**A.** Abnormal implantation

a. *Ectopic implantation* (ectopic pregnancy) occurs when the blastocyst implants in a site other than the uterine endometrium and is estimated at between 0.5 and 1.5% of all 1st trimester pregnancies in the United States [51, 52]. Ectopic implantation is most common in the fallopian tube (approximately 96% of ectopic pregnancies) [53], but it can occur in the uterine cornua, ovary, cervix, and even parasitically implanting into the intraabdominal organs and vessels [54–58]. Unlike the uterus, structures like the fallopian tube, cervix, cesarean scar, and ovary cannot accommodate a growing fetus, are prone to acute rupture, and the resulting hemorrhage can be life threatening. The current era in medicine, with diagnostic modalities such as ultrasound and Beta-HCG hormone blood and urine level testing, diagnosing ectopic pregnancy rapidly has led to decreased morbidity and mortality. In the United States, the mortality rate from ectopic pregnancy has decreased since the 1980s, with ectopic pregnancy comprising 3% of all cause pregnancy-related deaths in a 2017 study [59, 60]. Risk factors for ectopic pregnancy include history of sexually transmitted or other pelvic infection (such as chlamydia, gonorrhea, pelvic inflammatory disease and tubo-ovarian abscess), prior ectopic pregnancy, tubal surgery, tobacco smoking, pelvic adhesions (e.g., secondary to endometriosis, salpingitis, pelvic abscess, appendicitis), assisted reproductive technology, congenital fallopian tube abnormalities, diethylstilbestrol exposure, and Salpingitis isthmica

### *Placental Abnormalities DOI: http://dx.doi.org/10.5772/intechopen.81579*

nodosa [61–63]. Patient presentation and outcomes depend on the pregnancy location and range from pregnancy failure with reabsorption, to spontaneous abortion, to continued growth leading to surrounding structure rupture and hemorrhage. Management depends on a multitude of factors including the site of implantation, size of the gestational sac or fetus, beta-human chorionic gonadotropin (Beta-HCG) hormone level, and the patient's presenting signs and symptoms and range from expectant management, to intragestational or systemic methotrexate (MTX), to surgical intervention.

 b. *Placenta previa* is the term when placental implantation is either adjacent to or covering the internal cervical os. The prevalence varies per region, however, has been estimated between approximately 4 and 5.2 per 1000 pregnancies, with the incidence of marginal placenta previas decreasing as gestational age increases (see discussion below for further details) [64, 65]. Further distinction is made between complete coverage of the internal cervical os or *complete placenta previa* versus when the leading edge of the placenta is implanted within less than 2 cm from the internal cervical os or *marginal placenta previa*. The severity of complications varies widely based on the location of the placenta in relation to the cervical os, as well as the degree of placental separation. The location of the placenta over or at the margin of the internal cervical os leads to a predisposition for hemorrhage if cervical dilation occurs as any cervical dilation will expose placental blood vessels, leading to a range from concealed bleeding (i.e., no observed vaginal bleeding) to frank exsanguination. Complications during labor arise from both the placental separation and the structural blockage of fetal expulsion from the uterus by a complete previa. Depending on the placental implantation site, as the uterus grows throughout the gestation, marginal placenta previas, when followed by serial ultrasound examination have a documented tendency to become progressively distanced away from the internal cervical os. However, placenta previa remains at risk of interface separation and subsequent hemorrhage when contractions and/or cervical dilation occur at any time during the pregnancy. The etiopathogenesis of placenta previa remains elucidated, and the two current hypotheses are: 1. Lack of a suitable implantation site in the uterine fundus or corpus. Secondary to uterine trauma from previous surgery (e.g., cesarean deliveries, myomectomies, dilation & curettage) and/or multiple pregnancies, the sites of normal implantation develop areas of suboptimally vascularized uterine decidua, which predispose to implantation of the trophoblast in the lower uterine segments [64]. 2. Large placental surface area, secondary to conditions such as multiple gestations and *placenta membranacea*, increases the probability of the placenta implanting or extending over the internal cervical os. Known major risk factors include: 1. Previous placenta previa, which has a recurrence in 4–8% of future pregnancies [64, 66, 67]. 2. Previous Cesarean deliveries, with a dose–response pattern in the risk of placenta previa, the risk increasing with the number of cesarean deliveries previously performed [68, 69]. 3. Multiple gestations—in a retrospective cohort study that included 67,895 pregnancies, 2.1% of singleton and 2.5% of twin gestations had previa diagnosed. A subgroup analysis demonstrated that dichorionic twin gestations were at an increased risk for ultrasonography-diagnosed previa when compared with monochorionic or single gestations [70]. Minor risk factors include: 1. Increasing maternal age. 2. Increasing parity. 3. Previous non-cesarean delivery surgeries (uterine evacuation, myomectomy, infertility procedures). 4. Drug usage (tobacco smoking and cocaine usage). 5. Non-white race. 6. Male fetus. Management of placenta previa depends on if it is a complete or marginal previa, if there is a suspected concomitant placenta accreta, and then individualized

based on multiple factors: the estimated gestational age (EGA), the distance of the placental edge from the internal cervical os, any evidence of abruption, maternal vaginal bleeding, hemodynamic instability, or evidence of fetal distress. Therefore obstetricians must base management on their assessment of individual cases. An actively bleeding placenta previa is a potential obstetrical emergency, and should be handled as if having the potential for rapid hemorrhage and requirement for massive transfusion of blood products and crystalloid. Upon the onset of labor, if both the mother and fetus are stable, and the placenta is at least 2 cm from the internal cervical os, the patient can safely undergo labor.

