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Importance: Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants. Objective: To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula. Design, Setting, and Participants: The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020. Interventions: Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days. Main Outcomes and Measures: The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days. Results: The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies. Conclusions and Relevance: Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT02510560.

ispartof: J Neonatal Perinatal Med vol:15 issue:2 pages:427-439 ispartof: location:Netherlands status: published

Supplemental material, sj-pdf-1-pmj-10.1177_02692163221076365 for Barriers and facilitators for parents in end-of-life decision-making for neonates at the Neonatal Intensive Care Unit: A qualitative study by Veerle Piette, Laure Dombrecht, Luc Deliens, Filip Cools, Kenneth Chambaere, Linde Goossens, Gunnar Naulaers, Sabine Laroche, Luc Cornette, Eline Bekaert, Pauline Decoster, Kim Beernaert and Joachim Cohen in Palliative Medicine

Supplemental material, sj-pdf-2-pmj-10.1177_02692163221076365 for Barriers and facilitators for parents in end-of-life decision-making for neonates at the Neonatal Intensive Care Unit: A qualitative study by Veerle Piette, Laure Dombrecht, Luc Deliens, Filip Cools, Kenneth Chambaere, Linde Goossens, Gunnar Naulaers, Sabine Laroche, Luc Cornette, Eline Bekaert, Pauline Decoster, Kim Beernaert and Joachim Cohen in Palliative Medicine

Additional file 1.

Background: A female baby patient, first child of non-consanguineous couple of North-European origin was referred to the Genetics Clinic. During the second and third pregnancy trimester, foetal ultrasound assessment failed to detect any congenital abnormalities. The girl was born at 36 weeks of gestation by caesarean section with birth weight of 2230 grams and head circumference of 34.5 centimetres. She was hospitalized in the neonatal intensive care unit for respiratory support. Clinical assessment detected generalised arthrogryposis with severe bilateral clubfeet deformity, bilateral hip dislocation, clenched hands, ulnar finger deviation, clinodactyly, camptodactyly, and dysmorphic facial features such as brachycephaly, mild hypertelorism, central cleft palate, whistling face, low set, and posteriorly rotated ears. The initial treatment consisted of physiotherapy and casting. She was discharged from the neonatal intensive care unit after 20-days and follow-up was arranged in a specialized care facility. Methods: Gene panel testing for neuromuscular disorders was performed on Illumina NGS sequencing system and class 4 (likely pathogenic) or 5 (pathogenic) variants were reported and subsequently confirmed by Sanger sequencing. Results: A de novo heterozygous class 4 variant NM_022068.2(PIEZO2 ): c.8199_8202delAATA p.(Leu2733Phefs*10) in PIEZO2 gene was detected. Discussion: Congenital arthrogryposis is a broad spectrum of genetic and non-genetic conditions with overlapping clinical features. Heterozygous pathogenic variants in PIEZO2 are known to cause 3 types of arthrogryposis: Gordon syndrome (distal arthrogryposis type 3), Marden-Walker syndrome and Distal arthrogryposis type 5. These clinically and genetically overlapping syndromes are now considered to represent variable expression of the same disorder. Although there is no clear genotype- phenotype correlation, there are some differences among these syndromes. The clinical features of the presented patient tend most to correlate with Gordon syndrome phenotype, which is typically characterized by clenching of hands and feet, camptodactyly, clubfoot, and less frequently, cleft palate. The detected PIEZO2 variant is a frame shift variant, resulting in a premature stop codon. It is located 20 amino acids before the normal stop codon and has not been previously reported. This PIEZO2 gene variant was presumed to be likely pathogenic given that there is another reported patient with proven pathogenic PIEZO2 gene variant that is located downstream of this PIEZO2 position. Conclusion: A patient with phenotype of Gordon syndrome is presented, one of the three disorders known to be caused by PIEZO2 pathogenic variants.

Aim Perinatal death is often preceded by an end-of-life decision (ELD). Disparate hospital policies, complex legal frameworks and ethically difficult cases make attitudes important. This study investigated attitudes of neonatologists and nurses towards perinatal ELDs. Methods A survey was handed out to all neonatologists and neonatal nurses in all eight neonatal intensive care units in Flanders, Belgium in May 2017. Respondents indicated agreement with statements regarding perinatal ELDs on a Likert-scale and sent back questionnaires via mail. Results The response rate was 49.5% (302/610). Most neonatologists and nurses found nontreatment decisions such as withholding or withdrawing treatment acceptable (90-100%). Termination of pregnancy when the foetus is viable in cases of severe or lethal foetal problems was considered highly acceptable in both groups (80-98%). Physicians and nurses do not find different ELDs equally acceptable, e.g. nurses more often than physicians (74% vs 60%, p = 0.017) agree that it is acceptable in certain cases to administer medication with the explicit intention of hastening death. Conclusion There was considerable support for both prenatal and neonatal ELDs, even for decisions that currently fall outside the Belgian legal framework. Differences between neonatologists' and nurses' attitudes indicate that both opinions should be heard during ELD-making.