Placental chorioangioma and maternal mirror syndrome
Chorioangioma is the most common benign nontrophoblastic vascular tumor of the placenta and occurs in approximately 1% of pregnancies[10]. Most chorioangiomas are small and do not cause symptoms. The incidence of large chorioangiomas, defined as more than 4–5 cm in size, varies from 1:3500 to 1:9000 (0.29–0.11%)[11]. These larger tumors may cause maternal complications and adverse prenatal fetal outcomes, including polyhydramnios, maternal preeclampsia, maternal mirror syndrome, preterm delivery, fetal heart failure, fetal anemia and thrombocytopenia, fetal growth retardation, hydrops fetalis, fetal demise, severe neonatal microangiopathic hemolytic anemia, thrombocytopenia and neonatal death[10, 12]. The pathophysiological mechanisms of these complications are unclear, but a hypothesis that can explain these adverse outcomes is chronic arteriovenous shunting, which sequesters red blood cells and platelets within the tumor and develops into high-output fetal cardiac failure[10]. D Buca et al. also summarized that the risk may increase with increasing tumor size and that the prevalence of these adverse outcomes may be higher if the fetus presents with fetal hydrops[12].
Mirror syndrome (MS) is defined as the development of maternal edema combined with fetal hydrops. Despite the unclear pathogenesis and prevalence of MS, it is associated with rhesus iso-immunization (29%), twin-twin transfusion syndrome (18%), viral infection (16%), fetal congenital anomalies, and fetal or placental tumors (37.5%)[13]. There are several clinical manifestations that may be present in MS patients, such as maternal edema, headache, visual disturbances, elevated blood pressure, mild anemia with hemodilution, a low platelet count, elevated serum levels of liver enzymes, uric acid, and creatinine, oliguria, albuminemia and proteinuria[13]. Nevertheless, this disorder is often misdiagnosed because of preeclampsia-like manifestations. Differentiating between MS and preeclampsia-like syndromes may be difficult, and the only difference lies in fetal edema, which is present in MS[14, 15]. Our case demonstrated a larger chorioangioma, which was 8.5 cm in diameter, and the patient presented with severe pulmonary edema, progressive lower leg edema and hydrops fetalis. These findings indicate that a larger tumor size is associated with more maternal and fetal complications[16]. Although we did not discover chorioangioma at the time of arrival at our emergency department, fetal hydrops and maternal MS were still the major reasons for terminating tocolysis. We considered the chorioangioma to be the major cause of maternal MS because the patient did not initially present with these symptoms after seven days of intravenous ritodrine treatment at another hospital. However, ritodrine hydrochloride may have been the aggravating factor that induced MS. Therefore, early delivery and the cessation of tocolysis are the best management strategies for patients with MS and rare side effects of ritodrine.
Ritodrine-induced rhabdomyolysis
Rhabdomyolysis is a complex medical condition characterized by the dissolution of damaged muscle cells, which results in the release of intracellular contents, including electrolytes, myoglobin, and other sarcoplasmic proteins, such as creatine kinase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase, into the bloodstream. Both traumatic and nontraumatic rhabdomyolysis may manifest as limb weakness, myalgia, swelling, and gross pigmenturia without hematuria [17]. Rhabdomyolysis can be induced by genetic defects, muscle hypoxia, infections, body-temperature changes, metabolic disturbances, or drugs and toxins, any of which may result in multiple organ impairment due to the secretion of myoglobin into the blood circulation. Acute kidney injury may be complicated by severe rhabdomyolysis, which is thought to be a major factor determining prognosis[8]. The mechanism of ritodrine-induced rhabdomyolysis is still unclear, and three possible potential mechanisms have been reported: 1) Direct drug damage caused by administering ritodrine in rats[18]; 2) Hypokalemia, which leads to muscular necrosis[19]; and 3) Coexisting muscular disorders, such as dystrophia myotonica (DM), which makes an individual more susceptible to side effects of ritodrine[9, 20, 21]. Ritodrine-induced rhabdomyolysis associated with DM has a shorter onset interval between the administration of ritodrine and symptom manifestation[22]. In our case, the patient had been tested for DM genes, and the results of both cytosine-thymine-guanine and cytosine-cytosine-thymine-guanine expansion repeats were within the normal range.
Matsuda et al. concluded that after persistent use of tocolytic therapy for more than a week, approximately a quarter of patients may present elevated CK levels above the normal range. The increased in CK levels is correlated with the total dose of tocolytics, especially in patients with concomitant use of both ritodrine and magnesium sulfate[23]. Serum CK levels beyond five times the upper limit of normal are often used for diagnosing rhabdomyolysis[24]. Physicians should pay more attention to the potential development of rhabdomyolysis in patients with continuous use of tocolytic therapy. In addition, some experts have suggested that basal and routine measurements of CK levels are unnecessary in asymptomatic patients[9].
Ritodrine-induced acute liver injury
There are several publications describing the association between ritodrine and acute liver injury. One prospective study reported that ritodrine was rarely associated with liver function impairment, even when intravenous ritodrine was administered in 128 pregnant women[25]. In that study, the incidence of acute liver injury in singleton and multiple pregnancies was approximately 1.9% and 9.1%, respectively. The physiological mechanism of liver impairment induced by ritodrine has been presumed to be that beta-adrenergic agents may increase the metabolic response, which causes an overload of liver function. The authors concluded that although beta-adrenergic agonists may induce an associated metabolic response in a majority of women, the elevation of liver enzymes is still rare. Therefore, toxicity is probably a distinct side effect of ritodrine [26, 27]. In our case, impaired liver function was observed after the use of intravenous ritodrine for approximately one week. Liver function gradually improved after we discontinued the tocolytic agents. We considered that both ritodrine and ritodrine-induced rhabdomyolysis were the leading causes of liver damage.
The synergic effects of atosiban and ritodrine
Atosiban is a synthetic peptide that competitively blocks the oxytocin receptor and prevents the action of oxytocin, resulting in uterine relaxation. Atosiban is the only tocolytic agent approved by the European Medicine Agency to stop premature labor, and it is currently used for acute tocolysis throughout Europe[28]. Tractocile (atosiban) was given intravenously with an initial bolus dose (6.75 mg/0.9 ml), followed by a high-dose continuous infusion for 3 hours (loading infusion 300 micrograms/min) (Tractocile solution concentrate 37.5 mg/5 ml) and a lower dose with a subsequent infusion (100 micrograms/min) up to 45 hours. The total treatment time did not surpass 48 hours. Few side effects, including nausea, vomiting and headache, occurred[29].
There is limited evidence about the synergic effects of ritodrine and atosiban when used to stop preterm labor. Fu S et al. concluded that the extension of gestation in the combined treatment group was slightly shorter than that in the ritodrine-only group. However, the former group had a lower incidence of palpitations and adverse drug events. The authors suggested that the combination of ritodrine and atosiban can effectively treat premature labor and inhibit contractions with fewer adverse effects[30]. Wang R et al. found that the combined use of these tocolytic drugs could suppress uterine contractions faster and more effectively without increasing side effects, including nausea, headache, chest pain and tachycardia[31]. We combined both drugs for tocolysis and prolonged gestation by approximately two days without frequent uterine contractions, but side effects of ritodrine still occurred, such as acute liver injury and rhabdomyolysis.