 c. *Placenta accreta spectrum (PAS)*—a collection of conditions of abnormal placentation caused by trophoblastic invasion into the myometrial tissue beyond the normal boundary established by the Nitabuch fibrinoid layer. The PAS includes the diagnoses of *placenta accreta, increta and percreta*, with the definitions differing solely based on the depth of invasion of the placenta into the uterus and even beyond the uterus into adjacent structures and organs. Whereas, in normal placentation, placental villi attach to the decidual basalis, microscopic analysis of PAS has demonstrated partial or complete absence of the decidual layer such that the placental villi attach and/or interdigitate with myometrial fibers [71–75]. Mechanical disruption of the endometrial tissue from cesarean deliveries, myomectomies, uterine ablation, dilation and curettage, or endometritis is the current leading hypothesized etiopathogenesis of PAS [71–79]. Investigation is currently underway to identify other factors such as increased growth expression and angiogenesis that may contribute this pathologic process [75, 76, 80]. Physiologically, separation between placental cotyledons and the uterus occurs at the decidual layer, which functions as a cleavage line. In the absence of a decidual layer, separation between the placental cotyledons and the uterine spiral arteries does not occur, and the uterus continues to perfuse the cotyledons, which, in turn, leads to hemorrhage [77]. The current estimated incidence of PAS is 3.0 per 1000 pregnancies [81]. Secondary to the rise in frequency of operative procedures (specifically cesarean deliveries, with an estimated incidence increasing from 12.5% in 1982 to 32.2% in 2014 [78, 81]), there was a concomitant estimated increase in PAS of 0.8 per 1000 deliveries during the 1980s to the current estimate of 3.0 per 1000 pregnancies [78, 81–86]. Undiagnosed PAS can lead to massive intrapartum and postpartum hemorrhage, consumptive coagulopathy, disseminated intravascular coagulopathy, hypovolemic shock, and maternal mortality [71, 79, 87, 88]. The importance of antepartum placental analysis has been well established, and the individual practitioner must have a high index of suspicion at the time of delivery [89]. US and magnetic resonance imaging (MRI) are the diagnostic modalities most frequently used [90–93]. Identification of placental invasion of the myometrium can be made with US, with a positive predictive value (PPV) of 68%, a negative predictive value (NPV) of 98%, and a sensitivity of 89.5% [90]; with MRI, the sensitivity is 88%, specificity is 100%, PPV is 100%, and NPV is 82% [91]. Establishing a suspected diagnosis of PAS before delivery allows for a scheduled delivery and pre-operative planning with a multidisciplinary team based on the severity of the PAS. This can include consultation with a Maternal-Fetal Medicine specialists, gynecologic-oncologists, general surgeons, urologists, vascular surgeons, anesthesiologists, neonatologists, intensive care specialists, interventional radiologists, blood bank personnel, and nursing staff. There currently is inconclusive evidence for improved outcomes with pre-delivery placement of ureteral stents or internal iliac artery occlusive devices. Management of PAS varies as widely as the degree of abnormal placentation. Case by case

### *Placental Abnormalities DOI: http://dx.doi.org/10.5772/intechopen.81579*

management depends on whether or not it was identified before delivery, estimated gestational age (EGA), maternal factors (co-morbidities, previous surgery, status of labor), the size of the morbidly adherent placenta, the hemorrhage encountered, structures invaded by the placenta, adhesions, parity, presence of placenta previa, and other individualized factors. No randomized controlled trials (RCT) exist to guide management; therefore management varies between institutions and practitioners. The definitive treatment for PAS is cesarean-hysterectomy; however, experimental modalities aimed at uterine conservation have included leaving the placenta en situ followed by hypogastric artery ligation, uterine artery embolization, compression sutures, intrauterine balloon tamponade, and adjuvant methotrexate [94]. It should be noted that these experimental methods remain at risk for hemorrhage and delayed hysterectomy. It is the opinion of both the American College of Obstetricians and Gynecologists (Committee Opinion No. 529) as well as this author, that cases should be individualized, but "the recommended management of suspected placenta accreta is planned preterm cesarean hysterectomy with the placenta left in situ." [95] If the practitioner believes that adequate care cannot be administered, then transfer of care to a tertiary care center, specifically a center of excellence for PAS, is recommended.


and associated pathways [102–105]. For example, adhesion of the blastocyst to the endometrium depends on hormonally mediated Integrins, one of the four classes of cell receptors termed cellular adhesion molecules (CAMs) [106–108]. The mechanisms of impaired trophoblast migration are also currently being elucidated, and are associated with local placental hypoxia and abnormal placental growth factors, including placental growth factor (PlGF), hypoxia inducible factor (HIF), tyrosine kinase 1 (sFlt1), and reactive oxygen species [109–111]. Defective implantation and placentation clinically leads to recurrent spontaneous abortion, PPROM, IUGR, and preterm labor [112]. Inadequate or absence of secondary invasion of the endovascular trophoblast into the maternal spiral arteries of the myometrial layers during weeks 15 to 22 of gestation is associated with maternal chronic hypertension (CHTN), preeclampsia, and diabetes [112, 113].
