Review shows that thyroid hormone substitution could benefit transient hypothyroxinaemia of prematurity but treatment strategies need to be clarified.

AIM: Thyroid hormones are crucial for foetal and neonatal brain development. This paper provides an overview of the normal role of thyroid hormones in foetal brain development and the pathophysiology of transient hypothyroxinaemia of prematurity (THOP). It also discusses the diagnostic and therapeutic controversies around THOP and looks at directions for future research. METHODS: We used the PubMed and Embase databases to identify papers published in English from 1969 to June 2018. This identified 20 papers about the impact of THOP on neurodevelopment and seven randomised controlled trials about therapeutic approaches from 1981-2016. RESULTS: THOP has been researched for more than three decades. The impact of temporarily low thyroxine levels, without any increase in pituitary-secreted thyroid-stimulating hormone at a critical timeframe in an infant's brain development, is still debated. Heterogeneity in THOP definitions, difficulties with thyroid hormone assessment, identifying patients at risk and a clear lack of sufficiently powered studies add to the current controversy. There are indications that thyroid hormone substitution might be useful in extremely low gestational age neonates with THOP. CONCLUSION: Some preterm infants could benefit from THOP treatment, but more studies are needed to clarify further treatment strategies, including the optimal timing of initiation and duration.

Risk factors for large-for-gestational age infants in pregnant women with type 1 diabetes.

BACKGROUND: The rate of neonatal overweight remains generally high in type 1 diabetes (T1DM). Since glycemic control has improved over time other contributors need to be identified. Our aim is to evaluate the risk factors for large-for-gestational age infants (LGA) in women with T1DM and to evaluate whether the rate of LGA decreased over time. METHODS: Retrospective analysis of the medical files of pregnant women with T1DM attending our university hospital form 01-01-1992 till 31-07-2014. The generalized mixed model was used to adjust for several pregnancies over time in the same women. A multivariable model was used to evaluate independent risk factors for LGA. RESULTS: Over a 22-year period, 259 pregnancies in 180 T1DM women were identified. Mean diabetes duration of women was 13.7 ± 7.1 years, with a mean age of 29.5 ± 5.2 years. Macrosomia (>4Kg) was present in 16.2 % of deliveries, LGA was present in 45.2 % and these numbers did not change over time (resp. p = 0.19 and p = 0.70). Over time, significant more women were overweight (23.3 % vs. 39.3 %, p = 0.009) and more women had excessive weight gain during pregnancy (21.3 % vs. 37.7 %, p = 0.019). Compared to women with a non-LGA baby, women with a LGA baby had a higher weight at delivery (84.1 ± 11.1 vs. 80.4 ± 10.8, p = 0.016), had more often excessive weight gain (45.3 % vs. 25.2 %, p = 0.003) and had less strict glycaemic control in the first and third trimester [HbA1c of resp. 49 ± 10 mmol/mol (6.7 % ±0.9) vs. 47 ± 8 mmol/mol (6.5 % ±0.8), p = 0.01 and 44 ± 5 mmol/mol (6.2 % ±0.5) vs. 42 ± 6 mmol/mol (6.0 % ±0.6), p = 0.01]. In the forward multivariable analysis, excessive weight gain [OR 1.95 (1.08-3.53), p = 0.027], HbA1c level in early [OR 1.43 (1.05-1.95), p = 0.023] and late pregnancy [OR 1.70 (1.07-2.71), p = 0.026] remained independent predictors for LGA. CONCLUSIONS: LGA remains a frequent complication in T1DM. Excessive weight gain and HbA1c in early and late pregnancy are important risk factors for LGA in our population. These findings highlight the importance of strict maternal glycemic control and simultaneous striving to appropriate gestational weight gain to minimize the risk of fetal overgrowth in T1DM pregnancies.

Relationship between insulin-like growth factor I levels, early insulin treatment, and clinical outcomes of very low birth weight infants.

