Placental massive perivillous fibrinoid deposition is associated with adverse pregnancy outcomes: a clinicopathological study of 12 cases

Introduction

Maternal floor infarction (MFI) was first described by Benirschke and Driscoll in 1967 [1] and denotes a prominent basal layer of fibrinoid material along the maternal floor of the placenta grossly resembling a “thickened orange rind”. Massive perivillous fibrinoid deposition (MPFD) was first reported by Fox in 1976, in which the deposition of fibrin is more diffuse and can even be transmural [2]. Bernirschke subsequently noted MPFD significantly overlaps with MFI, sharing many clinical and pathological features. The two names are often used interchangeably in the literature, and the distinction between MFI and MPFD may be inconsequential [3], although some authors believe the term MFI is misleading because the lesion is not a true infarct. As there is no convincing evidence that MPFD and MFI are two distinct entities, we include both conditions in our study, and refer to all cases as MPFD. Pathologically, MPFD features significant areas of chorionic villi entrapped by excessive fibrinoid deposition, resulting in obliteration of the intervillous space and secondary villous atrophy. MPFD has been reported to be associated with intrauterine growth restriction (IUGR), intrauterine fetal death (IUD), preterm birth and neurological injuries in surviving children [4, 5]. The tendency to recur in subsequent pregnancies has also been reported [4, 6]. Due to its crucial impact on pregnancy and newborn outcome, it is important for obstetricians to be aware of and identify this rare condition early in pregnancy. In this study, we present clinical and pathological features of 12 consecutive cases of MPFD and document its association with adverse pregnancy outcome and antenatal risk factors in our local population.

Methods

This is a retrospective clinicopathological study of all placentas diagnosed with MPFD in our hospital over the period January 2010–July 2014. Placentas were submitted for formal pathological examination in accordance to published guidelines, and all submitted placentas were examined in a systematic protocol-based manner following practice guidelines developed by the College of American Pathologists (CAP) [7]. Clinical case records were reviewed for information on maternal age, race, parity, medical and surgical history, previous obstetric history, mode of current conception, antenatal course, ultrasound findings, concurrent maternal medical conditions, current pregnancy outcome and details on any subsequent pregnancy. Gross inspection of the placenta entailed review of the umbilical cord, placental membranes, and placental disk including fetal and maternal surfaces and serial cut surfaces of the villous parenchyma. Standard hemotoxylin and eosin-stained sections were examined [7]. Pathological and clinical findings were then correlated.

Results

Three thousand six hundred and forty placentas were submitted for formal pathological examination for the period January 2010–July 2014. Among these, 12 cases of placental MPFD were diagnosed (Table 1). During the same period, the total number of births was 52,804, giving an incidence of MPFD of 0.23 per 1000 births.

The mean maternal age at delivery was 32 years (range: 24–41 years). Eight patients were Chinese, two were Malay, and two were Indian. There were five multiparous patients, one of whom had one previous term small-for-gestational age (SGA) baby whose placenta was not examined. A majority of the patients (n=10) had spontaneous conceptions and two conceived by in vitro fertilization. Among the eight patients who had first trimester screening, three were reported to be at high risk for chromosomal trisomy, and all had abnormally low PAPP-A values (0.097, 0.057 and 0.481 MoM). All 12 patients underwent fetal anomaly (FA) scans, and no morphological abnormality was detected. One patient was noted to have bilateral uterine notching during FA scan at 20 weeks. Nine cases (75%) had IUGR, of which eight were diagnosed antenatally by ultrasound examination, and the onset of IUGR ranged from 20 to 31 weeks of gestation. Other abnormal ultrasound findings include abnormal umbilical Doppler studies (n=2), anhydramnios/oligohydramnios (n=1), and thickened placenta (n=1). One patient had mid-trimester pregnancy termination at 23 weeks, one fetus died in utero at 30 weeks, and six underwent emergency or elective lower segment cesarean sections (LSCS) at 25–38 weeks with corresponding birth weights of between 652 g and 2080 g, all of which represent values below the 10^th percentile except for one newborn whose birth weight was at the 15^th percentile. One patient had an uneventful antenatal course and spontaneous vaginal delivery at term of a live infant who was small for gestational age. Among the three pregnancies unaffected by IUGR, one patient had a second-trimester miscarriage of a normal weight abortus, one patient underwent emergency LSCS at 34 weeks for antepartum hemorrhage secondary to placenta praevia, and one patient had spontaneous preterm vaginal birth at 36 weeks. The male-female gender ratio was 5:7.

