Guía de práctica clínica para la prevención y manejo del parto pretérmino / Clinical practice guideline for the prevention and management of preterm labor

El parto pretérmino (PPT) es el que ocurre antes de la semana 37 de gestación. La Organización Mundial de la Salud (OMS) estimó que el 9.6% de los recién nacidos (RN) en el año 2010 fueron prematuros, lo que representa cerca de 13 millones de nacimientos. De éstos, más de 11 millones se concentran en África y Asia, y cerca de 1 millón en Latinoamérica (1). En el mismo año se reportó que el PPT es un importante problema de salud pública, que está en aumento, y se asocia a mortalidad y morbilidad neonatal (2). Los recién nacidos pretérmino (RN PT) son especialmente vulnerables a complicaciones respiratorias, infecciosas, vaso-proliferativas, neurológicas, de regulación térmica y de alimentación (3, 4). Sin embargo, la morbilidad y mortalidad infantil por el PPT se pueden reducir con intervenciones a gestantes antes y durante el parto, y al RN inmediatamente después del parto (5). Concordantemente, en Perú, casi la tercera parte de las muertes neonatales que se produjeron en el 2017 tuvieron su origen en complicaciones relacionadas a la prematuridad e inmaturidad (6). Por ello, resulta necesario que el Seguro Social de Salud establezca lineamientos basados en evidencia para gestionar de la mejor manera los procesos y procedimientos asistenciales para la prevención y manejo del PPT.

Comparative Study of Prenatal Development Between Myotis albescens (Chiroptera: Vespertilionidae) and Eumops patagonicus (Chiroptera: Molossidae): The Chorionic Vesicle and Extraembryonic Membranes Considerations.

We presented a comparative study of two species of South American bats, Myotis albescens and Eumops patagonicus, about prenatal development. This study was carried out using 60 specimens, which were measured and photographed, and the embryonic stage was assigned by the staging system for Carollia perspicillata. We observed that the chorionic vesicle showed similarities in the disposition of the extraembryonic membranes, but they differed in characteristics of their yolk sac; in E. patagonicus, it was more glandular than M. albescens. M. albescens presented a well-developed discoid placenta with a caudal antimesometrial position, but E. patagonicus presented a diffuse placenta, which persists until the end of gestation and a discoid placenta in the uterus-tubal junction. In the embryogenesis, early stages, middle stages, and late stages were defined. In the early stage, the embryonic morphology is similar in the two species. The middle stage is characterized by the muzzle and pinna formation, fore and hind limb regionalization, and the formation of the patagium primordium. In the late stage, the overall growth of the embryo occurs. Its fore and hind limbs, patagium, and the typical craniofacial features are configured. We conclude that in early stages of development, the embryonic morphology of M. albescens and E. patagonicus is similar, while in late stages differences are evident; mainly the craniofacial structures and uropatagium configuration characteristics that allow their classification at the family level. Moreover, differences in time of fusion of maxillary and mandibular process were registered. This could be related to the morphology of the muzzle of each species. Anat Rec, 301:1527-1543, 2018. © 2018 Wiley Periodicals, Inc.

Classics revisited: Miguel Fernández on germ layer inversion and specific polyembryony in armadillos.

BACKGROUND: Miguel Fernández was an Argentinian zoologist who published the first account of obligate polyembryony in armadillos. His contribution is here discussed in relation to his contemporaries, Newman and Patterson, and more recent work. FINDINGS: Fernandez worked on the mulita (Dasypus hybridus). He was able to get early stages before twinning occurred and show it was preceded by inversion of the germ layers. By the primitive streak stage there were separate embryonic shields and partition of the amnion. There was, however, a single exocoelom and all embryos were enclosed in a common set of membranes comprising chorion towards the attachment site in the uterine fundus and inverted yolk sac on the opposite face. He showed that monozygotic twinning did not occur in another armadillo, the peludo (Chaetophractus villosus). CONCLUSIONS: Fernández's work represented a major breakthrough in understanding how twinning occurred in armadillos. His work and that of others is of intrinsic interest to zoologists and has a direct bearing on the origin of monozygotic twins and birth defects in humans.

