Discussion
Placental mesenchymal disorder is an uncommon vascular anomaly affecting the placenta and its development (6). PMD is mainly detected after 13 weeks of GA when the placenta appears multicystic (1). Its etiology and pathogenesis are yet to be fully characterized (6).
Due to the low incidence of this disease as well as the lack of sizable studies preventing from issuing guidelines, diagnosis, management and follow-up might prove to be challenging for the medical team and the parents.
Here, we present a case where PMD was considered as a diagnosis since the earliest stages of the pregnancy, at only 9 weeks and 6 days, resulting in prompt management and eventually leading to the delivery of a healthy female baby.
When morphological placental anomaly is identified on ultrasound during the first trimester, the differential diagnosis must include partial molar pregnancy, complete mole with a coexisting normal fetus and PMD. These entities share similar ultrasound features such as enlarged or thickened placenta with multi cystic and grape-like hypo echoic lesions (1).
Anatomopathology
Macroscopically, pathologic examination of PMD reveals placentomegaly associated with dilatation of fetal chorionic vessels. Microscopically, the analysis shows thrombosis and oedematous stem villi without trophoblastic proliferation or hyperplasia, this last characteristic formally excluding a molar pregnancy (6).
Since the diagnosis is only confirmed by the pathologist’s team after birth, an early antenatal rigorous diagnostic approach should be adopted by the multidisciplinary medical team.
Firstly, invasive testing with CVS should be performed for genetic analysis.
Genetic testing
On a genetic level, a complete mole is characterized by an androgenetic diploid conception where the ovum is either fertilized by one duplicated sperm or, more rarely, by two sperms and has lost its maternal DNA (7). A partial mole originates from a diandric triploid conception where one ovum is fertilized by two sperms or one duplicated sperm, thus the genetic arrangement is built by two paternal and one maternal chromosomal complements (7). Therefore, PCR based DNA genotyping (STR) compared to the maternal and paternal, when possible, genomes can also be useful to distinguish complete moles, thanks to their androgenetic constitution, from the diandric triploidy nature of partial moles and both of these from the biparental allelic balance of non molar pregnancies like PMD (7).
As shown in the review of 66 cases of PMD conducted by Cohen et al, the majority of fetuses had a normal karyotype (78%), while 23% were affected by BWS and finally only 3 cases of chromosomal anomalies were reported, one triploidy (69, XXX), one Klinefelter Syndrome (47, XXY) and one trisomy 13 (8).
Therefore, if a normal karyotype is obtained, the differential diagnosis should rule out a partial hydatidiform mole.
The next challenge is to differentiate PMD and complete mole with a coexisting normal fetus with a normal karyotype and a multi-cystic appearing placenta. A molar pregnancy with a live fetus carries a high malignancy risk with a significant maternal morbidity (3). Persistent gestational trophoblastic disease can occur in up to 20% of these pregnancies (3), and this is why it is important to correctly diagnose the disease.
While CVS is primarily performed for a genetic analysis, it could also be used to obtain larger villi samples for a histological examination. A well known marker, p57, is a cyclin-dependent kinase inhibitor, derived from the maternally expressed and paternally imprinted CDKN1C gene located on chromosome 11p15.5 (9).
Due to the lack of contribution of maternal DNA in complete moles, the p57 expression is absent in villous stromal cells and cytotrophoblast and this characteristic may be exploited in an immunohistochemistry analysis to differentiate between PMD and complete mole (7, 9). These two entities can therefore be distinguished by p57 immunostaining combined with DNA genotyping. This is not performed as a matter of routine, but could be an extra option in some complicated cases.
Biological data
Along with the early invasive testing, hCG and MSAFP dosage performed right after the first trimester ultrasound had a valuable role for the PMD diagnosis. MSAFP levels have been shown to be elevated in PMD. It is hypothesized that the enlarged placental volume resulting in a substantial surface area combined with thin walled arteries, enables an increased transfer of AFP into the maternal circulation, while HCG levels can be normal to slightly elevated for GA (7).
Imaging
Magnetic Resonance Imaging (MRI) is an additional diagnostic tool allowing a thorough and wider placental evaluation as well as obtaining a more detailed fetal view, thanks to its relative independence from the patient’s body mass index (BMI) and high contrast resolution (10). MRI findings of PMD include an enlarged placenta with dilated vessels as well as heterogeneous signals (10, 11). Hemorrhage within the cystic part of the placenta might be associated with a molar pregnancy although it is not a specific sign (11). In our case, a large cystic area in the apical zone of the placenta was noted, supporting a PMD diagnosis.
Maternal and fetal complications
In the review of 64 reported cases conducted by Nayeri et al. it is reported that only a small number of pregnancies (9%) affected by PMD are free from feto-maternal complications (3). Maternal complications include gestational hypertension, preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and eclampsia (1-3, 6).
Thus, a daily regimen of low dose aspirin was introduced at only 13 weeks of GA by our team to lower our patient’s risk of developing preeclampsia. In our current knowledge, no other team has done the same.
Fetal complications consist of induced premature labor, spontaneous preterm delivery, in utero fetal growth restriction (IUGR), in utero fetal demise (IUFD) and BWS (1-3, 6). Neonatal complications include hematological disorders, such as anemia and thrombocytopenia and liver tumors, specifically mesenchymal hamartomas (1).
Up to 23% of fetuses can be affected by BWS (8), a multisystem genomic imprinting disorder characterized by mosaic genetic and epigenetic defects within the 11p15.5 region, which contains genes such asCDKN1C and IGF2 , regulators of fetal growth (12). Fetal clinical expression of BWS may be wide, with macrosomia, macroglossia, exomphalos and organomegaly as main suggestive features, if present (12). Although molecular testing is possible with CVS and amniocentesis, a negative result should not falsely reassure the medical team due to the genetic mosaicism of BWS.
Lastly, the rate of IUFD in a review of 109 cases was found to be as high as 29,4% at the median age of 31 weeks of GA (13). It is theorized that the combination of vascular malformations of the placental vessels and thrombosis in the stem villi blood vessels as well as their decreased functional capacity, leads to chronic hypoxia (14).
Joined to the high risk of hemorrhage secondary to the rupture of thin walled and dilated chorionic vessels, PMD ultimately might conduct to IUFD (1).
Hence our team’s decision to induce labor as soon as a novel thrombotic zone was noted in association with a subjective decrease in fetal movements.
PMD is a rare condition affecting the placenta’s histology, anatomy and function, altering the exchanges’ quality between mother and fetus and leading to a multitude of feto-maternal complications.
While it is essential to include PMD in the differential diagnosis when the placenta appears enlarged, thick and multicystic with a normal fetus to avoid an unnecessary pregnancy termination, it is also of the utmost importance to rule out gestational trophoblastic disease in light of the high maternal malignancy risk.
A multidisciplinary team involving obstetricians, pediatricians, MFM specialists, geneticists, radiologists, pathologists, midwives and psychologists is key to the diagnosis and a tailored management of the pregnancy in order to minimize fetal and/or maternal adverse outcomes.