Reduced fetal movements at term in singleton low risk pregnancies-Is there an association with placental histopathological findings?

INTRODUCTION: Maternal perception of fetal movements has long been considered an indicator of fetal well-being. A sudden decrease in the number of fetal movements is suggestive of fetal compromise. We aimed to determine whether the maternal perception of reduced fetal movements (RFM) is associated with placental pathological lesions in a low-risk term population. MATERIAL AND METHODS: Our study was a case-control study that was performed in a single university center. Placental histopathology, maternal demographics, labor characteristics, and neonatal outcomes of term, singleton pregnancies with maternal perception of RFM during the 2 weeks prior to delivery were collected. To isolate the effect of RFM on placental pathology, we excluded cases complicated by preterm birth, hypertensive disorders, diabetes mellitus, small-for-gestational-age and congenital/genetic anomalies. We compared pregnancy outcomes and placental pathology between the RFM group and a control group matched for gestational age and mode of delivery. Placental lesions were classified according to the "Amsterdam" criteria. Composite adverse neonatal outcome was defined as one or more of the following: sepsis, transfusion, hypoglycemia, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis and fetal/neonatal death. Multivariable regression analysis was performed to identify independent associations with adverse neonatal outcome. RESULTS: We included patients who gave birth from January 2008 until May 2019. The study group included 203 term pregnancies with RFM during the 2 weeks prior to delivery, which was matched with 203 controls. The RFM group was characterized by a higher rate of placental weight <10th percentile (22.6% vs. 3.9%, P < .001), a higher rate of maternal vascular malperfusion lesions (30.5% vs. 18.7%, P = .007) and lesions of maternal inflammatory response (43.3% vs. 29.5%, P = .005). At delivery, the RFM group had higher rates of cesarean delivery due to non-reassuring fetal heart rate monitoring (P = .01), 5-minute Apgar score ≤7 (P = .03), neonatal intensive care unit admissions (P < .001) and composite adverse neonatal outcomes (P = .007). Using multivariable analysis, RFM (adjusted odds ratio [aOR] 1.7, 95% confidence interval [CI] 1.1-4.8), and placental maternal vascular malperfusion lesions (aOR 1.2, 95% CI 1.0-2.9) were independently associated with adverse neonatal outcome. CONCLUSIONS: After excluding important placental-related morbidities, RFM was associated with a higher rate of placental weight <10th percentile and placental maternal vascular malperfusion lesions vs. controls. This study suggests a placental involvement in the association between RFM at term and adverse pregnancy outcomes.

Should we look for Hirschsprung disease in all children with meconium plug syndrome?

BACKGROUND: Meconium plug syndrome (MPS) is associated with Hirschsprung disease (HD) in 13-38% of cases. This study sought to assess institutional variation in utilization of rectal biopsy in children with MPS and the likelihood of diagnosing HD in this population. METHODS: Patients with MPS on contrast enema in the first 30 days of life from the Pediatric Health Information System database in 2016-2017 were included. Institutional rates of rectal biopsies performed during the initial admission were calculated and then used to predict institutional rates of early HD diagnoses using Poisson regression. RESULTS: Of 373 newborns with MPS, 106 (28.4%) underwent early rectal biopsy, of whom 43 (40.5%) had HD. Fifty-seven (15.3%) were ultimately diagnosed with HD. Eight (14%) of these patients had a delayed diagnosis. HD rates between institutions did not differ significantly (range 0-50%, p=0.52), but usage of early rectal biopsy did (range 0-80%, p=0.03). Each additional early biopsy increased the early HD diagnosis rate by 35% (ß=0.30, 95% CI 0.15-0.45, p<0.0001). CONCLUSION: The incidence of HD is increased in children with MPS. There is significant hospital variability in the utilization of early rectal biopsy, and opportunity exists to standardize practice. TYPE OF STUDY: Study of Diagnostic test Level of Evidence: Level III.

Perinatal Psychoneuroimmunology: Protocols for the Study of Prenatal Stress and Its Effects on Fetal and Postnatal Brain Development.

