Persistently elevated hCG.
Stage 4 tumors generally have the histologic pattern of CCA and commonly follow a nonmolar pregnancy, with protracted delays in diagnosis and large tumor burdens.
In order to predict the likelihood of drug resistance and to assist in selecting appropriate chemotherapy, a modified WHO prognostic scoring system was recommended by FIGO in year 2000. In general, patients with stage 1 disease have a low-risk score and patients with stage 4 disease have a high-risk score. Therefore, the distinction between low and high risk applies to stages 2 and 3.
Modified WHO prognostic scoring system as adapted by FIGO (2000)[18]
| Scores | 0 | 1 | 2 | 4 |
|---|---|---|---|---|
| Age | <40 years | >40 years | — | — |
| Antecedent pregnancy | Mole | Abortion | Term | — |
| Interval months from index pregnancy | <4 | 4 to <7 | 7 to <13 | ≥13 |
| Pretreatment serum hCG (IU/L) | <1,000 | >10,000 | <100,000 | >100,000 |
| Largest tumor size, including uterus (cm) | <3 | 3 to <5 | ≥5 | — |
| Site of metastases | Lung | Spleen/kidney | gastrointestinal | Liver/brain |
| Number of metastases | — | 1–4 | 5–8 | >8 |
| Previous failed chemotherapy | — | — | Single drug | Two or more drugs |
Women are assessed before chemotherapy using this scoring system. Women with scores ≤6 are at low risk and are treated with single agent intramuscular methotrexate alternating daily with folinic acid for 1 week followed by 6 rest days. Women with scores ≥7 are at high risk and are treated with intravenous multiagent chemotherapy, which includes combinations of methotrexate, dactinomycin, etoposide, cyclophosphamide and vincristine. Treatment is continued in all cases until the hCG level has returned to normal and then for a further 6 consecutive weeks. The need for chemotherapy following a CHM is 15% and 0.5% after a PHM. The development of postpartum GTN requiring chemotherapy occurs at a rate of 1 in 50,000 births. The cure rate for women with a score of less than or equal to 6 is almost 100% and for those with a score of ≥7 or more is 95%(15).
PSTT are rare and are generally not sensitive to chemotherapy as with other forms of malignant gestational trophoblastic disease. It is therefore important to distinguish these tumors histologically. They are characterized by the absence of villi with proliferation of intermediate trophoblast cells. The number of syncytiotrophoblast cells observed is decreased in PSTT, with relatively lower levels of hCG secreted by these tumors. Surgery is an important modality in the treatment of PSTT and fortunately most patients have disease confined to the uterus and are cured by hysterectomy.
Women who undergo chemotherapy should be advised not to conceive for 1 year after completion of treatment. In women who conceive within 12 months of completing chemotherapy there may be an increased risk of miscarriage, higher rate of termination of pregnancy and an increased rate of stillbirth compared with normal population[17].
Following completion of chemotherapy for GTN once hCG remission has been achieved, patients should undergo serial determinations of hCG levels at 2-week intervals for the first 3 months of remission and then at 1-month intervals until monitoring has shown 1 year of normal hCG levels. The risk of recurrence after 1 year of remission is less than 1% but late recurrences have rarely been observed. Patients should be advised to use a reliable form of hormonal contraception during the first year of remission[16].
Management of hydatidiform mole and a coexistent fetus
Both complete and partial moles with coexistent fetuses have been reported. This occurs in 1 in 22,000 to 1 in 100,000 pregnancies. Most of these pregnancies are diagnosed antepartum by ultrasound findings of a complex, cystic placental component distinct from the fetoplacental unit, but in some cases, the diagnosis is not suspected until examination of the placenta following delivery. Complications of hydatidiform mole with a coexistent fetus appear to be increased and include hyperthyroidism, hemorrhage, preterm labor and pregnancy-induced hypertension. In some studies, compared with singleton hydatidiform moles, twin pregnancies with a fetus and a mole were found to carry an increased risk for postmolar gestational trophoblastic disease with a higher proportion of patients having metastatic disease and requiring multiagent chemotherapy[16].
