Search

Background: Guidelines recommend non-invasive ventilatory (NIV) support as first-line respiratory support mode in preterm infants as NIV is superior to intubation and mechanical ventilation in preventing death or bronchopulmonary dysplasia. However, with an ever-expanding variety of NIV modes available, there is much debate about which NIV modality should ideally be used, how, and when. The aims of this work were to summarise the evidence on different NIV modalities for both primary and secondary respiratory support: nCPAP, nasal high-flow therapy (nHFT), and nasal intermittent positive airway pressure ventilation (nIPPV), bi-level positive airway pressure (BiPAP), nasal high-frequency oscillatory ventilation (nHFOV), and nasally applied, non-invasive neurally adjusted ventilatory assist (NIV-NAVA) modes, with particular focus on their use in preterm infants. Summary: This is a narrative review with reference to published guidelines by European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. nCPAP is currently the most commonly used primary and secondary NIV modality for premature infants. However, there is increasing evidence on the superiority of nIPPV over nCPAP. No beneficial effect was found for BiPAP over nCPAP. For the use of nHFT, nHFOV, and NIV-NAVA, more studies are needed to establish their place in neonatal respiratory care. Key Messages: The superiority of nIPPV over nCPAP needs to be confirmed by contemporaneous trials comparing nCPAP to nIPPV at comparable mean airway pressures. Future trials should study NIV modalities in preterm infants with comparable respiratory pathology and indications, at comparable pressure settings and with different modes of synchronisation. Importantly, future trials should not exclude infants of the smallest gestational ages. [ABSTRACT FROM AUTHOR]

Introduction: Three widely referenced growth curves classify infant birth anthropometric measurements as small (SGA), appropriate (AGA), or large (LGA) for gestational age (GA) differently. We assessed how these differences in assignment affect the identification and prediction of neonatal intensive care unit (NICU) mortality risk in US preterm infants. Methods: Birth data of infants admitted to NICUs from the Pediatrix Clinical Data Warehouse (2013–2018) were analyzed. Birth weight, length, and head circumference of 46,724 singleton infants (24–32 weeks GA) were classified as SGA, AGA, or LGA using the Olsen, Fenton, and INTERGROWTH-21st curves. NICU mortality risk based on birth size classification was analyzed using unadjusted and adjusted logistic regression stratified by GA. Results: Odds of mortality were increased with SGA classification at all GAs, size measurements, and curve sets, compared with AGA infants. LGA classification for weight was associated with lower mortality risk at 24 weeks GA and higher risk at 30 weeks GA. Odds of mortality did not differ significantly across curve sets. Classification of size at birth alone had relatively low predictive ability to identify mortality risk, with unadjusted AUCs near 0.5 for all analyses. Conclusion: There were no significant differences across curve sets in predicting mortality. Classification of size at birth is a relatively imprecise method to identify infants at risk for NICU mortality. [ABSTRACT FROM AUTHOR]

This article discusses the safety and effectiveness of growth hormone (GH) therapy for children who were born small for gestational age (SGA). The study analyzed data from the French National SGA Registry and found that GH therapy was generally safe, with few serious adverse events reported. In terms of effectiveness, GH therapy resulted in short-term growth improvement, but the effect on adult height was modest. The study also highlighted the importance of patient selection and adherence to treatment. Overall, the findings support the use of GH therapy for SGA children, but further research is needed to assess long-term safety and optimize treatment outcomes. [Extracted from the article]

Introduction: Direct comparisons of both short-term and long-term auxological outcomes of growth hormone therapy (GHT) between growth hormone deficiency (GHD) and small for gestational age (SGA) are scarce. Methods: One hundred three patients with GHD and 53 patients with SGA treated at our tertiary center were investigated. Short-term and long-term outcomes were compared between these groups using multivariable linear regression models with adjustment for age, sex, and height at therapy start, also allowing for sex-specific group comparisons. Results: Mean delta height standard deviation scores (SDS) after 1 year of treatment were significantly higher in GHD (0.90, CI: 0.82–0.99) compared to SGA (0.67, CI: 0.54–0.79) (p = 0.003) with no sex difference. As expected, the mean increase in height SDS at final height (FH) was significantly higher in GHD (2.21, CI: 2.00–2.42) compared to SGA (1.05, CI: 0.75–1.35) (p < 0.001), leading to a target height corrected FH of −0.39 SDS (CI: −0.62 to −0.15) in GHD and −1.22 SDS (CI: −1.57 to −0.87) in SGA (p < 0.001). Girls with GHD had a better long-term outcome, as did boys with SGA when compared to the respective opposite sex. The cut-off of delta height of 0.5 SDS during the first year had a low sensitivity to detect long-term non-responders. We found a relation between short-term and long-term outcomes in GHD but not in SGA (adjusted R2 = 0.66 vs. 0.01). Conclusion: In contrast to GHD, we observed practically no relationship between 1st-year and long-term outcomes in SGA patients treated with GH. [ABSTRACT FROM AUTHOR]

Introduction: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. Case Presentation: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, −2.2 SDS; length 47 cm, −2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 μg/L (−1.0 SD), and growth hormone (GH) after stimulation 6.2 μg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly – a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (−2.4 SD) and 177.8 cm (−0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; −2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (−2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (−0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. Conclusion: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone. [ABSTRACT FROM AUTHOR]

Introduction: The purpose was to compare thymus size measured during second trimester screening of fetuses who were subsequently small for gestational age at birth (weight below 10th percentile, SGA group) with fetuses with normal birth weight (control group). We hypothesized that measuring the fetal thymic-thoracic ratio (TT-ratio) might help predict low birth weight. Methods: Using three-vessel view echocardiograms from our archives, we measured the anteroposterior thymus size and the intrathoracic mediastinal diameter to derive TT-ratios in the SGA (n = 105) and control groups (n = 533) between 19+0 and 21+6 weeks of gestation. We analyzed the association between TT-ratio and SGA adjusted to the week of gestation using logistic regression. Finally, we determined the possible TT-ratio cut-off point for discrimination between SGA and control groups by means of receiver operating characteristics (ROC) curve analysis. Results: The TT-ratio was significantly higher in the SGA group than in the control group (p < 0.001). An increase of the TT-ratio by 0.1 was associated with a 3.1-fold increase in the odds of diagnosing SGA. We determined that a possible discrimination cut-off point between SGA and healthy controls was achieved using a TT-ratio of 0.390 (area under the ROC curve 0.695). Conclusion: An increased TT-ratio may represent an additional prenatal screening parameter that improves the prediction of birth weight below the 10th percentile. Prospective studies are now needed to evaluate the use of fetal thymus size as predictive parameter for adverse fetal outcome. [ABSTRACT FROM AUTHOR]