Prenatal stress (PS) impacts early behavioral, neuroimmune, and cognitive development. Pregnant rat models have been very valuable in examining the mechanisms of such fetal programming. A newer pregnant sheep model of maternal stress offers the unique advantages of chronic in utero monitoring and manipulation. This chapter presents the techniques used to model single and multigenerational stress exposures and their pleiotropic effects on the offspring.

Protective effect of garlic extract against maternal and foetal cerebellar damage induced by lead administration during pregnancy in rats.

BACKGROUND: In spite of its industrial usefulness and varied daily uses, lead (Pb) pollution is a widespread ecological problem that faces the humans in the 21th century. Pb was found to produces a wide range of toxic effects including neurotoxicity especially to the developing and young offspring. Recently, the utilisation of herbal plants has received a significant attention where there has been rising awareness in their therapeutic use; among these is the garlic. In light of the above, the current study is designed experimentally in female pregnant rats in order to investigate the beneficial role of garlic extract in the protection from the maternal and foetal cerebellar damage produced by administration of different doses of Pb during pregnancy. MATERIALS AND METHODS: Positively pregnant female rats were divided into five groups; one control group, two Pb-treated groups (exposed to 160 and 320 mg/kg b.w. of Pb, respectively) and two groups treated with both Pb and garlic (exposed to Pb as previous groups together with 250 mg/kg b.w./day of garlic extract). Treatments started from day 1 to day 20 of pregnancy, where the mother rats of different experimental groups were sacrificed to obtain the foetuses. Pb level in the maternal and foetal blood and cerebellum was estimated by spectrophotometry. Specimens of the cerebellum of different mother and foetal groups were processed to histological and immunohistochemical staining for microscopic examination. RESULTS: The results showed that administration of Pb to pregnant rats resulted in a dose-dependent toxicity for both mothers and foetuses in the form of decrease in maternal weight gain, placental and foetal weights, brain weight and diminished foetal growth parameters, which were prominent in rat's group treated with larger dose of Pb. In Pb-treated rats, Pb level in blood and cerebellum was high when compared with the control group. The histopathological examination of the cerebellum of treated dams and foetuses showed marked alterations mainly in the form of Purkinje cell degeneration and lack of development of foetal cerebellum. Co-treatment of garlic extract along with Pb resulted in a significant decrease in Pb levels as compared with those treated with Pb alone with improvement of the histopathological changes. CONCLUSIONS: This study was useful in evaluating the hazardous effects of uncontrolled use of Pb in general and in assessing the developmental and neurotoxicity of foetuses due to exposure during pregnancy in particular. Co-administration of garlic has beneficial effects in amelioration of Pb-induced neurotoxicity and reversing the histopathological changes of the cerebellum of mother rats and foetuses. (Folia Morphol 2018; 77, 1: 1-15).

Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida.

OBJECTIVE: Neural stem cells (NSCs) may promote spinal cord repair in fetuses with experimental spina bifida. We sought to determine the fate of amniotic-derived NSCs (aNSCs) after simple intra-amniotic injection in a syngeneic model of spina bifida. METHODS: Fetal neural tube defects were induced on 20 pregnant Lewis dams by prenatal administration of retinoic acid. Ten dams served as amniotic fluid donors for epigenetic isolation of aNSCs, which were expanded and labeled with 5-bromo-2'-deoxyuridine. The remaining 10 dams received intra-amniotic injections of the processed aNSCs, blindly in all their fetuses (n = 37) on gestational day 17 (term = E21-22). Fetuses with spina bifida underwent screening for the presence of donor aNSCs in the spinal cord at term. RESULTS: Donor cells were identified in 93.3% of the animals with spina bifida, selectively populating the neural placode, typically in clusters, retaining an undifferentiated morphology, and predominantly on exposed neural surfaces, though some were detected deeper in neighboring neural tissue. CONCLUSIONS: The amniotic cavity can serve as a route of administration of NSCs in experimental spina bifida. Simple intra-amniotic delivery of NSCs may be a practical adjuvant to regenerative strategies for the treatment of spina bifida.

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period - comparison with vitamin A-induced malformation spectrum.

Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high-dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8-15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg(-1) ). Embryonic lethality was observed in dams given KCZ on GDs 9-12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ-induced malformation are related to excessive vitamin A.