Fetal Membrane Ultrastructure and Development in the Oviparous Milksnake Lampropeltis triangulum (Colubridae) with Reference to Function and Evolution in Snakes.

In eggs of oviparous reptiles, fetal membranes maintain developing embryos through the exchange of respiratory gases and provision of water and calcium. As part of a survey of reptilian fetal membranes, we used scanning electron microscopy to study fetal membrane morphology in the oviparous Pueblan milksnake, Lampropeltis triangulum campbelli. The chorioallantois initially is an avascular structure lined by enlarged chorionic and allantoic epithelia. Upon vascularization, the chorionic epithelium becomes greatly attenuated, enhancing the potential for gas exchange; the allantoic epithelium also flattens. The bilaminar omphalopleure of the yolk sac lacks blood vessels, but it becomes vascularized by allantoic capillaries and transformed into an omphalallantois. Upon regression of the isolated yolk mass, this membrane is converted to chorioallantois, equipping it for gas exchange. Allantoic fluid serves as a water reservoir, and we postulate that it facilitates water uptake by establishing an osmotic gradient. Early in development, epithelia of both the chorion and the omphalopleure show apical microvilli that greatly increase the cell surface area available for water uptake. However, these features are incompatible with gas exchange and are lost as oxygen needs take precedence. A comparison of the fetal membranes to those of other squamate species (both oviparous and viviparous) reveals characteristics that are probably ancestral for snakes, some of which are plesiomorphic for Squamata. The widespread phylogenetic distribution of these features reflects their utility as adaptations that serve functional requirements of squamate embryos.

The embryo reunited with its membranes in Göttingen.

An EMBO workshop entitled 'Embryonic-Extraembryonic Interfaces' took place in Göttingen, Germany, in May 2015. It showcased the enormous breadth of this area not only by touching on the molecular and cellular mechanisms of development, but also because of its coverage of particularly interesting evolutionary questions and of several medically related aspects. This Meeting Review discusses some highlights from the workshop and the emerging themes in the field.

Placentation and fetal membrane development in the South American coati, Nasua nasua (Mammalia, Carnivora, Procyonidae).

BACKGROUND: Placental research in carnivores has concentrated on domestic species, which have zonary, labyrinthine placentas with an endotheliochorial barrier. Although the coati, Nasua nasua, is a widely distributed species in South America, data on the development of the placenta and the fetal membranes in this species are very sparse. FINDINGS: Four placentas from mid-gestation to near term were collected from wild individuals and were investigated based on gross morphology, histology, immunohistochemistry and electron microscopy. The available data support the concept that the ancestral condition of placentation in carnivores is phylogenetically characterized by a zonary and labyrinthine placental type with an endotheliochorial fetomaternal barrier, comprising extended epitheliochorial and haemochorial zones, such as hemophagous organs for iron supply and histiotrophe uptake and a yolk sac placenta. CONCLUSIONS: Because of the foundational mechanisms that lead to the considerable complexity of fetomaternal contact zones in carnivores have not been studied, carnivores are interesting animal models for interhaemal barrier differentiation.

BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity.

The visceral endoderm (VE) is an epithelial tissue in the early postimplantation mouse embryo that encapsulates the pluripotent epiblast distally and the extraembryonic ectoderm proximally. In addition to facilitating nutrient exchange before the establishment of a circulation, the VE is critical for patterning the epiblast. Since VE is derived from the primitive endoderm (PrE) of the blastocyst, and PrE-derived eXtraembryonic ENdoderm (XEN) cells can be propagated in vitro, XEN cells should provide an important tool for identifying factors that direct VE differentiation. In this study, we demonstrated that BMP4 signaling induces the formation of a polarized epithelium in XEN cells. This morphological transition was reversible, and was associated with the acquisition of a molecular signature comparable to extraembryonic (ex) VE. Resembling exVE which will form the endoderm of the visceral yolk sac, BMP4-treated XEN cells regulated hematopoiesis by stimulating the expansion of primitive erythroid progenitors. We also observed that LIF exerted an antagonistic effect on BMP4-induced XEN cell differentiation, thereby impacting the extrinsic conditions used for the isolation and maintenance of XEN cells in an undifferentiated state. Taken together, our data suggest that XEN cells can be differentiated towards an exVE identity upon BMP4 stimulation and therefore represent a valuable tool for investigating PrE lineage differentiation.

