Proteome-defined changes in cellular pathways for decidua and trophoblast tissues associated with location and viability of early-stage pregnancy.

BACKGROUND: In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics. METHODS: Trophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC-MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student's t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities. RESULTS: A total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways. CONCLUSIONS: Overall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.

Delivery management of a complete hydatidiform mole and co-existing viable fetus: A meta-analysis and systematic review.

OBJECTIVE: A twin pregnancy with a complete hydatidiform mole and co-existing viable fetus (CHMCF) is an exceedingly rare obstetric complication with few data related to perinatal treatment. This study determined the optimal timing of pregnancy termination and mode of delivery in women with CHMCF and a viable fetus. METHODS: The articles published involving CHMCF and a viable fetus from 1967 to 31 December 2020 in the PubMed and EMBASE databases were systematically reviewed. Observational cohort studies with three or more cases identified and data on delivery management were selected. The articles were analyzed independently for full text and the data were integrated. The timing of pregnancy termination and mode of delivery were calculated using Review Manager 5.4.1. RESULTS: There were 192 reports involving CHMCF; 209 cases had a viable fetus. According to the inclusion criteria, there were 6 case series, including 72 cases that were eligible for the analysis. The average rate of live births was 34.4%. The average duration of pregnancy was 34 weeks, ranging from 25 to 41 weeks. From 2000-2017 the live birth rate was increased year-after-year. Specifically, the live birth rate was16.7% in 2000, 33.3% in 2012, and 50% in 2017. Fifty-two cases (72.2%) had cesarean sections and 20 cases (27.8%) had vaginal deliveries. The incidence of gestational trophoblastic neoplasia was not significantly different between the two modes of delivery. CONCLUSIONS: Ideally, a twin pregnancy with a complete hydatidiform mole co-existing with a viable fetus is managed by an obstetrician, pediatrician, and oncologist. Appropriate timing of pregnancy termination and mode of delivery are related to the pregnancy outcome.

Viability and thresholds for treatment of extremely preterm infants: survey of UK neonatal professionals.

BACKGROUND: Decisions about treatments for extremely preterm infants (EPIs) born in the 'grey zone' of viability can be ethically complex. This 2020 survey aimed to determine views of UK neonatal staff about thresholds for treatment of EPIs given a recently revised national Framework for Practice from the British Association of Perinatal Medicine. METHODS: The online survey requested participants indicate the lowest gestation at which they would be willing to offer active treatment and the highest gestation at which they would withhold active treatment of an EPI at parental request (their lower and upper thresholds). Relative risks were used to compare respondents' views based on profession and neonatal unit designation. Further questions explored respondents' conceptual understanding of viability. RESULTS: 336 respondents included 167 consultants, 127 registrars/fellows and 42 advanced neonatal nurse practitioners (ANNPs). Respondents reported a median grey zone for neonatal resuscitation between 22+1 and 24+0 weeks' gestation. Registrars/fellows were more likely to select a lower threshold at 22+0 weeks compared with consultants (Relative Risk (RR)=1.37 (95% CI 1.07 to 1.74)) and ANNPs (RR=2.68 (95% CI 1.42 to 5.06)). Those working in neonatal intensive care units compared with other units were also more likely to offer active treatment at 22+0 weeks (RR=1.86 (95% CI 1.18 to 2.94)). Most participants understood a fetus/newborn to be 'viable' if it was possible to survive, regardless of disability, with medical interventions accessible to the treating team. CONCLUSION: Compared with previous studies, we found a shift in the reported lower threshold for resuscitation in the UK, with greater acceptance of active treatment for infants <23 weeks' gestation.

Early embryo-maternal communication in the oviduct: A review.

An intact embryo-maternal communication is critical for the establishment of a successful pregnancy. To date, a huge number of studies have been performed describing the complex process of embryo-maternal signaling within the uterus. However, recent studies indicate that the early embryo communicates with the oviductal cells shortly after fertilizationand that this is important for the successful establishment of pregnancy. Only if the early embryo is capable to signal the mother within a precise timeframe and to garner a response, will the embryo be able to survive and reach the uterus. This review will give an overview of all the experimental designs which have investigated embryo-maternal interaction in the oviduct. In addition to that, it will provide a comprehensive analysis of the findings to date elucidating the morphological and molecular changes in the oviduct which are induced by the presence of the early embryo highlighting how the tubal responses affect embryo development and survival.

Relation between Apgar scoring and physical parameters in 44 newborn Amiata donkey foals at birth.

