Pontosubicular apoptosis ("necrosis") in human neonates with intrauterine growth retardation and placental infarction.

In a previous study of 37 autopsied stillbirths with non-dysmorphic intrauterine growth retardation (IUGR), 26 cases were associated with placental infarction, a morphologic marker of uteroplacental insufficiency. Nine of the 26 cases with both IUGR and placental infarction, where archival tissue was available, had grey matter ischaemic lesions that were subsequently identified as "pontosubicular necrosis". This lesion is now regarded as a localized form of apoptosis. A further eight third trimester stillbirth cases with both IUGR and placental infarction were ascertained prospectively. Sixteen of these 17 cases showed pontosubicular apoptosis, identified morphologically and verified using activated caspase-3 and TUNEL. Five of the 17 cases showed apoptosis in the frontal or temporal cortex as well. In this current study, pontosubicular apoptosis was strongly associated with IUGR and placental infarction in third trimester stillborns, suggesting that uteroplacental insufficiency leading to chronic fetal hypoxaemia may cause cerebral apoptosis.

The antiphospholipid syndrome in pregnant rabbits and their offspring. Neuropathological aspects.

OBJECTIVE: Although the obstetric consequences of antiphospholipid syndrome (APS) in pregnant rabbits have been described, there are no data on the serological and neuropathological aspects of the syndrome in their offspring. It would also be interesting to recognize whether the CNS abnormalities in rabbit fetuses relate to placental damage or depend on the antiphospholipid antibodies, transmitted from the pregnant animal through the placenta to the fetal serum. MATERIAL AND METHODS: A post-mortem neuropathological examination was done on 36 adult female New Zealand rabbits, and their offspring (100 fetuses). The material was divided into 4 groups: Group I--26 pregnant rabbits with experimental APS, Group IC 10--pregnant rabbits without APS (control group I), Group II--64 fetuses derived from animals included in Group I, and Group IIC--36 fetuses derived from individuals included in Group IC (control group II). The platelet count, activated partial thromboplastin time (APTT), antiplatelet antibodies in serum and coated on the platelets were evaluated to identify the APS in adult rabbits and their offspring. RESULTS: A significantly higher number of fetuses demonstrating weaker vitality and shorter survival time was observed in Group II. The percentage of dead and reabsorbed fetuses was also considerably higher in Group II. The serum markers of APS occurred both in Group I and II while the neuropathological evidences of APS: the thrombo-necrotic and inflammatory changes were found exclusively in APS pregnant animals. Moreover, cytoarchitecture of the fetal brains was intact. There were no disturbances in neuronal migration and abnormalities of cytodifferentiation. CONCLUSIONS: 1. The antiphospholipid syndrome in pregnant rabbits results in serological markers of the syndrome in their offspring. 2. The central nervous system of fetuses delivered from pregnant rabbits with the antiphospholipid syndrome remains intact despite the serological markers of the syndrome in fetus circulation. 3. The miscarriages in pregnant rabbits with the antiphospholipid syndrome depend rather on placental pathology related to the syndrome than on the syndrome per se transmitted from adult females to fetal circulation.

[Thrombophilias and vascular placental pathology. A survey of the literature]. / Thrombophilies et pathologies vasculaires placentaires. Revue de la littérature.

PURPOSE: Hereditary thrombophilia as antiphospholipid syndrome (APS) may represent a new risk factor for placental vascular diseases. CURRENT KNOWLEDGE AND KEY POINTS: General screening for biological abnormalities related to thrombophilia is poorly associated with placental vascular diseases and therefore, may be unwarranted. Women with an history of thrombotic diseases may be at risk for late fetal loss or preeclampsia. Adverse obstetric outcomes are particularly high despite anticoagulation regimens in patients with APS. A high frequency for biological abnormalities related to thrombophilia was detected in pregnancies complicated by late fetal loss in comparison with controls. However, no beneficial strategy prevention was clearly reported and therefore, a selective testing was actually debated for these patients. FUTURE PROSPECTS AND PROJECTS: Searching for acceptable treatment alternatives in patients with APS in order to reduce the high rate for pregnancy complications which may be persistent despite anticoagulation regimens. To determine by controlled studies the role for a prophylactic low molecular weight heparin regimens in patients with haemostatic abnormalities and previous pregnancy complications.

