Human epididymis protein 4 and fetal lung maturity.

OBJECTIVES: To document the maternal and fetal cord blood levels of human epididymis protein 4 (HE-4) in term and preterm newborns in order to investigate the possible physiological role of HE-4 in fetal lung development. METHODS: This cross-sectional study was conducted in a university-affiliated hospital between April 2018 and September 2018. The study population consisted of cesarean section (C-section) deliveries after 24 weeks of pregnancy. Both maternal and umbilical cord HE-4 levels (mHE-4 and uHE-4, respectively) were measured using chemiluminescent microparticle immunoassay. Amniotic fluid was sampled from each case to determine the lamellar body count (LBC) as the gold standard test for lung maturation. All the parameters, including the uHE-4 levels, were compared between the term delivery (≥37 weeks) (n=52) and preterm delivery (24-37th weeks) (n=30) groups. The best cut-off value of uHE-4 was calculated for fetal lung maturity. RESULTS: There were no statistically significant differences between the groups regarding the demographic data. The mHE-4 levels did not statistically significantly differ between the groups (p>0.05) whereas the uHE-4 level of the preterm newborns was significantly higher than that of the term newborns (p<0.05). There was a significant negative association between the uHE-4 level and LBC (r=-0.389; p<0.001). The uHE-4 level was the only statistically significant fetal parameter indicating fetal lung maturity confirmed by LBC. At a cut-off value of 281 pmol/L, uHE-4 had 96.8% sensitivity, 45% specificity, 84.5% positive predictive value, and 81.8% negative predictive value for fetal lung maturity. CONCLUSIONS: Although the exact physiological role of HE-4 has not yet been elucidated, this preliminary study supports the idea that HE-4 plays a role in fetal lung maturation to some extent.

Maturation of the cardiac autonomic regulation system, as function of gestational age in a cohort of low risk preterm infants born between 28 and 32 weeks of gestation.

OBJECTIVES: The maturation of the sympathetic nervous system (SNS) occurs steadily throughout gestation while the myelinated vagus has accelerated maturation periods, between 25 and 32 weeks of gestation and a further increase around 37-38 weeks of gestation. The aim was to quantify the cardiac autonomic regulation maturation, as a function of gestational age (GA) in a cohort of low risk preterm infants born between 28 and 32 weeks of gestation by assessing heart rate variability (HRV) at week 32, and at week 35 postmenstrual age (PMA). METHODS: Forty preterm infants were recruited, 24 h recordings of breathing rate and RR intervals were obtained at week 32 and week 35 PMA. RESULTS: A significant difference was noted between preterm infants born before 32 weeks GA and preterm infants born at week 32; the latter present higher HRV values throughout the follow-up period. No significant change over time was noted for the parasympathetic HRV measures while a significant increase was found in the sympathetic system. Moreover, a significant interaction effect of time and system was found, the increase in values of the sympathetic system over time was significantly larger than the change noted in the vagal HRV measures. CONCLUSIONS: Given the beneficial influence of vagal tone on health and developmental outcomes in preterm infants, the findings of the current study highlight the need for further studies on the impact of specifics gestational age on vagal development and later assessing interventions associate with its continue development and maturation at these specific periods.

Ultrasonographic analysis of fetal gastrointestinal motility during the peripartum period in the dog.

The aim of this study was to investigate fetal gastrointestinal motility (FGM) of dogs using ultrasonic imaging and its association with vaginal and rectal temperature, serum progesterone concentrations and fetal heart rate. Pregnant bitches were examined after day 54 of gestation and there were determinations of vaginal and rectal temperature and serum progesterone concentrations. The fetal abdomen was evaluated for 30 s using longitudinal and transversal assessments, and FGM was scored as 0 (no peristalsis) or 1 (evident peristalsis). Number of fetuses with a 1 or 0 score were determined for each bitch (number and the percentage of fetuses with FGM). A total of 135 FGM measurements were recorded. There was FGM in 0/3, 0/6, 1/6 (16.7 %), 3/20 (15 %), 5/18 (27.3 %), 18/28 (64.3 %), 12/17 (70.6 %), 14/22 (63.6 %), 6/9 (66.7 %), 4/6 (66.7 %) fetuses from day -9 until 0 preceding parturition, respectively. In the last 5 days before parturition, 63.3 % of fetuses had FGM. Vaginal and rectal temperature were strongly and positively correlated (P < 0.001). Vaginal temperature was positively correlated with progesterone concentrations and fetal heart rate (P < 0.01), and there was a small negative correlation with FGM (r = -0.331, P < 0.05). Due to ease of data collection, the assessment of FGM is a valuable procedure for evaluation of fetal maturity in dogs. Vaginal and rectal temperatures are reliable variables to be assessed during the last week of pregnancy for estimating the time of parturition.

