Jonneke J. Hollanders

No Association Between Transient Hypothyroxinemia of Prematurity and Neurodevelopmental Outcome in Young Adulthood

CONTEXT Transient hypothyroxinemia of prematurity (THoP) has been associated with neurodevelopmental impairment in infancy and childhood. It is not known whether these relations persist into adulthood. OBJECTIVE The objective was to examine whether there is an effect of THoP on intelligence quotient (IQ) score and motor functioning at a young adult age. DESIGN This study was part of the 19-year follow-up of the Project On Preterm and Small-for-gestational-age birth (POPS) cohort, which included infants born very preterm (ie, <32 wk) and/or with a very low birth weight (ie, <1500 g). SETTING This was a multicenter study. PATIENTS There were 398 19-year-old participants of the POPS cohort, of whom 120 had THoP. EXPOSURE T4 concentrations were obtained through the national neonatal screening program for congenital hypothyroidism. THoP was defined as a total T4 concentration < -3 SD of the daily mean (approximately 60 nmol/L). MAIN OUTCOME MEASURES Main outcome measures were IQ and motor functioning, measured with the digital Multicultural Capacities Test-Intermediate Level and a revised version of Touwens examination of minor neurological dysfunction, respectively. RESULTS THoP was not associated with IQ score (mean difference, 0 [95% confidence interval, -3.8 to 3.8] points) or motor function (mean difference, 0.6 [95% confidence interval, -1.3 to 2.5] points) after adjustment for demographic and perinatal characteristics. CONCLUSIONS No associations between THoP and neurodevelopmental outcome at age 19 years were found.

Growth pattern and final height of very preterm vs. very low birth weight infants

BackgroundBoth very preterm (VP; i.e., gestational age <32 weeks) and very low birth weight (VLBW; i.e., birth weight <1,500 g) are used as inclusion criteria by studies on preterm birth. We aimed to quantify the impact of these entities on postnatal growth until final height.MethodsSubjects born VP and/or with VLBW from the Project On Preterm and Small-for-gestational-age infants cohort were classified as follows: (1) VP+/VLBW+ (n=495), (2) VP+/VLBW− (n=207), or (3) VP−/VLBW+ (n=296) infants. Anthropometric data were collected at birth, 3, 6, 12, and 24 months’ corrected age, and at 5 and 19 years. At 19 years, 590/998 (59%) of the subjects enrolled in 1983 were followed up.ResultsBirth size was smallest in the VP−/VLBW+ group compared with the VP+/VLBW+ and VP+/VLBW− groups. During childhood, length, weight, and head circumference SD scores increased in the VP−/VLBW+ group, whereas SD scores in the VP+/VLBW+ and VP+/VLBW− groups either remained stable or decreased. Despite catch-up growth, VP−/VLBW+ infants remained the shortest and lightest at age 19.ConclusionClassification on the basis of VP and VLBW impacts growth, causing different growth patterns for infants born VP+/VLBW+, VP+/VLBW−, or VP−/VLBW+. For future studies, we recommend, at least for industrialized countries, including preterm infants based on gestational age.

Cortisol in human milk: The good, the bad, or the ugly?

We found that breast-milk cortisol and cortisone concentrations peaked at 0700 h and declined during the afternoon, mirroring saliva analysis that was conducted at the same time (3). The early-morning peak was approximately five times as high as the nadir. Moreover, cortisone (which can be converted to cortisol by 11b-reductase activity) was much more abundant in breast milk than cortisol (3). Recently, another group demonstrated replication of this typical diurnal pattern in human milk (4).

Programming of the Hypothalamus-Pituitary-Adrenal Axis by Very Preterm Birth

Background: Many very preterm (i.e., <32 weeks of gestation) newborns fail to mount an adequate adrenocortical response to stress or illness, termed relative adrenal insufficiency. Conversely, later in life these infants show features of increased glucocorticoid bioactivity, such as abdominal adiposity, insulin resistance, raised blood pressure, shorter stature and internalizing problem behavior. Summary: Studies suggested that very preterm newborns have impairments along multiple levels of the hypothalamus-pituitary-adrenal (HPA) axis. Among the impairment were defects in: (1) the pituitary responsiveness to exogenous corticotropin-releasing hormone, (2) 11β-hydroxylase activity, and (3) the interconversion between cortisol and inert cortisone. There is some evidence suggesting that later in life these infants have an increased basal secretion rate of cortisol and adrenal hyperandrogenism. However, the response to acute (psychosocial) stress was blunted rather than enhanced in them. The mechanisms explaining this switch in HPA axis activity are complex and not yet fully understood. Key Messages: Very preterm newborns have several impairments along the HPA axis that could impede an adequate adrenocortical response to stress or illness. Later in life, these infants are predisposed to increased HPA axis activity, which could partially explain their phenotype.

Transient hypothyroxinemia of prematurity and problem behavior in young adulthood.

INTRODUCTION Preterm newborns are at risk of developing transient hypothyroxinemia of prematurity (THoP), which has been associated with subsequent neurodevelopmental impairments. Behavioral outcomes at adult age after THoP have never been reported. AIM To examine whether there is an association between THoP and problem behavior at young adult age. METHODS This study was part of the follow-up of 19-year-old subjects born very preterm (i.e., <32 weeks) and/or with a very low birth weight (i.e.,<1500g) from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. We included 468 subjects of the POPS cohort; of whom 123 had THoP. Thyroxine (T4) concentrations were obtained through the national neonatal screening program for congenital hypothyroidism. THoP was defined as a T4 concentration <-3 SD (approximately 60nmol/L). At age 19, behavior was assessed using the Young Adult Self Report and the Young Adult Behavioral Checklist for parents. RESULTS THoP was associated with a 1.8 (95% confidence interval (CI): 1.01-3.4) -fold increased odds of self-reported Internalizing behavior, as well as with a 1.9 (95% CI: 1.1-3.1) -fold increased odds of parent-reported Total problem behavior. These relations persisted after correction for demographic and perinatal variables. Similar associations were absent for the other self-reported and parent-reported syndrome and problem scales. CONCLUSIONS THoP was associated with more internalizing and total problem behavior at age 19. While our observations warrant more awareness of problem behavior in preterm infants, at present, it is unclear whether these associations are causal and screening for THoP does not seem necessary.

Nutritional programming by glucocorticoids in breast milk: Targets, mechanisms and possible implications

Vertical transmission of glucocorticoids via breast milk might pose a mechanism through which lactating women could prepare their infants for the postnatal environment. The primary source of breast-milk glucocorticoids is probably the systemic circulation. Research from our group showed that milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis activity, with a higher abundance of cortisone compared to cortisol. Measurement of breast-milk glucocorticoid concentrations is challenging due to possible cross-reactivity with progestagens and sex steroids, which are severely elevated during pregnancy and after parturition. This requires precise methods that are not hindered by cross reactivity, such as LC-MS/MS. There are some data suggesting that breast-milk glucocorticoids could promote intestinal maturation, either locally or after absorption into the systemic circulation. Breast-milk glucocorticoids might also have an effect on the intestinal microbiome, although this has not been studied thus far. Findings from studies investigating the systemic effects of breast-milk glucocorticoids are difficult to interpret, since none took the diurnal rhythm of glucocorticoids in breast milk into consideration, and various analytical methods were used. Nevertheless, glucocorticoids in breast milk might offer a novel potential pathway for signal transmission from mothers to their infants.