The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda.

We examined the association of placental malaria and mother-to-child transmission (MTCT) of HIV in a prospective community-randomized trial in Rakai District, Uganda. In the 746 HIV-positive mother-infant pairs, the MTCT rate was 20.4%. Placental malaria was more common in HIV-positive than HIV-negative women. After multivariate adjustment for HIV viral load, the risk of MTCT associated with placental malaria was 2.89 and with HIV viral load the risk was 2.85. Interventions to prevent malaria during pregnancy could potentially reduce MTCT.

Thrombophilia and fetal loss.

Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome-an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past two years suggest that heritable thrombophilia is associated with increased risk of fetal loss and pre-eclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimes for the prevention of fetal loss in women with thrombophilia.

The correlation of prenatal brain damage with placental pathology.

Several epidemiological studies have emphasized that prenatal factors are the best predictors for cerebral palsy. Many placental pathologists have anecdotally recognized an association between placental pathology and poor pregnancy outcome, including neurologic injury. This study was undertaken to determine if correlations exist between specific types of placental pathology and prenatal brain injury. Ninety-eight stillbirths and livebirths with < 1 hour survival and complete placental and neuropathologic exams were reviewed. Most brain damage was in three categories: germinal matrix/intraventricular hemorrhage (GMH), white matter gliosis/necrosis (WMG/N), and neuronal necrosis. Statistical analysis of contingency tables showed significant associations of WMN with placental chronic vascular changes (PCV), umbilical cord problems, old infarction/abruptio, and meconium staining of the placenta. Associations were found between neuronal necrosis and PCV, surface vessel thrombosis, and old infarction/abruptio. GMH was associated with funisitis, but no other factors. Fetuses with WMN or neuronal necrosis were older than fetuses with GMH or no neuropathology. It is likely that these types of placental pathology can also be correlated with prenatal brain injury in liveborn infants, and examination of the placenta may indicate which infants are at greater risk for neurologic injury.

Twin transfusion syndrome causing cutaneous erythropoiesis.

Two cases of twin transfusion syndrome are described in which the donor twin exhibited blueberry muffin-like macules and papules associated with cutaneous erythropoiesis. No evidence was found in either case for intrauterine viral infection, the most common cause of cutaneous erythropoiesis. Cutaneous erythropoiesis is these two cases is considered to be due to persistence or reactivation of fetal dermal erythropoiesis secondary to prolonged, severe intrauterine anemia.

Microangiopathic hemolytic anemia and thrombocytopenia in a neonate associated with a large placental chorioangioma.

The case of an infant born in association with a large chorioangioma of the placenta is presented. The maternal complications of polyhydramnios, preeclampsia, and premature labor are those described in the "syndrome" of a chorioangioma. The immediate neonatal course was unusually complicated by severe microangiopathic anemia with persistent thrombocytopenia and hemolysis which required three exchange blood transfusions. The relationship between the neonatal complications and the placental tumor is discussed in terms of possible pathophysiologic mechanisms.

The clinical significance of placental villous edema.

A study was undertaken to determine why there is such variability in morbidity and mortality in neonates exposed to antenatal chorioamnionitis. Villous edema provides a clue. It was present in 72/83 placentas with chorioamnionitis. The extent and severity of the edema had a strong, positive correlation with cord arterial blood pH values, low Apgar scores, the need to resuscitate vigorously at birth, the subsequent need for assisted ventilation, the frequency of hyaline membrane disease, and neonatal mortality. Most of the difference in morbidity and mortality between preterm and full-term infants was related to the greater severity and extent of villous edema in those born prematurely.

Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent--the Nîmes Obstetricians and Haematologists Study5 (NOHA5).