Current clinical guidelines provide information about the diagnostic workup of children with growth failure. This mini-review focuses on the nutritional assessment, which has received relatively little attention in such guidelines. The past medical history, in particular a low birth size and early feeding problems, can provide information that can increase the likelihood of nutritional deficits or several genetic causes. The current medical history should include a dietary history and can thereby reveal a poorly planned or severely restricted diet, which can be associated with nutritional deficiencies. Children on a vegan diet should receive various nutritional supplements, but insufficient compliance has been reported in one-third of cases. While proper use of nutritional supplements in children consuming a vegan diet appears to be associated with normal growth and development, insufficient intake of supplements may impede growth and bone formation. Physical examination and analysis of height and weight over time can help differentiating between endocrine causes, gastrointestinal disorders, psychosocial problems, or underlying genetic conditions that prevent adequate nutritional intake. Laboratory screening should be part of the workup in every child with short stature, and further laboratory tests can be indicated if warranted by the dietary history, especially in children on a poorly planned vegan diet. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is unclear. We aimed to review systematically published evidence on the effect of rhGH on pubertal timing. Methods: Embase, MEDLINE, and Cochrane Library databases were searched until December 2021 on randomized and non-randomized controlled studies of rhGH in children. Results: Twenty-five articles (n = 1,433 children) were identified, describing 12 randomized and 13 non-randomized controlled studies in children with idiopathic short stature (ISS; 15 studies), small for gestational age (n = 6 studies), chronic renal failure (n = 3), Noonan syndrome (n = 1), and growth hormone deficiency (n = 1). Significant differences in the effects of rhGH on pubertal timing were found by clinical indication. Only among children with ISS, rhGH promoted earlier age at pubertal timing (mean difference = −0.46 years; 95% CI, −0.90 to −0.03; 9 studies; n total = 397) or higher relative risk for pubertal onset during study follow-up (1.26; 95% CI, 1.03 to 1.54; 6 studies; n total = 284). Conclusions: Treatment with rhGH appears to promote earlier pubertal timing among children with ISS. Evidence was lacking in children with growth hormone deficiency due to the absence of studies with untreated controls. [ABSTRACT FROM AUTHOR]

Introduction: Among children born small for gestational age, 10–15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <−2 SD for gestational age and life-minimum height <−2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. Conclusions: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling. [ABSTRACT FROM AUTHOR]

Introduction: Growth hormone (GH) therapy improves height outcomes in short children born small for gestational age (SGA); however, real-world data on long-term GH exposure are few. Methods: We report results from an observational study (NCT01578135) including children born SGA, treated with GH at 126 sites in France, and followed up for >5 years until achieving final adult height (FAH) or until study termination. Primary endpoints were the proportion of patients with normal (>−2) height standard deviation score (SDS) at the last visit and with normal FAH SDS. Post hoc analyses were performed by multivariate logistic regression analysis with stepwise elimination to identify factors associated with GH dose modulation and normal height SDS achievement. Results: Of 1,408 registered patients, a representative sample (n = 291) was selected for long-term follow-up. At the last visit, 193/291 (66.3%) children achieved normal height SDS and 72/291 (24.7%) reached FAH. FAH SDS was >–2 for chronological age in 48 (66.7%) children and >–2 for adult age in 40 (55.6%) children. In the post hoc analyses, height SDS at the last visit was a significant determinant of whether GH dose had been modulated. Factors significantly associated with reaching normal height SDS were baseline height SDS (taller, better), age at treatment start (younger, better), treatment duration excluding discontinuation periods (longer, better), and absence of a chronic disease. Most (70%) adverse events were non-serious, with 39% considered possibly/probably related to GH treatment. Conclusions: GH therapy was fairly effective in most short children born SGA. No new safety concerns were identified. [ABSTRACT FROM AUTHOR]

Introduction: Our objective was to evaluate the temporal trend of systemic postnatal steroid (PNS) receipt in infants of 24–28 weeks' gestational age, identify characteristics associated with PNS receipt, and correlate PNS receipt with the incidence of bronchopulmonary dysplasia (BPD) and BPD/death from an international cohort included in the iNeo network. Methods: We conducted a retrospective study using data from 2010 to 2018 from seven international networks participating in iNeo (Canada, Finland, Israel, Japan, Spain, Sweden, and Switzerland). Neonates of 24 and 28 weeks' gestational age who survived 7 days and who received PNS were included. We assessed temporal trend of rates of systemic PNS receipt and BPD/death. Results: A total of 47,401 neonates were included. The mean (SD) gestational age was 26.4 (1.3) weeks and birth weight was 915 (238) g. The PNS receipt rate was 21% (12–28% across networks) and increased over the years (18% in 2010 to 26% in 2018; p < 0.01). The BPD rate was 39% (28–44% across networks) and remained unchanged over the years (35.2% in 2010 to 35.0% in 2018). Lower gestation, male sex, small for gestational age status, and presence of persistent ductus arteriosus (PDA) were associated with higher rates of PNS receipt, BPD, and BPD/death. Conclusion: The use of PNS in extremely preterm neonates increased, but there was no correlation between increased use and the BPD rate. Research is needed to determine the optimal timing, dose, and indication for PNS use in preterm neonates. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy cause fetal growth restriction and increased maternal morbidity and mortality, especially in women of African ancestry. Recently, preeclampsia risk was associated with polymorphisms in the apolipoprotein L1 (APOL1) gene in women of African ancestry. Objectives: We assessed APOL1 genotype effects on pregnancies with and without preeclampsia. Method: We conducted an unmatched case-control study of 1,358 mother-infant pairs from two independent cohorts of black women. Results: Term preeclampsia cases with high-risk APOL1 genotypes were more likely to be small for gestational age compared to APOL1 low-risk term cases (odds ratio [OR] 2.8) and APOL1 high-risk controls (OR 5.5). Among preterm pregnancies, fetal APOL1 genotype was associated with preeclampsia. Conclusions: Fetal APOL1 genotype was associated with preeclampsia in preterm infants and with altered fetal growth in term infants. This may indicate APOL1 genotype impacts a spectrum of pregnancy complications mediated by a common pathophysiological event of placental insufficiency. [ABSTRACT FROM AUTHOR]

MIRAGE syndrome is characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. This report describes heat stroke and rhabdomyolysis caused by anhidrosis as a symptom of MIRAGE syndrome in a small-for-gestational-age (SGA) female neonate born at 32 weeks of gestation (birth weight, 911 g [−3.8 SD]). She developed severe temperature instability with anhidrosis, growth failure, mild developmental delay, hypothyroidism, and intractable enteropathy. On day 156, her temperature reached 42.0°C; her fever persisted for 2 h with prolonged irritability. Her serum creatine kinase level increased to a peak value of 12,716 (normal range, 43–321) IU/L. The clinical feature was diagnosed as rhabdomyolysis caused by heat stroke, which resulted from physical exertion with anhidrosis. Her SAMD9 variant was c.2945G>A, p. (Arg982His). Neonatologists should be aware of MIRAGE syndrome as a differential diagnosis of SGA with temperature instability. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 47% of women with an episode of preterm labor deliver at term; however, their infants are at greater risk of being small for gestational age and for neurodevelopmental disorders. In these cases, a pathologic insult may disrupt the homeostatic responses sustaining pregnancy. We tested the hypothesis of an involvement of components of the insulin-like growth factor (IGF) system. Methods: This is a cross-sectional study in which maternal plasma concentrations of pregnancy-associated plasma protease (PAPP)-A, PAPP-A2, insulin-like growth factor-binding protein 1 (IGFBP-1), and IGFBP-4 were determined in the following groups of women: (1) no episodes of preterm labor, term delivery (controls, n = 100); (2) episode of preterm labor, term delivery (n = 50); (3) episode of preterm labor, preterm delivery (n = 100); (4) pregnant women at term not in labor (n = 61); and (5) pregnant women at term in labor (n = 61). Pairwise differences in maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 among study groups were assessed by fitting linear models on log-transformed data and included adjustment for relevant covariates. Significance of the group coefficient in the linear models was assessed via t-scores, with p < 0.05 deemed a significant result. Results: Compared to controls, (1) women with an episode of premature labor, regardless of a preterm or a term delivery, had higher mean plasma concentrations of PAPP-A2 and IGFBP-1 (each p < 0.05); (2) women with an episode of premature labor who delivered at term also had a higher mean concentration of PAPP-A (p < 0.05); and (3) acute histologic chorioamnionitis and spontaneous labor at term were not associated with significant changes in these analytes. Conclusion: An episode of preterm labor involves the IGF system, supporting the view that the premature activation of parturition is a pathologic state, even in those women who delivered at term. [ABSTRACT FROM AUTHOR]

