Hypothesis acardiac twin pregnancies: Pathophysiology-based hypotheses suggest risk prediction by pump/acardiac umbilical venous diameter ratios.

BACKGROUND: A total of 75% of monozygotic twins share 1 monochorionic placenta where placental anastomoses cause several serious complications, for example, acardiac twinning. Acardiac twins lack cardiac function but grow by perfusion of arterial blood from the pump twin. This rare pregnancy has 50% natural pump twin mortality but accurate risk prediction is currently impossible. Recent guidelines suggest prophylactic surgery before 18 weeks, suggesting 50% unnecessary interventions. We hypothesize that (1) adverse pump twin outcome relates to easy-to-measure pump/acardiac umbilical venous diameter (UVD) ratios, representing acardiac perfusion by the pump's excess cardiac output. This hypothesis suggests that (2) UVD-ratios are large, mildly varying in cases without complications but small and decreasing when complications develop, thus predicting that (3) UVD-ratios may allow risk prediction of pump twins. In this exploratory clinical pilot, we tested whether UVD-ratio measurements support these predictions. METHODS: We included 7 uncomplicated (expectant management), 3 elective surgical, and 17 complicated cases (pump decompensation, emergency intervention/delivery or demise). Nine UVD-ratios were measured sonographycally and 18 by pathology. RESULTS: Uncomplicated cases have larger, two serial measurements showing mildly varying UVD-ratios; elective surgical cases show larger UVD-ratios; complicated cases have smaller, two serial measurements showing decreasing UVD-ratios. There were no false-positives, no false-negatives and noncrossing linear trendlines of uncomplicated and complicated cohorts. CONCLUSION: Our data provide first evidence that UVD-ratios allow risk prediction of pump twins. More early uncomplicated and late complicated cases are needed, for example, in a prospective trial, before the separation between uncomplicated and complicated cohorts is accurate enough to support a well-founded decision on (early) intervention.

Treatment of Complicated Spontaneous Twin Anemia-Polycythemia Sequence via Fetoscopic Laser Ablation of the Vascular Communications.

Monochorionic diamniotic twins share a single placenta and have intertwin vascular communications that link the circulatory systems of the twins together. Twin anemia-polycythemia sequence (TAPS) is an atypical form of twin-twin transfusion syndrome (TTTS) caused by net transfer of blood from one fetus to the other and is characterized by large intertwin hemoglobin differences in the absence of oligohydramnios and polyhydramnios. This condition may develop spontaneously (sTAPS) or as a result of residual vascular communications after prior laser surgery. Because of the relatively low prevalence and lack of clinical awareness, the natural history of sTAPS is unclear and the antenatal treatment remains controversial. Case series of sTAPS have described expectant management with timed delivery, intrauterine blood transfusion, and fetoscopic laser treatment. Favorable outcomes have been described in cases of uncomplicated sTAPS that underwent conservative measures. However, we believe that there may be a subgroup of high-risk or complicated sTAPS patients that may benefit from definitive treatment afforded by fetoscopic laser therapy. We describe 3 complicated cases of sTAPS successfully treated with selective laser photocoagulation of communicating vessels. In 2 of the cases, placental pathology identified thrombosed fetal vessels of the polycythemic twin.

Altered lipid metabolism in gastroschisis: a novel hypothesis.

Gastroschisis is a congenital abdominal wall defect where there is herniation of abdominal organs. Optimal maternal nutritional intake, in particular, fatty acids, are vital for proper growth and development of the fetus. This pilot case-control study explored the association of several biomarkers of fatty acids and gastroschisis. Between 2008 and 2011, we recruited 13 pregnant women in mid-gestation who were referred to the UCSD Prenatal Center for evaluation of an abnormal maternal serum alpha-fetoprotein (MSAFP) test and subsequently identified as carrying a baby with gastroschisis. Nine controls were selected from a false positive MSAFP or from the UCSD prenatal clinic. At enrollment, maternal blood was drawn for analysis of fatty acids. Mann-Whitney-Wilcoxon tests were used to test for mean differences between erythrocyte fatty acid biomarkers and the fatty acid lipogenic (palmitic acid: linoleic acid) and desaturation (palmitoleic acid: palmitic acid) indices and gastroschisis. Mothers carrying a baby with gastroschisis and gastroschisis babies had consistently higher levels of palmitoleic acid (all P's < 0.05), gastroschisis mothers had lower levels of oleic acid during pregnancy and at delivery, and higher levels of DHA at delivery (all P's < 0.05). The lipogenic index was significantly lower at delivery for gastroschisis mothers (P < 0.05) and the desaturation index was consistently higher in gastroschisis mothers and babies (all P's < 0.01). These findings suggest that early maternal inflammation possibly resulting from an imbalance of fatty acids, leading to a vascular disruption, may be the underlying mechanism responsible for at least some cases of gastroschisis.

