The ethics and practice of perinatal care at the limit of viability: FIGO recommendations.

An arbitrary gestational age limit of viability cannot be set, and in clinical practice the focus should be on a periviability interval-the so-called "gray zone" of prognostic uncertainty. For cases within this interval, the most appropriate decision-making process remains debatable and periviability has emerged as one of the greatest challenges in bioethics. Universally recognized ethical principles may be interpreted differently due to socioeconomic, cultural, and religious aspects. In the case of periviability, there is considerable uncertainty over whether interventions result in a greater balance of clinical good over harm. Furthermore, the fetus or neonate is unable to exercise autonomy and the physicians and parents will act as patient surrogates. When parents and physicians disagree about the infant's best interest, a dialogue without paternalistic attitudes is essential, whereby physicians should only offer, but not recommend, perinatal interventions. Parental choice, based on thorough information, should be respected within the limits of what is medically feasible and appropriate. When disagreements between parents and physicians occur, how is consensus to be achieved? Professional guidelines can be helpful as a framework and starting point for discussion. In reality, however, guidelines only rarely draw categorical lines and in many cases remain vague and ambiguously worded. Local ethics committees can provide counseling and function as moderators during discussions, but ethics committees do not have decision precedence. Counseling assumes the most significant role in periviability discussions, taking into consideration the particular fetal and maternal characteristics, as well as parental values. Several caveats should be observed relative to counseling: message fragmentation or inconsistence should be minimized, prognosis should preferably be presented in a positive framing, and overreliance on statistics should be avoided. It is recommended that decisions regarding neonatal resuscitation in the periviability interval be made before birth and not conditional on the newborn's appearance at birth. Regardless of decision, it is important to assure pre- and postnatal coherence. The present article describes how individual physicians, centers, and countries differ in the approach to the decision to initiate or forgo intensive care in the periviability interval. It is impossible to provide a global consensus view and there can be no unifying ethical, moral, or practical strategy. Nevertheless, ethically justified, quality care comprises early involvement of the obstetric and neonatal team to enable a coherent, comprehensible, nonpaternalistic, and balanced plan of care. Ultimately, physicians will need to adjust the expectations to the local standards, local outcome data, and local neonatal support availability.

The Ethics and Practice of Periviability Care.

Since the 1960s, the gestational age at which premature infants typically survive has decreased by approximately one week per decade [...].

Evidence based medicine - decades later.

After more than two decades of enthusiasm surrounding the concept of evidence based medicine, wide variation in its implementation is still present. Some have suggested that evidence based medicine may be a failed model. We propose that the highly formulaic approach of evidence based medicine has evolved toward a more personalized, integrated and contextualized method, consistent with the principle of shared decision making advanced by the Institute of Medicine. Evidence based medicine remains an essential prerequisite but ultimately, only the practitioner's clinical expertise, knowledge and practical wisdom will provide the ability to apply general rules of evidence to particular clinical situations.

Antenatal corticosteroids in COVID-19 perspective.

The aim of this manuscript is to discuss the practice of antenatal corticosteroids administration for fetal maturation in severe acute respiratory syndrome coronavirus 2 positive pregnant women. Recent high-quality evidence supports the use of dexamethasone in the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Randomized disease outcome data have identified an association between disease stage and treatment outcome. In contrast to patients with more severe forms who benefit from dexamethasone, patients with mild disease do not appear to improve and may even be harmed by this treatment. Therefore, indiscriminate usage of fluorinated corticosteroids for fetal maturation, regardless of disease trajectory, is unadvisable. Obstetrical care needs to be adjusted during the COVID-19 pandemic with careful attention paid to candidate selection and risk stratification.

Preeclampsia: The Need for a Biological Definition and Diagnosis.