BACKGROUND: Women with familial thrombophilia have an increased risk of still birth. We postulated that the presence of asymptomatic risk factors for venous thrombosis might be a risk factor for late foetal loss. METHODS: We performed a case-control study on the prevalence of heritable thrombophilic defects, of antiphospholipid-related markers and of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with at least one episode of late unexplained foetal loss and in control women with successful pregnancies. Partners of cases and controls were also studied. Written conclusions of the pathological examination of the placentas, when available, were also reviewed. RESULTS: We found at least one positive biological risk factor for venous thrombosis in 21.1% of the patients and in 3.9% of the controls (p < 10(-4)). In women, the crude odds ratio for still birth associated with any positive biological risk factor for venous thrombosis was 5.5, 95% confidence interval (95%CI) [3.4-9.0]. No difference was found between partners of cases and controls (5.2% and 4.7%). Using conditional logistic regression analysis, 4 adjusted risk factors for still birth remained: protein S deficiency, positive anti beta2 glycoprotein I IgG antibodies, positive anticardiolipin IgG antibodies and the factor V Leiden mutation. The C677T mutation in the MTHFR gene was not an individual risk factor but an homozygous genotype was strongly associated with the former 4 risk factors (16.8% of patients vs. 0.9% of controls). In women with such associations, still births always occurred in absence of folic acid supplementation during pregnancy. Available conclusions of pathological analysis of placentas were found to have a very high proportion of "maternal vascular disease of the placenta" in patients with at least one positive risk marker for thromboembolism, specially in case of association with the C677T MTHFR homozygous genotype, compared to patients with negative markers (p <10(-4)). CONCLUSIONS: Late foetal loss, through placenta thrombosis, may sometimes be the consequence of a maternal multifactorial prothrombotic state associating traditional heritable or acquired thrombosis risk factors to conditions predisposing to an acute mild hyperhomocysteinaemia (coexistence of a genetic predisposition with late pregnancy-related increased folate needs).

Chronic villitis of unknown aetiology in recurrent intrauterine fetal growth retardation.

Although recurrent chronic villitis of unknown aetiology (CVUA) has been documented in a few instances, placental lesions in recurrent intrauterine growth retardation have not, to the best of our knowledge, been reported. In the present study ten cases of recurrent intrauterine growth retardation have been described; a high incidence of severe CVUA was found in both first and successive pregnancies. If, as has been proposed, CVUA is due to a maternal immune response to placental antigens, subsequent pregnancies with the same father might be similarly affected.

Haemorrhagic endovasculitis of the placenta: a review with clinical correlation.

Haemorrhagic endovasculitis (HEV) is a recently described vasodestructive process within the placenta. Similarities to several forms of thrombotic microangiopathy are evident. Clinical studies have shown strong associations between HEV, still birth and intrauterine growth retardation (IUGR). Liveborn infants, with affected placentae, evaluated at the age of five, exhibit a high incidence of neurological abnormalities. HEV has been recurrent in successive pregnancies in some patients. Clinicopathological processes, which appear to be associated with HEV, include the presence of chronic villitis (VUA) and maternal hypertension. Viral- and/or Mycoplasma-type particles have been identified in a number of affected placentae examined by electron microscopy. Associated pathological events suggest an infectious aetiology possibly acting in concert with an environmental toxin. Biochemical factors and alterations of immune response within the maternal-placental-fetal unit may be involved.

Fetal thrombotic vasculopathy in the placenta: a thrombophilic connection between pregnancy complications and neonatal thrombosis?

