Improving growth in preterm infants through nutrition: a practical overview.

The primary purpose of this practical overview is to provide a practical update on appropriate nutritional strategies to improve growth in preterm infants. Current recommendations for improving preterm growth concern both macronutrients and micronutrients, with tailored nutrition since the first days of life, particularly when fetal growth restriction has been reported. Human milk is undoubtedly the best nutrition for all newborns, but, in some populations, if not adequately fortified, it does not adequately support their growth. In all preterms, growth should be correctly monitored weekly to intercept a negative trend of growth and implement nutritional strategies to avoid growth restriction. Similarly, growth should be accurately supported and monitored after discharge to improve long-term health consequences.

From intra- to extra-uterine: early phase design of a transfer to extra-uterine life support through medical simulation.

Introduction: Extra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure. Methods: Our objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother's uterus to an extra-uterine life support system. To facilitate a user-centered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians. Results & discussion: Through analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context.

Risk assessment of extra-uterine involvement and prognosis in young type I endometrial carcinoma with high or moderate differentiation and less than 1/2 myometrial invasion.

PURPOSE: The aim of this study was to investigate whether young patients with endometrial carcinoma can preserve adnexa and lymph nodes to improve their quality of life without compromising their prognosis. METHODS: A total of 319 patients with type I endometrial carcinoma (high or moderate differentiation and less than 1/2 myometrial invasion) hospitalized in the First Affiliated Hospital of Zhengzhou University from May 2012 to July 2021 were included. The patients were divided into four groups: high differentiation without myometrial invasion group (G1MI-), high differentiation with superficial myometrial invasion group (G1MI+), moderate differentiation without myometrial invasion group (G2MI-), and moderate differentiation with superficial myometrial invasion group (G2MI+). Logistic regression analysis was conducted to identify risk factors for extra-uterine involvement. Kaplan-Meier method was used to draw the survival curve to compare the prognosis in subgroups and rates of extra-uterine involvement were also compared using Chi-square test or Fisher's exact test. RESULTS: Multivariable logistic regression revealed that differentiation (HR = 14.590, 95%CI = 1.778-119.754, p = 0.013) and myometrial invasion (HR = 10.732, 95%CI = 0.912-92.780, p = 0.037) were the independent risk factors for extra-uterine involvement. The overall difference was statistically significant (p < 0.001). In the subgroups analysis, both adnexal metastasis and lymph node metastasis were statistically significant in the G2MI+ group compared with G1MI- (p = 0.007, p = 0.008). There were no significant differences in the overall survival (OS) rate and progression free survival (PFS) rate among the four subgroups (p > 0.05). CONCLUSIONS: Surgery with adnexal preservation and without systematic lymphadenectomy could be employed for the patients who are high differentiation with less than 1/2 myometrial invasion or moderate differentiation without myometrial invasion, but not recommended to the patients with moderate differentiation and superficial myometrial invasion.

Pharmacological treatment of ectopic pregnancy: Accuracy, safety and cost-effectiveness of day 1-7 ß-hCG measurements.

OBJECTIVE: The aim of the present study was to compare accuracy, safety and cost-effectiveness of three ß-hCG measurements protocols, applied in managing ectopic pregnancies (EP) with methotrexate (MTX): (1) day 1 to 7 ß-hCG levels, (2) day 1 to 4 ß-hCG levels and (3) day 4 to 7 ß-hCG levels. METHODS: Cost-minimization analysis (CMA) based on a retrospective study of patients treated with single-dose MTX for EP, was evaluated at a single institution between January 2001 to May 2021. Successful MTX treatment was defined as no surgical intervention. We evaluated safety by analyzing cases of day 4 interventions and cases of inconsistency between the different protocols. Predicting accuracy was assessed by the area under the receiver operating characteristic (AUC) curve. RESULTS: A total of 229 patients with single dose MTX treatment were included. Overall, 184 (80.3%) patients were treated successfully with a single dose of MTX. For days 1 and 7 the optimal cutoff point was 7% reduction in ß-hCG levels with sensitivity, specificity and PPV of 76.6% (69.9-82.5, 95% CI), 75.5% (60.5-87.1, 95% CI) and 92.8% (88.4-95.6, 95% CI), respectively. There was no significant difference between the protocols' AUC. None of the patients had any change of management during their day 4 visit in our 20 years of records. The cost for each visit day (day 4 and 7) was calculated with a total cost of 251 USD per patient. CONCLUSION: Patients treated with MTX for EP, measurement of day 1 and day 7 ß-hCG serum levels has a cost minimization advantage and is not inferior to the traditional protocol for predictive accuracy and safety.

