Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial.

BACKGROUND: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP. METHODS: A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations. RESULTS: Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration. CONCLUSION: Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

Successful Propranolol Treatment of a Kaposiform Hemangioendothelioma Apparently Resistant to Propranolol.

A newborn with unresectable kaposiform hemangioendothelioma associated with Kasabach Merritt phenomenon, unresponsive to vincristine and prednisone, received second-line treatment with propranolol at a dose of 2 mg/kg/day, starting at 2 months of life and continued for 13 months. There was only slight reduction in tumor mass, but measurement of propranolol levels showed extremely low plasma concentrations. The propranolol dose was progressively increased to 3.5 mg/kg/day, leading to a substantial increase in plasma levels associated with clinically relevant tumor reduction. This case highlights the importance of relating propranolol dose to its plasma concentration before considering the treatment ineffective for this vascular tumor.

Application of Pattern Recognition Techniques to the Classification of Full-Term and Preterm Infant Cry.

OBJECTIVES: Scientific and clinical advances in perinatology and neonatology have enhanced the chances of survival of preterm and very low weight neonates. Infant cry analysis is a suitable noninvasive complementary tool to assess the neurologic state of infants particularly important in the case of preterm neonates. This article aims at exploiting differences between full-term and preterm infant cry with robust automatic acoustical analysis and data mining techniques. STUDY DESIGN: Twenty-two acoustical parameters are estimated in more than 3000 cry units from cry recordings of 28 full-term and 10 preterm newborns. METHODS: Feature extraction is performed through the BioVoice dedicated software tool, developed at the Biomedical Engineering Lab, University of Firenze, Italy. Classification and pattern recognition is based on genetic algorithms for the selection of the best attributes. Training is performed comparing four classifiers: Logistic Curve, Multilayer Perceptron, Support Vector Machine, and Random Forest and three different testing options: full training set, 10-fold cross-validation, and 66% split. RESULTS: Results show that the best feature set is made up by 10 parameters capable to assess differences between preterm and full-term newborns with about 87% of accuracy. Best results are obtained with the Random Forest method (receiver operating characteristic area, 0.94). CONCLUSIONS: These 10 cry features might convey important additional information to assist the clinical specialist in the diagnosis and follow-up of possible delays or disorders in the neurologic development due to premature birth in this extremely vulnerable population of patients. The proposed approach is a first step toward an automatic infant cry recognition system for fast and proper identification of risk in preterm babies.

Fetal programming and systemic sclerosis.

OBJECTIVE: This study investigated whether birthweight is linked to an increased risk of the development of systemic sclerosis. STUDY DESIGN: This was a multicenter case-control study with perinatal data that were obtained from 332 cases with systemic sclerosis and 243 control subjects. Birthweight was treated as a dichotomous variable (<2500 g vs ≥2500 g); low birthweight was defined as a weight <2500 g; small for gestational age was defined as birthweight <10th percentile for gestational age adjusted for sex. The relationship between systemic sclerosis and both low birthweight and small for gestational age was expressed with the crude (univariate analysis) and adjusted (multivariate analysis) odds ratio (OR). RESULTS: Significantly increased ORs were observed in the univariate analysis for low birthweight (OR, 2.59; 95% confidence interval [CI], 1.39-5.05) and small for gestational age (OR, 2.60; 95% CI, 1.34-5.32) subjects. Similarly increased risks were confirmed for both conditions in the multivariate analysis (OR, 3.93; 95% CI, 1.92-8.07; and OR, 2.58; 95% CI, 1.28-5.19), respectively. CONCLUSION: Low birthweight and small for gestational age at birth are risk factors for the adult onset of systemic sclerosis.

The perception of the fetus in mothers with liver transplantation. Brief communication.

