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.

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.

Modulation of higher-primate adrenal androgen secretion with estrogen-alone or estrogen-plus-progesterone intervention.

OBJECTIVE: Circulating adrenal steroids rise during the menopausal transition in most middle-aged women and may contribute to differences in between-women symptoms and ultimate health outcomes. However, the mechanisms for this shift in adrenal steroid production in middle-aged women are not known. This study aims to determine whether hormone therapy (HT) for 1 year can modulate adrenal androgen production. METHODS: Younger (9.8 [0.4] years, n = 20) and older (22.7 [0.4] years, n = 37) female laboratory macaques were ovariectomized, and each group was treated with different regimens of HT for up to 1 year. Changes in adrenal histology and circulating adrenal androgens were monitored after estrogen-alone (E) or estrogen plus progesterone (E + P) treatment, and these changes were compared with the same measures in similarly aged animals given vehicle. RESULTS: Zona reticularis area, serum dehydroepiandrosterone (DHEA), and serum dehydroepiandrosterone sulfate (DHEAS) were higher in younger vehicle-treated animals compared with older vehicle-treated animals (P < 0.02). Both E and E + P treatments decreased circulating DHEAS in the younger group (P < 0.05). Although E treatment also decreased DHEAS in the older group, this was not statistically significant. In contrast, E + P treatment in the older group resulted in a rise in DHEAS over vehicle, which was significantly higher than the results of E treatment (P < 0.01). Circulating concentrations of DHEA exhibited similar trends, but these changes did not reach statistical significance. CONCLUSIONS: These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determine adrenal response.

Monozygotic Twinning.

This article discusses pathologies found in monozygotic twinning. Detailed information is provided regarding the development during monozygotic twin formation: embryo development, twin-to-twin transfusion syndrome, acardiac twinning, vanishing twins, conjoined twins, and Beckwith-Weidmann syndrome twins. An algorithm describing the approach for identifying pathology in a placenta with multiple pregnancies is presented.

Elephant transcriptome provides insights into the evolution of eutherian placentation.

The chorioallantoic placenta connects mother and fetus in eutherian pregnancies. In order to understand the evolution of the placenta and provide further understanding of placenta biology, we sequenced the transcriptome of a term placenta of an African elephant (Loxodonta africana) and compared these data with RNA sequence and microarray data from other eutherian placentas including human, mouse, and cow. We characterized the composition of 55,910 expressed sequence tag (i.e., cDNA) contigs using our custom annotation pipeline. A Markov algorithm was used to cluster orthologs of human, mouse, cow, and elephant placenta transcripts. We found 2,963 genes are commonly expressed in the placentas of these eutherian mammals. Gene ontology categories previously suggested to be important for placenta function (e.g., estrogen receptor signaling pathway, cell motion and migration, and adherens junctions) were significantly enriched in these eutherian placenta-expressed genes. Genes duplicated in different lineages and also specifically expressed in the placenta contribute to the great diversity observed in mammalian placenta anatomy. We identified 1,365 human lineage-specific, 1,235 mouse lineage-specific, 436 cow lineage-specific, and 904 elephant-specific placenta-expressed (PE) genes. The most enriched clusters of human-specific PE genes are signal/glycoprotein and immunoglobulin, and humans possess a deeply invasive human hemochorial placenta that comes into direct contact with maternal immune cells. Inference of phylogenetically conserved and derived transcripts demonstrates the power of comparative transcriptomics to trace placenta evolution and variation across mammals and identified candidate genes that may be important in the normal function of the human placenta, and their dysfunction may be related to human pregnancy complications.

Placental histologic criteria for diagnosis of cord accident: sensitivity and specificity.