Introduction: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. Objective: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. Methods: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. Results: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97–1.25) for preterm birth and 1.03 (95% CI = 0.76–1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13–1.73) for ASD and 1.15 (95% CI = 0.94–1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66–1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50–2.09; ASD: wHR = 1.10, 95% CI = 0.70–1.72; ADHD: wHR = 1.04, 95% CI = 0.57–1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. Conclusions: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems. [ABSTRACT FROM AUTHOR]

Introduction: Gestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited. Methods: We used data from a prenatal micronutrient supplementation trial among a cohort of human immunodeficiency virus-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and neonatal outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index-specific guidelines. Neonatal outcomes assessed were stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy. Results: Of 7,561 women included in this study, 51% had severely inadequate (<70%) or inadequate GWG (70 to <90%), 31% had adequate GWG (90 to <125%), and 18% had excessive GWG (≥125%). Compared to adequate GWG, severely inadequate GWG was associated with a higher risk of low birthweight, SGA, stunting at birth, and microcephaly, whereas excessive GWG was associated with a higher risk of LGA and macrosomia. Conclusion: Interventions to support optimal GWG are needed and may contribute to preventing adverse neonatal outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate body composition at the time of hospital discharge in very preterm infants following rapid transition to full enteral feeding. Study Design: We conducted a prospective, observational, cross-sectional study and included 105 preterm infants <32 gestational age or birth weight <1,500 g, born between April 2015 and December 2020, following rapid transition to full enteral feeding (≥140 mL/kg/day). Fat mass/total body mass (BF%) and fat-free mass (FFM) were measured at the time of hospital discharge using air displacement plethysmography. Results: Median and interquartile range (Q1–Q3) of gestational age at birth (GA) was 27.3 (26.1–28.7) weeks and birth weight 845 (687–990) g. Time to reach full enteral feeding was 5 (5–7) days. At 37.6 weeks (36.1–39.0) postmenstrual age (PMA), BF% was 17.0% (14.9–19.8) and FFM 2,161 g (1,966–2,432). BF% was not associated with GA, and not different between small and appropriate for gestational age infants. FFM was significantly lower in infants born small for gestational age. Conclusions: Following rapid transition to full enteral feeding, FFM and BF% at discharge were similar to other preterm populations. BF% and FFM were not associated with GA at birth but with PMA at measurement. FFM was lower and BF% higher compared to term infants at birth, suggesting diminished parenchymal growth in preterm infants. Continued monitoring of body composition, metabolic health, and neurological development is needed to study long-term effects. [ABSTRACT FROM AUTHOR]

Background: Prematurity and low birth weight are major risk factors for neonatal sepsis. Zinc supplements have been previously shown to be beneficial in pregnancy and small for gestational age birth outcomes. There is sparse information, however, on the potential benefits of zinc supplementation to prevent or treat serious infections in this age group. Objective: The aim of this study was to assess the efficacy of preventive and therapeutic zinc supplementation in young infant (<4 months) sepsis. Methods: MEDLINE, Cochrane CENTRAL, and other databases were searched from inception until 18 June 2021. Studies assessing preventive and therapeutic zinc supplementation in young infants in relation to incidence and outcomes of suspected sepsis were included. Meta-analyses of pooled effects were calculated for sepsis-related outcomes. Results: Eleven randomized controlled trials involving 2,819 infants were included. Eight studies reported therapeutic efficacy, whereas 3 evaluated preventive benefits of zinc supplementation. Preventive studies suggest a protective effect of zinc supplementation on neonatal mortality rate (NMR) (risk ratio (RR) 0.28; 95% CI 0.12–0.67, LOW certainty), but with no effect on the incidence of sepsis, both in preterm neonates. Among young infants, therapeutic zinc was associated with significant reductions in infant mortality-rate (RR 0.61; 95% CI 0.41–0.93, LOW certainty) and treatment failure (RR 0.61; 95% CI 0.44–0.85; LOW certainty). Therapeutic zinc supplementation in neonates was associated with significant increase in serum zinc concentrations (mean difference 81.97; 95% CI 34.57–129.37; LOW certainty), but without an effect on hospital stay or NMR. Conclusion: Zinc supplementation could potentially reduce mortality and treatment failure in young infants but has no noteworthy influence on hospital stay and in the prevention of sepsis. Further studies with larger sample sizes are needed to confirm the direction and magnitude of effects if any. [ABSTRACT FROM AUTHOR]

Introduction: Type A insulin resistance syndrome is a rare type of congenital insulin resistance often caused by heterozygous mutations in the insulin receptor gene (INSR). The aim of this study was to explore the clinical and genetic characteristics of three patients with type A insulin resistance syndrome from two Chinese families. Methods: The peripheral blood samples were collected from each family member. Whole-exome sequencing was performed on three patients. Results: Patient #1 was diagnosed with hyperinsulinemia at the age of 11 years and presented with hirsutism, acanthosis nigricans, and polycystic ovaries by 13 years. A heterozygous c.3470A>G mutation in the INSR gene was identified in patient #1. Patient #2 was a 13-year-old girl who presented with insulin resistance, polycystic ovary, and hyperandrogenemia. A novel c.3601C>G INSR mutation was identified in patient #2. Co-segregated analysis showed that the c.3601C>G mutation was also found in her father, who had hyperinsulinemia and diabetes mellitus, which was consistent with autosomal dominant inheritance. SIFT and PolyPhen-2 predicted that the c.3470A>G and c.3601C>G mutations in INSR had damaging effects. Conclusion: Our study expands the genotypic and phenotypic spectrum of type A insulin resistance syndrome. Awareness of the clinical features coupled with INSR gene screening is key to early detection and active intervention. [ABSTRACT FROM AUTHOR]

Introduction: Protocols to identify asymptomatic neonatal hypoglycemia (NH) rely on the presence of established risk factors (late preterm gestation, large or small for gestational age, and infant of a diabetic mother) for inclusion. We analyzed the performance of these risk factors in identifying hypoglycemia in modern practice, and additionally evaluated the optimal duration of screening blood glucose measurements. Methods: We analyzed a retrospective cohort of 830 infants with 1 or more known risk factor(s) for NH admitted to the mother-baby unit of a single tertiary-care center from May 2017 to April 2018. Manual chart review was performed for data extraction and confirmation of risk factor(s). Infants were excluded if glucose measurements were obtained for any reason other than screening for asymptomatic NH. Results: Of the 830 included infants, 31 (3.7%) ultimately received intravenous dextrose (IVD). Most screened infants (n = 510, 61.4%) did not develop hypoglycemia. None of the established risk factors showed strong association with hypoglycemia. Cesarean delivery was associated with hypoglycemia, although not strongly. All infants who received IVD for feeding-refractory hypoglycemia were identified by the first 2 measurements with nearly all (30/31, 97%) identified at the initial measurement. Conclusions: Currently accepted risk factors are limited in their ability to identify infants who subsequently develop hypoglycemia, and as a result, most screened infants do not develop hypoglycemia. The majority of infants in our cohort who did develop hypoglycemia achieved normoglycemia with feeding-based interventions and did not require IVD. Those that received IVD were more likely to develop hypoglycemia early and to a more severe degree. Together, our data suggest further refinement of protocol duration and risk factors utilized for screening as potential areas of screening protocol optimization. [ABSTRACT FROM AUTHOR]

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition. [ABSTRACT FROM AUTHOR]

If patient data submitted to the DGRF are consistent with one of the categories that are considered appropriate for rhGH treatment, rhGH will be reimbursed and can be prescribed by a paediatric endocrinologist. Dear Editor, With interest, we read the Commentary by David B. Allen on the diagnosis of growth hormone deficiency (GHD) [[1]] in response to the paper by Bright et al. [[2]]. Furthermore, in case of uncertainty about the diagnosis of GHD, anonymized patient data are discussed by a panel of three paediatric endocrinologists to assess whether GHD is plausible and rhGH should be prescribed. [Extracted from the article]