BACKGROUND: In this brief note we present the preliminary findings of a study of 16 women who underwent liver transplants before becoming pregnant and giving birth. The aim of the study was to show the similarities and differences between ways women experience the transplanted organ (liver) and the fetus. METHODS: To explore bodily experiences, a semi-structured ad hoc interview was done on a sample of 16 transplanted women who had completed a pregnancy. The interview was designed to explore the possible similarities between their perception of the transplanted organ (liver) and of the fetus. RESULTS: The main findings that emerge from our study are the following: a) in the post-transplant, pre-pregnancy phase, these women develop a polarized attention on the transplanted organ; b) during pregnancy this attention shifts towards the fetus; c) after childbirth the hyper-attention on the transplanted organ disappears and the subject resumes a normal relationship with her body. CONCLUSIONS: Therefore, pregnancy and childbirth are experiences that can normalize relations between a person who has undergone a transplant and their transplanted organ.

Sleeping problems in mothers and fathers of patients suffering from congenital central hypoventilation syndrome.

PURPOSE: Advanced medical technology has resulted in an increased survival rate of children suffering from congenital central hypoventilation syndrome. After hospitalization, these technology-dependent patients require special home care for assuring ventilator support and the monitoring of vital parameters mainly during sleep. The daily challenges associated with caring for these children can place primary caregivers under significant stress, especially at night. Our study aimed at investigating how this condition affects mothers and fathers by producing poor sleep quality, high-level diurnal sleepiness, anxiety, and depression. METHODS: The study included parents of 23 subjects with congenital central hypoventilation syndrome and 23 healthy subjects. All parents filled out the Pittsburgh Sleep Quality Index (PSQI) questionnaire, Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). RESULTS: A comparison between the two groups showed that parents of patients had poorer sleep quality, greater sleepiness, and higher BDI-II scores compared to that of parents of healthy subjects (respectively, PSQI score 6.5 vs 3.8, ESS score 6.2 vs 4.3, BDI-II score 8.4 vs 5.7). Specifically, mothers of patients showed poorer sleep quality and higher BDI-II scores compared to that of mothers of controls (respectively, PSQI score 7.5 vs 3.8, BDI-II score 9.3 vs 5.9), whereas fathers of patients showed greater levels of sleepiness with respect to fathers of healthy children (respectively, ESS score 6.8 vs 4.0). These differences emerged in parents of younger children. CONCLUSIONS: Congenital central hypoventilation syndrome impacts the family with different consequences for mothers and fathers. Indeed, while the patients' sleep is safeguarded, sleeping problems may occur in primary caregivers often associated with other psychological disorders. Specifically, this disease affects sleep quality and mood in the mothers and sleepiness levels in the fathers.

The role of narrative medicine in pregnancy after liver transplantation.

UNLABELLED: Narrative medicine allows professionals from all fields of medical sciences to understand the patient's total experience of illness, and meet his/her needs in an empathetic environment. Narrative medicine helps spread holistic knowledge of a multitude of complex clinical conditions, including transplantation. OBJECTIVE: To underline the role of narrative medicine in women who become pregnant after a liver transplant by using their narrations of this very special experience. METHODS: We describe our study with narration and listening to the stories of three women expecting their first child after a liver transplant, by analysing the structure and role of narration in the context of relationships between patients and caregivers. The narrations were transcribed verbatim with the main plot analysed in order to address all the aspects of this rare clinical condition and the transition to parenthood. RESULTS: The women narrated this experience in three phases: transplantation, pregnancy and delivery, and post-partum. They described all phases of pregnancy as stressful but satisfying, whereas the fact of becoming a mother was perceived as a victory both as a woman and as a transplant patient. CONCLUSIONS: Our results suggest that narrative medicine represents a significant professional tool for caring for transplant patients during pregnancy.

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants.

Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed.To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age.The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research.

Breastfeeding during pregnancy: position paper of the Italian Society of Perinatal Medicine and the Task Force on Breastfeeding, Ministry of Health, Italy.