"Cord accident" (compromised umbilical blood flow) as a cause of stillbirth is underreported, mainly due to a lack of diagnostic criteria. Based on fetal vascular pathology in the placenta, we have previously established histologic criteria for the diagnosis of cord accident. In the current study, we set out to test the sensitivity and specificity of these criteria by reviewing an independent set of stillbirth cases. Placental slides from 26 cases (in which cord accident was deemed the cause of death) and 62 controls (in which the cause of death was anything other than cord accident) were reviewed. The following histologic changes were noted: (1) dilated fetal vessels, (2) thrombosis in fetal vessels, and (3) avascular or near-avascular chorionic villi. "Minimal" criteria were defined as the presence of dilated and thrombosed fetal vessels, while the additional presence of focal or regional avascular or near-avascular villi satisfied the complete criteria. Of the 62 stillbirth controls with cause of death other than cord accident, 13 (21%) met the minimal criteria (specificity 79%) and only 4 (6%) met the complete criteria for cord accident (specificity 94%). In contrast, of the 26 cases with a cause of death related to cord accident, 16 met the minimal criteria (sensitivity 62%) and 12 met the complete criteria (sensitivity 46%). These histologic criteria identify cases of cord accident as a cause of stillbirth with very high specificity. This study confirms the utility of these criteria for diagnosis of cord accident and further stresses placental examination in evaluation of stillbirths.

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.

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.

Biomedical differences between human and nonhuman hominids: potential roles for uniquely human aspects of sialic acid biology.

Although humans are genetically very similar to the evolutionarily related nonhuman hominids (chimpanzees, bonobos, gorillas, and orangutans), comparative studies suggest a surprising number of uniquely human differences in the incidence and/or severity of biomedical conditions. Some differences are due to anatomical changes that occurred during human evolution. However, many cannot be explained either by these changes or by known environmental factors. Because chimpanzees were long considered models for human disease, it is important to be aware of these differences, which appear to have been deemphasized relative to similarities. We focus on the pathophysiology and pathobiology of biomedical conditions that appear unique to humans, including several speculative possibilities that require further study. We pay particular attention to the possible contributions of uniquely human changes in the biology of cell-surface sialic acids and the proteins that recognize them. We also discuss the metabolic incorporation of a diet-derived nonhuman sialic acid, which generates a novel xeno-autoantigen reaction, and chronic inflammation known as xenosialitis.

Effects of triclocarban on intact immature male rat: augmentation of androgen action.

Triclocarban (TCC; 3,4,4'-trichlorocarbanilide) is an antimicrobial agent used widely in various personal hygiene products including soaps. Recently, TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. This study was designed to evaluate the effects of TCC on intact age-matched male rats and on human prostate LNCaP and C4-2B cells. Seven-week-old male Sprague-Dawley rats received either a normal diet or a diet supplemented with TCC (0.25% in diet) for 10 days. Triclocarban induced hyperplasia of accessory sex organs in the absence of significant qualitative histological changes. Serum luteinizing hormone (LH) and testosterone were not significantly altered by TCC treatment. In prostate cancer-derived LNCaP and C4-2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. In conclusion, TCC significantly affects intact male reproductive organs and potentiates androgen effects in prostate cancer cells.

Spontaneous twin anemia-polycythemia sequence complicated by recipient placental vascular thrombosis and hydrops fetalis.