Objective: This study aimed to assess reduced fetal growth between 35 weeks of gestation and birth in non-small for gestational age fetuses associated with adverse perinatal outcomes (APOs). Material and Method: It is a retrospective cohort study of 9,164 non-small for gestational age fetuses estimated by ultrasound at 35 weeks. The difference between the birth weight percentile and the estimated percentile weight (EPW) at 35 weeks of gestation was calculated, and we studied the relationship of this difference with the appearance of APO. APOs were defined as cesarean or instrumental delivery rates for nonreassuring fetal status, 5-min Apgar score <7, arterial cord blood pH <7.10, and stillbirth. Fetuses that exhibited a percentile decrease between both moments were classified into 6 categories according to the amount of percentile decrease (0.01–10.0, 10.01–20.0, 20.01–30.0, 30.01–40.0, 40.01–50.0, and >50.0 percentiles). It was evaluated whether the appearance of APO was related to the amount of this percentile decrease. Relative risk (RR) was calculated in these subgroups to predict APOs in general and for each APO in particular. Receiver operating characteristic and area under curves (AUC) for the difference in the percentile was calculated, used as a continuous parameter in the entire study population. Results: The median gestational age at delivery in uncomplicated pregnancies was 40.0 (39.1–40.7) and in pregnancies with APOs 40.3 (49.4–41.0), p < 0.001. The prevalence of APOs was greater in the group of fetuses with a decrease in percentile (7.6%) compared to those with increased percentile (4.8%) (p < 0.001). The RR was 1.63 (95% CI: 1.365–1.944, p < 0.001). Although the differences were significant in all decreased percentile groups, RRs were significantly higher when decreased growth values were >40 points (RR: 2.036, 95% CI: 1.581–2.623, p < 0.001). The estimated value of the AUC for percentile decrease was 0.58 (0.56–0.61, p < 0.001). Conclusion: Fetuses with a decrease in the EPW between the ultrasound at 35 weeks of gestation and birth have a higher risk of APOs, being double in fetuses with a decrease of >40 percentile points. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to test the hypothesis that cardiac size is maintained in small fetuses presenting with cardiomegaly. Materials and Methods: We identified singleton fetuses with estimated fetal weight <10th centile and with cardiomegaly without another more likely cardiac or extra-cardiac cause. We used Z-scores for cardiac and thoracic circumferences normalized for gestational age (GA), biparietal diameter (BPD), head circumference (HC), and femur length (FL), obtained from 188 normally grown fetuses. Results: When comparing chest size, small fetuses had significantly lower thoracic circumferences median Z-scores (IQR) for GA = −4.82 (−6.15 to −3.51), BPD = −2.42 (−4.04 to −1.48), HC = −2.72 (−4.53 to −1.90), and FL = −1.60 (−2.87 to −0.71); p < 0.001 for all. When comparing heart size, small fetuses showed lower cardiac circumferences median Z-scores (IQR) for GA = −1.59 (−2.79 to −0.16); p < 0.001, similar cardiac circumferences Z-scores for BPD = 0.29 (−0.65 to 1.28); p = 0.284 and HC = 0.11 (−1.13 to 0.96); p = 0.953, and higher cardiac circumferences Z-scores for FL = 0.94 (−0.05 to 2.13); p < 0.001. Conclusions: Our results show that in small fetuses with cardiomegaly, the heart maintains normal dimensions when normalized to cranial diameters and higher dimensions when normalized to long bones. This provides insight into cardiac adaptation to adverse intrauterine environment. [ABSTRACT FROM AUTHOR]

Introduction: Gestational hypertension (GH) pregnancies are at a high risk of developing adverse outcomes, including progression to preeclampsia. Prediction of GH-related adverse outcomes is challenging because there are no available clinical tests that may predict their occurrence. Objective: The aim of the study was to determine the clinical usefulness of the soluble endoglin (sEng) and parameters of uterine artery flow (UtAF) measured by Doppler ultrasonography as markers of progression to preeclampsia in women with GH. Setting: Mexico City, Mexico. Material and Methods: We included 77 singleton pregnant women with GH in a nested case-control study. Cases were women who progressed to preeclampsia (n = 36), and controls were those who did not (n = 41). Serum sEng and UtAF measurements were performed at enrollment. The main outcomes measured were progression to preeclampsia and occurrence of preterm delivery (PD) <37 and <34 weeks of gestation, small for gestational age infant (SGA), and fetal growth restriction (FGR). Results: Women with sEng values in the highest tertile had higher risk of progression to preeclampsia, preterm delivery <34 weeks of gestation, and fetal growth restriction, odds ratios (ORs) ≥3.7. Patients with abnormal UtAF Dopp-ler-pulsatility index had higher risk of progression to preeclampsia, preterm delivery <34 weeks of gestation, small for gestational age infant, and fetal growth restriction (ORs ≥3.3). The presence of notch was associated with higher risk of progression to preeclampsia, preterm delivery <37 and <34 weeks of gestation, SGA infant, and fetal growth restriction (ORs ≥2.9). However, logistic regression analysis revealed that only serum sEng was a significant and independent risk factor for progression of GH to preeclampsia, preterm delivery <34 weeks of gestation, and fetal growth restriction (ORs ≥3.1). Conclusions: In GH pregnancies, UtAF Doppler ultrasonography is associated with increased risk of adverse outcomes and progression to preeclampsia. However, serum sEng concentration appears to be a better predictor to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to determine the effect and clinical impact of physiological characteristics on the 95th/5th centile of the umbilical artery (UA) Doppler and the cerebroplacental ratio (CPR), at 36+ weeks. Methods: From the multicenter randomized trial "Ratio37," we selected 4,505 low-risk pregnant women between June 2016 and January 2020. We registered physiological characteristics and the pulsatility indexes (PI) of the UA and middle cerebral artery (36–39 weeks). The 95th/5th centile of the UA PI and CPR was modeled by quantile regression. To evaluate the clinical impact of adjusting Doppler, we retrospectively applied gestational age (GA) and fully adjusted standards to 682 small for gestational age (SGA)-suspected fetuses (37 weeks) from a cohort of consecutive patients obtained between January 2010 and January 2020. Results: Several physiological characteristics significantly influenced the 95th/5th centile of the UA and CPR PI. The fully adjusted 95th centile of the UA was higher, and the 5th centile of the CPR was lower than GA-only-adjusted standards. Of the 682 SGA fetuses, 150 (22%) were classified as late fetal growth restricted only by GA and 112 (16.4%) when we adjusted Doppler. These 38 fetuses had similar perinatal outcome than the SGA group. Discussion: The 95th/5th centile of the UA and CPR PI is significantly influenced by physiological characteristics. Adjusting Doppler standards could differentiate better between FGR and SGA. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated whether fetal growth deceleration in term, appropriate-for-gestational-age (AGA) fetuses is associated with placental insufficiency and nonreassuring fetal heart rate (NRFHR) at birth. Methods: In this prospective study, 246 low-risk, singleton pregnancies at term with AGA fetuses were recruited. Correlation between decreased growth velocity (decline in estimated fetal weight [EFW] percentile), low EFW (EFWQ1 = latest EFW between 11 and 25% percentiles), umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, and cerebro-placental ratio (CPR) with cesarean and instrumental deliveries due to NRFHR were tested. Results: The median change between fetal weight estimates (percentiles/week) was +0.49% (95% CI: −4 to +5%). Ten percent had decreased EFW percentile >3.5%/week. Fetal growth velocity/week was associated with MCA (r = 0.21, p < 0.001) and CPR (r = 0.24, p < 0.001) and inversely correlated with UA PI (r = −0.28, p < 0.001). NRFHR and cesarean section (CS) rates due to NRFHR were associated with decreased growth velocity, EFWQ1, and low CPR. The combination of abnormal CPR with decreased growth velocity occurred in 12 pregnancies, of which 5 (42%) had urgent CS due to NRFHR. The combination of abnormal CPR with EFWQ1 occurred in 9 pregnancies, of which 4 (44%) had urgent CS due to NRFHR. These combinations increased the likelihood ratio of CS due to NRFHR two-fold (8.41; 2.54–24.5) but did not significantly alter the number needed to treat by elective CS (3.78–4.68). Conclusion: Fetal growth velocity, EFW between 10 and 25th percentiles (EFWQ1), and abnormal CPR improves prediction of unplanned CS due to NRFHR among term AGA fetuses. This should be considered when counseling about the delivery method. [ABSTRACT FROM AUTHOR]

