, which is often viable but may be at risk of haemorrhage, and the other, in which the gestational sac is implanted deep in the cesarean uterine scar defect and grows towards the bladder and abdomen, which is more prone to spontaneous uterine rupture. In other words, the depth and direction of development of the implanted placenta in the abnormal location are the main determinants of the course and outcome of CSP. However, some scholars believe that early CSP is indicative of abnormal trophoblast invasion and the future direction of disease development is difficult to predict. Some scholars proposed to distinguish CSP as “above the scar” and “within the diverticulum” [17-19]. However, Timor-Tritsch et al [5] suggested that the subsequent placenta in both cases will be implanted and anchored in the scar and invade into the myometrium and even penetrate the plasma layer of the uterus and the bladder, and as the gestational sac increases in size, it will expand into the uterine cavity, without any distinction between “above the scar” and “within the diverticulum”. “within the diverticulum”. The distinction between the two is not helpful for the subsequent management according to the natural course of CSP, which is an early lesion of placental implantation.
In addition, it has been suggested that trophoblastic cells covering the uterine scar are not the only high-risk factor for the development of placental implantation. data by Stirnemann et al [8] showed that 5.8% of pregnant women with a history of ≥1 cesarean delivery had ultrasound signs at 12 weeks of gestation consistent with the type of high risk for placental implantation. Miller et al [20] showed that in patients with a history of 1 cesarean delivery, placental The incidence of placental implantation was 3.7% in pregnant women <35 years of age compared with 9.1% in those ≥35 years of age; the incidence was 2% in pregnant women <35 years of age with no history of cesarean delivery and 38% in pregnant women ≥35 years of age with a history of two or more cesarean deliveries. It has also been suggested that a short time between the previous cesarean delivery and the current pregnancy is associated with an increased risk of CSP or placental implantation [20]; however, the findings of Timor-Tritsch et al [5] do not support this conclusion.
V. Management and prognosis of patients with CSP secondary to early placental implantation
In patients with symptomatic CSP, the appropriate clinical management is based on the most urgent clinical requirements of the patient. However, with the development of vaginal ultrasound technology, more asymptomatic or minimally symptomatic CSPs are being detected, and it is difficult to make a decision on the trade-off for patients with a request to keep the pregnancy after a review to confirm the diagnosis of CSP. Although there is no evidence that early termination is necessary, most patients and physicians prefer early termination of CSP based on concerns about the serious consequences of placental implantation. the probability of serious complications and hysterectomy is clearly lower when elective surgical or pharmacologic termination is performed in early pregnancy. Evidence from studies showing that most patients successfully treated for CSP are subsequently able to have another pregnancy with a low probability of recurrence of CSP supports the aggressive management of CSP during early pregnancy [21].
On the other hand, some pregnant women with CSP will persist in their pregnancy. In this regard, it is important to understand that the embryo or fetus with CSP is also exposed to a number of pathological conditions, the outcome of which can be embryonic arrest in early pregnancy, spontaneous resorption, stillbirth in midtrimester, spontaneous or medically induced preterm delivery [22-24]. In patients presenting with low amniotic fluid, slow fetal heart rate and early fetal growth restriction, a wait of 1 to 2 weeks may be recommended before deciding whether to continue the pregnancy. In patients with CSP in midtrimester, the questions of whether the fetus will survive, whether uterine rupture will occur, whether the uterus will be preserved during delivery, and what is the risk of CSP invading the bladder and surrounding organs cannot be answered precisely.
Some authors also believe that pregnant women with a history of cesarean delivery in early pregnancy should routinely undergo transvaginal ultrasound and if the gestational sac is found to be attached in the lower part of the anterior wall, it should be considered as CSP until the diagnosis of CSP is excluded by subsequent ultrasound follow-up [5]. Patients with a diagnosis of CSP may be faced with the choice of termination or continuation of the pregnancy. If the choice is to continue the pregnancy, the patient should be informed of these possible problems and risks in continuing the pregnancy: embryonic arrest or intrauterine death, preterm delivery, uterine rupture, life-threatening hemorrhage, permanent loss of fertility by removal of the uterus, damage to peripheral organs, and even death.
The specific management of CSP and early placental implantation includes drugs, surgery, interventions or a combination of methods, and there are dozens of them, and there is a lack of clinical studies comparing the results. The management of the placenta during surgical delivery in patients with placental implantation has been studied in the field of obstetrics, but is still inconclusive. However, the general principles are indisputable: ensure life safety, strive to preserve the uterus, reduce perinatal bleeding, avoid peripheral organ damage, and minimize the possible trauma of the disease and treatment.
In conclusion, neither the natural course nor the trend of CSP is well understood, and the available evidence on the prognosis of CSP is not yet sufficient to allow us to make definitive decision guidance to patients. However, at this stage, it is most important that obstetricians and gynecologists remain alert to CSP and early placental implantation during early pregnancy, recognize the diagnosis in a timely and accurate manner, screen patients at high risk for placental implantation, fully understand the patient’s condition and her fertility wishes, give rationalized advice, implement closer monitoring, and make the correct decision to deliver early or terminate the pregnancy to avoid or minimize the risk to maternal and child life from acute and critical illnesses. The aim is to avoid or minimize the threat to the life of the mother and the child.