OBJECTIVES: Insulin regulates the secretion of insulin-like growth factor I (IGF-I) in the newborn, and low levels of IGF-I have been linked to neonatal morbidity. As part of the Neonatal Insulin Replacement Therapy in Europe Trial, we investigated the impact of early insulin treatment on IGF-I levels and their relationship with morbidity and growth. STUDY DESIGN: Prospective cohort analyses of data collected as part of an international randomized controlled trial. Blood samples (days 1, 3, 7, and 28), were taken for IGF-I bioassay from 283 very low birth weight infants (<1500 g). RESULTS: Early insulin treatment led to a late increase in IGF-I levels between day 7 and 28 (P = .028). In the first week of life IGF-I levels were lower in infants with early hyperglycemia; mean difference -0.10 µg/L (95% CI -0.19, -0.02, P = .02). Lower levels of IGF-I at day 28 were independently associated with an increased risk of chronic lung disease, OR 3.23 (95% CI, 1.09-9.10), and greater IGF-I levels were independently associated with better weight gain, 0.10 kg (95% CI, 0.03-0.33, P = .02). CONCLUSIONS: Early intervention with insulin is related to increased IGF-I levels at 28 days. Low IGF-I levels are associated with hyperglycemia, increased morbidity, and reduced growth. Increasing IGF-I levels may improve outcomes of very low birth weight infants.

Early Postnatal Outcome and Care after in Utero Exposure to Lithium: A Single Center Analysis of a Belgian Tertiary University Hospital.

Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36-39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56-0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87-1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8-12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed.

Early insulin therapy in very-low-birth-weight infants.

BACKGROUND: Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates. METHODS: In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm. RESULTS: As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04). CONCLUSIONS: Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)

Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects.

OBJECTIVES: To investigate different aspects of the introduction of array comparative genomic hybridization (aCGH) in clinical practice. STUDY DESIGN: A total 150 patients with a syndromic congenital heart defect (CHD) of unknown cause were analyzed with aCGH at 1-Mb resolution. Twenty-nine of these patients, with normal results on 1Mb aCGH, underwent re-analysis with 244-K oligo-microarray. With a logistic regression model, we assessed the predictive value of patient characteristics for causal imbalance detection. On the basis of our earlier experience and the literature, we constructed an algorithm to evaluate the causality of copy number variants. RESULTS: With 1-Mb aCGH, we detected 43 structural variants not listed as clinically neutral polymorphisms, 26 of which were considered to be causal. A systematic comparison of the clinical features of these 26 patients to the remaining 124 patients revealed dysmorphism as the only feature with a significant predictive value for reaching a diagnosis with 1-Mb aCGH. With higher resolution analysis in 29 patients, 75 variants not listed as clinically neutral polymorphisms were detected, 2 of which were considered to be causal. CONCLUSIONS: Molecular karyotyping yields an etiological diagnosis in at least 18% of patients with a syndromic CHD. Higher resolution evaluation results in an increasing number of variants of unknown significance.

Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study.

OBJECTIVES: To investigate the prevalence and determinants of hyperglycemia in the preterm population, as part of the Neonatal Insulin Therapy in Europe (NIRTURE) Trial. STUDY DESIGN: We conducted prospective cohort analyses of continuous glucose monitoring data from control infants participating in an international randomized controlled trial. Data were collected from 188 very low birth weight infants (<1500 g). RESULTS: In the first week of life, 80% of infants had evidence of glucose levels >8 mmol/L, and 32% had glucose levels >10 mmol/L >10% of the time. Independent risk factors for hyperglycemia included increasing prematurity, small size at birth, use of inotropes, lipid infusions, and sepsis. There was a lack of association between rate of dextrose infused and risk of hyperglycemia. CONCLUSION: The prevalence of hyperglycemia in the very low birth weight infant is high, with marked variability in prevalence between infants, not simply related to rates of glucose infused, but to other potentially modifiable risk factors.

The effect of glycaemia on the cerebral oxygenation in very low birthweight infants as measured by near-infrared spectroscopy.

The cerebral tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) reflect the cerebral oxygenation. We studied the effect of glycaemia on the TOI and FTOE, as measured by near-infrared-spectroscopy (NIRS). We continuously measured TOI, glycaemia, mean arterial blood pressure (MABP), saturation (SaO(2)) and transcutaneous carbon dioxide pressure (tPCO(2)) for at least 4 h during the first week of life in neonates with gestational age (GA) < 32 weeks and weight < 1500 g. FTOE was calculated. 24 measurements in 11 neonates were analyzed. We found a significant negative correlation (r = -0.077; p = 0.0344) between glycaemia and TOI, also after correction for MABP, SaO(2) and tPCO(2) (r = -0.118; p = 0.002) and a significant positive correlation between glycaemia and FTOE (r = 0.147; p < 0.000) which remained significant after correction for MABP and tPCO(2) (r = 0.116; p = 0.001). Our results indicate that in neonates during the first days of life glycaemia - even within the normal ranges and after correction for MABP, SaO(2) and tPCO(2) - influences the cerebral oxygenation.