Pregnant women with inherited long QT syndrome (iLQTS) are at an increased risk for preterm delivery and intrauterine growth retardation (IUGR) due to their underlying disease. Additionally, they are at a risk of arrhythmogenic events, particularly during the postpartum period because of physiological changes and increased emotional/physical stress. β-receptor blockers can effectively prevent life-threatening Torsades de Pointes ventricular tachycardia and they are the treatment of choice in iLQTS. Use of β-receptor blockers in pregnancy is recommended, although IUGR is commonly reported for prenatally exposed infants. IUGR, particularly in preterm infants, can result in adverse neonatal outcomes. This review was performed to support clinicians in their selection of β-receptor blocker treatment for their pregnant iLQTS women by (i) summarizing the available literature addressing the impact of different β-receptor blockers on IUGR and (ii) reporting additional aspects which might influence the β-receptor blocker selection. In general, experts recommend to use nonselective β-receptor blockers, such as nadolol and propranolol, for iLQTS management as these drugs seem to be superior in effectiveness. However, β-1-selective receptor blockers, such as bisoprolol or metoprolol, seem to affect less likely uterine contraction, peripheral vasodilation, and are associated with lower IUGR rates and fetal hypoglycemia. They are therefore recommended, except atenolol, as first-line therapy for pregnant women. Additionally, maternal factors such as iLQTS genotype, other underlying comorbidities (e.g., diabetes mellitus type 1, asthma bronchiale), and uteroplacental dysfunction or fetal factors have to be taken into account. Therefore, each woman with iLQTS who wants to become pregnant should be well-advised for a personalized β-receptor blocker therapy according to the individual risk-benefit evaluation by a multidisciplinary team of cardiologists, gynecologists, pediatric cardiologists, neonatologists, and clinical pharmacologists. During pregnancy, a close monitoring of IUGR and, after birth, monitoring of bradycardia, hypoglycemia, and respiratory depression in the neonate is mandatory. This review summarizes available data on β-receptor blocker-related risk for IUGR in prenatally exposed infants and illustrates which factors might influence β-receptor blocker selection with the aim to support clinicians in their pharmacological management of their pregnant iLQTS patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to determine if customized fetal growth charts developed excluding obese and underweight mothers (CC(18.5–25)) are better than customized curves (CC) at identifying pregnancies at risk of perinatal morbidity. Material and Methods: Data from 20,331 infants were used to construct CC and from 11,604 for CC(18.5–25), after excluding the cases with abnormal maternal BMI. The 2 models were applied to 27,507 newborns and the perinatal outcomes were compared between large for gestational age (LGA) or small for gestational age (SGA) according to each model. Logistic regression was used to calculate the OR of outcomes by the group, with gestational age (GA) as covariable. The confidence intervals of pH were calculated by analysis of covariance. Results: The rate of cesarean and cephalopelvic disproportion (CPD) were higher in LGAonly by CC(18.5−25) than in LGAonly by CC. In SGAonly by CC(18.5−25), neonatal intensive care unit (NICU) and perinatal mortality rates were higher than in SGAonly by CC. Adverse outcomes rate was higher in LGAonly by CC(18.5−25) than in LGAonly by CC (21.6%; OR = 1.61, [1.34–193]) vs. (13.5%; OR = 0.84, [0.66–1.07]), and in SGA only by CC(18.5−25) than in SGAonly by CC (9.6%; OR = 1.62, [1.25–2.10] vs. 6.3%; OR = 1.18, [0.85–1.66]). Conclusion: The use of CC(18.5–25) allows a more accurate identification of LGA and SGA infants at risk of perinatal morbidity than conventional CC. This benefit increase and decrease, respectively, with GA. [ABSTRACT FROM AUTHOR]

Introduction: Late preterm infants (LPIs) are infants born between 340/7 and 366/7 weeks gestation. Morbidities in these infants are commonly considered a result of prematurity; however, some research has suggested immaturity may not be the sole cause of morbidities. We hypothesize that antecedents leading to late preterm birth are associated with different patterns of morbidities and that morbidities are the result of gestational age superimposed by the underlying etiologies of preterm delivery. Methods: This is a retrospective cohort study of late preterm neonates born at a single tertiary care center. We examined neonatal morbidities including apnea of prematurity, hyperbilirubinemia, hypoglycemia, and the requirement for continuous positive airway pressure (CPAP). Multivariable logistic regression analysis was performed to estimate the risk of each morbidity associated with 3 categorized antecedents of delivery, that is, spontaneous preterm labor, preterm premature rupture of membranes (PPROM), and medically indicated birth. We calculated the predictive probability of each antecedent resulting in individual morbidity across gestational ages. Results: 279 LPIs were included in the study. Decreasing gestational age was associated with significantly increased risk of apnea of prematurity, hyperbilirubinemia, and requirement of CPAP. In our cohort, the risk of hypoglycemia increased with gestational age, with the greatest incidence at 360−6 weeks. There was no significant association of risk of selected morbidities and the antecedents of late preterm delivery, with or without adjustment for gestational age, multiple gestation, small for gestational age (SGA), antenatal steroids, and delivery method. Discussion and Conclusion: This study found no difference in morbidity risk related to 3 common antecedents of preterm birth in LPIs. Our research suggests that immaturity is the primary factor in determining adverse outcomes, intensified by factors resulting in prematurity. [ABSTRACT FROM AUTHOR]

Introduction: Very low-birth weight (VLBW) infants represent a high-risk population for morbidity and mortality in the neonatal period. Variability in practices and outcomes between centers has been acknowledged. Multicenter benchmarking studies are useful to detect areas of improvement and constitute an interesting research tool. Objectives: The aim of the study was to determine the perinatal variables and interventions associated with survival and survival without major morbidity in VLBW infants and compare the performance of 2 large networks. Methods: This is a prospective study analyzing data collected in 2 databases, the Spanish SEN1500 and the South American NEOCOSUR networks, from January 2013 to December 2016. Inborn patients, from 240 to 306 weeks of gestational age (GA) were included. Hazard ratios for survival and survival without major morbidity until the first hospital discharge or transfer to another facility were studied by using Cox proportional hazards regression. Results: A total of 10,565 patients, 6,120 (57.9%) from SEN1500 and 4,445 (42.1%) from NEOCOSUR, respectively, were included. In addition to GA, birth weight, small for gestational age (SGA), female sex, and multiple gestation, less invasive resuscitation, and the network of origin were significant independent factors influencing survival (aHR [SEN1500 vs. NEOCOSUR]: 1.20 [95% CI: 1.15–1.26] and survival without major morbidity: 1.34 [95% CI: 1.26–1.43]). Great variability in outcomes between centers was also found within each network. Conclusions: After adjusting for covariates, GA, birth weight, SGA, female sex, multiple gestation, less invasive resuscitation, and the network of origin showed an independent effect on outcomes. Determining the causes of these differences deserves further study. [ABSTRACT FROM AUTHOR]