A mouse model of spontaneous preterm birth based on the genetic ablation of biglycan and decorin.

Preterm premature rupture of membranes is responsible for one-third of preterm births. Ehlers-Danlos syndrome (EDS) is associated with preterm premature rupture of membranes in humans. In particular, an EDS variant is caused by a genetic mutation resulting in abnormal secretion of biglycan and decorin, two small leucine-rich proteoglycans highly expressed in reproductive tissues. Because biglycan/decorin null mutant (Bgn(-/-)Dcn(-/-)) mice demonstrate phenotypic changes similar to EDS, we used this model to test whether either biglycan or decorin or both play a role in the attainment of successful term gestation. Wild-type biglycan null mutant, decorin null mutant, and biglycan/decorin null mutant pregnancies were assessed for the length of gestation, pup and placenta weight, and litter size. Quantitative real-time PCR was performed to measure biglycan and decorin gene expression, and immunohistochemistry was performed to assess protein expression in placenta and fetal membranes at embryonic days E12, E15, and E18. Bgn(-/-)Dcn(-/-) dams displayed preterm birth, whereas the possession of at least two biglycan or decorin wild-type alleles was protective of preterm birth. The number of Bgn(-/-)Dcn(-/-) pups was decreased at postnatal day P1 but not at E18. Biglycan and decorin were upregulated in the placenta in the absence of each other and were developmentally regulated in fetal membranes, suggesting that these two proteoglycans demonstrate genetic complementation and contribute to gestational success in a dose-dependent manner. Thus, the biglycan/decorin null mutant mouse is a model of genetically induced preterm birth and perinatal loss. This model presents novel targets for preventive or therapeutic manipulation of preterm birth.

Pluripotent hybrid cells contribute to extraembryonic as well as embryonic tissues.

The restricted gene expression of a differentiated cell can be reversed by forming hybrid with embryonic stem cells (ESCs). The resulting hybrid cells showed not only an ESC-specific marker expression but also a differentiation potential similar to the pluripotent fusion partner. Here, we evaluated whether the tetraploid fusion hybrid cells have a unique differentiation potential compared with diploid pluripotent cells. The first Oct4-GFP-positive cells were observed at day 2 following fusion between ESCs and neurosphere cells (OG2(+/-)/ROSA26(+/-)). Reprogramming efficiency was as high as 94.5% at passage 5 and 96.4% at passage 13. We have found that the tetraploid hybrid cells could form chimera with contribution to placenta after blastocyst injection. This result indicates that the tetraploid pluripotent fusion hybrid cells have wide range of differentiation potential. Therefore, we suggest that once the somatic cells are reprogrammed by fusion with ESCs, the tetraploid hybrid cells contributed to the extraembryonic as well as embryonic tissues.

Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos.

Mutations in the gene encoding the cholesterol biosynthetic enzyme NSDHL are associated with the X-linked male-lethal bare patches (Bpa) mouse. Mutant male embryos for several Nsdhl alleles die in midgestation with placental insufficiency. We examined here a possible role of the maternal genotype in such placental pathology. Pre-pregnancy plasma cholesterol levels were similar between wild-type (WT) and Bpa(1H)/+ dams fed a standard, cholesterol-free diet. However, there was a marked decrease in cholesterol levels between embryonic day (E)8.5 and E10.5 for both genotypes. Further, there was a significant lag between E11.5 and E13.5 (P = 0.0011) in the recovery of levels in Bpa(1H)/+ dams to their pre-pregnancy values. To investigate possible effects of the maternal genotype on fetal placentation, we generated transgenic mice that expressed human NSDHL and rescued the male lethality of the Bpa(1H) null allele. We then compared placenta area at E10.5 in WT and Bpa(1H)/+ female embryos where the mutant X chromosome was transmitted from a heterozygous mother or a rescued mutant father. In mutant conceptuses, placental areas were approximately 50% less than WT. Surprisingly, expression of Nsdhl in trophoblast lineages of the placenta and yolk sac endoderm, which occurs only from the maternally inherited allele in a female embryo, had the largest effect on placental area (-0.681 mm(2); P < 0.0001). The maternal genotype had a smaller effect, independent of the fetal genotype (-0.283 mm(2); P = 0.024). These data demonstrate significant effects of the mother and fetal membranes on pregnancy outcome, with possible implications for cholesterol homeostasis during human pregnancy.