OBJECTIVE: Fetal thrombotic vasculopathy (FTV) has been related to pregnancy complications and neonatal thrombosis separately. We assessed whether a relationship existed in our population of women with neonates who were admitted to our Neonatal Intensive Care Unit (NICU). In addition, the presence of thrombophilic factors in children and parents was investigated. METHODS: Two groups were detected by a search of the departmental databases. Group A was a cohort of 5000 neonates admitted to our NICU (1992-2002). Infants who developed thrombotic complications were selected. Group B was a cohort of placentae from our institution (2000, n = 141). Those with a diagnosis of FTV were selected. Case-notes and laboratory results were obtained through the hospital information system. RESULTS: Of Group A, thrombosis was reported in 55 children. Of these, 20 matching placentae were available. Eight placentae showed FTV (40 per cent). Of the eight corresponding pregnancies, seven were complicated by pre-eclampsia and/or intra uterine growth restriction (IUGR). Of the 12 placentae without FTV, five of the pregnancies had pre-eclampsia and/or IUGR (odds ratio for relation FTV-Complications: 9.8, 95 per cent CI = 0.9-107). In Group B, nine placentae showed FTV (6.4 per cent). Of these nine, six of the pregnancies were complicated by pre-eclampsia and/or IUGR. None of the neonates developed thrombosis. CONCLUSION: Pre-eclampsia and/or IUGR as well as neonatal thrombosis are both associated with fetal thrombotic vasculopathy in the placenta. However, in our selected-tertiary centre-population, FTV did not predict neonatal thrombosis. The thrombophilic investigations of parents and children were incomplete. A standard approach for evaluating parents at risk for FTV and evaluating neonates at risk for thrombosis should be developed.

Fibrinous vasculosis in the human placenta.

Approximately 6 per cent of placentae of babies admitted to a special care paediatric unit show evidence of peripheral villous stem branch oedema. In more than half of these cases there is evidence of fibrinous vasculosis (FV) in truncal veins. The affected placentae are generally thick and of small diameter, often of extrachorialis type, very congested and often cyanosed. The aetiology of the lesions is discussed with reference to abnormal fetal vascular patterns, poor perfusion, anoxia, oedema and spasm and the effect such factors may have on vessels with an irregularly distributed muscle coat and tendency to a spiral course. A small heterogeneous group with FV lesions unassociated with stem branch oedema was also identified. Chorionic vessels were more commonly involved in this group, and it would seem that, in addition to the other factors mentioned above, pressure variations may have some aetiological significance. Lesions of FV occurred mainly in mature placentae. The mothers showed a high incidence of pregnancy-induced hypertension and other complications. Fetal distress and asphyxia at birth were common. Where chorionic vessels were involved there was a high risk of intrauterine death (40 per cent) and coagulopathy among survivors (46.7 per cent). FV lesions affecting truncal vessels carried no greater risk than truncal arterial thrombotic lesions, which have been assessed in the past. In both these groups the hypoxia and intrauterine growth retardation which the babies showed are probably the most important factors, though one could postulate that their clotting mechanism was already triggered.

Syphilitic placentitis: an immunopathy.

The placentas of eight infants with congenital syphilis were examined by both immunohistochemical and immunofluorescent techniques. Significant IgM, C3 and rheumatoid factor reactivity were observed in all the syphilitic placentas. We postulate that their presence plays an important role in the evolution of the pathological changes.

Enterovirus associated placental morphology: a light, virological, electron microscopic and immunohistologic study.

The purpose of this study was to identify the possible effect of enteroviruses on placental tissue. Seventy-eight pregnant women were studied throughout their pregnancy: enteroviral infection was detected by faecal viral isolation and seric neutralization of previously identified virus in cell culture. In 19 cases of confirmed maternal infection, placentae were examined grossly, by optical microscopy, immunohistochemical and electron microscopic methods. Ten term placentae from women included in the study, with no clinical, serological or virological evidence of enteroviral infection, were used as control, and examined by gross and optical microscopy. In 17 specimens (echovirus-coxsackievirus) an haematogenous placentitis was suspected on the basis of gross observation. Microscopic lesions were similar to those found in other viral infections, with specific features. The nature of the inflammatory reaction pointed to the presence of an acute type of haematogenous placentitis, not present in placentae of the control group. The authors (AA) comment on the results and present the hypotheses about the available data: (1) maternal enteroviremia and faecal virus shedding without placental invasion, placentary damage being an unspecific consequence of infection; (2) direct virus-induced injury is not the only possible cause for the lesions: (3) placental enteroviral infection occurred with placental pathology but the virus did not cross the organ as the newborn had no signs of infection.

Discordancy for maternal floor infarction in dizygotic twin placentas.