None of the 12 patients was known to be smokers or to drink to excess. One patient had latent syphilis but no treatment was given during pregnancy. Three had pregnancy-induced hypertension or pre-eclampsia during the pregnancy, and the rest had unremarkable past medical and antenatal histories. Four patients had serological screening for intrauterine infections such as toxoplasm, and cytomegalovirous, and the results were negative. Three patients were screened for autoimmune diseases (including anti-cardiolipin antibodies, lupus anticoagulant, antinuclear antibodies, extractable nuclear antigen) and the results were negative. Two of these 12 patients subsequently had spontaneous first-trimester miscarriages, but histological examination of the products of conception did not show recurrence of similar placental abnormalities of MPFD.

Pathological examination of the placentas all revealed markedly increased deposition of waxy pale-gray material consistent with fibrinoid affecting 25–100% of the villous parenchyma (Figure 1). Histological examination confirmed diffuse pink acellular fibrinoid deposition encasing the chorionic villi (Figure 2). Concurrent placental pathologies detected included intervillous thrombi (n=6), villous ischemia/infarcts (n=4), villitis of unknown etiology (n=2), abnormal vacuolization of trophoplastic cytoplasm (n=1), placental abruption (n=1), large subchorionic cysts (n=1) and acute chorioamniotis/acute vasculitis (n=1). An autopsy of the fetus was performed for the electively terminated pregnancy; this showed a female infant with low normal growth parameters, microcephaly and dolicocephaly, and changes consistent with Potter syndrome secondary to oligohydramnios. This case was previously published as a case report [8].

Figure 1:

Gross photography of a cut section of the placental disc showing diffuse deposition of waxy pale-gray fibrinoid material. Scale in centimeters.

Figure 2:

Low-power (magnification 40×) hemotoxylin and eosin-stained photomicrograph of placenta showing diffuse deposition of pink acellular fibrinoid material around widely separated chorionic villi.

Discussion

MPFD is a rare pathological disorder of pregnancy and is associated with significant fetal morbidity and mortality. It is characterized by extensive fibrinoid deposition encasing the villi to the extent that normal villous perfusion is impeded [9]. At present, the underlying etiology remains poorly understood. Hypothesized causes include autoimmune disease [10], infection [11, 12], toxic insults [13], abnormal host-placental interactions [14], coagulation disorders [15–17] and genetic conditions [18]. Other investigators have postulated that this condition represents a final common pathway for a number of varied disorders culminating in chorionic villus injuries associated with intervillous circulation stasis [19].

The incidence of MPFD in our study is 0.023%. The reported incidence from literature ranges between 0.028% and 0.5% [20]. Our relatively lower incidence may represent an underestimation as not all placentas from births in our institution were submitted for formal pathological examination. Following published practice guidelines [7], indications for submission of placentas for formal pathological examination include abnormal perinatal outcomes, including IUD/late miscarriage, IUGR, preterm birth, placenta abruptio, chorioamnionitis, etc. Although recurrence rate has been reported to be as high as 50% [9], in our series, no well-documented recurrence was identified. However, this may be a reflection of our small sample size and the predominance of small families in the local population.

At early pregnancy, three cases had abnormally low PAPP-A (pregnancy associated plasma protein-A) values. PAPP-A is a serum marker utilized in first trimester screening for chromosomal aneuploidy [21]. PAPP-A is synthesized by the syncytiotrophoblast and is a protease for insulin-like growth factor (IGF) binding protein-4. Therefore, low levels of PAPP-A are associated with increased levels of binding protein, and subsequently low levels of free IGF. IGF controls the uptake and transport of glucose and amino acids in trophoblasts and plays a role in autocrine and paracrine invasion of trophoblasts into the decidua. Low levels of PAPP-A (<0.4–0.5 MoM) in first trimester have been associated with adverse fetal outcomes, especially those that may be linked to abnormal trophoblastic invasion/placentation [22]. In our series, there were three cases with an abnormally low PAPP-A in first trimester screening. Degeneration of syncytiotrophoblast is a typical pathological feature of MPFD which may explain the low PAPP-A levels. This also raises the possibility that the pathogenesis of MPFD may commence during early pregnancy. Thus far, we are not aware of any publication describing this relation between PAPP-A levels and MPFD.

