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.