The assessment of the behavior and physiological parameters of neonatal foals is essential in the detection of early signs of illness. Modified Apgar scoring systems from human medicine exist and have been validated in foals as a guide for assessing neonatal viability after birth. This study evaluated the viability of 44 Amiata donkey foals at birth, by assessing the Apgar score and comparing the relationship between viability and various physical parameters. A total of 44 Amiata donkey foals and 27 jennies were enrolled in this study. An expert operator examined each foal within 5 min of birth. A complete physical examination was performed, along with an existing four-parameter Apgar score. The presence of the suckling reflex was evaluated. The interval time needed to acquire sternal recumbency and quadrupedal position, as well as nurse from the mare, were recorded. In addition, heart rate (HR), respiratory rate (RR), and rectal body temperature (BT) were measured. Results were expressed as median ± standard error, minimum and maximum values. The effects of the Apgar score on time to reach sternal position and quadrupedal standing, time to nurse from the mare, RR, HR, and BT were estimated along with the differences related to Apgar scoring and gender. Differences between female and male donkey foals regarding the time to acquire sternal position and quadrupedal standing, time to nurse from the mare, RR, HR, and BT were also assessed. Differences between female and male donkey foals regarding the Apgar score was evaluated using a chi-Square test. Finally, the reference values for Amiata donkeys were also calculated. Twenty/44 (45.4%) foals were colts and 24/44 (54.5%) were fillies born from 27 jennies. None of the foals showed an Apgar score lower than 6. Twenty-nine out of 44 foals showed an Apgar score of 8/8, 10/44 a score of 7/8, while 5 foals (11.3%) showed a score of 6/8. No differences between fillies and colts in relation to the Apgar score were obtained.

Vaginal delivery in the 30+4 weeks of pregnancy and organ donation after brain death in early pregnancy.

A 28-year-old woman suffered a traffic accident resulting in severe head injuries with deleterious prognosis. Diagnostics further revealed a hitherto unknown pregnancy, at suspected week 9. Based on the patient's wish to donate organs, brain death protocol confirmed irreversible loss of brain function. Yet, vital pregnancy rendered organ transplantation impossible. Multiple ethical and legal issues arose, from invalidation of established legal care after brain death to the delivery of a healthy child after trauma and long-term critical care. After medicolegal and ethical counselling, pregnancy was sustained, and the goal of organ donation postponed. Critical care focused on foetal homeostasis. At 30+4 weeks, a viable girl was born via assisted vaginal delivery. Postpartal organ donation resulted in heart, kidney and pancreas transplantation. The case emphasises the medical, legal and ethical challenges to combine two apparently diametrical goals: the successful full-term pregnancy and the fulfilment of a patient's wish to donate organs.

Intrauterine position and adjacent fetal sex affects fetal and placental growth throughout gestation, but not embryonic viability, in pigs selected for component traits of litter size.

Intrauterine position and sex of adjacent fetuses in litter bearing species have been implicated in physiological and behavioral differences of offspring. The effects of uterine position and sex status of flanking fetuses with crowded uterine conditions on fetal and placental growth rate was tested. Gilts were unilaterally hysterectomized-ovariectomized at 160 d of age and mated at approximately 280 d of age, with fetal harvest at 45, 65, 85, or 105 d of gestation. Uterine position relative to the cervix, fetal status (alive, dead, sex), fetal weight, and placental weight were recorded at harvest. Each fetus was coded as adjacent to 0, 1, or 2 opposite sex fetuses and analyzed using an ANOVA fitting contemporary group, line, and flanking fetal sex code as fixed effects with sire as a random effect. The fraction of live fetuses in each classification (0, 1, 2) was 26.4%, 50.1%, and 23.4%, respectively, indicating no effect on fetal survival. Fetal weight was affected by flanking sex status between 65 d (P < 0.05) and 105 d (P < 0.001), with means at 105 d of 800.0 ± 20.3, 748.5 ± 17.8, and 672.7 ± 25.2 g, respectively for flanking sex status codes 0, 1, 2. Placental weight was similarly affected (P < 0.01) by flanking sex code, but only at 105 d. It is concluded that fetal growth and placental development in pigs is influenced by sex status of adjacent fetuses. This could be a potential source of variation in behavioral and reproductive differences later in life.

Advancing metabolism research to overcome low litter survival in metabolically stressed mice.

