Etiology and pathogenesis
The exact etiology of Mirror syndrome remains unclear but it is thought to be secondary to fetal hydrops5. To broaden the analysis, we review fetal hydrops‘ mechanisms and causes. Then, taking into account Mirror syndrome‘s similarities with preeclampsia (PE), we compare the pathophysiology of both diseases to aid the comprehension of Mirror syndrome.
Fetal hydrops is defined as the accumulation of fluid in at least two of the four fetal cavities (pleura, pericardium, peritoneum or skin). It is a multifactorial condition and is the result of several physiological conditions of the fetus. The fetal weight is 90-95% water at 8-weeks and gradually decreases to 70% in a full-term. This greater water ratio is possible because the amino acid and bicarbonate concentrations in the fetal blood are higher than in the mother, therefore, drawing water from the maternal to the fetal circulation. The newly formed endothelium has a thin layer of glycocalyx, increasing its permeability. In addition, the fetal interstitial space is highly compliant, meaning that it doesn’t alter much of its hydrostatic pressure when it absorbs water6.It has been hypothesized that some aquaporins may play a role in the control of ion homeostasis, water balance and angiogenesis in the human placenta7. This might indicate that disturbed aquaporin functioning could also lead to hydrops formation. All these physiological factors make the fetus more prone to develop edema in some decompensations.
Since the prevention of Rhesus immunization started in 1970, the prevalence of immune fetal hydrops lowered to about 10%8. A systematic review of non-immune fetal hydrops showed the following primary causes: Cardiovascular disorders (21.7%), chromosome imbalances (13.4%), hematologic abnormalities (10.4%), infections (6.7%), intra-thoracic masses (6.0%), lymph vessel dysplasias (5.7%), twin-to-twin transfusion syndrome and placental causes (5.6%), syndromes (4.4%), urinary tract malformations (2.3%), inborn errors of metabolism (1.1%), extra-thoracic tumors (0.7%), gastrointestinal disorders (0.5%), miscellaneous causes (3.7%), and idiopathic (17.8%)8. These primary conditions can lead to increased central venous pressure, reduced lymph flow or low oncotic pressure and, due to the singular physiological characteristics previously discussed; the fetus can develop fetal hydrops. Sacrococcygeal teratoma is the most common congenital tumor (incidence of 1 in 35,000 births) and has been shown to cause fetal hydrops due to a high output failure, caused by anemia or tumor hemorrhage and/or an arteriovenous shunt in a low resistance, rapidly growing tumor9. The fluid dynamics between vascular and interstitial spaces is then altered by cardiac failure and the resulting imbalance of interstitial fluid production and lymphatic return eventually leads to fetal hydrops 10.
A comparison between cases of fetal hydrops associated with Mirror syndrome and cases of non- Mirror syndrome fetal hydrops suggested that 29% of fetal hydrops cases developed Mirror syndrome. Additionally, those associated with Mirror syndrome showed an earlier onset and significantly lower levels of serum hemoglobin and albumin11. Not much is known of why some cases of fetal hydrops evolve to Mirror syndrome and others do not. There have been no animal models that successfully reproduce the disease and its rare nature makes understanding the mechanism of the disease that much harder.
PE is characterized by abnormal placentation during the second trophoblastic invasion stage. Cytotrophoblasts fail to form an invasive endothelial subtype and remodel the spiral uterine arteries. This leads to narrow maternal vessels and relative placental ischemia. Histological evaluation of placentas with PE show decidual vasculopathy characterized by acute atherosclerotic lesions, loose edematous endothelium, medial hypertrophy, and perivascular lymphocytes12. In this scenario, there is an oxidative stress that leads to an overproduction of reactive oxygen species (ROS) and a consequent imbalance of oxidants and antioxidants. In response, there is the transcription of antiangiogenic factors, such as soluble FMS-like tyrosine kinase 1 (sFlT-1) and soluble endoglobin (sENG), thus, these factors’ serum concentration is highly predictive of PE13. They bind to angiogenic factors, such as PlGF, VEGF and TGF-β1, that are necessary to maintain endothelial homeostasis, especially of fenestrated endothelium found in kidneys, liver and brain12. This leads to protein loss from these capillaries resulting in proteinuria and loss of oncotic blood pressure, with resultant interstitial edema and hemoconcentration.
Knockout models have been used to reproduce hypertension and proteinuria, hallmarks of PE and are used to explain the pathophysiology. However, none have been able to reproduce severe complications such as HELLP syndrome (characterized by hemolysis, elevated liver enzymes and low platelet count) putting the full applicability of these models into question12.A rodent model study by Moffett-King et al.14 suggests that dysfunctional uterine natural killer lymphocytes (uNK) fail to remodel the spiral arterioli of the decidua and lead to a dysfunctional placenta and reproduce PE symptoms, therefore suggesting an immunological component to the disease. Obesity, hypertension, diabetes mellitus and renal disease are some of the risk factors, suggesting the role of systemic inflammation and previous vasculopathy in the placental ischemia12. Other rodent models show the role of heme oxygenase on of ROS clearance in the uterine microenvironment15. Therefore, the many explanations for the pathogenesis of PE suggest it is a multifactorial disease.
A case report by Hobson et al.3 analyzed Mirror syndrome secondary to twin-to-twin transfusion syndrome (TTTS). Hematocrit and serial concentration of factors that are increased in PE12 such as sFlT, endothelin I (ET-1), follistatin, von Willebrand Factor (vWF), activin A, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1(ICAM) and hemoglobin were drawn. It was observed that inflammatory markers (sFlT, ET-1, ICAM-1 and vWF) were higher during the onset of symptoms and lowered after pregnancy resolution. In this study, PE was ruled out due postnatal placental histopathology. The high levels of these factors suggest a PE-like systemic pathogenesis. The case-control study conducted by Espinoza et al compared the blood levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), an antiangiogenic factor, in mirror syndrome patients (n=4) and in normal pregnancies (n=40). The levels of sVEGFR-1 were elevated in all cases. In this case, microscopic view revealed immature intermediate villi with edematous changes increased syncytial knots, increased intervillous fibrin, and multifocal villous calcifications14.These findings are also seen in PE. Thus, Mirror syndrome and PE share a similar pathogenesis. A case report about Mirror syndrome secondary to Ebstein abnormality showed high levels of hCG16. Some hypothesize that placentomegaly results in an overproduction of hCG that leads to ischemia. Because of this, there is an overproduction of renin and activation of the renin-angiotensin-aldosterone system (RAAS) leading to hypertension. However, it cannot be concluded whether the rise in hCG is cause or consequence of Mirror syndrome.
Since placental increase in expression of placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) are hypothesized to be involved in the development of Mirror syndrome, these have been studied as markers that may aid diagnosis. It has been proposed that noticeable increase in sFlt-1 levels17, 18 and decrease in the sFlt-1: PlGF ratio19 could point to a diagnosis of Mirror syndrome; still, further investigation on this matter is needed to allow for significant conclusions.