Fetal kidney charts of a novel measurement of the renal parenchymal thickness to evaluate fetal kidney growth and potential function.

OBJECTIVE: The objective of this study was to develop new standard growth charts for fetal renal parenchymal thickness, length, and volume to define normal ranges for use in clinical practice and to assess the reliability of these measurements. METHODS: This was a prospective, longitudinal study of 72 low-risk singleton pregnancies undergoing serial ultrasound examinations at least every four weeks. Multiple renal measurements were performed on both kidneys at each scan. The renal parenchymal thickness was measured in the mid-sagittal plane. Standard charts were developed and the intra and interobserver reliability for the renal measurements was analysed. RESULTS: Standard charts were developed for fetal renal parenchymal thickness, length, and volume. CONCLUSION: We present novel charts, which demonstrate the growth of the fetal renal parenchyma during pregnancy. They will be useful in clinical practice to identify any alterations from these normal ranges, which may be an important criterion for assisting prenatal diagnosis of renal pathologies and future studies in the prediction of kidney function.

Lipidomic profiling of amniotic fluid and its application in fetal lung maturity prediction.

BACKGROUND: The pulmonary surfactant especially lipids in amniotic fluid can reflect the development stage of fetal lung maturity (FLM). However, the conventional lecithin/sphingomyelin (L/S) ratio method by thin layer chromatography (TLC) is insufficient and inconvenient for FLM prediction in clinical practice. METHODS: The amniotic fluid samples were collected from the pregnant women in labor or undergoing amniocentesis and analyzed for its lipid contents with the liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) method and the lamellar body count (LBC) method. To reveal the lipidomic profiling of different FLM stages, three groups of amniotic fluid samples including 8 from premature group (gestational week (GW) < 37), 10 from mature group (GW < 37), and 10 from mature group (GW > 38) were compared with the control group (n = 6) of 18 GWs separately. RESULTS: In the FLM prediction study, the sensitivity of the LC-HRMS method and LBC method was 91% and 73%, respectively; the specificity was 100% and 95%, respectively. The most significant metabolic pathway was linoleic acid metabolism between the premature group and the control group. Both glycerophospholipid metabolism and glycosylphosphatidylinositol-anchor biosynthesis were enriched in the mature groups. In search of potential FLM prediction markers in amniotic fluid, 8 phosphatidylcholines, 1 sphingomyelin, and 1 phosphatidylethanolamine were significantly increased in the mature groups compared with the premature group. CONCLUSION: An efficient LC-HRMS method for L/S ratio in predicting FLM was established. The linoleic acid metabolism may play an important role in the fetal lung development.

Sonographic appearance of the late gestation equine fetal intestine.