The centuries-old approach to the prevention of eclampsia and its associated maternal morbidity and mortality is based on the recognition of the presence of premonitory signs and symptoms such as hypertension and proteinuria. The spectrum of preceding signs and symptoms came to be known as preeclampsia, which is debatably considered to be an early stage on a clinical continuum possibly leading to eclampsia. The premonitory signs and symptoms were then construed as diagnostic criteria for the poorly understood syndrome of preeclampsia, and this led to a perpetual debate that remains subject to wide disagreement and periodic updates. In this commentary, we will draw attention to the fact that the criteria for preeclampsia should be viewed from the prism of a screening test rather than as diagnostic of a condition in itself. Focusing research on developing better diagnostic and screening methods for what is clinically important, namely maternal and perinatal morbidity and mortality from hypertensive disorders of pregnancy, a long overdue upgrade from what was possible centuries ago, will ultimately lead to better management approaches to what really matters.

Retrospective surveys of obstetric red cell transfusion practice in the UK and USA.

OBJECTIVE: To examine whether professional guidance promoting a policy of restrictive blood transfusion is being followed. METHODS: A retrospective analysis of post-delivery transfusion data from 17 maternity units in the UK (1988-2000) was undertaken. Additionally, an audit was performed of women receiving one or two units of red cells 6-24 hours after delivery at three centers in the UK and USA in 2013-2016. RESULTS: Between 1988 and 2000, 4700 women received one or two transfusions: 303 (6.4%) received one unit and 4397 (93.6%) received two. Median estimated blood loss (EBL) was similar in both groups (600 mL [IQR 400-1000] vs 700 mL [IQR 400-1000], respectively; P=0.862]. Between 2013 and 2016, 41, 22, and 64 women received one or two units during transfusion at centers A, B, and C, respectively. Two units were transfused for 40 (97.6%) of the women in center A, 21 (95.5%) at center B, and 58 (90.6%) at center C. Median EBL was similar, irrespective of whether one or two units were given. CONCLUSION: Current transfusion practice deviates from evidence-based guidelines. Either by default or longstanding tradition, more women receive two rather than one unit despite similar EBL.

Interpreting a randomized trial report: evidence-based practice for the clinician.

The purpose of this article is to present a structured approach to help the reader with the objective interpretation of published randomized clinical trials. This process will promote an organized and critical appraisal of scientific evidence, which we believe to be an essential step prior to the introduction of published scientific findings into clinical practice. The reason to personally scrutinize and critically assess published reports is that the process of peer review is by no means perfect and methodological flaws can be uncovered, even in articles published in prestigious journals. The article elaborates on the substance of the consolidated standards of reporting trials (CONSORT) statements intended to facilitate the complete reporting of trials and aid in their critical assessment. The structure of the CONSORT guidelines was used as a basis for specific commentary, including cautions for the clinical interpretation, implications and impact of published randomized trial reports.

Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia.

OBJECTIVE: To determine the second-trimester amniotic fluid concentrations of complement split products in pregnancies subsequently affected by early-onset preeclampsia. STUDY DESIGN: Cohort of 731 women with singleton pregnancies undergoing second-trimester genetic amniocentesis followed up to delivery and analyzed as a nested case-control study. Cases of preeclampsia developing before 34 weeks' gestation (n = 15) were compared with 47 uncomplicated term controls. Amniotic fluid collected at amniocentesis was tested for complement split products Bb, C4a, C3a, and C5a. RESULTS: Women who developed early-onset preeclampsia as compared with the term pregnant controls had significantly higher (P = 0.04) median amniotic fluid C3a levels (318.7 ng/mL versus 254.5 ng/mL). Median amniotic fluid Bb levels were also significantly higher (P = 0.03) in preeclamptic women than in normal pregnant women (1127 ng/mL versus 749 ng/mL). Median levels of C4a and C5a were not significantly different between the groups. CONCLUSION: Our data suggest that complement activation in early pregnancy is associated with early-onset preeclampsia. We believe this to be the first prospective study to link complement activation in amniotic fluid in early pregnancy and later development of preeclampsia. Our findings provide evidence that immune dysregulation may precede the clinical manifestations of preeclampsia and that the alternative complement pathway is principally involved.

Cross-cultural barriers to health care.

Culturally sensitive health care represents a real ethical and practical need in a Western healthcare system increasingly serving a multiethnic society. This review focuses on cross-cultural barriers to health care and incongruent aspects from a cultural perspective in the provision of health care. To overcome difficulties in culturally dissimilar interactions and eventually remove cross-cultural barriers to health care, a culturally sensitive physician considers his or her own identity, values, and beliefs; recognizes the similarities and differences among cultures; understands what those similarities and differences mean; and is able to bridge the differences to accomplish clear and effective communication.