E2F4 cooperates with pRB in the development of extra-embryonic tissues.

The retinoblastoma gene, RB-1, was the first identified tumor suppressor. Rb(-/-) mice die in mid-gestation with defects in proliferation, differentiation and apoptosis. The activating E2F transcription factors, E2F1-3, contribute to these embryonic defects, indicating that they are key downstream targets of the retinoblastoma protein, pRB. E2F4 is the major pRB-associated E2F in vivo, yet its role in Rb(-/-) embryos is unknown. Here we establish that E2f4 deficiency reduced the lifespan of Rb(-/-) embryos by exacerbating the Rb mutant placental defect. We further show that this reflects the accumulation of trophectoderm-like cells in both Rb and Rb;E2f4 mutant placentas. Thus, Rb and E2f4 play cooperative roles in placental development. We used a conditional mouse model to allow Rb(-/-);E2f4(-/-) embryos to develop in the presence of Rb wild-type placentas. Under these conditions, Rb(-/-);E2f4(-/-) mutants survived to birth. These Rb(-/-);E2f4(-/-) embryos exhibited all of the defects characteristic of the Rb and E2f4 single mutants and had no novel defects. Taken together, our data show that pRB and E2F4 cooperate in placental development, but play largely non-overlapping roles in the development of many embryonic tissues.

Loss of mouse Ikbkap, a subunit of elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP.

Familial dysautonomia (FD), a devastating hereditary sensory and autonomic neuropathy, results from an intronic mutation in the IKBKAP gene that disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP) in the nervous system. To better understand the roles of IKAP in vivo, an Ikbkap knockout mouse model was created. Results from our study show that ablating Ikbkap leads to embryonic lethality, with no homozygous Ikbkap knockout (Ikbkap(-)(/)(-)) embryos surviving beyond 12.5 days postcoitum. Morphological analyses of the Ikbkap(-)(/)(-) conceptus at different stages revealed abnormalities in both the visceral yolk sac and the embryo, including stunted extraembryonic blood vessel formation, delayed entry into midgastrulation, disoriented dorsal primitive neural alignment, and failure to establish the embryonic vascular system. Further, we demonstrate downregulation of several genes that are important for neurulation and vascular development in the Ikbkap(-)(/)(-) embryos and show that this correlates with a defect in transcriptional elongation-coupled histone acetylation. Finally, we show that the embryonic lethality resulting from Ikbkap ablation can be rescued by a human IKBKAP transgene. For the first time, we demonstrate that IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human.

Developmental changes in insulin-like growth factor (IGF)-I and -II mRNA abundance in extra-embryonic membranes and small intestine of avian embryos.