Introduction: This paper aimed to assess the knowledge of healthcare professionals (obstetric and gynecology residents, specialists, and midwives) in the field of perinatal medicine regarding fetal growth diagnosis and management. Methods: A questionnaire was created consisting of a set of questions regarding demographic data, methods of growth assessment, and management. It was a handout survey. The results were analyzed with the use of descriptive statistics and χ2 analysis using the program Statistica. Results: 190 medical professionals have participated in the questionnaire. 86.3% of respondents agreed that pregnancy dating should be modified based on first-trimester ultrasound. 90.9% agreed that III trimester ultrasound has a ±15% margin of error. When asked which growth charts are best fit for assessing growth in a studied population, 10.7% marked standard, 37.4% reference, 26.2% customized, and 26.2% did not know the difference between the three choices. 60.3% stated that they use a growth chart to assess growth and qualify fetuses for monitoring. 70.2% used the 10th centile as a cutoff, 20.1% 5th centile, and 9.7% 3rd centile. Only 40.9% would diagnose fetal growth restriction based on fetal weight only. 28.7% using the 10th centile cutoff, 16.1% 5th centile, and 54.0% 3rd centile. Only a quarter of the respondents were able to name the growth chart or tool that they use for assessment. The most common responses were Yudkin, Hadlock, and online calculators of Fetal Medicina Barcelona and the Fetal Medicine Foundation. Discussion: A lot of confusion is observed primarily in the aspect of cutoff values for identification, subsequent monitoring, and management of fetal growth restriction. There is a need for extensive training and education in this field and uniform national recommendations. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to assess the predictive ability of the ultrasound estimated percentile weight (EPW) at 35 weeks to predict large for gestational age (LGA) at term delivery according to 6 growth standards, including population, population-customized, and international references. The secondary objectives were to determine its predictive ability to detect adverse perinatal outcomes (APOs) and whether the ultrasound-delivery interval influences the detection rate of LGA newborns.Methods: This was a retrospective cohort study of 9,585 singleton pregnancies. Maternal clinical characteristics, fetal ultrasound data obtained at 35 weeks, and pregnancy and perinatal outcomes were used to calculate EPWs to predict LGAs at delivery according to the customized and the non-customized (NC) Miguel Servet University Hospital (MSUH), the customized Figueras, the NC Fetal Medicine Foundation (FMF), the NC INTERGROWTH-21st, and the NC World Health Organization (WHO) standards.Results: For a 10% false-positive rate, detection rates for total LGAs at delivery ranged from 31.2% with the WHO (area under the curve [AUC] 0.77; 95% confidence interval [CI], 0.76-0.79) to 56.5% with the FMF standard (AUC 0.85; 95% CI, 0.84-0.86). Detection rates and values of AUCs to predict LGAs by ultrasound-delivery interval (range 1-6 weeks) show higher detection rates as the interval decreases. APO detection rates ranged from 2.5% with the WHO to 12.6% with the Figueras standard.Conclusion: The predictive ability of ultrasound estimated fetal weight at 35 weeks to detect LGA infants is significantly greater for FMF and MSUH NC standards. In contrast, the APO detection rate is significantly greater for customized standards. The shorter ultrasound-delivery interval relates to better prediction rates. [ABSTRACT FROM AUTHOR]

Introduction: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. Materials and Methods: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. Results: We included 252 patients with an average birth length of −2.0 ± 0.7 SD and birth weight of −1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from −2.2 ± 0.9 SD to −1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). Conclusion: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment. [ABSTRACT FROM AUTHOR]

Objective: To determine the contribution of short femur diaphysis length (FDL) at 19-22 weeks of gestation in the prediction of adverse pregnancy outcomes.Methods: The study included singleton pregnant women who underwent a routine anomaly scan at 19-22 weeks of gestation at the Virgen de la Arrixaca University Clinical Hospital (Murcia, Spain) between August 2011 and August 2012. Fetal biometry and Doppler ultrasound of uterine arteries were assessed as part of the anomaly scan, and the mean pulsatility index of both uterine arteries was recorded. Maternal obstetric characteristics, such as ethnicity, age, weight, parity, cigarette smoking, and medical history including hypertension and diabetes mellitus were collected from our database system.Results: A total of 6,366 women were included in the study after excluding cases with abnormal karyotype, major fetal abnormalities, or termination of pregnancy. There were 88 cases of preeclampsia (PE) (1.4%). Logistic regression was performed including maternal and fetal characteristics. Short FDL at 19-22 weeks was significantly associated with subsequent development of PE (OR = 0.89, 95% CI: 0.80-0.99, p = 0.025). The best model to predict PE from our sample included gestational age at scan, parity, maternal weight, chronic hypertension, mean pulsatility index in the uterine arteries, and FDL (AUC = 0.78, 95% CI: 0.71-0.84). Regarding small for gestational age (SGA) neonates, there were also significant differences in FDL and FDL <5th centile between the control group and SGA newborns below the 3rd, 5th, and 10th centile. In the groups of preterm births (delivery before 32, 34, and 37 weeks), there were no differences in FDL compared with the control group (term births).Discussion: Our results suggest that FDL at 19-22 weeks of gestation is an independent predictor of PE and SGA newborns. [ABSTRACT FROM AUTHOR]

The association between birth size and cardiometabolic disease risk may be U-shaped. Being born small for gestational age (SGA) has a definitive association with later cardiovascular risk, but the impact of being born large for gestational age (LGA) on cardiometabolic health is more controversial. In addition to birth size, early postnatal growth pattern and later weight gain affect cardiometabolic risk in adulthood. Most SGA-born children have catch-up and LGA-born children have catch-down growth during the first years of life. The extent of this early compensatory growth may contribute to the adverse health outcomes. Both SGA- and LGA-born children are at an increased risk for overweight and obesity. This may have a long-term impact on cardiometabolic health as overweight tends to track to adulthood. Other cardiometabolic risk factors, including alterations in glucose metabolism, dyslipidemia, hypertension, and low-grade inflammation are associated with birth weight. Many of these risk factors are related to overweight or adverse fat distribution. Since later cardiometabolic risk is often mediated by early growth pattern and later overweight in SGA and LGA children, it is important to focus on staying normal weight throughout life. Hence, effective interventions to reduce cardiometabolic risk in LGA and SGA children should be developed. [ABSTRACT FROM AUTHOR]