Comparison of the effects of betamethasone and dexamethasone on surfactant protein A mRNA expression in human lung cells.

OBJECTIVE: While prenatal administration of synthetic corticosteroids stimulates both fetal lung development and expression of pulmonary surfactant, the specific effects may depend on the corticosteroid formulation used. We compared the dose-dependent effects of various concentrations of two synthetic corticosteroids, betamethasone and dexamethasone, on steady state levels of surfactant protein A (SP-A) mRNA in human lung cells. METHODS: Cultured human NCI-H441 bronchoalveolar epithelial cells were exposed to varying concentrations of betamethasone or dexamethasone (10-7 to 10-12 M) for 48 h alone or in combination with dibutyryl cAMP (1 mM), which augments surfactant protein gene expression. RNA was harvested and SP-A mRNA levels were quantified by real-time quantitative reverse transcriptase polymerase chain reaction analysis. Results were compared using the Kruskal-Wallis test. RESULTS: A dose-dependent modification in SP-A mRNA levels was demonstrated with both dexamethasone and betamethasone. Cells treated with cAMP expressed higher levels of SP-A mRNA than untreated cells. A biphasic curve in the SP-A mRNA response to corticosteroids was elicited only in the presence of cAMP: at lower concentrations (10-10 through 10-12 M), SP-A mRNA levels were upregulated, whereas at higher concentrations (10-7 and 10-8 M), SP-A mRNA levels were reduced. Dexamethasone was more effective than betamethasone in inducing these changes. CONCLUSIONS: Our results support a biphasic effect on SP-A mRNA levels after exposure to corticosteroids in combination with cAMP. At higher corticosteroid concentrations, betamethasone is less inhibitory than dexamethasone on SP-A mRNA.

Critical appraisal of the efficacy, safety, and patient acceptability of hydroxyprogesterone caproate injection to reduce the risk of preterm birth.

Prevention of preterm delivery is a major desiderate in contemporary obstetrics and a societal necessity. The means to achieve this goal remain elusive. Progesterone has been used in an attempt to prevent preterm delivery since the 1970s, but the evidence initially accumulated was fraught by mixed results and was based on mostly underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. More recent randomized controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone may favorably influence the rate of preterm delivery. Preterm delivery is a complex disorder and consequently it is unlikely that one generalized prevention strategy will be effective in all patients. Further, an additional impediment in accepting progesterone as the "magic bullet" in the prevention of preterm delivery is that its mechanism of action is not fully understood and the optimal formulations, route of administration, and dose have yet to be established. We have concerned ourselves in this review with the most recent status of 17 alpha-hydroxyprogesterone caproate (17OH-PC) supplementation for prevention of preterm delivery. Our intention is to emphasize the efficacy, safety, and patient acceptability of this intervention, based on a comprehensive and unbiased review of the available literature. Currently there are insufficient data to suggest that 17OH-PC is superior or inferior to natural progesterone. Based on available evidence, we suggest a differential approach giving preferential consideration to either 17OH-PC or other progestins based on obstetric history and cervical surveillance. Progestin therapy for risk factors other than a history of preterm birth and/or a short cervix in the current pregnancy is not currently supported by the published evidence. The experience to date with 17OH-PC indicates that there are population subgroups that may be harmed by administration of 17OH-PC. Therefore, extending the use of 17OH-PC to unstudied populations or for indications that are not evidence-based is inadvisable outside of a research protocol.

Corticosteroids effect on caspase 3 expression in an in-vitro model of hypoxic brain cells.