Twin anemia-polycythemia sequence (TAPS) is an atypical form of twin-twin transfusion syndrome (TTTS) that presents as a large intertwin hemoglobin difference with one twin developing anemia and the other developing polycythemia, without oligohydramnios-polyhydramnios sequence (Lopriore et al., Placenta 2007;28:47-51). The prenatal diagnostic criteria for TAPS require that the middle cerebral artery-peak systolic velocity (MCA-PSV) measure greater than 1.5 multiples of median (MoM) in the donor twin and less than 0.8 MoM in the recipient twin (Robyr et al., Am J Obstet Gynecol 2006;194:796-803; Klaritsch et al., Ultrasound Obstet Gynecol 2009;34:149-154; Mari et al., N Engl Med 2000;342:9-14). The presumed etiology of TAPS involves the presence of small caliber arteriovenous anastomoses, which generate a slow transfusional process allowing for hemodynamic compensation (Lopriore et al., Placenta 2007;28:47-51; Lopriore et al., Placenta 2009;30:223-225; Lewi et al., Am J Obstet Gynecol 2006;194:790-795; Lopriore et al., Am J Obstet Gynecol 2008;112:753-758; Van den Wijngaard et al., Placenta 2007;28:611-615). The resulting polycythemia in the recipient twin is a risk factor for fetal and placental thrombosis (Van den Wijngaard et al., Am J Physiol 2005;288:R799-R814). We present a case of spontaneous TAPS complicated by a large placental vessel thrombosis and hydrops fetalis. Treatment via selective laser photocoagulation of communicating vessels (SLPCV) resulted in normalization of the MCA-PSV discordance.

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.

Discordant blood chimerism in dizygotic monochorionic laser-treated twin-twin transfusion syndrome.

BACKGROUND: Twin-twin transfusion syndrome occurs in 10% of monozygotic monochorionic twin gestations and results from an unbalanced exchange of blood from the donor to the recipient fetus through placental anastomoses. CASE: We present a case of twin-twin transfusion syndrome with differing fetal sex treated with in utero laser surgery. Genetic analyses showed 46,XX/46,XY hematologic chimerism in both twins at birth and at 6 months, with the recipient twin being significantly more chimeric than the donor. Placental pathologic examination confirmed monochorionicity and laser ablation of all anastomoses. CONCLUSION: Despite in utero separation of the fetal circulations remote from delivery, hematologic chimerism persisted after birth. We speculate that the greater degree of blood chimerism in the recipient compared with the donor was related to the pathophysiology of twin-twin transfusion syndrome before laser surgery.

Perinatal survival following preferential sequential selective laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: To describe our experience with preferential use of sequential selective laser photocoagulation of communicating vessels (SQLPCV) in women with twin-twin transfusion syndrome (TTTS). METHODS: Women with TTTS received treatment using the SQLPCV technique whenever possible. SQLPCV mandates ablation of all donor-to-recipient arteriovenous communications first, in comparison to the standard non-sequential selective technique. RESULTS: Of 99 consecutive women treated, 64 received SQLPCV. Overall survival of one or both twins was 91% and dual survival was 72%. Higher dual survival rates (80 vs. 57%, p=0.0317) and donor survival rates (83 vs. 63%, p=0.0489) were noted in the SQLPCV group. Multivariable logistic regression demonstrated that the SQLPCV technique was highly associated with dual survivorship (OR=4.64 [1.57-13.74], p=0.0056), when controlling for gestational age at surgery, duration of laser treatment and number of anastomoses lasered. Neither Quintero stage, placental location, preoperative discordance prior to surgery, nor preoperative cervical length contributed to this equation. The SQLPCV technique was also associated with donor survivorship (OR=4.43 [1.44-13.67], p=0.0095), when controlling for the same covariates. CONCLUSION: Treatment of TTTS via SQLPCV technique was associated with higher dual survival and donor twin survival rates as compared to standard SLPCV.

Deportation of trophoblastic emboli to maternal lung: A source of cell-free DNA in maternal blood?

During human pregnancy there is a continuous transport of numerous syncytiotrophoblastic cells from the intervillous space of the placenta into the maternal lung. There these cells undergo apoptosis and the fetal nuclear DNA is liberated within the pulmonary capillaries to become cffDNA in the maternal serum. We have examined the sections of lungs of 11 pregnant women (from 8 weeks to term gestation) who had come to the Medical Examiner's Offices after their traumatic demise. We then identified the deported, embolized trophoblastic cells in pulmonary capillaries and attempted to show them to contain hCG immunohistochemically but were unable to do this. We also determined their apoptotic profiles by TUNEL reaction.