One case in our series had latent syphilis in pregnancy. Infection has been proposed as a potential cause of MPFD as chronic villitis coexists in some cases [11]. MFI has also been described as one of the manifestations of intrauterine HSV infection [12]. However, there has been no report on interaction between syphilis and MPFD. In our case, there were no histological features of either acute chorioamnionitis or chronic infectious-type villitis, and the newborn did not have congenital syphilis. It is therefore unlikely that syphilis was the cause of MPFD.

There is a striking association with adverse pregnancy outcome in our study. This included IUGR in 75%, premature deliveryin 58.3%, and IUD including late pregnancy loss in 25%. During antenatal screening, most patients were considered to be of low risk in the first trimester, and the pregnancies were typically normal until mid-second trimester or later, which is characteristic of this condition. Nine (75%) cases showed fetal growth restriction. Fetal growth restriction is a more consistent feature in other large series such as that of Bane and Gillan [5] in which all of the 13 cases studied had IUGR. The nine IUGR cases in our series had fibrinoid deposition in the placentas ranging from 25 to 100%. Interestingly, the three non-IUGR cases had significant proportions of 50–60% of fibrinoid deposition in the placentas. There were three IUGR cases complicated by PIH/PET which itself is a common underlying cause for IUGR/IUD.

In six cases of our series, intervillous thrombi (IVT) were also observed by placental examination. Intervillous thrombi are common, occurring in up to 20% of term placentas. There is an association between feto-maternal hemorrhage and the presence of large or numerous IVT [23]. It can also result from thrombosis of maternal blood and may be caused by increased turbulence of blood in intervillous space. Maternal diseases such as thrombophilia or pre-eclampsia are associated with increased likelihood of IVT. IVT usually do not have fetal effects unless extensive. In our series, the IVT are generally small in size (largest measuring <2 cm). One of these cases underwent the Kleihauer test, and result was negative. Thus, in our case series, there was no evidence for the presence of IVT to be directly related to the pathophysiology of MPFD.

Besides features of placental vasculopathy, two placentas had co-existing villitis of unknown etiology (VUE) which is an immunological condition reflecting breakdown of maternal-fetal tolerance [24], and which can be complicated by fetal death, growth restriction and neurological injuries in the newborn. The co-existence of these two pathologies and similar clinical course may be pointing to a common pathogenesis – maternal immunological reaction in a subset of patients of MPFD, as has been raised by other investigators [14].

Other concurrent pathologies in our series include subchorionic cysts and abnormal vacuolization of trophoblastic cytoplasm. Frequency of subchorionic cysts has been reported to be 5–7% among placental cysts. Microscopically, the wall of these cysts consists of amniotic and chorionic membranes; the cells that surround the cyst are called X-cells whose function remains unknown. There is evidence that X-cells produce pregnancy-associated major basic protein which is highly toxic and causes tissue degeneration, fibrin formation and cyst formation. Increased proliferation of X-cells has been noted in MPFD. Vernof et al. [13] postulated abnormalities of the X-cell and pregnancy-associated major basic protein in the pathology of MPFD. Although a firm conclusion cannot be drawn on the basis of this study, it remains possible that the subchorionic cysts observed in our case series may reflect such a phenomenon. The abnormal vacuolization of trophoblastic cytoplasm seen in one case raises consideration of a storage or metabolic disease. However, this vacuolization was a focal feature histologically, and the child did not have any evidence of an inborn error of metabolism, and therefore this feature is likely a degenerative-type change.

In summary, MPFD is a very rare condition which may be unfamiliar to many obstetricians. The diagnosis of MPFD mandates re-designation of the pregnancy as a high-risk pregnancy, and the obstetrician and parents must be alerted to the possibility of adverse outcomes to the newborn. Unfortunately, antenatal diagnosis of MPFD remains extremely challenging in the absence of clinical history of a previous pregnancy similarly affected by MPFD. Fetal growth restriction in the second or third trimester is a feature, albeit non-specific, of MPFD which should raise consideration of this condition affecting the pregnancy. Use of serum markers, such as PAPP-A or other novel biomarkers, to identify cases of MPFD deserves further research. Ultrasonographic features of MPFD in the antenatal period, including placental, amniotic fluid and Doppler changes, are also deserving of further study [25, 26]. The benefit of maternal antiplatelet and/or heparin and immunosuppressive therapy remains unclear at present [15]. Since MPFD is such a rare condition, the setting up of an international consortium focused at studying this condition may be an effective way of gathering sufficient cases for research of this disease.