Variable gestation length in the mare poses a challenge for determination of fetal readiness for birth. The objectives of this study were to describe sonographic characteristics of the fetal GI tract in the late gestation mare and identify changes that occur with progressing fetal maturity. Based on these characteristics, a grading scale modeled after the existing human and canine scoring system was developed. Weekly sonographic examination of the fetus by one observer beginning 2-3 weeks prior to a calculated due date of 330 days was performed. Fetal assessment included; presence of stomach rugae, bowel segment definition (uniform echogenic, some defined, clearly defined), bowel segment dilation (none, segmental dilation), intestinal contents (none, mixed echogenicity) and peristalsis (none, occasional, every 3 s, continuous). Based on these characteristics a phase was assigned to the GI tract (1-5). Phase 1 was defined as a uniform echogenic grey area caudal to the diaphragm. The differentiation of Phase 2-5 was based primarily on the frequency of peristalsis, with Phase 2 exhibiting no peristalsis, Phase 3 exhibiting occasional peristalsis, Phase 4 exhibiting peristalsis every 3 s and Phase 5 exhibiting continuous peristalsis. Only data from mares with a normal parturition and healthy foals were included in the statistics (N = 10). Associations amongst sonographic fetal GI characteristics and days prepartum were validated using a simulation-based bootstrap approach with 1000 replicates using Stata 14. Stomach rugae, peristalsis, intestinal contents, tail head relaxation and udder development were all highly correlated with days prepartum. Using a multiple linear regression model, tail head relaxation and peristalsis predicted days prepartum with a 95% CI ±â€¯6 days. The same model predicted days prepartum with a 95% CI ±â€¯4 days when day of gestation, tail head relaxation and peristalsis were included as variables. Based on these findings, characterization of the fetal GI tract could provide valuable information concerning the maturity of the equine fetus. Further studies are needed comparing high risk mares to normal mares before this information could be used with confidence in the clinical setting.

Characterization of a reversible thermally-actuated polymer-valve: A potential dynamic treatment for congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a fetal defect comprising an incomplete diaphragm and the herniation of abdominal organs into the chest cavity that interfere with fetal pulmonary development. Though the most promising treatment for CDH is via interventional fetoscopic tracheal occlusion (TO) surgery in-utero, it has produced mixed results due to the static nature of the inserted occlusion. We hypothesize that a suitable noninvasively-actuatable, cyclic-release tracheal occlusion device can be developed to enable dynamic tracheal occlusion (dTO) implementation. OBJECTIVE: To conduct an in-vitro proof-of-concept investigation of the construction of thermo-responsive polymer valves designed for targeted activation within a physiologically realizable temperature range as a first step towards potential development of a noninvasively-actuatable implantable device to facilitate dynamic tracheal occlusion (dTO) therapy. METHODS: Six thermo-responsive polymer valves, with a critical solution temperature slightly higher than normal physiological body temperature of 37°C, were fabricated using a copolymer of n-isopropylacrylamide (NIPAM) and dimethylacrylamide (DMAA). Three of the valves underwent ethylene oxide (EtO) sterilization while the other three served as controls for EtO-processing compatibility testing. Thermal response actuation of the valves and their steady-state flow performances were evaluated using water and caprine amniotic fluid. RESULTS: All six valves consisting of 0.3-mole fraction of DMAA were tested for thermal actuation of caprine amniotic fluid flow at temperatures ranging from 30-44°C. They all exhibited initiation of valve actuation opening at ~40°C with full completion at ~44°C. The overall average coefficient of variation (CV) for the day-to-day flow performance of the valves tested was less than 12%. Based on a Student t-test, there was no significant difference in the operational characteristics for the EtO processed versus the non-EtO processed valves tested. CONCLUSIONS: We successfully fabricated and demonstrated physiological realizable temperature range operation of thermo-responsive polymer valves in-vitro and their suitability for standard EtO sterilization processing, a prerequisite for future in-vivo surgical implantation testing.

Association of Surfactant Protein with Expression of Hoxa5 and Hoxb5 in Rabbit Fetal Lung.

Hox genes regulate organ formation and identity of the embryo, and expressed in specific temporo-spatial patterns in the developing embryo. We compared the expression levels of the Hoxa5, Hoxb5, surfactant protein (SP)-A, and SP-B genes in immature and mature rabbit fetal lung tissues, and to uncover roles for Hoxa5, Hoxb5, SP-A, and SP-B. Cesarean sections were performed after rabbits were divided into two groups of 30-31 days of gestation (term group, n = 24) and 26-27 days of gestation (preterm group, n = 24). mRNA levels of Hoxa5, Hoxb5, SP-A, and SP-B were compared by quantitative reverse transcriptase polymerase chain reaction, and protein expression of Hoxa5 and Hoxb5 was compared by western blot analysis. Fetal lung tissue histology was observed by hematoxylin and eosin (H&E) staining. The relative expression ratios of SP-A and SP-B mRNA in the term to preterm groups were 2.45:1 and 2.94:1, respectively. Hoxb5 mRNA and protein levels decreased in the term group, with a relative expression ratio of 0.48:1 and 0.50:1, however, Hoxa5 mRNA and protein levels increased in the term group with a relative expression ration of 2.99:1 and 2.33:1, respectively, for the term to preterm groups. Moreover, a significant positive correlation was found between the expression of Hoxa5 and SP-A, SP-B in the term group. Hoxa5 gene may be essential for the expression of SP-A and SP-B in term rabbits. The Hoxb5 gene may be an important factor for lung maturation in preterm rabbits.