Maternal floor infarction (also known as massive perivillous fibrin/fibrinoid deposition) is a rare and devastating pregnancy disorder associated with prematurity, fetal growth restriction, spontaneous abortion, and long-term neurologic impairment. Recurrence in multiple pregnancies is common. Little is known regarding either the pathophysiology or the management and treatment of patients at risk for recurrence in subsequent pregnancies. Most authors have emphasized maternal risk factors believed to act in a dominant fashion irrespective of fetal genotype. We report on dizygotic twins discordant for the development of placental maternal floor infarction and fetal growth restriction. The mother was a poorly controlled class C diabetic, and the onset of disease was coincident with the clinical onset of preeclampsia. This case demonstrates that fetal genotype, or some other factor specific to an individual fetoplacental unit, can lead to the differential expression of maternal floor infarction in dizygotic twins gestating in the same intrauterine environment.

Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy.

Neonatal encephalopathy (NE) remains an important cause of morbidity and mortality in the term infant, and many cases have an antepartum, rather than an intrapartum, etiology. Chronic processes such as thrombosis result in changes in the placenta. We sought to determine whether histopathological examination of the placenta in cases of NE, focusing on these changes, could identify significant antenatal processes that are not recognized by clinical assessment alone. Infants born at term with NE were identified retrospectively over a 12-year period. Placental tissue from deliveries during the study period was available for reexamination. Controls were selected from a cohort of 1000 consecutive deliveries on which clinical and pathological data were collected as part of an earlier study. Bivariate and multivariate analyses of clinical and pathological factors for cases and controls were used to test for an independent association with NE. Clinical and placental data was collected on 93 cases of NE and 387 controls. The placental features of fetal thrombotic vasculopathy (FTV), funisitis (signifying a fetal response to infection), and accelerated villous maturation were independently associated with NE. Of the clinical factors studied, meconium-stained liquor and abnormal cardiotocograph were independently associated. There were no independently associated clinical antenatal factors. Placental features of infection, thrombosis, and disturbed uteroplacental flow are significant independent factors in the etiology of NE in this study. Acute and chronic features suggest that NE may result from acute stress in an already compromised infant. The absence of significant clinical antenatal factors supports the value of placental examination in the investigation of infants with NE.

Massive chronic intervillositis associated with recurrent abortions.

Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology induced massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alpha-fetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.

Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy.

Thrombi in the fetal circulation of the placenta cause a pattern of clustered fibrotic villi called fetal thrombotic vasculopathy (FTV), which has been associated with serious injuries to neonates, especially brain injuries. Correlation of FTV with visceral thrombi in autopsy specimens might lead to a more accurate estimate of the prevalence of somatic thrombi as a significant and underrecognized cause of prenatal injury or perinatal death, and show the potential validity of placental FTV as an indicator of thrombotic lesions in the fetus and newborns who survive. Clinicopathologic correlation was used to perform a 3-year retrospective autopsy review. We identified 16 cases (19%) among 84 perinatal autopsy specimens in which placental FTV was associated with stillbirth, intrapartum, or neonatal death. Two liveborn neonates survived 2.5 hours, and one for 24 hours; there was one intrapartum death, and the rest were stillborn. Clinical evidence of severe central nervous system (CNS) injury to two of the liveborn infants was evident at birth. Twelve stillborns died from 12 to 48 hours before delivery. Placental FTV had features of organization that clearly antedated the fetal death. Autopsy findings confirmed somatic thrombi in six cases (37.5%) of the 16 with FTV, including cerebral thrombi or infarcts (three cases), renal thromboemboli (three cases), and pulmonary thromboemboli (two cases). One mother had history of deep vein thrombosis, and four of eight tested had abnormal coagulation test results. Placental FTV indicates a significant probability of thrombi in the fetus and represents an important, possibly underrecognized cause of perinatal mortality and neonatal injury. Parental coagulopathy as a significant factor in prenatal injury and death deserves more comprehensive study. The placenta remains an undervalued and underutilized surgical specimen in the evaluation of perinatal injury, especially cerebral palsy.