Prevalence of noncardiac structural anomalies in twin-twin transfusion syndrome.

OBJECTIVES: Compared to singleton pregnancies, monochorionic twins have increased rates of perinatal morbidity and mortality, believed due in part to both twin-twin transfusion syndrome and an increased risk of congenital anomalies. Here we describe the prevalence of noncardiac structural anomalies in monochorionic twins with twin-twin transfusion syndrome who underwent laser surgery. METHODS: In a retrospective study of 221 consecutive cases of twin-twin transfusion syndrome treated with laser surgery, noncardiac anomalies were identified by review of antepartum and neonatal medical records. RESULTS: Of 377 live-born twins, 19 (5.0%) had a noncardiac anomaly. This rate was increased for donor versus recipient twins (8.5% versus 2.0%; P < .01). The presence of an anomaly was unrelated to the Quintero stage, the presence of donor intrauterine growth restriction, or 30-day survival of the donor or recipient. CONCLUSIONS: The prevalence of noncardiac anomalies in pregnancies complicated by twin-twin transfusion syndrome who underwent laser surgery was higher in donors versus recipients.

Ancient origin of placental expression in the growth hormone genes of anthropoid primates.

In anthropoid primates, growth hormone (GH) genes have undergone at least 2 independent locus expansions, one in platyrrhines (New World monkeys) and another in catarrhines (Old World monkeys and apes). In catarrhines, the GH cluster has a pituitary-expressed gene called GH1; the remaining GH genes include placental GHs and placental lactogens. Here, we provide cDNA sequence evidence that the platyrrhine GH cluster also includes at least 3 placenta expressed genes and phylogenetic evidence that placenta expressed anthropoid GH genes have undergone strong adaptive evolution, whereas pituitary-expressed GH genes have faced strict functional constraint. Our phylogenetic evidence also points to lineage-specific gene gain and loss in early placental mammalian evolution, with at least three copies of the GH gene present at the time of the last common ancestor (LCA) of primates, rodents, and laurasiatherians. Anthropoid primates and laurasiatherians share gene descendants of one of these three copies, whereas rodents and strepsirrhine primates each maintain a separate copy. Eight of the amino-acid replacements that occurred on the lineage leading to the LCA of extant anthropoids have been implicated in GH signaling at the maternal-fetal interface. Thus, placental expression of GH may have preceded the separate series of GH gene duplications that occurred in catarrhines and platyrrhines (i.e., the roles played by placenta-expressed GHs in human pregnancy may have a longer evolutionary history than previously appreciated).

A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death.

Galectins are proteins that regulate immune responses through the recognition of cell-surface glycans. We present evidence that 16 human galectin genes are expressed at the maternal-fetal interface and demonstrate that a cluster of 5 galectin genes on human chromosome 19 emerged during primate evolution as a result of duplication and rearrangement of genes and pseudogenes via a birth and death process primarily mediated by transposable long interspersed nuclear elements (LINEs). Genes in the cluster are found only in anthropoids, a group of primate species that differ from their strepsirrhine counterparts by having relatively large brains and long gestations. Three of the human cluster genes (LGALS13, -14, and -16) were found to be placenta-specific. Homology modeling revealed conserved three-dimensional structures of galectins in the human cluster; however, analyses of 24 newly derived and 69 publicly available sequences in 10 anthropoid species indicate functional diversification by evidence of positive selection and amino acid replacements in carbohydrate-recognition domains. Moreover, we demonstrate altered sugar-binding capacities of 6 recombinant galectins in the cluster. We show that human placenta-specific galectins are predominantly expressed by the syncytiotrophoblast, a primary site of metabolic exchange where, early during pregnancy, the fetus comes in contact with immune cells circulating in maternal blood. Because ex vivo functional assays demonstrate that placenta-specific galectins induce the apoptosis of T lymphocytes, we propose that these galectins reduce the danger of maternal immune attacks on the fetal semiallograft, presumably conferring additional immune tolerance mechanisms and in turn sustaining hemochorial placentation during the long gestation of anthropoid primates.