The placenta in fetal thyroid hormone delivery: from normal physiology to adaptive mechanisms in complicated pregnancies.

Context: Thyroid hormones are indispensable for normal fetal development. Since the fetus depends to a large extent on maternal thyroid hormone supply through the placenta, this challenges maternal thyroid economy. Several molecular mechanisms are involved in placental thyroid hormone transport and metabolism. Chronic pregnancy complications, associated with utero-placental hypoxia, trigger the development of accelerated placental maturation in order to improve fetal-placental exchange to strengthen the offspring's chance of survival. This review provides an overview of normal maternal-fetal thyroid hormone supply and explores the presence of placental adaptive mechanisms in complicated pregnancies with chronical utero-placental hypoxia to improve the thyroid hormone supply to the fetus under pressure, to end with reflections about the long term health consequences.Evidence acquisition: This work is based on a comprehensive literature review of the PubMed and Embase database, including relevant articles from 1969 to June 2018.Conclusions: The placenta is actively involved in fetal thyroid hormone delivery through a combination of stimulatory and inhibitory mechanisms. Parallel with histological adaptations to improve transplacental fetal-maternal exchange, there are indications of placental adaptive mechanisms in thyroid hormone transport and metabolism in case of complicated pregnancies, from animal models and in-vitro experiments. Evidence from human in-vivo studies is limited due to heterogeneity in study populations, small study samples, and technical limitations. Further research is necessary to reveal the role of the placenta in pathological circumstances. The placenta might thus be considered as the infants' black box of pregnancy. Results will contribute to more insights in the concept of fetal programming, which lays the foundations of optimum health, growth, and neurodevelopment across the lifespan.

Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration.

In preterms, low serum levels of IGF (IGF-I) correlate with retinopathy of prematurity (ROP). In mice, IGF-I is a prerequisite for normal retinal development. We further explored the link between IGF-I and oxygen-induced retinopathy (OIR). To assess the role of endogenous IGF-I, pups were redistributed into smaller versus larger litters at birth; in one subgroup, we measured body weight and circulating IGF-I; in another, we applied hyperoxia and assessed retinal neovascularization (NV). To screen for the potential role of exogenous IGF-I, we administered a single bolus of rhIGF-I on postnatal day (P) 4 to pups in normal litters, and applied hyperoxia; body weight and IGF-I were measured; maturation and NV were assessed. Neonatal mice in larger litters had a lower body weight than mice in smaller litters; they had lower levels of circulating IGF-I, and developed more OIR (p = 0.002). Mice who had received rhIGF-I, weighed more and had higher endogenous IGF-I levels; they matured faster and developed less OIR (p = 0.00001). These findings in mice are the first to support the notion that higher availability of endogenous or exogenous IGF-I reduces OIR risk, and thus sharpen the perspective that ROP may be preventable by briefly up-regulating IGF-I after birth.

Vallecular cyst as a cause of congenital stridor: report of five patients.

BACKGROUND: Vallecular cysts are an unusual cause of congenital stridor. OBJECTIVE: To describe the imaging findings in five patients, with emphasis on the usefulness of sonographic studies. MATERIALS AND METHODS: Between 1990 and 2007, five patients with a cystic lesion situated in the anterior neck, at the vallecular space, were seen in our institution. Clinical records and imaging findings were retrospectively reviewed. RESULTS: All patients presented with persistent inspiratory stridor that was present from the first week of life. Neck US was performed as part of the investigations in four and showed a vallecular cyst. The diagnosis was confirmed with flexible bronchoscopy in four infants and CT in one; all were resected. Pathology showed a multilayered epithelial border with normal thickness and differentiation; there were no signs of malignancy. CONCLUSION: Although vallecular cysts are very rare, they should be considered in the differential diagnosis of congenital stridor. When the commonest causes have been ruled out, neck US may be diagnostic. The diagnosis can be confirmed with flexible bronchoscopy or further imaging such as CT or MRI.

Cefazolin plasma protein binding saturability during pregnancy.