Introduction: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Objective: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children – an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. Methods: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. Results: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0–133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). Conclusions: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Background: Preterm birth is associated with impaired brain functions, but it is unknown whether fetal growth restriction (GR) makes these deficits worse. Using piglets as a model for preterm infants, we hypothesized that moderate GR reduces growth rate, physical activity, and spatial memory in the first weeks after preterm birth. Methods: Preterm pigs were delivered by caesarean section and fed until 19 days (n = 830 from 55 pregnant sows) and received intensive clinical care. GR pigs were classified as animals with the lowest 5–20% percentile birth weight within each litter and were compared with litter-mate controls (21–100% percentile birth weight). Basic motor skill development, physical activity, and morbidities (e.g., necrotizing enterocolitis) were recorded within the first week. Weight of internal organs and data from a T-maze spatial memory test were noted until 19 days. Results: Moderate GR and control preterm pigs (birth weights 728 ± 140 and 1,019 ± 204 g, respectively) showed similar relative weights of internal organs (relative to body), except higher adrenal gland weights in GR pigs (+20–50%, p < 0.05). This was associated with a tendency to higher plasma cortisol (p < 0.05 on day 11). GR preterm pigs showed delayed ability to stand and walk (days 2–5, p < 0.01), but physical activity and proportion of correct choices in a T-maze test (70.3 vs. 71.6%) were similar. Conclusion: Moderate GR has limited effect on motor function and spatial memory in the early postnatal period of preterm pigs, despite some initial delays in basic motor skills. In the postnatal period, moderately growth-restricted preterm infants may adapt well with regards to organ growth and neurodevelopment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the potential utility of serum HtrA1 and HtrA3, serine proteases that are highly expressed in the developing placenta, at 15 and 20 weeks of gestation for predicting later development of adverse pregnancy outcomes of preeclampsia (PE), gestational hypertension (GHT), preterm birth (PTB), and small for gestational age (SGA) birth.Methods: This is a nested case control study of 665 samples (330 controls, 335 cases) from the Adelaide SCOPE cohort. The cases included were 92 PE, 71 GHT, 56 PTB, and 116 SGA. Samples were assessed by ELISA and data adjusted for maternal age, BMI, socioeconomic index, hCG, and smoking status. Multivariate logistic regression was performed with other biochemical and biophysical parameters available for these samples.Results: HtrA1 did not differ between the controls and cases. In contrast, HtrA3 was significantly lower at 15 weeks in pregnancies that later developed late-onset PE (LPE) or resulted in SGA birth, with an area under the ROC curve (AUC) of 0.716 and 0.790, respectively. The combination of HtrA3 with PAPP-A, uterine, and umbilical Doppler improved the AUC to 0.755 for LPE and 0.844 for SGA.Conclusion: HtrA3 at 15 weeks is associated with, and may be useful for, the early detection of LPE development and SGA birth. [ABSTRACT FROM AUTHOR]

Background: Pregnancies complicated with small for gestational age (SGA) neonates are reported with maternal circulatory maladaptations.Objectives: We aimed to understand the pathophysiology of the maternal circulation in normotensive SGA pregnancies and to point out the trimestral differences from those with appropriate-to-large (non-SGA [NGA]) neonates.Methods: An observational study was conducted in 3 trimestral cohorts of normotensive pregnancies, categorized after birth according to neonatal birth weight percentile (BW%) as SGA (BW% ≤10, n = 158) or NGA (BW% > 10, n = 1,038). Standardized electrocardiogram-Doppler ultrasound, impedance cardiography, and bio-impedance were used to assess the maternal heart, arteries, veins, and fluid.Results: Diastolic blood pressure and mean arterial pressure were not significantly different, unless in the third trimester. In SGA compared to NGA pregnancies, total peripheral resistance (TPR) was higher and total arterial compliance, cardiac output (CO), and total body water (TBW) were lower throughout pregnancy. Venous return-enhancing functions were activated. In NGA but not SGA pregnancies, a positive correlation was found between BW% and CO + TBW and a negative correlation between BW% and TPR.Conclusions: SGA pregnancies are characterized by lower maternal body fluid volume and CO, while normal blood pressures are maintained via increased TPR already from the first trimester onwards. Pregnancy-induced hemodynamic changes are superimposed on these characteristics. [ABSTRACT FROM AUTHOR]

Background: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) – insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth. Conclusion: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. Proteolysis of IGFBP-3 appears to be increased. [ABSTRACT FROM AUTHOR]

Objectives: To perform a longitudinal assessment comparison between estimated fetal weight (EFW) and abdominal circumference (AC) in the prediction of late fetal growth restriction (FGR) as opposed to small for gestational age (SGA).Patients and Methods: A cohort of unselected singleton pregnancies scanned at 32±2 and 37±1 weeks was created. Longitudinal growth assessment by calculating the conditional AC and conditional EFW was performed, and both parameters were compared for their prediction capacity for late FGR and SGA. Conditional standards set an expected size (EFW or AC) given a first measurement performed earlier. A declining growth was defined as a conditional growth of <10th centile.Results: A total of 938 pregnancies were included. As expected, declining growth between 32±2 and 37±1 weeks was associated with late FGR and SGA, but the predictive capacity of both conditional AC and conditional EFW was comparably poor, with detection rates of 28% at a 10% rate of false positives for late FGR.Conclusions: Longitudinal assessment of fetal growth during the third trimester has a low predictive capacity for late FGR, with no differences between conditional AC and conditional EFW. [ABSTRACT FROM AUTHOR]

Background: Feeding is often used for the initial treatment of hypoglycaemia, but it is not known if pre-feed alertness and observed quality of breastfeeding are related to the subsequent change in blood glucose concentration. Objective: We sought to determine if assessment of pre-feed alertness and the observed quality of the breastfeed were related to the subsequent change in blood glucose concentration in hypoglycaemic babies. Methods: Babies were ≥35 weeks, ≤48 h old, identified as being at-risk for hypoglycaemia (infants of diabetic mothers, small [< 2,500 g or < 10th centile] or large [birthweight > 4,500 g or > 90th centile] birthweight) and hypoglycaemic (< 2.6 mM). Midwives assessed pre-feed alertness and quality of feeding at each hypoglycaemic episode. Change in blood glucose concentration was assessed within 15–90 min. Results: One hundred and thirty-one babies had 163 hypoglycaemic episodes. Babies assessed as alert had a greater increase in blood glucose concentration than sleepy babies (mean [95% CI] awake 0.71 [0.61–0.82] vs. sleepy 0.51 [0.35–0.66] mM, p = 0.04). The change in blood glucose concentration was similar after feeds of different observed quality (offered, 0.50 [0.29–0.72], latched, 0.66 [0.52–0.81], swallowing 0.65 [0.54–0.76] mM, p = 0.13). Conclusions: Observed quality of breastfeeding is not a useful predictor of the change in blood glucose concentration in hypoglycaemic babies. [ABSTRACT FROM AUTHOR]

Objective: To assess cardiovascular function and damage in term small-for-gestational-age (SGA) and intrauterine growth-restricted (IUGR) fetuses by echocardiography and biomarkers in cord blood.Methods: This was a cohort study including 60 normal fetuses and 47 term small fetuses subclassified as small for gestational age (SGA) with estimated fetal weight (EFW) between the 3rd and 9th centiles and normal fetoplacental Doppler (n = 14) or intrauterine growth restriction (IUGR, n = 33) if EFW <3rd centile or EFW <10th centile together with cerebroplacental ratio <5th and/or mean uterine artery pulsatility index >95th centile. Fetal echocardiography included left myocardial performance index (MPI) and annular plane systolic excursion. Fetal B-type natriuretic peptide (BNP), troponin-I, heart-type fatty acid-binding proteins (H-FABP), and homocysteine concentrations were measured in cord blood collected at delivery.Results: Both SGA and IUGR cases presented echocardiographic signs of systolic and diastolic dysfunction with increased MPI (mean controls 0.43 [SD 0.12], SGA 0.47 [0.03], and IUGR 0.57 [0.08], p < 0.01) and decreased mitral annular plane systolic excursion (controls 6.0 mm [1.0], SGA 5.5 mm [0.6], and IUGR 4.9 mm [0.8], p = 0 01). IUGR fetuses presented increased levels of cord blood BNP (controls 17.2 pg/mL [11.5], SGA 22.4 pg/mL [10.7], and IUGR 31.2 pg/mL [26.8], p < 0.01). Troponin I was increased in both SGA and IUGR cases (controls 0.004 ng/mL [0.007], SGA 0.012 ng/mL [0.02], and IUGR 0.018 ng/mL [0.05], p < 0.01). H-FABP and homocysteine showed similar values among groups.Conclusions: Cardiac dysfunction and cell damage is a common feature of term SGA and IUGR fetuses despite of the severity criteria for perinatal outcome. Further research is needed to evaluate the potential long-term consequences on their cardiovascular system. [ABSTRACT FROM AUTHOR]