Transferring an extremely premature infant to an extra-uterine life support system: a prospective view on the obstetric procedure.

To improve care for extremely premature infants, the development of an extrauterine environment for newborn development is being researched, known as Artificial Placenta and Artificial Womb (APAW) technology. APAW facilitates extended development in a liquid-filled incubator with oxygen and nutrient supply through an oxygenator connected to the umbilical vessels. This setup is intended to provide the optimal environment for further development, allowing further lung maturation by delaying gas exposure to oxygen. This innovative treatment necessitates interventions in obstetric procedures to transfer an infant from the native to an artificial womb, while preventing fetal-to-neonatal transition. In this narrative review we analyze relevant fetal physiology literature, provide an overview of insights from APAW studies, and identify considerations for the obstetric procedure from the native uterus to an APAW system. Lastly, this review provides suggestions to improve sterility, fetal and maternal well-being, and the prevention of neonatal transition.

[Prevention of Rh D alloimmunization in the first trimester of the pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice]. / Prévention de l'allo-immunisation anti-RH1 au premier trimestre de la grossesse : recommandations pour la pratique clinique du Collège national des gynécologues-obstétriciens français.

OBJECTIVE: To provide recommendations for the prevention of Rh D alloimmunization in the first trimester of pregnancy. MATERIALS AND METHODS: The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the PICO format (Patients, Intervention, Comparison, Outcome) and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed on Pubmed, Cochrane, EMBASE, and Google Scholar databases. The quality of evidence was assessed (high, moderate, low, very low) and a recommendation was formulated: (i) strong, (ii) weak, or (iii) no recommendation. The recommendations were reviewed in two rounds with reviewers from the scientific board of the French College of the OB/GYN (Delphi survey) to select the consensus recommendations. RESULTS: The three recommendations from PICO questions reached agreement using the Delphi method. It is recommended not to administer Rh D immunoglobulin before 12 weeks of gestation to reduce the risk of alloimmunization in case of abortion or miscarriage, in RhD negative patients when the genitor is RhD positive or unknown (Weak recommendation. Very low-quality evidence). It is recommended not to administer Rh D immunoglobulin before 12 weeks of gestation to reduce the risk of alloimmunization in cases of bleeding in an ongoing intrauterine pregnancy (Weak recommendation. Very low-quality evidence). The literature data are insufficient in quality and quantity to determine if the injection of Rh D immunoglobulin reduces the risk of alloimmunization in the case of an ectopic pregnancy (No recommendation. Very low-quality evidence). CONCLUSION: Even though the quality of evidence from the studies is very low, it is recommended not to administer Rh D immunoglobulin in case of abortion, miscarriage or bleeding before 12 weeks of amenorrhea. The quality of evidence was too low to issue a recommendation regarding ectopic pregnancy.

Early Extra-Uterine Growth Restriction in Very-Low-Birth-Weight Neonates with Normal or Mildly Abnormal Brain MRI: Effects on a 2-3-Year Neurodevelopmental Outcome.