Effect of perinatal glucocorticoids on vascular health and disease.

The benefits of antenatal glucocorticoids are now firmly established in the perinatal management of threatened preterm birth. Postnatal glucocorticoid therapy, however, remains controversial in neonatal medicine, with the need to balance short-term physiological benefits against the potential for long-term adverse consequences. This review focuses on the vascular effects of prenatal and postnatal glucocorticoids, synthesizing data from both experimental animal models and human infants with the goal of better appreciation of the short and long-term effects of these commonly used drugs. Due to their widespread and varied use, improved understanding of the cellular and molecular impact of glucocorticoids is important in guiding current practice and future research.

Cardiovascular Transition of the Extremely Premature Infant and Challenges to Maintain Hemodynamic Stability.

The intricate fetal circulatory blood flow undergoes abrupt changes and restructuring at birth, allowing transition to extrauterine life and survival. In the extremely low-birth-weight newborn infant (birth weight <1000 g), these changes are affected by the immaturity of the fetal cardiovascular and pulmonary systems. The immature physiology associated with the inability to transition properly can lead to a poor prognosis and create problematic issues for the clinical management of these infants. Potentially problematic issues and complications include immature myocardium, adrenal insufficiency, patent ductus arteriosus, hypotension, and anemia. Understanding the unique transition to extrauterine life for these infants, problems that arise from immaturity and incomplete transition, and current approaches to management will help nurses and physicians caring for ELBW infants to improve the care they give and minimize mortality and morbidity in this vulnerable population. This article will review transitional physiology for term and preterm newborns, potential problems and complications, and current management approaches.

Amniotic fluid LPCAT1 mRNA correlates with the lamellar body count.

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is required in the biosynthesis of pulmonary surfactant. This short communication describes our assessment of LPCAT1 mRNA levels in human amniotic fluid. We found a direct correlation between LPCAT1 mRNA copies and the amniotic fluid lamellar body count (LBC). This finding corroborates an association between LPCAT1 and surfactant phospholipid biosynthesis in humans. It may provide a model for future research in perinatal medicine.

Assessment of fetal lung maturity by ultrasound: objective study using gray-scale histogram.

OBJECTIVE: To evaluate lung maturity using ultrasound (US), comparing the subjective and gray-scale histogram (GSH) techniques. METHODS: A total of 77 single pregnancies were evaluated and divided into the following two groups: 11 women of gestational age 28 to 35 + 6 weeks and 66 women ≥ 36 weeks. The women underwent to emergency or planned cesarean section, according to fetal-maternal indications. The US was performed on the mean sagittal plane of the fetal torso, in order to observe the lung and hepatic areas. Fetal lung maturity was evaluated subjectively and through GSH. After delivery, the incidence of respiratory distress in the newborn was evaluated. The analyses were considered to be correct or incorrect, and comparisons were made using the McNemar test. In order to compare lung/hepatic echogenicity using GSH in groups with and without respiratory distress, the Student's t-test was used. RESULTS: The subjective evaluation identified 41 cases (53.2%) correctly and 36 (46.8%) incorrectly, while GSH found 58 (75.3%) correctly and 19 (24.7%) incorrectly (p = 0.006). There was a significant difference in mean lung/hepatic echogenicity between the groups with and without respiratory distress (1.05 versus 1.26; p = 0.002). In the group of 28 to 35 + 6 weeks, GSH presented sensitivity, specificity and accuracy in predicting respiratory distress of 61.9%, 89.1% and 81.6%, respectively. CONCLUSION: The evaluation of fetal lung maturity through GSH was more effective than the subjective method in predicting respiratory distress among newborns.