OBJECTIVE: Effects of corticosteroids (CS) in the brain of growth-restricted fetus remain largely unstudied. We investigated if dexamethasone (DXM) exposure contributes to neuronal injury in an in-vitro model of neuronal cells under hypoxic conditions (surrogate for fetal growth restriction). STUDY DESIGN: U87 glioblastoma cells exposed to hypoxic or normoxic conditions for 10 h were incubated in the absence or presence of DXM for 48 h. Apoptosis as possible indicator of neurotoxicity was determined using a caspase-3-specific activity assay and western blotting. Caspase-3 was calculated as percentage of mean caspase-3 cleavage. Each experiment was performed in triplicate (n = 48). Caspase 3 activity in cell culture media was also measured by ELISA. RESULTS: Pro-caspase-3 (32 kDa) was expressed in culture, but activated 17 Kd caspase 3 was not expressed in cell lysate. There was no difference in ratio of caspase 3 activation when U87 cells were exposed to 10 v of hypoxia as compared to normoxia (0.46 ± 0.44 versus 0.37 ± 0.37). The pro-apoptotic effects of DXM were not increased by pre-exposure to hypoxia: (0.37 ± 0.37 versus 0.47 ± 0.40). CONCLUSION: The addition of DXM to hypoxic U87 cells had no additive or synergistic effects on the activation of caspase 3. Therefore, we speculate that the administration of CS in the setting of fetal growth restriction would not lead to increased apoptosis with potential neuronal injury.

Is thrombin activation predictive of subsequent preterm delivery?

OBJECTIVE: To determine the relation between thrombin generation (measured by thrombin-antithrombin [TAT] complexes) early in pregnancy and subsequent preterm delivery. STUDY DESIGN: Select cohort of 731 women undergoing indicated second trimester amniocentesis prospectively followed to delivery. Primary outcome was preterm delivery. TAT levels were examined continuously and categorized by quartiles. Multivariable techniques were applied to adjust for potential confounders. Receiver operating characteristic curve analysis was used to determine a discriminatory cutoff level for TAT complexes. RESULTS: TAT concentration was significantly higher in women who delivered preterm (median, 98.9 mcg/L) than in those who did not (median, 66.3 mcg/L; P < .001). This difference persisted when 55 spontaneous preterm deliveries (median, 87.6 mcg/L) and 34 indicated preterm deliveries (median, 117.7 mcg/L) were separately compared with controls (P = .04 and P < .001, respectively). Crude and adjusted odds ratio for preterm delivery in the upper 2 TAT quartiles relative to the uppermost quartile relative to the lowest quartile were 2.45 (95% confidence interval [CI], 1.36-4.72; P = .004) and 2.31 (95% CI, 1.18-4.65; P = .017), respectively. Despite these distinct differences, the area under the receiver operating characteristic curve was only 0.62 (95% CI, 0.56-0.69), indicating poor performance of TAT concentration as a risk discriminator. CONCLUSION: Amniotic fluid levels of TAT complexes in the second trimester are elevated in women who subsequently deliver preterm, suggesting that thrombin generation may be involved in the various etiopathogenic mechanisms leading to preterm delivery.

The diagnosis of rupture of fetal membranes (ROM): a meta-analysis.

AIM: The aim of this study was to compare the performance of tests based on the detection of insulin-like growth factor binding protein 1 (IGFBP-1) and placental α-microglobulin-1 (PAMG-1) in diagnosing rupture of fetal membranes (ROM) across different patient populations. METHODS: A meta-analysis was conducted on prospective observational or cohort studies investigating ROM tests based on the detection of IGFBP-1 and PAMG-1 meeting the following criteria: (1) performance metrics calculated by comparing results to an adequate reference method; (2) sensitivity thresholds of the investigated tests matching those of the currently available tests; (3) study population, as a minimum, included patients between 25 and 37 weeks of gestation. Sensitivities, specificities, and diagnostic odds ratios were calculated. RESULTS: Across all patient populations, the analyzed performance measures of the PAMG-1 test were significantly superior compared with those of the IGFBP-1 test. Of particular clinical relevance, PAMG-1 outperformed IGFBP-1 in the equivocal group, which comprised patients with uncertain rupture of membranes (sensitivity, 96.0% vs. 73.9%; specificity, 98.9% vs. 77.8%; PAMG-1 vs. IGFBP-1 tests, respectively). CONCLUSIONS: Compared with its performance in women with known membrane status, the accuracy of the IGFBP-1 test decreases significantly when used on patients whose membrane status is unknown. In this latter clinically relevant population, the PAMG-1 test has higher accuracy than the IGFBP-1 test.