Elucidating the mechanism underlying the transmission of metabolic disease to subsequent generations requires robust preclinical mouse breeding strategies. Western diets rich in fat and carbohydrates are contributing factors in the rise of diabetes and obesity rates worldwide. Therefore, determining the impact of Western diets consumed by parents on offspring and future generations is critical for understanding the perpetuation of these diseases. Specifically, epigenetic regulation and transgenerational inheritance of metabolic disease is an emerging field of study requiring robust murine models. However, a major challenge to transgenerational studies is offspring mortality, exacerbated by maternal stress during pregnancy. Here, we describe a challenge experienced in our metabolic research in Western diet-fed female mice leading to the loss of litters via pup mortality and cannibalism by the mother. Furthermore, our study evaluates various breeding schemes with pregnancy efficiency and refined husbandry techniques to overcome pup mortality and infanticide, to characterize dams' and pups' metabolic characteristics, and to determine the impact on physiology of dams under detailed breeding schemes.

A multicentre study to predict neonatal survival according to lung-to-head ratio and liver herniation in fetuses with left congenital diaphragmatic hernia (CDH): Hidden mortality from the Latin American CDH Study Group Registry.

OBJECTIVE: To evaluate natural history of fetuses congenital diaphragmatic hernia (CDH) prenatally diagnosed in countries where termination of pregnancy is not legally allowed and to predict neonatal survival according to lung area and liver herniation. METHODS: Prospective study including antenatally diagnosed CDH cases managed expectantly during pregnancy in six tertiary Latin American centres. The contribution of the observed/expected lung-to-head ratio (O/E-LHR) and liver herniation in predicting neonatal survival was assessed. RESULTS: From the total population of 380 CDH cases, 144 isolated fetuses were selected showing an overall survival rate of 31.9% (46/144). Survivors showed significantly higher O/E-LHR (56.5% vs 34.9%; P < .001), lower proportion of liver herniation (34.8% vs 80.6%, P < .001), and higher gestational age at birth (37.8 vs 36.2 weeks, P < 0.01) than nonsurvivors. Fetuses with an O/E-LHR less than 35% showed a 3.4% of survival; those with an O/E-LHR between 35% and 45% showed 28% of survival with liver up and 50% with liver down; those with an O/E-LHR greater than 45% showed 50% of survival rate with liver up and 76.9% with liver down. CONCLUSIONS: Neonatal mortality in CDH is higher in Latin American countries. The category of lung hypoplasia should be classified according to the survival rates in our Latin American CDH registry.

Pregnancy after periviable birth: making the case for innovative delivery of interpregnancy care.

Objective: Women who have had a spontaneous periviable delivery are at high risk for recurrent preterm delivery. The objective of our study was to determine interpregnancy interval (IPI) after periviable birth as well as percentage of women taking 17 alpha hydroxyprogesteronecaproate (17OHP-C) after periviable birth. We then examined the association between adherence with a postpartum visit after a periviable birth and IPI as well as receipt of 17OHP-C. Materials and methods: We included all women with a periviable delivery (20-26-week gestation) due to spontaneous preterm birth at Magee Women's Hospital between 2009 and 2014, who had their subsequent delivery at our institution during or before May of 2016. Information on maternal, fetal, and neonatal outcomes was obtained from the Magee Obstetrical Medical and Infant (MOMI) database as well as chart abstraction. We calculated IPI, proportion of women who received 17OHP-C in their next pregnancy, and attendance rates with a postpartum visit. The relationship between attendance with a postpartum visit and IPI, and receipt of 17OHP-C was examined with a logistic regression. Results: During the study period, 361 women had a spontaneous periviable birth. A total of 60 women had a subsequent delivery at Magee Women's Hospital. Only 33/60 (52.5%) presented for a postpartum visit after their periviable delivery. The median IPI for the cohort was 12.5 months (interquartile range: 6.4, 17.5 months) and 21.0% (n = 13) had an IPI less than 6 months. Adherence with the postpartum visit was not associated with an IPI less than 6 months. A total of 18.33% (11 women) did not receive 17OHP-C in their subsequent pregnancy. Women who attended a postpartum visit were much more likely to receive 17OHP-C (p = .001). Conclusions: Many women with a history of a periviable birth do not optimize strategies to reduce their risk of recurrent preterm birth. While attendance with a postpartum visit was associated with greater receipt of 17OHP-C in the subsequent pregnancy, given the overall poor rate of attendance with the postpartum visit in this cohort, novel strategies to counsel women about interpregnancy health are needed.

The Swedish Approach to Management of Extreme Prematurity at the Borderline of Viability: A Historical and Ethical Perspective.