Extra-uterine growth restriction (EUGR) is a common complication and a known risk factor for impaired development in very-low-birth-weight (VLBW) neonates. We report a population of 288 patients with no or with low-grade MRI lesions scanned at a term equivalent age (TEA) born between 2012 and 2018. Griffiths Mental Development Scale II (GMDS II) at 2 and 3 years, preterm complications and weight growth were retrospectively analyzed. EUGR was defined for weight z-score ˂ 10 percentile at TEA, 6 and 12 months of correct age or as z-score decreased by 1-point standard deviation (SDS) from birth to TEA and from TEA to 6 months. Multivariate analysis showed that a higher weight z-score at 6 months is protective for the global developmental quotient (DQ) at 2 years (OR 0.74; CI 95% 0.59-0.93; p = 0.01). EUGR at 6 months was associated with worse locomotor, personal/social, language and performance DQ at 2 years and worse language and practical reasoning DQ at 3 years. In conclusion, a worse weight z-score at 6 months of age seems to be an independent risk factor for significantly reduced GMDS in many areas. These results suggest that we should invest more into post-discharge nutrition, optimizing family nutritional education.

Does Early Fortification of Human Milk Decrease Time to Regain Birth Weight as Compared to Late Fortification Among Preterm Infants? - A Randomized Controlled Trial.

OBJECTIVES: To compare the duration required to regain birth weight following early fortification of human milk vs. late fortification among preterm infants. METHODS: This randomized controlled trial included hemodynamically stable 120 preterm infants (≤32 wk of gestation). The intervention and comparator groups received standard fortification with human milk fortifier when enteral feeds reached 30 ml/kg/d (early fortification) and 80 ml/kg/d (late fortification) respectively. Neonates in both the groups received feed increments as per standard NICU protocol. Anthropometric measurements (weight, length, and head circumference) at birth and during postnatal follow-up were done following standard precautions and plotted on the sex-specific Fenton growth charts. Primary outcome was the mean duration required to regain birth weight. Secondary outcomes included weight gain velocity, linear growth, increase in head circumference and occurrence of sepsis, feed intolerance and necrotizing enterocolitis. RESULTS: Preterm neonates who received early fortification regained birth weight earlier compared to those in the late fortification group (10.13 ± 2.90 vs. 11.26 ± 3.06, p <0.05). The weight gain velocity, linear growth and increase in head circumference were better in the early fortification group. There was no increased risk of culture proven sepsis, feed intolerance and necrotizing enterocolitis in the early fortification group compared to late fortification. CONCLUSIONS: Standard fortification with human milk fortifier when enteral feeds reach 30 ml/kg/d helps preterm neonates regain birth weight earlier. Early fortification is well tolerated and safe for the population studied.

Simulation-based development: shaping clinical procedures for extra-uterine life support technology.

BACKGROUND: Research into Artificial Placenta and Artificial Womb (APAW) technology for extremely premature infants (born < 28 weeks of gestation) is currently being conducted in animal studies and shows promising results. Because of the unprecedented nature of a potential treatment and the high-risk and low incidence of occurrence, translation to the human condition is a complex task. Consequently, the obstetric procedure, the act of transferring the infant from the pregnant woman to the APAW system, has not yet been established for human patients. The use of simulation-based user-centered development allows for a safe environment in which protocols and devices can be conceptualized and tested. Our aim is to use participatory design principles in a simulation context, to gain and integrate the user perspectives in the early design phase of a protocol for this novel procedure. METHODS: Simulation protocols and prototypes were developed using an iterative participatory design approach; usability testing, including general and task-specific feedback, was obtained from participants with clinical expertise from a range of disciplines. The procedure made use of fetal and maternal manikins and included animations and protocol task cards. RESULTS: Physical simulation with the active participation of clinicians led to the diffusion of tacit knowledge and an iteratively formed shared understanding of the requirements and values that needed to be implemented in the procedure. At each sequel, participant input was translated into simulation protocols and design adjustments. CONCLUSION: This work demonstrates that simulation-based participatory design can aid in shaping the future of clinical procedure and product development and rehearsing future implementation with healthcare professionals.

Extrauterine Growth Restriction: Need for an Accurate Definition.