Quantitative ultrasound texture analysis of fetal lungs to predict neonatal respiratory morbidity.

OBJECTIVE: To develop and evaluate the performance of a novel method for predicting neonatal respiratory morbidity based on quantitative analysis of the fetal lung by ultrasound. METHODS: More than 13,000 non-clinical images and 900 fetal lung images were used to develop a computerized method based on texture analysis and machine learning algorithms, trained to predict neonatal respiratory morbidity risk on fetal lung ultrasound images. The method, termed 'quantitative ultrasound fetal lung maturity analysis' (quantusFLM™), was then validated blindly in 144 neonates, delivered at 28 + 0 to 39 + 0 weeks' gestation. Lung ultrasound images in DICOM format were obtained within 48 h of delivery and the ability of the software to predict neonatal respiratory morbidity, defined as either respiratory distress syndrome or transient tachypnea of the newborn, was determined. RESULTS: Mean (SD) gestational age at delivery was 36 + 1 (3 + 3) weeks. Among the 144 neonates, there were 29 (20.1%) cases of neonatal respiratory morbidity. Quantitative texture analysis predicted neonatal respiratory morbidity with a sensitivity, specificity, positive predictive value and negative predictive value of 86.2%, 87.0%, 62.5% and 96.2%, respectively. CONCLUSIONS: Quantitative ultrasound fetal lung maturity analysis predicted neonatal respiratory morbidity with an accuracy comparable to that of current tests using amniotic fluid.

Cystatin C in newborns: a promising renal biomarker in search for standardization and validation.

OBJECTIVE: Neonatologists still commonly use creatinine as a proxy for renal clearance, despite issues related to neonatal (patho)physiology and methodology (assay variability). Cystatin C (CysC) has been suggested to be a more reliable biomarker, but assay related differences have also been reported in children and adults. We are unaware of any review on the assay related impact on CysC reference values in newborns. METHODS: A structured literature search was performed on published CysC values in (pre)term neonates. RESULTS: The extensive range (>5-fold) in serum CysC observations in neonates in part relates to the fact that CysC concentrations are higher at birth with subsequent decrease and that CysC concentrations are higher in preterm compared to term neonates. The CysC assay matters while disease characteristics also affect CysC values, but not always in the predicted direction. CONCLUSIONS: Similar to creatinine, the extensive CysC range in neonates is only in part explained by renal (patho)physiology. Its applicability in neonatal medicine can be further improved by use of assay specific reference values, adapted to neonatal renal physiology (e.g. weight, age) and should be compared to a gold standard such as inulin clearance.

Conceitos atuais sobre avaliação da maturidade pulmonar fetal / Current concepts on the assessment of fetal lung maturity

A Síndrome do Desconforto Respiratório (SDR), também conhecida como Doença da Membrana Hialina, é uma das principais causas de morbidade e mortalidade neonatal. O principal fator associado à SDR é a produção insuficiente de surfactante pulmonar, o que geralmente está associada à prematuridade. Alguns protocolos internacionais recomendam que a confirmação da maturidade pulmonar fetal seja realizada em partos eletivos antes de 39 semanas de gestação. Diversos são os métodos capazes de avaliar a maturidade pulmonar fetal, como a Relação Lecitina/Esfingomielina,a Pesquisa de Corpos Lamelares, a Relação Surfactante/Albumina, o percentual deFosfatidilglicerol, o Índice de Estabilidade da Espuma e o Shake Test ou Teste de Clements. Este estudo visa apresentar os principais métodos disponíveis e as recomendações atuais sobre quando realizar a avaliação da maturidade pulmonar fetal.(AU)

The Respiratory Distress Syndrome (RDS), also known as hyaline membrane disease, is a major cause of neonatal morbidity and mortality. The main factor associated with RDS is the insufficient production of pulmonary surfactant, which is usually associated with prematurity. Some international guidelines recommend that the confirmation of fetal lung maturity is performed in elective deliveries before 39 weeks of gestation. There are several methods to assess fetal lung maturity, such as the Lecithin/Sphingomyelin ratio, the Lamellar Body Count, the Surfactant/Albumin ratio, the percentage of phosphatidylglycerol, the Foam Stability Index and the Shake Test or Clements test. This study aims to present the main available methods and current recommendations on when to conduct the evaluation of fetal lung maturity.(AU)

Neonatal morbidity occurs despite pulmonary maturity prior to 39 weeks gestation.

