暂无摘要。

Finding infant rib fractures was for many years an almost undisputed proof that physical child abuse took place. Yet, these rib fractures are virtually always occult and asymptomatic and are only identified when looked for, usually with X-rays, from physical child abuse accusations related to, e.g., suspicion of the shaken baby syndrome. In a recent systematic literature review (searched in Cochran, Embase, PubMed and Sociological Abstracts), Güvensel questioned the diagnostic accuracy of rib fractures to be caused by abuse, due to lack of sufficient scientific evidence. Further, there is currently a world-wide disagreement between physicians considering themselves child abuse specialized, and physicians that explore non-abuse-related symptoms that may mimic physical abuse, which, it is hoped, will significantly reduce current unjustified child abuse diagnoses. In an attempt to help resolving this disagreement, we hypothesize that the probability of physical child abuse-related infant rib fractures is significantly lower than the probability of all other possible non-abuse-related causes of occult asymptomatic infant rib fractures, e.g., from birth trauma, prematurity, osteogenesis imperfecta, hypermobile Ehlers-Danlos Syndrome, severe chronic placental pathology (e.g., massive perivillous fibrin depositions and severe chronic histiocytic intervillositis), and vitamin-D deficiency. As method, we attempted to assess the incidence of these various causes of infant rib fractures, in the Netherlands and the USA. The results are that the estimated Dutch and USA physical abuse-related infant rib fracture incidences are at least about 250 and 45 times lower than the sum of all the non-abuse-related estimates. Because these latter rib fractures are occult and asymptomatic, it is likely that (many) more could be out there. In conclusion, occult asymptomatic rib fractures develop perinatally, virtually always as birth trauma, in infants with sufficiently weak bones due to vitamin D deficiency, transmitted by their vitamin D deficient pregnant mothers. This group also includes cortical rib cracks due to deformation forces, with an estimated 186/100,000 incidence. And, despite obvious uncertainties in all estimated incidences, we provided strong evidence that our hypothesis has relevance, implying that the abundant occult asymptomatic rib fractures, when found in infants, should not be used to assess potential physical child abuse.

UNASSIGNED: Chronic histiocytic intervillositis (CHI) is associated with adverse pregnancy outcomes and high recurrence risk. Recent studies suggest that CHI may represent a host-vs-graft rejection, and that C4d immunostain can be used as a marker for complement activation and antibody-mediated rejection in the CHI.
UNASSIGNED: This retrospective cohort study focused on 5 fetal autopsy cases associated with CHI (5 index cases) from 5 women. We analyzed placentas from the index cases (fetal autopsy cases associated with CHI) and placentas from the women\'s previous and subsequent pregnancies. We assessed the presence and extent of CHI and C4d immunostaining in these placentas. We evaluated each available placenta and graded the severity of CHI as either <50% or ≥50%. Additionally, we conducted C4d immunostaining on one representative section from each placenta and graded the staining levels as follows: 0+ for staining <5%; 1+ for staining between 5% and <25%; 2+ for staining between 25% and <75%; and 3+ for staining ≥75%.
UNASSIGNED: Three of the 5 women had pregnancies prior to their index cases (fetal autopsy cases associated with CHI). Despite the absence of CHI in their initial pregnancies, the placentas displayed positive C4d staining with grades of 1+, 3+, and 3+, respectively. These results suggest the presence of complement activation and antibody-mediated rejection in placentas from their prior pregnancies without CHI. Three of the 5 women received immunomodulatory therapy after experiencing pregnancy losses associated with CHI. After treatment, 2 of these women had live births at 35 and 37 gestational weeks, respectively, while the third had a stillbirth at 25 gestational weeks. The severity of CHI and the degree of C4d staining in the placentas decreased in all 3 cases following immunomodulatory therapies. Specifically, the level of C4d staining decreased from 3+ to 2+, 2+ to 0+, and 3+ to 1+ in these 3 cases, respectively.
UNASSIGNED: In women with a history of recurrent pregnancy loss associated with CHI, C4d immunostaining was present in the placentas from their previous non-CHI pregnancies, suggesting activation of the classical complement pathway and antibody-mediated reaction in their prior non-CHI pregnancies before the development of CHI in subsequent pregnancies. Immunomodulatory therapy may improve pregnancy outcomes by reducing complement activation, as shown by the reduction of C4d immunopositivity in the placentas after immunomodulatory treatment. Although we believe that the study provides valuable insights, we acknowledge that there are limitations to the findings. Therefore, to further elucidate the pathogenesis of CHI, additional research efforts with a collaborative and multidisciplinary approach are necessary.

Pregnancy is a fascinating immunological paradox: the semi-allogeneic fetus generally grows without any complications. In the placenta, fetal trophoblast cells come into contact with maternal immune cells. Inaccurate or inadequate adaptations of the maternal immune system could lead to problems with the functioning of the placenta. Macrophages are important for tissue homeostasis, cleanup, and the repair of damaged tissues. This is crucial for a rapidly developing organ such as the placenta. The consensus on macrophages at the maternal-fetal interface in pregnancy is that a major proportion have an anti-inflammatory, M2-like phenotype, that expresses scavenger receptors and is involved in tissue remodeling and the dampening of the immune reactions. Recent multidimensional analyses have contributed to a more detailed outlook on macrophages. The new view is that this lineage represents a highly diverse phenotype and is more prevalent than previously thought. Spatial-temporal in situ analyses during gestation have identified unique interactions of macrophages both with trophoblasts and with T cells at different trimesters of pregnancy. Here, we elaborate on the role of macrophages during early human pregnancy and at later gestation. Their possible effect is reviewed in the context of HLA incompatibility between mother and fetus, first in naturally conceived pregnancies, but foremost in pregnancies after oocyte donation. The potential functional consequences of macrophages for pregnancy-related immune reactions and the outcome in patients with recurrent pregnancy loss are also discussed.

Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI.
Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuohistochemical staining, and placental dysfunction was assessed via thrombomodulin staining.
This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight.
More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI.

暂无摘要。

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.

BACKGROUND: Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined.
OBJECTIVE: To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes.
METHODS: A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks\' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded.
RESULTS: A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks\' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks\' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death.
CONCLUSIONS: Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.

UNASSIGNED: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis.
UNASSIGNED: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected.
UNASSIGNED: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described.
UNASSIGNED: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike \'classical\' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation.
UNASSIGNED: There was not funding associated with this study.