Current practices in determining amnionicity and chorionicity in multiple gestations.

OBJECTIVE: To evaluate the accuracy of amnionicity and chorionicity (A/C) diagnosis of referral physicians and a tertiary care center as compared to histopathologic diagnosis. METHOD: A retrospective study of 289 multi-fetal gestations was performed comparing A/C diagnoses of referring physicians, a tertiary care center, and histopathology. RESULTS: Two hundred and eighty-nine multi-fetal pregnancies were referred for evaluation; only 43.6% (126/289) carried an accurate diagnosis of A/C before tertiary care center evaluation. The tertiary care center accurately identified A/C in 94.8% (274/289) overall and 100% in first trimester twins and triplets. Referrals with an unspecified A/C diagnosis included 46.1% (113/245) twins and 64.1% (25/39) triplets. CONCLUSION: Accurate diagnosis of A/C can be obtained by the early assessment of key sonographic findings. Referral providers are less accurate at determining A/C of multifetal gestation when compared to a tertiary center, suggesting that an emphasis should be placed on enhancing these diagnostic skills in the general community or encouraging referral when diagnosis is ambiguous.

Emergence of hormonal and redox regulation of galectin-1 in placental mammals: implication in maternal-fetal immune tolerance.

Galectin-1 is an anti-inflammatory lectin with pleiotropic regulatory functions at the crossroads of innate and adaptive immunity. It is expressed in immune privileged sites and is implicated in establishing maternal-fetal immune tolerance, which is essential for successful pregnancy in eutherian mammals. Here, we show conserved placental localization of galectin-1 in primates and its predominant expression in maternal decidua. Phylogenetic footprinting and shadowing unveil conserved cis motifs, including an estrogen responsive element in the 5' promoter of LGALS1, that were gained during the emergence of placental mammals and could account for sex steroid regulation of LGALS1 expression, thus providing additional evidence for the role of galectin-1 in immune-endocrine cross-talk. Maximum parsimony and maximum likelihood analyses of 27 publicly available vertebrate and seven newly sequenced primate LGALS1 coding sequences reveal that intense purifying selection has been acting on residues in the carbohydrate recognition domain and dimerization interface that are involved in immune functions. Parsimony- and codon model-based phylogenetic analysis of coding sequences show that amino acid replacements occurred in early mammalian evolution on key residues, including gain of cysteines, which regulate immune functions by redox status-mediated conformational changes that disable sugar binding and dimerization, and that the acquired immunoregulatory functions of galectin-1 then became highly conserved in eutherian lineages, suggesting the emergence of hormonal and redox regulation of galectin-1 in placental mammals may be implicated in maternal-fetal immune tolerance.

Idiopathic persistent pulmonary hypertension in an infant with Smith-Lemli-Opitz syndrome.

Persistent pulmonary hypertension (PPHN) of the newborn remains a challenging condition to diagnose and treat. It has been reported in infants with Smith-Lemli-Opitz syndrome (SLOS), a rare defect in cholesterol synthesis. Typically, there is evidence of pulmonary hypoplasia. We report the first case of PPHN in the absence of pulmonary hypoplasia or other parenchymal diseases in an infant with SLOS. Perturbations in cholesterol metabolism interrupt key signaling pathways that participate in the normal maintenance of pulmonary vascular tone. We found that caveolae-dependent signaling may be involved in this process since our patient had altered expression of caveolin-1.

Keratin 8 protection of placental barrier function.

The intermediate filament protein keratin 8 (K8) is critical for the development of most mouse embryos beyond midgestation. We find that 68% of K8-/- embryos, in a sensitive genetic background, are rescued from placental bleeding and subsequent death by cellular complementation with wild-type tetraploid extraembryonic cells. This indicates that the primary defect responsible for K8-/- lethality is trophoblast giant cell layer failure. Furthermore, the genetic absence of maternal but not paternal TNF doubles the number of viable K8-/- embryos. Finally, we show that K8-/- concepti are more sensitive to a TNF-dependent epithelial apoptosis induced by the administration of concanavalin A (ConA) to pregnant mothers. The ConA-induced failure of the trophoblast giant cell barrier results in hematoma formation between the trophoblast giant cell layer and the embryonic yolk sac in a phenocopy of dying K8-deficient concepti in a sensitive genetic background. We conclude the lethality of K8-/- embryos is due to a TNF-sensitive failure of trophoblast giant cell barrier function. The keratin-dependent protection of trophoblast giant cells from a maternal TNF-dependent apoptotic challenge may be a key function of simple epithelial keratins.