As more women breastfeed for longer, it is increasingly likely that women may be still breastfeeding when they become pregnant again. The Italian Society of Perinatal Medicine (SIMP) Working Group on Breastfeeding has reviewed the literature to determine the medical compatibility of pregnancy and breastfeeding. We found no evidence indicating that healthy women are at higher risk of miscarriage or preterm delivery if they breastfeed while pregnant. No evidence indicates that the pregnancy-breastfeeding overlap might cause intrauterine growth restriction, particularly in women from developed countries. Little information is available on the composition of human milk of pregnant women, and we found no data on the growth of infants nursed by a pregnant woman. However, both the composition of postpartum breast milk and the growth of the subsequent newborn appear to be partly affected, at least in developing countries. SIMP supports breastfeeding during pregnancy in the first 2 trimesters, and we believe it to be sustainable in the third trimester. Based on the hypothetical risk, caution may be warranted for women at risk of premature delivery, although no evidence exists that breastfeeding could trigger labor inducing uterine contractions. In conclusion, currently available data do not support routine discouragement of breastfeeding during pregnancy. Further studies are certainly needed to explore the consequences of breastfeeding during pregnancy on maternal health, on the breastfed infant, on the embryo/fetus, and, subsequently, on the growth of the newborn.

Neonatal hemoperitoneum: unexpected birth trauma with fatal consequences.

We report a case of fatal intra-abdominal bleeding in a term newborn delivered by vacuum extractor and Kristeller manouvre. Although autopsy was not performed in compliance with the parents' wishes, there is strong evidence of a massive abdominal haemorrhage due to injuries of the hypochondriac organs probably leading to disconnection of a vascular pedicle.

Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives.

OBJECTIVE: To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN: Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS: Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47-0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION: This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).

BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS/DESIGN: Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.

Hypothermia for neonatal hypoxic-ischemic encephalopathy: may an early amplitude-integrated EEG improve the selection of candidates for cooling?

OBJECTIVE: To report our experience in the selection of newborns candidate to therapeutic hypothermia. METHODS: Retrospective study involving 47 newborns suffering from perinatal asphyxia from January 2008 to September 2011. RESULTS: Thirty-five of 47 newborns admitted to our hospital fulfilled metabolic and neurological criteria for recruitment and were cooled. aEEG was carried out in 26 of them and resulted always abnormal. In three of the 12 newborns with only metabolic criteria, aEEG was moderately abnormal. They were cooled and their outcome (evaluated by General Movements and Griffiths Mental Development Scales for children aged 0-2 years) is good. Three additional newborns who only met the metabolic criterion reached our hospital after the therapeutic window for hypothermia and exhibited seizures; their outcome is poor. CONCLUSIONS: In our experience, the inclusion of aEEG in the entry criteria would not have precluded newborns with neurological criteria from cooling. On the contrary, without an early aEEG, we would have excluded from hypothermia infants with moderate hypoxic-ischemic encephalopathy without precocious neurological signs who exhibited only the metabolic criterion, but with abnormal aEEG. If further studies will confirm that early aEEG might identify newborns suitable for cooling even in the absence of clinical signs, a revision of the entry criteria should be considered.

Early perinatal diagnosis of mothers at risk of developing post-partum depression--a concise guide for obstetricians, midwives, neonatologists and paediatricians.

OBJECTIVE: In this article, we tried to provide all those involved in perinatal medicine with a concise guide to detect mothers at risk of developing post-partum depression. Motherhood is a critical situation characterized by role conflicts because conflicts among the role of mother, worker and wife are the norm in the post-partum period and may jeopardize the mother's existence. METHODS: We have described a kind of personality that is at great risk of developing post-partum depression because of the incapacity to creatively manage situations of role conflict. This personality structure is called typus melancholicus, and we operationally defined its main features: orderliness, conscientiousness, hypernomia/heteronomia and intolerance of ambiguity. RESULTS: We have shown how these mothers may typically behave during pregnancy and early motherhood: they cannot avoid behaving with feverish perfectionism, developing an exaggerated preoccupation towards the unborn child and hostility towards persons and events that are experienced as an obstacle to their search for perfection. They ultra-carefully follow all the steps concerning paediatric check-ups and feel all the responsibility relating to the care of the child, without being able to delegate to someone else or share their feelings. CONCLUSION: We hope to provide those clinicians who are engaged in the care of pregnant women and their children with a valuable and user-friendly instrument for understanding and making a timely diagnoses of at-risk psychopathological phenomena.