Sweden has a long tradition of being at the forefront of the management of extremely preterm infants. In this article, we explore the historical background, ethical discussions, and evidence from national surveys combined with data from quality registers that form the background of the current Swedish guidelines for the care of extremely preterm infants. The current Swedish national guidelines suggest providing active care for preterm infants from 23 weeks' gestation and considering active care from 22 weeks' gestation. The survival of infants in gestational weeks 22 and 23 has increased and now exceed 50% and 60%, respectively; importantly, the Swedish proactive approach to care at the border of viability has not resulted in an increased proportion of functional impairment among survivors.

Don't Rush It: Conservative Care in Denmark.

One of the first European NICUs was established at Rigshospitalet in Copenhagen in 1965, and mechanical ventilation became the standard of care for preterm infants in 1971. After a failed attempt to extend this to the most immature infants in the early 1980s, a policy with minimally invasive support after birth with nasal continuous positive airway pressure was adopted from the neonatal unit in Odense. The conservative approach was consolidated by a national consensus conference; the lay panel concluded that a lower limit of gestation should be installed and priority should be given to parental counseling and support. This was confirmed some years later by the majority of the members of the Danish Council on Ethics, and questionnaire-based research revealed a significant proportion of the general population that would forego life support in extremely preterm infants. Since the year 2002, the treatment of infants <28 weeks' gestation at birth has been centralized to 4 university-based NICUs, the treatment policies have been rather uniform, and the survival of infants at 23 weeks' gestation or less has been unusual. Most recently, however, a professional initiative has been undertaken to centralize all births >22 weeks' gestation to improve parental counseling and neonatal intervention.

Should Parents of Neonates With Bleak Prognosis Be Encouraged to Opt for Another Child With Better Odds? On the Notion of Moral Replaceability.

The notion of moral exchangeability is scrutinized and its proper place in neonatal care is examined. On influential moral outlooks, the neonate is morally exchangeable. On these views, if the parents are prepared to let go of the neonate with a poor prognosis and opt instead for another child who is healthy, this may be the morally right thing for them to do, and neonatal care ought to ease their choice. The notion of moral exchangeability has a different place in different moral theories. Three theories are examined: deontological ethics (insisting on the sanctity of innocent human life), according to which there is no place for the replacement of 1 child for another. It is different, however, with utilitarianism and in the moral rights theory based on self-ownership. According to utilitarianism, we are all replaceable. According to the moral rights theory, neonates are replaceable to the extent that they have not developed personhood. Even a deontological ethicist of a Kantian bent would concur here with the moral rights theory. Because influential moral theories imply that the neonate is morally exchangeable, it is reasonable within neonatal care, as a general rule, to grant the parents a veto against any attempts to save a child with a poor prognosis. In particular, if the parents are prepared instead to have another, healthy child, this is to be recommended. However, this rule cannot be strict. In rare cases, it is necessary to yield to parents who insist that their neonate be saved despite a poor prognosis.

NICU Dialects: Understanding Norwegian Practice Variation.

In Norway, a national consensus-based guideline used to address thresholds for offering life support at extreme preterm birth was issued in 1998. Since then, therapeutic advances may have changed attitudes and expectations to treatment, both within the medical community and the public, and there are concerns that systematic variations in treatment practices may exist. With this article, we describe current practices and relate them to other ethical and legal comparable areas in health care. We conclude that a revision of the 1998 guideline is warranted to obtain a common understanding of prognoses and appropriate decision processes at the limit of viability.

In the Best Interest of the. . .Parents: Norwegian Health Personnel on the Proper Role of Parents in Neonatal Decision-making.

OBJECTIVES: The role of parents in life-and-death decision-making for infants born at the border of viability is challenging. Some argue that parents should have the final say in decisions about life-sustaining treatment. Others disagree. In this article, we report views from health care personnel (HCP) on the appropriate parental role. METHODS: Focus group interviews with 5 different groups of HCP (neonatal nurses, midwifes, obstetricians, mother-fetal specialists, and neonatologists) dealing with life-and-death decisions throughout pregnancy and birth were performed at the Norwegian University of Science and Technology and at St Olav's Hospital in Trondheim, Norway in 2014-2017. Interviews were taped and transcribed. Inductive analysis was performed for each group discussion for emergent ethical themes. A summary of the transcribed discussion was sent to the relevant focus group participants for comments. RESULTS: Our participants felt strongly that doctors, not parents, should have the final say. They did not think parents should have to live with the burden of the decision. The possible disagreement between parents, lack of necessary knowledge, experience, time, and emotional stability all point toward the neonatologist as the optimal decision-maker, within a model of "Patient Preference-Satisfaction Paternalism." CONCLUSIONS: The general attitude of our groups was that parents should have a say and be included in a thorough information and decision-making process. The doctor, or a team of HCP, however, should make the final decision, being in the best position both epistemologically and normatively to promote the best interest of both parents and the child.