Neonates show considerable variation in growth that can be recognized through serial measurements of basic variables such as weight, length, and head circumference. If possible, measurement of subcutaneous and total body fat mass can also be useful. These biometric measurements at birth may be influenced by demographics, maternal and paternal anthropometrics, maternal metabolism, preconceptional nutritional status, and placental health. Subsequent growth may depend on optimal feeding, total caloric intake, total metabolic activity, genetic makeup, postnatal morbidities, medications, and environmental conditions. For premature infants, these factors become even more important; poor in utero growth can be an important reason for spontaneous or induced preterm delivery. Later, many infants who have had intrauterine growth restriction (IUGR) and are born small for gestational age (SGA) continue to show suboptimal growth below the 10th percentile, a condition that has been defined as extrauterine growth restriction (EUGR) or postnatal growth restriction (PNGR). More importantly, a subset of these growth-restricted infants may also be at high risk of abnormal neurodevelopmental outcomes. There is a need for well-defined criteria to recognize EUGR/PNGR, so that correctional steps can be instituted in a timely fashion.

Comparing two different placental transfusion strategies for very preterm infants at birth: a matched-pairs study.

OBJECTIVE: To evaluate the clinical outcomes of using the extra-uterine placental transfusion (EPT) approach in very preterm infants (VPIs, gestational age <32 weeks) and compare this to delayed cord clamping (DCC) after birth. METHODS: In this matched pairs study, we compared the clinical outcomes of the EPT group to those of the DCC group. EPT were performed in fifty-three VPIs, of whom 27 were singletons and 25 were twins. The singleton VPIs were matched for gestational age (±5 days) and delivery mode, and the twin VPIs were matched between each other with the first twin subjected to DCC and the second twin to EPT. Data on the infants were collected and analysed as an overall group. A twin subgroup consisting of DCC and EPT groups was also analysed separately. The primary study outcome was either death or major morbidities. RESULTS: In total, 100 infants were included (n = 50 EPT group, n = 50 DCC group). The gestational ages of the DCC and EPT groups were (29.16 ± 1.76) and (29.12 ± 1.84) weeks, respectively. There were no differences in either deaths or major morbidities and other clinical outcomes, including the resuscitation variables, haemoglobin levels and red blood cell transfusion, between the two groups. In twin subgroups (gestational age 29.05 ± 1.89 weeks), EPT was associated with a higher rate of necrotizing enterocolitis (NEC) when compared with DCC (odds ratio = 7 (95% CI, 1.06 to 56.89), p = 0.031). CONCLUSIONS: In twin subgroups, the incidence of NEC was higher in the EPT group when compared to the DCC group and therefore based on an abundance of caution the use of EPT in very preterm twins is not recommended.

Extra-uterine placental transfusion (EPT) is an alternative new form of placental transfusion. It can alleviate the problem of delayed respiratory support during DCC. It can also be performed in some placental abruption cases.EPT may lead to the same clinical outcome as DCC in singleton pregnancies but based on an abundance of caution it is not recommended for very preterm twins.

Adenocarcinoma of Mullerian Origin Presenting as Small Bowel Obstruction.

We report a case of an 84-year-old female with a history of total abdominal hysterectomy with bilateral salpingo-oophorectomy 20 years previously who presented with small bowel obstruction. Computed tomography (CT) scan with contrast showed a large mass in the mesentery of the small bowel. Exploratory laparotomy was performed, and segmental resection of 25 cm of small bowel with the mesenteric mass was performed. The histopathological features were suggestive of recurrent adenocarcinoma of Mullerian origin. The patient was offered palliative chemotherapy and referred to oncology and palliative care as a part of multidisciplinary treatment.

[Embryo stage impact on the risk of ectopic pregnancy after In Vitro Fecondation]. / Impact du stade embryonnaire lors du transfert sur le risque de grossesse extra-utérine en Fécondation In Vitro.

OBJECTIVES: Ectopic pregnancies are still the first mortality cause of the first semestre of pregnancy. They are much more frequent in IVF (2-5%) than in the standard population (1-2%). The aim of this study was to compare the rate of ectopic pregnancies following a fresh embryo transfer done whether at an clived embryo stage (day 2 or 3 of the embryo development) or at a blastocyst stage (day 5 or 6 of the embryo development). METHODS: This is a monocentric retrospective study including all 18 to 43 year-old patients getting pregnant (ßHCG>100 UI/L) after a fresh embryo transfer from In Vitro Fecondation with or without Intra-Cytoplasmic Sperm Injection, between January 1st 2014 and December 30th 2020 in the Hospital of Besançon (France). This population has been divided into 2 groups according to the embryo stage on the day of transfer. RESULTS: Nine hundred and twenty two patients have been included. There were statistically more ectopic pregnancies after a blastocyst transfer (n=4; 5.4%) than after a clived embryo transfer (n=14; 1.7%). (P=0.049) CONCLUSION: In our population, there were more ectopic pregnancies from blastocyst(s) transfers than from clived embryo(es).