This article aims to document cefazolin (CFZ) plasma binding and its covariates during pregnancy and compare these observations with previously reported observations in nonpregnant adults. Maternal CFZ plasma samples were collected during in utero surgery. The unbound CFZ fraction was reported by median and range. Correlation (Spearman) and multiple regression were used to identify covariates (total CFZ concentration, albuminemia, gestational age) of the unbound CFZ fraction. Observations during pregnancy were compared with observations in nonpregnant adults (unpaired t test, multiple regression). Plasma (N = 130) samples were collected during 30 interventions. The median unbound CFZ fraction was 0.25 (range 0.14-0.41). Correlations between the unbound CFZ fraction and total CFZ plasma concentration (0.46), time after administration (-0.38), albuminemia (-0.39) and gestational age (-0.19) were statistically significant. The median unbound CFZ fraction was higher during pregnancy when compared to observations in nonpregnant adults (0.25 vs. 0.19, P < 0.001). In a multiple-regression model, total plasma CFZ concentration and albuminemia were covariates of the unbound CFZ fraction (r(2) = 0.4). The concept of saturability of CFZ plasma protein binding has been confirmed during pregnancy, but the free CFZ fraction is higher, likely explained by the lower albuminemia during pregnancy.

Evolution of circulating thyroid hormone levels in preterm infants during the first week of life: perinatal influences and impact on neurodevelopment.

Background For several decades, transient hypothyroxinemia of prematurity (THOP) has been a topic of debate. The pathophysiology is incompletely understood and consensus on the therapeutic approach is lacking. This study aimed at gaining a better insight into the pathogenesis by studying the trends in thyroid hormone (TH) levels during the first week of life. Methods This single-center prospective observational study analyzed the plasma levels of total thyroxine (T4) and free thyroxine (fT4), total triiodothyronine (T3), thyroid-stimulating hormone (TSH) and T4-binding globulin (TBG) in cord blood and at the end of the first week of life in 120 preterm infants (gestational age [GA] <37 weeks). The change over time was calculated (delta, ∆). The impact of perinatal and subsequently postnatal variables on ∆ was studied by hierarchical multiple regression. The impact of ∆ on the neurodevelopmental outcome at the corrected ages of 9 and 24 months, measured by the Bayley Scales of Infant Development (BSID)-II, was assessed by logistic regression. Results ∆fT4 levels were negatively affected by GA and use of dopamine, whereas only GA was associated with low ∆T3 levels. Negative ∆fT4 levels were present in 75% of the extremely low-for-gestational-age infants, whereas 23.5% had a negative ∆T3 level. There was an increased risk for an abnormal mental developmental score (<85) with decreasing ∆T3 at 9 months, corrected age, but not at 24 months. Conclusions A negative evolution in circulating TH levels is principally an immaturity phenomenon, whereas dopamine can further suppress the hypothalamic-pituitary-thyroid axis. There is at least a temporary negative effect of this evolution on the infants' neurodevelopment.

Maternal and placental responses before preterm birth: adaptations to increase fetal thyroid hormone availability?

BACKGROUND: During pregnancy, maternal thyroid hormone supply is crucial for fetal development. Preterm infants often present with hypothyroxinemia. Preterm birth, either spontaneous or medically indicated, is always the result of a complicated pregnancy. We hypothesized that in preterm birth, the maternal transplacental thyroid hormone supply is influenced by the pregnancy complication and we questioned whether maternal and placental compensatory mechanisms are activated to increase thyroid hormone transfer. METHODS: Observational case-control study in mother-infant-dyads with complicated pregnancies ending in spontaneous preterm birth (n = 31) or indicated preterm birth due to vascular complications (n = 45) and normal pregnancies (healthy term controls; n = 41). At delivery, maternal and cord blood and placenta samples were collected. Cord and maternal plasma concentrations of thyroid stimulating hormone (TSH), total T4, fT4/FTI, total T3, and T4 binding globulin (TBG), and maternal serum concentrations of thyroid peroxidase (TPO)-antibodies were measured. Placental maturity was evaluated histologically and mRNA and/or protein levels of thyroid hormone deiodinases (DiO) 1, 2 and 3, and transporters (MCT8, MCT10, and OATP1c1) were quantified. RESULTS: In indicated and spontaneous preterm births, cord plasma T4 concentrations were lower than in healthy term controls (p ≤ .001), whereas T3 was only decreased in spontaneous preterm birth (p ≤ .001). Compared with spontaneous preterm births and healthy term controls, indicated preterm birth was characterized by higher maternal plasma TSH (p ≤ .05), earlier placental maturation, higher placental DiO2 gene and MCT10 protein levels and lower DiO3 gene levels (all p ≤ .01). CONCLUSIONS: Low T4 was observed in preterm infants irrespective of the cause of preterm birth, while maternal (TSH) and placental (DiO2, DiO3, and MCT10) compensatory responses were only activated in indicated preterm birth due to vascular complications. This may have mediated the normal fetal T3 availability in preterm infants born after indicated preterm birth but not after spontaneous preterm birth.