There are no clear guidelines for management of such patients, and so advice should be sought from the regional fetal medicine unit and the relevant trophoblastic screening center. The ultrasound examination should be repeated to exclude retroplacental hematoma, other placental abnormalities or degenerating myoma, and to fully evaluate the fetoplacental unit for evidence of a partial mole or gross fetal malformations. If the diagnosis is still suspected and continuation of pregnancy is desired, fetal karyotyping should be considered. A chest X-ray may be also considered to screen for metastases and serial serum hCG values monitored. After delivery, the placenta should be histologically evaluated and the patient followed closely with serial hCG values, similar to management of a woman with a singleton hydatidiform mole.
Placental abruption
Placental abruption is a complication of pregnancy resulting from placental separation from the uterus before birth of the baby. It is amongst the most common causes of antepartum hemorrhage (APH) in the third trimester and is a significant contributor of maternal and fetal mortality worldwide. In the 2009–2012 report on confidential enquiry in to maternal death, hemorrhage was the third most common direct cause of maternal death in the UK[19]. Of the 17 maternal deaths due to hemorrhage, three were due to APH. Maternal and fetal outcome depends on early diagnosis, skilled intervention, severity of abruption, gestational age and speed of intervention. The estimate of incidence of placental abruption is about 6.5 per 1,000 births.
Etiology
Etiology is unknown but known risk factors include trauma (road traffic accident, domestic violence and external cephalic version, pre-eclampsia, multiparity, previous abruption, previous cesarean section, smoking, cocaine use, multiple pregnancy, thrombophilia, intrauterine infections, polyhydramnios and assisted reproductive technique. Of the risk factors, the most predictive is abruption in a previous pregnancy. A study from Norway reported a 4.4% incidence of recurrent abruption[20]. It recurs in 19–25% of women who have had two previous pregnancies complicated by abruption[21]. Bleeding and sonographic detection of intrauetrine hemotaoma in the first trimester increases the risk of subsequent placental abruption.
Placental abruption is concealed in 20% of cases where there is no external bleeding. In concealed abruption, blood pools behind the placenta becoming evident at the time of or after delivery.
Abruptions can be mild without symptoms, with blood clots seen after delivery at routine placental examination. The mother may present with vaginal bleeding with mild uterine contractions and tenderness, with or without tetany and no evidence of abnormality on CTG and normal neonatal outcome, only for abruption to be confirmed on placental examination. In women with significant abruption, vaginal bleeding may or may not be enough to cause hemodynamic shock and abnormality on CTG. Abruption in such cases is often evident after delivery of the infant followed by significant placental bleeding. In severe classical placental abruption, the mother presents with shock, vaginal bleeding, rigid tense abdomen (board-like rigidity) and fetal death. These cases may be associated, immediately or shortly after presentation, with disseminated intravascular coagulation. In some cases of significant abruption, blood arising from separation of placenta, trying to force its way through the uterine wall into the serosa, turns the uterus bluish in a condition known as “couvelaire uterus.”
Diagnosis and treatment
Placental abruption suspicion should be made when a pregnant woman presents with a sudden localized abdominal pain with or without vaginal bleeding. The fundus may be large for date suggesting bleeding. Abdomen examination may reveal gradually progressing tenderness and rigidity of the uterus. Initially, CTG could be normal but gradually becomes abnormal due to fetal distress. Placental abruption is a clinical diagnosis and there are no sensitive or reliable diagnostic tests available. Ultrasound has limited sensitivity in the identification of retroplacental hemorrhage. The Kleihauer test is not a sensitive test for diagnosis of abruption.
Treatment depends on the amount of blood lost and fetal status. If the fetus is preterm and neither mother or fetus are in distress, immediate delivery should be kept on hold for steroid administration to optimize fetal lung maturity while maternal and fetal monitoring is in progress, with immediate surgical delivery avaialble if fetal or maternal distress occurs. In the course of monitoring, blood volume replacement to maintain blood pressure and plasma replacement should be initiated. Vaginal birth is preferred over cesarean, if possible, unless evidence of progressive distress becomes evident. Cesarean section is contraindicated in the presence of disseminating coagulopathy, which must be corrected before surgical inervention.
In severe cases, postdelivery monitoring should be performed in a high-dependency unit.
Anti-D administration should be undertaken in Rhesus-negative women with a Rhesus-positive fetus.
Morbidly adherent placenta
Morbidily adherent placentation occurs when the placenta invades the uterus making it difficult to remove following delivery of the infant.
Three grades of abnormal placental adhesion are described based on degree of invasion of the uterus – accreta, increta and percreta.
In accreta, placental invasion of the myometrium is diffuse rather than being restricted within the decidua basalis, and is inseparable from the uterine wall.