Challenges in the growth and development of newborns with extra-uterine growth restriction.

INTRODUCTION: Extra-uterine growth restriction (EUGR) is a condition caused by the failure of very preterm infants to reach their potential growth during the NICU hospital stay. Despite enormous improvements in nutritional support and strategies, the growth pattern of preterm infants is still far from the one expected. AREAS COVERED: This review focuses on what EUGR is, highlighting controversial aspects of this topic. EUGR is still missing a univocal definition, and the international debate is also open on what is the best growth chart to use. Moreover, professionals in NICU may not be trained on how to perform anthropometric measurements, increasing the risk of over- or underestimation, especially for length assessment. EUGR has recently been described as one of the main comorbidities in NICU, influencing growth, metabolism, and neurodevelopment later in life. EXPERT OPINION: There is still much to investigate about what the best growth pattern in the NICU should be. What is known so far is that the majority of preterm neonates develop EUGR, and this leads to several short- and long-term consequences. It is imperative that neonatologists and pediatric endocrinologists work together, to modulate growth in the NICU.

The Efficacy and Success Rate of Methotrexate in the Management of Ectopic Pregnancy.

Background Ectopic pregnancy is a life-threatening medical condition wherein pregnancy occurs outside the uterus. This study primarily aimed to evaluate the efficacy of methotrexate (MTX) in treating patients diagnosed with early ectopic pregnancy between 2016 and 2021. Second, it aimed to investigate the clinical outcomes of subsequent pregnancies following ectopic pregnancy treatment. Methods A retrospective cohort study was carried out at a tertiary care centre in Jeddah, Saudi Arabia. The sample for this study comprised 59 patients who were diagnosed with ectopic pregnancy and treated with MTX at King Abdulaziz Medical City, Jeddah, between 2016 and 2021. The data were stored in the Microsoft Office Excel format and analyzed using the SPSS software. Results There were 10 reported cases of ruptured ectopic pregnancy; seven of these underwent surgery, while three were successfully treated conservatively using MTX. Success rates of 55.9% and 93.8% were recorded after administering the first and second dose of MTX, respectively, based on beta-human chorionic gonadotrophin (ß-hCG) drop between day 4 and day 7. Among those treated with MTX, 37.3% of the patients reported a successful subsequent pregnancy, of which 54.5% delivered a live, healthy infant and 13.6% had a second ectopic pregnancy. Conclusion MTX proved effective in treating ectopic pregnancy, with a ß-hCG drop of more than 15%. Patients who received a second dose of MTX showed a higher drop in ß-hCG level, indicating greater success as a cumulative effect. The clinical outcome after MTX treatment of ectopic pregnancy was shown to be significant with a p-value <0.05.

Complex Perinatal Syndromes Affecting Early Human Growth and Development: Issues to Consider to Understand Their Aetiology and Postnatal Effects.