A randomised controlled trial of early insulin therapy in very low birth weight infants, "NIRTURE" (neonatal insulin replacement therapy in Europe).

BACKGROUND: Studies in adult intensive care have highlighted the importance of insulin and improved glucose control on survival, with 32% reduction in mortality, 22% reduction in intensive care stay and halving of the incidence of bacteraemia. Very low birth weight infants requiring intensive care also have relative insulin deficiency often leading to hyperglycaemia during the first week of life. The physiological influences on insulin secretion and sensitivity, and the potential importance of glucose control at this time are not well established. However there is increasing evidence that the early postnatal period is critical for pancreatic development. At this time a complex set of signals appears to influence pancreatic development and beta cell survival. This has implications both in terms of acute glucose control but also relative insulin deficiency is likely to play a role in poor postnatal growth, which has been associated with later motor and cognitive impairment, and fewer beta cells are linked to risk of type 2 diabetes later in life. METHODS: A multi-centre, randomised controlled trial of early insulin replacement in very low birth weight babies (VLBW, birth weight < 1500 g). 500 infants will be recruited from 10 centres in the UK and Europe. Babies will be randomised to receive a continuous insulin infusion (0.05 units/kg/h) or to receive standard neonatal care from the first day of life and for the next 7 days. If blood glucose (BG) levels fall infants will receive 20% dextrose titrated to maintain normoglycaemia (4-8 mmol/l). If BG is consistently above 10 mmol/l babies will receive standard treatment with additional insulin infusion. The primary end point will be mortality on or before expected date of delivery, secondary end points will be markers of morbidity and include episodes of sepsis, severity of retinopathy, chronic lung disease and growth.

Neonatal creatinemia trends as biomarker of subsequent cognitive outcome in extremely low birth weight neonates.

BACKGROUND AND AIMS: Serum creatinine is traditionally used as a marker of renal function in neonates and relates to gestational age and disease severity in extremely low birth weight (ELBW) infants. Creatinine is commonly used as a biomarker for early morbidity, but we aim to compare postnatal creatinemia trends as a biomarker for subsequent cognitive outcome. We hypothesize that impaired microcirculation not only in the kidney, but also in general (i.e. brain development) can explain this possible link. STUDY DESIGN AND OUTCOME MEASURES: A cohort of ELBW infants was analyzed by Bayley Scales of Infant Development (BSID-II) at the corrected age of 2years old. Besides other perinatal indicators, neonatal creatinemia trends of survivors (n=140) and BSID scores (n=96) are compared and analyzed using optimal matching analysis. Hierarchical clustering analysis is applied to identify createnimia trends. RESULTS: Four different creatinemia trends were identified (persistently high, normal, low, high but normalizing). A low creatinemia trend is significantly associated with the lowest percentages of postnatal corticosteroids, NSAIDS and intraventricular hemorrhage (p=0.005, p=0.013 and p=0.041 respectively) compared to a normal or persistently high creatinemia trend and associated with the best cognitive outcome (+13 points compared to the mean creatinemia trend and +23 points compared to a persistently high creatinemia trend). CONCLUSIONS: Creatinemia trends after birth are not only useful to predict renal function, but are also associated with cognitive outcome in extremely low birth weight infants. Neonates who have low creatinemia trends after birth, have the highest BSID scores at the age of two years old.

Association of patent ductus arteriosus and severe hypothyroidism in term newborns: coincidence or causal?

We report on 3 term newborns with the association of patent ductus arteriosus (PDA) and severe hypothyroidism attributed to thyroid agenesis (n = 2) or feto-maternal pit-1 deficiency (n = 1). This association suggests that sufficient thyroid hormone availability is among the prerequisites for normal postnatal ductal closure. Unravelling the maturational effects of thyroid hormone on the ductus arteriosus might also be relevant in preterm infants as further studies of the perinatal thyroid axis may clarify the potential role of thyroid hormone in PDA closure in preterm infants. Based on our observation, hypothyroidism should be considered in term infants with PDA.