Diffusion-weighted imaging in fetuses with severe congenital heart defects.

Fetal diffusion MR imaging was performed in 3 fetuses with CHD. ADC values in the periatrial WM, thalamus, and basal ganglia were compared with those in a control population of fetuses. Diffusivity in the periatrial WM and thalamus was higher for the fetuses with CHD compared with controls. These observations support the finding of abnormal in utero brain development in fetuses with CHD.

Field investigation of perinatal mortality in friesian cattle associated with myocardial degeneration and necrosis.

Perinatal mortality and stillbirths were investigated in an extensively managed herd of Friesian cows and heifers calving over a 2-year period: 504 cows were calved and 215 heifers. Cows were bred to Friesian and Jersey bulls using natural service. The perinatal fetal mortality rate was 7.5% for cows and 30% for heifers. An experienced stockman managed these calvings and veterinary assistance was required only on nine occasions. All stillborn fetuses were examined post-mortem by the Veterinary Laboratories Agency, Carmarthen and no infectious agent was identified on any occasion. Thyroid hyperplasia was found in two fetuses. In blood samples taken from 10 late pregnant heifers, mean glutathione peroxidase values were 7.9 +/- 1.7 IU/ml Packed Cell Volume (PCV). Tissues from eight fetuses were submitted to the University of Liverpool for histopathological examination; all presented lesions consistent with myocardial degeneration and necrosis of the left ventricle. Following treatment of 205 late pregnant heifers with sodium selenite and vitamin E, the overall perinatal mortality rate in these cattle fell to below 11%.

Regional specificity of magnetic resonance imaging and histopathology following cerebral ischemia in preterm fetal sheep.

Early and accurate evaluation of the nature and extent of cerebral injury in the preterm infant brain is important for prognostication and decision making in the neonatal intensive care unit. The capability of magnetic resonance imaging (MRI) to define acute ischemic changes in white and gray matter in comparison to contemporaneous histopathology has not been adequately ascertained. The aim of this study is to assess whether postmortem MRI predicts the nature and extent of brain injury in a preterm fetal sheep model of cerebral hypoperfusion. MRI examinations were performed on fetal sheep brains (d99-100 gestation), perfusion fixed 72 hours after an ischemic insult (n = 7) with left-hemispheric placement of a microdialysis probe and compared with sham-occlusion (n = 3) and unoperated-control fetuses (n = 4). Cerebral ischemia was associated with MRI changes including global cerebral injury and diffuse white matter signal abnormality, which corresponded closely with histological damage. However, histological changes in deep structures, including the corona radiata, thalamus, and globus pallidus were not reliably detected on MRI. These findings confirm that in preterm fetal sheep, MRI can accurately assess cortical gray matter and subcortical and periventricular white matter abnormalities 3 days after hypoxic-ischemic injury but appears to have limited sensitivity to detect injury to deep structures.

Maternal diet alters exencephaly frequency in SELH/Bc strain mouse embryos.

BACKGROUND: The SELH/Bc mouse inbred strain, with a high frequency of nonsyndromic, genetically-multifactorial exencephaly, is a model for human cranial neural tube defects (NTDs). Maternal diet affects risk of human NTDs. METHODS: Exencephaly frequencies in SELH/Bc embryos were compared in 8 studies in which dams were fed alternative commercial Purina diets (5015 and 5001) or semisynthetic diets, and in several studies in which maternal diet was supplemented with a specific nutrient, either in drinking water or food before and during pregnancy, or by intraperitoneal injection on E7 and/or E8. RESULTS: The exencephaly frequency in SELH/Bc embryos was 2- to 8-fold higher when the dams were fed Purina 5015 (averaging 23% exencephaly) or a semisynthetic diet modeled on Purina 5015 (averaging 28%) or NIH-31 standard diet (23%), compared with Purina 5001 (averaging 7%). The exencephaly frequency remained high (41%) on a semisynthetic diet modeled on Purina 5001. The exencephaly frequency was not reduced significantly by maternal supplementation with folic acid, nor with each of zinc, methionine, niacin, brewers' yeast, riboflavin, vitamin B12, or inositol. Nor was it reduced by maternal diets with supplemental methyl donors and cofactors or with reduced fat. CONCLUSIONS: The frequency of exencephaly in SELH/Bc embryos is strongly influenced by a specific unidentified aspect of the commercial ration Purina 5001 that prevents 55-85% of exencephaly in SELH/Bc embryos, when directly compared with an alternative commercial ration Purina 5015 or its semisynthetic mimic. This strong maternal diet effect on NTD frequency may point to novel nutritional approaches to prevention of human NTDs.