OBJECTIVE: Numerous researchers have evaluated the insulin-like growth factors (IGF) influence on mammalian fetal development. Although IGF has been explored in the avian system, questions remain on the role of IGF in avian development. Therefore, the current study evaluated the mRNA abundance of IGF in the amnion and allantoic membranes and developing small intestine in the chicken, duck, and turkey during the incubation and post-hatch period. DESIGN: Broiler, duck, and turkey eggs were incubated with small intestinal, allantoic, and amniotic membranes collected in the final days of incubation and 1 week post-hatch. RNA was extracted using Trizol and qRT-PCR was utilized to compare differences during embryo development within and across species. RESULTS: The expression of the IGF mRNA varied between species in the final days of incubation in the amniotic and allantoic membranes. The turkey had higher (0.38-1.72 log) transcript abundance of IGF-I and IGF-II in the amnion and allantois compared to the chicken and duck. Evaluating the mRNA abundance within the chicken duodenum, jejunum, and ileum, the duodenum had the lowest expression of IGF-I and IGF-II (P<0.05) at day -4 of incubation compared to the jejunum and ileum. Focusing on differences in jejunal IGF expression among the three species, the turkey had the lowest IGF-I abundance at day -4 of incubation and highest IGF-I abundance at day of hatch (P<0.05). Transcript abundance of both IGF-II and IGF-R was highest in the turkey at day of hatch and day 1 post-hatch compared to the duck and chicken. The whole tissue versus the mucosal expression of the IGF mRNA abundance was evaluated during the post-hatch period. Duodenal, jejunal, and ileal segments had higher IGF-I transcript abundance (P<0.05) at day 1, day 3, and day of hatch, respectively. No differences were observed between segment and mucosa for IGF-II in the post-hatch period. The duodenal and jejunal mucosa IGF-R transcript abundance was greater (P<0.05) at day of hatch compared to the intestinal segment. The duck IGF mRNA in the jejunal mucosa was higher than the whole segment and decreased from day of hatch to day 3 post-hatch while the IGF mRNA abundance increased in the whole segment during the same time period. The turkey IGF-I transcript abundance decreased in both the segment and mucosa following hatch while the IGF-II mRNA expression increased by 1.5 logs from hatch to day 1 post-hatch. CONCLUSION: The transcript abundance of the IGF axis in the extra-embryonic membranes and gastrointestinal tissue of the developing chicken, duck, and turkey are influenced by embryonic age and species. A better understanding of the IGF axis in the small intestine during embryonic development may allow for increasing the optimal growth of both the gastrointestinal tract and the neonate.

[Fetal membranes: embryological development, structure and the physiopathology of the preterm premature rupture of membranes]. / Les membranes foetales : développement embryologique, structure et physiopathologie de la rupture prématurée avant terme.

Fetal membranes development is a complex process. The amniotic and exo-celomic cavities are appearing first. The rapid growth of the amniotic cavity is leading to the disappearance of the exo-celomic cavity and the chorion is merging with the decidua. Fetal membranes consist of three layers: the amnion and the chorion, issued from fetal tissues and the decidua issued from maternal tissue. A balance between the synthesis and the degradation of membranes components is physiologic throughout the gestation. Two main mechanisms are involved in the degradation process: apoptosis in the cellular compartment and matrix metalloproteinase (MMP) in the extracellular matrix. Regulation of MMP is depending on factors increasing their expression (cytokines) and factors decreasing their activity tissue inhibitor of metalloproteinases (TIMPS). Particular conditions can induce an unbalance between synthesis and degradation leading to the weakening of the membranes. Different factors can be associated to induce this unbalance: infection, hormonal factors, default in membranes fusion, oxidative stress and mechanic factors. In fine, the spontaneous rupture of the membranes is always occurring in regard of the uterine cervix after a process started several weeks before.

Extraembryonic development in insects and the acrobatics of blastokinesis.

Extraembryonic development is familiar to mouse researchers, but the term is largely unknown among insect developmental geneticists. This is not surprising, as the model system Drosophila melanogaster has an extremely reduced extraembryonic component, the amnioserosa. In contrast, most insects retain the ancestral complement of two distinct extraembryonic membranes, amnion and serosa. These membranes are involved in several key morphogenetic events at specific developmental stages. The events of anatrepsis and katatrepsis--collectively referred to as blastokinesis--are specific to hemimetabolous insects. Corresponding events in holometabolous insects are simplified and lack formal names. All insects retain dorsal closure, which has been well studied in Drosophila. This review aims to resurrect both the terminology and awareness of insect extraembryonic development--which were last common currency in the late nineteenth and early twentieth centuries--as a number of recent studies have identified essential components of these events, through RNA interference of developmental genes and ectopic hormonal treatments. As much remains unknown, this topic offers opportunities for research on tissue specification, the regulation of cell shape changes and tissue interactions during morphogenesis, tracing the origins and final fates of cell and tissue lineages, and ascertaining the membranes' functions between morphogenetic events.

Oxygen consumption as related to the development of the extraembryonic membranes and cardiovascular system in the European pond turtle (Emys orbicularis) embryogenesis.