OBJECTIVE: To compare outcomes among late-preterm or early-term neonates according to fetal lung maturity (FLM) status. STUDY DESIGN: We conducted a retrospective cohort study of 234 eligible singletons delivered after FLM testing before 39 weeks gestation at our center over a 2-year time period. A primary composite neonatal outcome included death and major morbidities. RESULT: The overall rate of primary composite morbidity was 25/46 (52.2%) and 61/188 (32.4%) in the immature/transitional and mature groups, respectively. After adjustment for confounders including gestational age, the composite outcome was not significantly different; adjusted odds ratio (aOR)=1.4 (confidence interval (CI)=0.7-3.0). The rate of respiratory distress syndrome was significantly higher in the immature/transitional group; odds ratio=3.4 (CI=1.1-10.3) as expected. CONCLUSION: FLM status did not correlate with the spectrum of neonatal morbidities in late-preterm and early-term births. Neonatal complications remained common in both groups.

Testicular migration chronology: do the right and the left testes migrate at the same time? Analysis of 164 human fetuses.

OBJECTIVE: To determine if the right and the left testes migrate at the same time during the human fetal period. SUBJECTS AND METHODS: We studied 164 human fetuses (328 testes) ranging in age from 12 to 35 weeks post-conception. The fetuses were carefully dissected with the aid of a stereoscopic lens at ×16/25. The abdomen and pelvis were opened to identify and expose the urogenital organs. Testicular position was classified as: (a) Abdominal, when the testis was proximal to the internal ring; (b) Inguinal, when it was found between the internal and external inguinal rings); and (c) Scrotal, when it was inside the scrotum. RESULTS: The testes were abdominal in 71% of the cases, inguinal in 9.41%, and scrotal in 19.81%. There was asymmetry in testicular migration in nine cases (5.5%). In three of these nine cases, one testis was situated in the abdomen and the other in the inguinal canal; in another three one testis was situated in the abdomen and the other in the scrotum, and in the remaining three, one testis was in the inguinal canal and the other in the scrotum. In five of the nine cases of asymmetry, the right testis completed the migration first, but this was not statistically significant. CONCLUSION: Asymmetry in testicular migration is a rare event, accounting for <6% of the cases. The right testis seems to complete migration first.

Does lung development differ in male and female fetuses?

Preterm male infants have a higher incidence of morbidity and mortality due to respiratory insufficiency than females of the same gestational age. This male disadvantage could be due to differences in lung architecture; however, few studies have compared lung architecture in male and female fetuses during late gestation. Our principal objectives were to compare the morphology of the fetal lung and the maturity of the surfactant system in preterm male and female fetuses. Lungs from male (n = 9) and female (n = 11) fetal sheep were collected at 0.9 of term (131 days of the 145-day gestation) for morphological and molecular analyses. In separate groups, tracheal liquid was obtained from male (n = 9) and female (n = 9) fetuses at 0.9 of term for determination of surfactant phospholipid composition. We found no sex-related differences in body weight, lung weight, right lung volume, lung tissue and airspace fractions, mean linear intercept, septal crest density, septal thickness, the proportion of proliferating and apoptotic cells, and the percentages of collagen or elastin. The gene expression of surfactant protein -A, -B, -C, and -D and tropoelastin was similar between sexes. There were no differences in the proportion of the major phospholipid classes in the tracheal liquid between sexes; however there was a significantly higher percentage of the phospholipid species phosphatidylinositol 38:5 in males. The greater morbidity and mortality in preterm male lambs do not appear to be related to differences in lung structure or surfactant phospholipid synthesis before birth, but may relate to physiological adaptation to air-breathing at birth.