Do Sociocultural Factors Influence Periviability Counseling and Treatment More Than Science? Lessons From Scandinavia.

All of us (doctors, parents, bioethicists, and health policy makers) think differently about premature infants who require neonatal intensive care than we do about other patients who are critically ill. In most other clinical circumstances, those that involve patients other than premature infants, our first impulse when confronted with a patient in an emergency is to do whatever we can to rescue the patient. We offer life-sustaining treatments first and ask questions later. With extremely premature infants, by contrast, we first ask questions, ponder our options, and try to develop policies about whether it is appropriate to try to save these infants. We wonder aloud whether these tiny patients are even worth saving. In most countries that have NICUs, and in many hospitals, doctors and policy makers have explicitly specified which infants ought to be offered life-sustaining treatment and which should be allowed to die. Regarding the treatment of infants who are born at the borderline of viability, there are markedly distinct approaches in Sweden, Norway, and Denmark. In each country, the prevailing approaches were developed after careful consideration of many factors, including public sentiment, professional preferences, reported outcomes, philosophical factors, and considerations of cost and cost-effectiveness. In this article, we comment on some of these considerations and the soundness of the resulting practice variations.

Artificial womb technology and the frontiers of human reproduction: conceptual differences and potential implications.

In 2017, a Philadelphia research team revealed the closest thing to an artificial womb (AW) the world had ever seen. The 'biobag', if as successful as early animal testing suggests, will change the face of neonatal intensive care. At present, premature neonates born earlier than 22 weeks have no hope of survival. For some time, there have been no significant improvements in mortality rates or incidences of long-term complications for preterms at the viability threshold. Artificial womb technology (AWT), that might change these odds, is eagerly anticipated for clinical application. We need to understand whether AWT is an extension of current intensive care or something entirely new. This question is central to determining when and how the biobag should be used on human subjects. This paper examines the science behind AWT and advances two principal claims. First, AWT is conceptually different from conventional intensive care. Identifying why AWT should be understood as distinct demonstrates how it raises different ethico-legal questions. Second, these questions should be formulated without the 'human being growing in the AW' being described with inherently value laden terminology. The 'human being in an AW' is neither a fetus nor a baby, and the ethical tethers associated with these terms could perpetuate misunderstanding and confusion. Thus, the term 'gestateling' should be adopted to refer to this new product of human reproduction: a developing human being gestating ex utero. While this paper does not attempt to solve all the ethical problems associated with AWT, it makes important clarifications that will enable better formulation of relevant ethical questions for future exploration.

Simple trachelectomy with pelvic lymphadenectomy as a viable treatment option in pregnant patients with stage IB1 (≥2 cm) cervical cancer: Bridging the gap to fetal viability.

OBJECTIVE: Cervical cancer is the most common gynecologic cancer in pregnancy. This study aims to evaluate simple trachelectomy and pelvic lymphadenectomy in patients with stage IB1 (≥2 cm) cervical cancer wishing to maintain their pregnancy. METHODS: We included patients with stage IB1 (≥2 cm) cervical cancer who underwent simple trachelectomy and minimally invasive pelvic lymphadenectomy during pregnancy from January 2004 to August 2016. Data analysis included demographics, perioperative, obstetrics, and oncologic outcomes. RESULTS: A total of 5 patients were included. Median age was 30 years (range; 26-38). Median gestational age (GA) at diagnosis was 12 weeks (range; 7-18) and at treatment intervention 16.5 weeks (range; 12-19). Histologic subtypes included: adenocarcinoma (3 patients) and squamous cell carcinoma (2 patients). Median tumor size by clinical exam was 27 mm (range; 20-40), grade 2 (range; 2-3) and depth of invasion 10 mm (range; 1.5-12). All patients underwent laparoscopic (1) or robotic (4) pelvic lymphadenectomy followed by vaginal simple trachelectomy. Median operative time was 193 min (range; 155-259), estimated blood loss 100 ml (range; 50-550) and length of stay 2 days (range; 1-3). There were no intraoperative or postoperative complications (<30 days). Median number of lymph nodes removed was 14 (range; 5-15). One patient had bilateral microscopic positive nodes. The median gestational age at delivery was 39 weeks (range; 28-40.6). After median follow-up of 75 months (range; 18-168), all patients are alive without disease. CONCLUSION: Simple trachelectomy with pelvic lymph node dissection may be a safe option in pregnant patients with stage IB1 (>2 cm) cervical cancer wishing to maintain their pregnancy.