The rate of oxygen consumption (V(O2)), embryo mass, distribution and mass of the chorioallantoic membrane (CAM), heart rate (HR), heart mass, and amnion rhythmic contractions (ARC) were studied in eggs of the European pond turtle (Emys orbicularis) incubated at 28 degrees C for 62.5+/-0.3 days. The V(O2) rapidly increased beginning from incubation day 19 (D19) to a maximum on D50 and then decreased until pipping. The rapid V(O2) rise was correlated with an increase in the CAM surface and mass, heart mass, and ARC amplitude, whereas the functional parameters such as HR and ARC frequency remained unchanged. The drop in V(O2) before pipping was accompanied by a decrease in HR, while the heart and CAM masses were almost constant. In the cases of short-term temperature deviations of +/-3 degrees C from 28 degrees C, changes in (O2) were significant until D50 and nonsignificant after that, the changes in ARC frequency and HR being significant at all stages studied. Thus, the developmental V(O2) changes were contributed mainly by the slow morphogenetic processes during D19-D50, whereas changes in functional parameters began to play a role at later stages. The response to temperature fluctuations was mediated by a rapid change in functional parameters at all these stages.

[Expression of aquaporins 1, 3, 8, 9 mRNA in human fetal membranes].

OBJECTIVE: To investigate the expression of aquaporin (AQP)-1, 3, 8, 9 in human fetal membrane and their role in the human amniotic fluid circulation. METHODS: RT-PCR was employed for detection of the expressions of AQP-1, 3, 8, 9 mRNA in human amnion and chorion from 20 women with normal term pregnancy. RESULTS: AQP-1, 3, 8, 9 mRNA expression was detected in both human amnion and chorion, and no significant difference was found in their expression levels or between the amnion and chorion (P>0.05). CONCLUSION: AQP-1, 3, 8, 9 can be associated with intramembranous transport and volume regulation of amniotic fluid.

The anterior visceral endoderm-turning heads.

The Anterior Visceral Endoderm is an extraembryonic tissue that plays a pivotal role during embryogenesis, being responsible for the proper orientation of the anterior-posterior axis of the embryo and for appropriate pattering of adjacent embryonic tissue. In this review I discuss the formation and migration of the AVE, and attempt to place some recent findings in the context of a working model.

Early steps in neural development.

We studied early neurulation events in vitro by transplanting quail Hensen's node, central prenodal regions (before the nodus as such develops), or upper layer parts of it on the not yet definitively committed upper layer of chicken anti-sickle regions (of unincubated blastoderms), eventually associated with central blastoderm fragments. We could demonstrate by this quail-chicken chimera technique that after the appearance of a pronounced thickening of the chicken upper layer by the early inductive effect of neighboring endophyll, a floor plate forms by insertion of Hensen's node-derived quail cells into the median part of the groove. This favors, at an early stage, the floor plate "allocation" model that postulates a common origin for notochord and median floor plate cells from the vertebrate's secondary major organizer (Hensen's node in this case). A comparison is made with results obtained after transplantation of similar Hensen's nodes in isolated chicken endophyll walls or with previously obtained results after the use of the grafting procedure in the endophyll walls of whole chicken blastoderms.

A review of the evolution of viviparity in lizards: structure, function and physiology of the placenta.

The aim of this review is to collate data relevant to understanding the evolution of viviparity in general, and complex placentae in particular. The wide range of reproductive modes exhibited by lizards provides a solid model system for investigating the evolution of viviparity. Within the lizards are oviparous species, viviparous species that have a very simple placenta and little nutrient uptake from the mother during pregnancy (lecithotrophic viviparity), through a range of species that have intermediate placental complexities and placental nutrient provision, to species that lay microlecithal eggs and most nutrients are provided across the placenta during development (obligate placentotrophy). In its commonest form, lecithotrophic viviparity, some uptake of water, inorganic ions and oxygen occurs from the mother to the embryo during pregnancy. In contrast, the evolution of complex placentae is rare, but has evolved at least five times. Where there is still predominantly a reliance on egg yolk, the omphaloplacenta seems to be paramount in the provision of nutrition to the embryo via histotrophy, whereas the chorioallantoic placenta is more likely involved in gas exchange. Reliance on provision of substantial organic nutrient is correlated with the regional specialisation of the chorioallantoic placenta to form a placentome for nutrient uptake, particularly lipids, and the further development of the gas exchange capabilities of the other parts of the chorioallantois.