With increta, placental invasion extends to the myometrium and serosa.
In percreta, placental invasion extends beyond the uterine wall to the pertoneum. It is associated with significant maternal and fetal mortality and morbidity. Hemorrhage and its consequences mainly affect the mother, and for the fetus the main risk arises from consequences of prematurity.
Risk factors include previous uterine scar, damage to myometrium due to previous placenta praevia, maternal age and multiparity. Other risk factors are uterine ablations, previous uterine curettage, Asherman’s syndrome, myomectomy and surgical termination of pregnancy, and congenital uterine abnormalities. Women at risk should have ultrasound at 20 weeks’ gestation, if necessary complemented with MRI in equivocal cases, although accuracy of MRI over ultrasound scan is controversal[22–24].
Diagnosis
The prevalence of placental accreta is on the increase because of rising cesarean section rates. A high index of suspicion should be exercised about morbidly adherent placenta at the routine 20 weeks’ anomaly scan in women at risk if the placenta is located in the lower uterine segment or overlaps the internal cervical os at this gestation. A transvaginal scan can help localize the placenta more accurately. Risk factors of morbid adhesion of placenta include previous placental adhesion, previous cesarean section(s) and traumatic injuries or surgery to the uterus such as myomectomy. Firm diagnosis is crucial to enable determination of appropriate management due to the potential risk of life-threatening hemorrhage. Clarification of diagnosis is therefore necessary by 32 weeks. Definitive diagnosis is made at the time of surgery.
Antenatal imaging techniques, which can help raise strong suspicion of morbidly adherent placenta are grey-scale ultrasound, color Doppler and MRI.
Criteria for diagnosis of morbid adhesion of placenta is shown in table 1 [25, 26, 27, 28, 29].
Because of variations in nomenclature and inter-observer perception of ultrasound findings, a standard reporting system is useful. This will help comparative analysis and clinical audit of diagnostic methods and outcome. For an example of a standard proforma for reporting ultrasound findings in suspected abnormally invasive placenta, the reader is referred to the work by Alfirevic et al [30, 31].
MRI is more costly than abdominal ultrasound, requiring experience and expertise in evaluation of placental invasion. Several studies have suggested comparable diagnostic accuracy with ultrasound. The role of MRI in diagnosing placenta accrete is still debated; however, many studies recommend MRI for women in whom ultrasound findings are inconclusive. MRI is particularly helpful when there is a risk of morbid adhesion of a posterior positioned placenta. Several MRI findings have been described with the main features of MRI consisting of uterine bulging or widening of the lower uterine segment producing an hourglass-shaped uterus, heterogeneous signal intensity within the placenta or increased placental vascularity, tenting of the urinary bladder, direct invasion of adjacent pelvic structures by placental tissue, interruption of the normal layered appearance of the myometrium and dark intraplacental bands on T2-weighted imaging. On most occasions, when MRI is used, it is usually used in conjunction with ultrasound for such diagnosis[32].
| Type of placenta | Grey scale ultrasound features | Two dimensional colour Doppler ultrasound features |
| Normal | Homogeneous appearance. (See figure 26.1.) | Linear flow near basal plate and the fetal surface. |
| Retro-placental sonolucent area. (See figure 26.1.) | No or minimal vascular projections in to the interface of uterine serosa and urinary bladder. | |
| Well defined echogenic interface of uterine serosa and bladder. (See figure 26.1.) | ||
| Vascular flow parallel to basal plate. | ||
| Absence of irregular projection or bulge in to bladder. | ||
| Morbidly adherent placenta | Loss of or irregular retro-placental hypoechoic area. (See figure 26.2.) | Diffuse or focal lacunar flow. (See figure 26.3.) |
| Placenta filled with prominent lacunae. (See figure 26.3.) | Vascular lakes with turbulent flow (peak systolic velocity over 15 cm/sec). (See figures 26.4 and 26.7.) | |
| Thinning or disruption of the echogenic interface between uterine serosa and bladder. (See figure 26.2.) | Hyper-vascular serosa-bladder interface. (See figure 26.4.) | |
| Presence of focal exophytic mass invading urinary bladder. (See figures 26.4, 26.6 and 26.7.) | Markedly dilated and aberrant blood vessels in the peripheral sub-placental zone. (See figure 26.5 and 26.6.) | |
| Area of placental implantation in lower segment bulging in to urinary bladder. (See figure 26.8.) |
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