Acardiac fetus: evidence in support of a vascular/hypoxia pathogenesis for isolated oral clefting.

BACKGROUND: The acardiac human fetus represents an accident of monozygotic twinning or higher multiple births due to an artery-to-artery and a vein-to-vein anastomosis in the monochorial placenta. Blood returning to the placenta through the umbilical artery of a normal cotwin is directed into the umbilical artery of the acardiac twin such that blood reaching the cranial end of the embryo is likely to be poorly oxygenated resulting in a number of structural defects including oral clefts. Although retrograde perfusion as a cause of hypoxia is unique to the acardiac fetus, there is ample evidence from animal studies that hypoxia is associated with facial clefting. METHODS: Twenty-six acardiac fetuses were examined at UCSD Medical Center between 1974 and 2003. RESULTS: In 12 of the 26, the cephalic end of the fetus was sufficiently intact to document the structures of the face. Of these, cleft lip +/- palate was present in five and cleft palate alone was present in one. In all six, the oral cleft followed the normal planes of facial closure. The cotwin in all six cases was normal. CONCLUSIONS: This article suggests that decreased blood flow/hypoxia to the cephalic end of the fetus may be an important contributor to the development of cleft lip +/- palate and cleft palate alone in the acardiac fetus and raises the possibility that this may also be a mechanism responsible for oral clefting in singletons.

Placenta accreta: an association with fibroids and Asherman syndrome.

OBJECTIVE: Placenta accreta is a life-threatening problem that is rising in incidence in the developed world. The increased risk of placenta accreta in women with placenta previa and 1 or more prior cesarean deliveries is well established and prompts careful sonographic evaluation. Our objective was to emphasize that accreta is also identified at sites other than cesarean scars. METHODS: Two cases of placenta accreta without placenta previa seen in association with uterine scarring from myomectomy and uterine fibroids are described. RESULTS: The sonographic and magnetic resonance imaging findings of accreta are reviewed in the classic setting of prior cesarean deliveries as well as myomectomy and uterine fibroids. CONCLUSIONS: We suggest that when the placenta overlies any uterine abnormality, a careful search for invasive placentation is warranted.

A retrospective analysis of placentas from twin pregnancies derived from assisted reproductive technology.

There are conflicting studies associating twin pregnancies derived from assisted reproductive technology (ART) with preterm birth, low birthweight, and other negative outcomes. This work investigates whether ART is linked with any placental pathology, given that placentation significantly influences fetal development. A 5-year, retrospective cohort study was conducted on placentas from twin pregnancies. The placental information from 417 patients was divided into two groups: placentas derived from ART and placentas derived from spontaneous pregnancies (non-ART). Available clinical information and pathologic findings from both groups then were compared. There was no statistical difference in the prevalence of placental pathology between the non-ART and ART cohorts (i.e., cord insertion, single umbilical artery, cord knot, retroplacental hemorrhage, infarction, vasculopathy, vascular anastomoses, chorangiosis, villitis, deciduitis, chorioamnionitis, meconium staining). However, 8% of ART multiple pregnancies were monochorionic. While monochorionicity is a known risk factor for adverse obstetric and neonatal outcomes, the rate of monochorionic placentation did not increase as a result of ART. Nevertheless, it is interesting to note that this small percentage of monochorionic placentation occurred in the ART cohort despite the implantation of individual embryos. Overall, the data suggests that ART does not have a role in the pathologic placentation of twin pregnancies.

The core transcriptome of mammalian placentas and the divergence of expression with placental shape.