Introduction: Fetuses who fail to reach their genetic growth potential are thought to have sub-optimal placental function. Low placental growth factor (PlGF) levels have been shown to be predictive of placentally mediated conditions, such as pre-eclampsia or fetal growth restriction. We investigated the screening performance of PlGF for the prediction of low birth weight (<10th centile for gestation) and adverse intrapartum and neonatal outcomes in apparently low-risk term pregnancies.Materials and Methods: Maternal PlGF levels were measured fortnightly in a blinded, prospective, observational study from 36 weeks of pregnancy. Women and clinicians were blinded to PlGF results, and pregnancies were managed according to local policies and guidelines. Intrapartum and neonatal outcomes were recorded. PlGF was analysed for association with, and predictive capacity for, low birth weight, caesarean section for intrapartum fetal compromise (CS-IFC) and adverse neonatal outcomes.Results: A total of 438 women were included in the final analysis. Lower PlGF levels were associated with low birth weight, CS-IFC and adverse neonatal outcome. For a false-positive rate of 10 and 20%, respectively, the corresponding sensitivities were 9.7-11.1% and 22.2-26.8%.Conclusion: As a sole predictor for low birth weight, CS-IFC and adverse neonatal outcome, PlGF was poor as a test. [ABSTRACT FROM AUTHOR]

Objective: To compare placental histopathological lesions and pregnancy outcomes in singleton and twin pregnancies complicated by preeclampsia (PE).Methods: Maternal characteristics, neonatal outcomes, and placental histopathology reports of pregnancies complicated by PE between January 2008 and October 2016 were reviewed. Results were compared between singletons (singleton group) and dichorionic-diamniotic twins (twin group). Placental lesions were classified into maternal and fetal vascular supply lesions. Small for gestational age (SGA) was defined as birth weight ≤10th percentile. Composite adverse neonatal outcome was defined as one or more early neonatal complications.Results: Compared to the twin group (n = 67), the singleton group (n = 275) was characterized by lower maternal age (p = 0.003), higher gestational age (p < 0.001), higher rates of previous PE (p = 0.017), chronic hypertension (p = 0.036), and severe features (p < 0.001). Placentas from the singleton group were characterized by higher rates of maternal vascular malperfusion lesions (p < 0.001) and fetal vascular supply lesions (p = 0.002). Using multivariable regression analysis, composite maternal and fetal vascular malperfusion lesions were independently associated with singletons (aOR = 2.7, 95% CI = 1.2-7.8, p < 0.001, and aOR = 1.2, 95% CI = 1.2-5.6, p = 0.025, respectively). SGA was more common in the singleton group (p = 0.002). Neonatal outcome did not differ between the groups.Conclusion: Placentas from singleton pregnancies complicated by PE were characterized by higher rates of maternal and fetal vascular lesions compared to those from twin pregnancies, suggesting that different mechanisms participate in the development of PE in these two groups. [ABSTRACT FROM AUTHOR]

Background/Aims: An increased preterm birth survival rate is associated with long-term neurological and metabolic risks; thus, our aim was to evaluate whether early patterns of infancy anthropometry and metabolic hormonal profile differ in preterm infants born small for gestational age (SGA) or appropriate for gestational age (AGA) from birth to 36 months of corrected age (CA). Methods: We recruited 110 very-low-birth-weight (VLBW) preterm infants (AGA = 60 and SGA = 50) with a mean birth weight of –2.39 ± 0.77 versus 0.57 ± 0.54 standard deviation scores (SDS) (p < 0.01) and birth length of –2.1 ± 1.05 versus –0.44 ± 0.82 SDS (p < 0.01), respectively. Anthropometry and blood sampling for insulin, insulin-like growth factor (IGF)-II, IGF-I, and leptin were performed for up to 3 years. Results: All neonates increased their weight, length, and head circumference SDS during the early inpatient period. Up to 90% reached a normal length within this period. The IGF-II, insulin, and glycemia concentrations changed in parallel with weight. In the first year of CA, only SGA infants gained weight and height SDS. The homoeostatic model assessment had a trend toward higher values in SGA infants at 24 and 36 months (p = 0.06 and p = 0.07). Conclusion: Being SGA is the strongest predictor of early recovery of height in VLBW preterm infants. Follow-up will allow us to determine whether the differences in the growth patterns of VLBW preterm infants by birth weight SDS persist. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the screening performance and best threshold centile (5th vs. 10th) of the cerebroplacental ratio (CPR) in low-risk, term pregnancies to predict low birthweight and adverse intrapartum and neonatal outcomes in a term, low-risk population.Methods: This was a blinded, prospective, cross-sectional study of low-risk singleton pregnancies at term. Women attended fortnightly from 36 weeks for CPR and estimated fetal weight assessment. Intrapartum and neonatal outcomes were recorded. Primary outcomes assessed were low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome.Results: A total of 483 women participated in the study. The CPR 10th centile (1.48) threshold resulted in the best screening performance. Sensitivities for low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome of 41.9, 61.1, and 38.3% were achieved for false-positive rates of 17.7, 17.7, and 15.2%, respectively. The corresponding areas under the receiver operating characteristic curves were 0.62, 0.72, and 0.62.Conclusion: The CPR 10th centile resulted in the best screening performance, although this would be considered fair at best. The CPR 10th centile may be useful as part of a risk stratification tool for prediction of low birthweight and adverse intrapartum and neonatal outcomes. [ABSTRACT FROM AUTHOR]

Background: Adiponectin, which may have a growth-promoting effect through its insulin-sensitizing action, is thought to play a key role in fetal growth. This study was performed to determine whether maternal and/or cord blood adiponectin concentrations differ between small for gestational age (SGA) and healthy controls. Methods: Databases were searched to identify good quality English language studies providing the number of SGA and healthy controls, and the means and standard deviations of maternal or cord blood adiponectin concentration in both groups. A meta-analysis was performed to summarize the standardized mean differences (SMDs) in maternal and cord blood adiponectin concentrations between SGA and healthy controls. Results: There was no statistically significant difference in maternal blood adiponectin concentration between SGA and healthy controls (n = 8, p = 0.951). However, cord blood adiponectin concentration was significantly lower in SGA than in healthy controls (n = 6, p = 0.028), and the effect was large (i.e., SMD >0.7). Conclusions: Maternal blood adiponectin concentration is not low in SGA compared with healthy controls. However, SGA shows lower cord blood adiponectin concentration than healthy controls. [ABSTRACT FROM AUTHOR]

Objectives: To compare the accuracy of the INTERGROWTH-21st (IG-21) with the Italian Society of Ultrasound in Obstetrics and Gynecology (SIEOG) abdominal circumference (AC) standards in the detection of small-for-gestational-age (SGA) fetuses in a high-risk population.Material and Methods: Our study included all pregnant patients with an increased risk of placental insufficiency that were seen in two Italian university hospitals between 2014 and 2015. The accuracy of IG-21 and SIEOG AC standards in the detection of SGA neonates was analyzed by means of the area under the receiver operating characteristic curve (ROC-AUC) at 4 gestational age intervals (24-27, 28-31, 32-35, >35 weeks).Results: We enrolled 428 patients (278 Italians). There was no significant difference between the ROC-AUC of AC according to IG-21 and SIEOG standards for all birthweight thresholds and gestational intervals that were considered. The diagnostic performance was similar in Italian and non-Italian patients. The accuracy was, however, limited, with values of ROC-AUC ranging between 0.80 and 0.89.Conclusions: The IG-21 and SIEOG AC standards are interchangeable for the diagnosis of SGA fetuses. The diagnostic accuracy is, however, limited. We provide figures that can be used to stratify the probability that an infant will be SGA in an obstetric population at increased risk of growth restriction. [ABSTRACT FROM AUTHOR]