Complex perinatal syndromes (CPS) affecting pregnancy and childhood, such as preterm birth, and intra- and extra-uterine growth restriction, have multiple, diverse contexts of complexity and interaction that determine the short- and long-term growth, health and development of all human beings. Early in life, genetically-guided somatic and cerebral development occurs alongside a psychism "in statu nascendi," with the neural structures subjected to the effects of the intra- and extra-uterine environments in preparation for optimal postnatal functioning. Different trajectories of fetal cranial and abdominal growth have been identified before 25 weeks' gestation, tracking differential growth and neurodevelopment at 2 years of age. Similarly, critical time-windows exist in the first 5-8 months of postnatal life because of interactions between the newborn and their environment, mother/care-givers and feeding practices. Understanding these complex relational processes requires abandoning classical, linear and mechanistic interpretations that are placed in rigid, artificial biological silos. Instead, we need to conduct longitudinal, interdisciplinary research and integrate the resulting new knowledge into clinical practice. An ecological-systemic approach is required to understand early human growth and development, based on a dynamic multidimensional process from the molecular or genomic level to the socio-economic-environmental context. For this, we need theoretical and methodological tools that permit a global understanding of CPS, delineating temporal trajectories and their conditioning factors, updated by the incorporation of new scientific discoveries. The potential to optimize human growth and development across chronological age and geographical locations - by implementing interventions or "treatments" during periods of greatest instability or vulnerability - should be recognized. Hence, it is imperative to take a holistic view of reproductive and perinatal issues, acknowledging at all levels the complexity and interactions of CPS and their sensitive periods, laying the foundations for further improvements in growth and development of populations, to maximize global human potential. We discuss here conceptual issues that should be considered for the development and implementation of such a strategy aimed at addressing the perinatal health problems of the new millenium.

Extra-Uterine Leiomyoma Presenting After Hysterectomy.

Leiomyomas are a common gynaecological finding affecting 20-30% of women over the age of 35, with prevalence decreasing following menopause. Around 25% of women present clinically with a leiomyoma, which are most commonly found within the uterus. Rarer extra-uterine locations include the broad ligament, cervix, and vagina. We present a rare case of an extra-uterine leiomyoma located in the perineum of a 59-year-old female. Our case highlights the importance for extra-uterine leiomyoma to be considered as a differential diagnosis in patients presenting with a pelvic mass following hysterectomy.

The EXTrauterine Environment for Neonatal Development: Present and Future.

Despite advances in clinical care and modest improvement in mortality rates for extreme prematurity, morbidity remains a significant challenge. The ideal environment to support prematurity would be fluidic and rely on natural fetal circulation to mimic the natural fetal amniotic environment, yet such an environment has been unsuccessful in long-term support until recently. Our group has succeeded in developing such a support system to foster fetal growth in the premature lamb model that shows promise for clinical translation. Here, we describe the EXTrauterine Environment for Neonatal Development (EXTEND) from its conception onwards, review published literature on fetal development and support of the premature lamb model in EXTEND, and discuss future applications.

Primary low-grade extrauterine endometrial stromal sarcoma: analysis of 10 cases with a review of the literature.

BACKGROUND: This study aimed to analyze the clinical and pathological features of extrauterine endometrial stromal sarcoma (EESS) and explore an effective therapeutic regimen to reduce the recurrence rate in low-grade EESS patients. METHODS: Ten LG-EESS patients who were treated at the Chinese Academy of Medical Sciences Cancer Institute and Hospital from June 1999 to June 2019 were collected and analyzed. RESULTS: (1) Patient demographics are summarized in manuscript. Preoperative CA125 examination showed that 8 patients had a median level of 49.5 U/L (15.4-168.0 U/L). (2) All ten patients underwent tumor cytoreductive surgery. Five patients underwent optimal tumor resection and achieved an R0 resection. After the initial surgery, 7 patients who had multiple metastasis were treated with adjuvant chemotherapy, 2 patients with vaginal ESS were treated with chemotherapy and radiation therapy, and 6 patients with ER/PR positive received hormone therapy with or without chemotherapy. (2) Most EESS patients had multiple tumors. The omentum was the most commonly affected site, followed by the ovaries. (3) The median follow-up was 94 (range: 27-228) months, and recurrence was observed in 3 patients (n = 10, 30%) who underwent non-optimal surgery and no hormone therapy. The 5-year and 10-year DFS rates were both 70%, as shown in Fig. 2. OS was both 100% at 5 and 10 years. CONCLUSION: As a conclusion, EESS is a rare disease and LG-EESS has a good prognosis. Surgery remains the available treatment for patients. LG-EESS has a risk of late recurrence which requires a long-term follow-up. With a limited sample size, our study shows optimal tumor reductive surgery and adjuvant hormone therapy may significantly reduce the risk of recurrence.