INTRODUCTION: The placenta is arguably the most anatomically variable organ in mammals even though its primary function is conserved. METHOD: Using RNA-Seq, we measured the expression profiles of 55 term placentas of 14 species of mammals representing all major eutherian superordinal clades and marsupials, and compared the evolution of expression across clades. RESULTS: We identified a set of 115 core genes which is expressed (FPKM ≥10) in all eutherian placentas, including genes with immune-modulating properties (ANXA2, ANXA1, S100A11, S100A10, and LGALS1), cell-cell interactions (LAMC1, LUM, and LGALS1), invasion (GRB2 and RALB) and syncytialization (ANXA5 and ANXA1). We also identified multiple pre-eclampsia associated genes which are differentially expressed in Homo sapiens when compared to the other 13 species. Multiple genes are significantly associated with placenta morphology, including EREG and WNT5A which are both associated with placental shape. DISCUSSION: 115 genes are important for the core functions of the placenta in all eutherian species analyzed. The molecular functions and pathways enriched in the core placenta align with the evolutionarily conserved functionality of the placenta.

Placental mesenchymal dysplasia is associated with high rates of intrauterine growth restriction and fetal demise: A report of 11 new cases and a review of the literature.

Placental mesenchymal dysplasia (PMD) is a rare condition of placentomegaly and abnormal chorionic villi often clinically mistakenly as partial hydatidiform mole. However, it is clinicopathologically distinct with high incidence of intrauterine growth restriction (IUGR) and fetal death. This study presents 11 new PMD cases and provides a meta-analysis of the associated IUGR and fetal death rates. The cases were identified between 1971 and 2005, mostly from consultation files. To our knowledge, 71 PMD cases have previously been reported; 15 of these were associated with Beckwith-Wiedemann syndrome (BWS). With the addition of our new results, among all cases without BWS, 50% had IUGR and 43% had intrauterine fetal demise (IUFD) or neonatal death. Females represented 82% of cases. Thus, PMD is associated with high IUGR and IUFD/neonatal death rates and disproportionally affects females. The cause and pathogenesis are yet unknown. The current understanding and hypotheses involving PMD are discussed.

Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta.

BACKGROUND: The incidence of placenta accreta has increased dramatically over the last three decades, in concert with the increase in the cesarean delivery rate. Optimal management requires accurate prenatal diagnosis. The purpose of this study was to determine the precision and reliability of ultrasonography and magnetic resonance imaging (MRI) in diagnosing placenta accreta. METHODS: A historical cohort study was performed with information gathered from our obstetric, radiologic, and pathology databases. Records from January 2000 to June 2005 were reviewed to identify patients with a diagnosis of placenta previa, low-lying placenta with a prior cesarean delivery, or history of a myomectomy to determine the accuracy of pelvic ultrasonography in the diagnosis of placenta accreta. The records of those considered to be suspicious for placenta accreta and subsequently referred for additional confirmation by MRI were also analyzed. The sonographic and MRI diagnoses were compared with the final pathologic or operative findings or with both. RESULTS: Of the 453 women with placenta previa, previous cesarean delivery and low-lying anterior placenta, or previous myomectomy, 39 had placenta accreta confirmed by pathological examination. Ultrasonography accurately predicted placenta accreta in 30 of 39 of women and correctly ruled out placenta accreta in 398 of 414 without placenta accreta (sensitivity 0.77, specificity 0.96). Forty-two women underwent MRI evaluation because of findings suspicious or inconclusive of placenta accreta by ultrasonography. Magnetic resonance imaging accurately predicted placenta accreta in 23 of 26 cases with placenta accreta and correctly ruled out placenta accreta in 14 of 14 (sensitivity 0.88, specificity 1.0). CONCLUSION: A two-stage protocol for evaluating women at high risk for placenta accreta, which uses ultrasonography first, and then MRI for cases with inconclusive ultrasound features, will optimize diagnostic accuracy.

"Lumpy jaw" in exotic hoof stock: a histopathologic interpretation with a treatment proposal.

"Lumpy jaw" of artiodactyls and macropods, although often considered a manifestation of actinomycosis, is actually an osteomyelitis, perhaps commencing with a dental root abscess or trauma to the jaw. Anaerobes may be cultured from the lesions, and vegetable matter may be impacted in them. It is a chronic disease and difficult to treat. Successful treatment may include draining the abscess, cleaning the cavity with saline and antibiotics, flushing with a combination of hydrogen peroxide-sodium hypochlorite and Betadine, and apicoectomy and endodontic filling when active inflammation has subsided.