Abnormal mineral composition of osteogenesis imperfecta bone as determined by electron probe X-ray microanalysis on conventional and cryosections.

Osteogenesis imperfecta (OI) is a genetic disorder of the connective tissue characterized by frequent bone fractures. The cause of bone fragility is still unknown even though substantial work on collagen has been done. We measured the calcium to phosphorus ratio (Ca/P) of bone mineral from 35 OI bone samples and 25 age- and site-matched control specimens, using electron probe X-ray microanalysis in the transmission electron microscope. Ultra-thin cryosections and conventionally prepared resin sections were used. Cryo-ultramicrotomy avoids any possible artifactual demineralization that may occur in conventional aqueous media. The Ca/P ratio obtained by these two methods was compared and there was no statistical difference between them. The results were differentiated according to the clinical types of OI for the first time. The Ca/P ratio of OI bone mineral was lower than normal in both resin and cryosections, and mirrored the severity of the disease. OI type II had the lowest ratio (Ca/P = 1.49) compared with normal age- and site-matched controls (Ca/P = 1.69). This abnormal mineral composition in OI type II could be a contributory factor to bone fragility in OI bone.

Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.

Twin fetuses with abnormalities that overlap with three midline malformation complexes.

Twin fetuses aborted at an estimated gestational age of 145 days were concordant for oral, facial, skeletal, and central nervous system malformations. The twins were discordant for other anomalies including cardiac defects, polydactyly, and malrotated short bowel. The combination of malformations observed overlaps with that of the oral-facial-digital syndrome, hydrolethalus syndrome, and Pallister-Hall syndrome. The problem of phenotypic overlap between these syndromes is discussed.

Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings.

Clinical, radiographic and morphologic analysis of nineteen cases of perinatal (lethal) hypophosphatasia was performed. Three families each had two affected offspring. All of the patients had lethal short limb dwarfism with very soft calvaria. Other clinical findings included polyhydramnios, blue sclerae and spurs in the mid-portion of the forearms and lower legs. Considerable variability was found in the skeletal radiographs. In addition to the well known radiographic features such as generalized decrease in the size of ossified bones with some bones not ossified at all, other changes observed included: 1) marked variability in the amount of bone ossification; 2) variability between patients as to which bones were most severely affected; 3) unusually dense, round, flattened, butterfly shaped; and sagittally clefted vertebral bodies; 4) variability in femoral shape including "chromosome" like, "campomelic" like, and shortening with or without metaphyseal cupping or irregularities; 5) osteochondral projections (Bowdler spurs) of the midshaft of the fibula and ulna. Recognition of the marked clinical and radiographic variability in this autosomal recessive lethal skeletal dysplasia is important for accurate genetic counseling and prenatal diagnosis.

Fetal brain injury after maternal carbon monoxide intoxication. Clinical and neuropathologic aspects.

In a model of brain damage in the rhesus monkey fetus, carbon monoxide inhalation by the mother was used to produce graded fetal hypoxia. Four fetuses with aterial oxygen contents of 2.1 to 2.4 ml per 100 ml during the most severe insult hour appeared neurologically normal, and their brains contained no lesions. A single animal with an intermediate degree of hypoxia was moderately abnormal; its brain showed extensive necrosis of the basal ganglia. Four fetuses with arterial oxygen contents of 1.6 to 1.8 ml per 100 ml during the most severe insult hour showed profound clinical deficits, and on postmortem examination the brains were markedly swollen and showed an extensive hemorrhagic necrosis. The fetal brain exhibits a high threshold to the effects of sustained hypoxia, but once a critical level of deoxygenation is exceeded, extensive brain damage with early death results.