Delayed Surgical Closure of the Patent Ductus Arteriosus: Does the Brain Pay the Price?

OBJECTIVE: To investigate the relation between duration of hemodynamically significant patent ductus arteriosus (PDA), cerebral oxygenation, magnetic resonance imaging-determined brain growth, and 2-year neurodevelopmental outcome in a cohort of infants born preterm whose duct was closed surgically. STUDY DESIGN: Infants born preterm at <30 weeks of gestational age who underwent surgical ductal closure between 2008 and 2018 (n = 106) were included in this observational study. Near infrared spectroscopy-monitored cerebral oxygen saturation during and up to 24 hours after ductal closure and a Bayley III developmental test at the corrected age of 2 years is the institutional standard of care for this patient group. Infants also had magnetic resonance imaging at term-equivalent age. RESULTS: In total, 90 infants fulfilled the inclusion criteria (median [range]: 25.9 weeks [24.0-28.9]; 856 g [540-1350]. Days of a PDA ranged from 1 to 41. Multivariable linear regression analysis showed that duration of a PDA negatively influenced cerebellar growth and motor and cognitive outcome at 2 years of corrected age. CONCLUSIONS: Prolonged duration of a PDA in this surgical cohort is associated with reduced cerebellar growth and suboptimal neurodevelopmental outcome.

Neonatal haemodynamic effects following foetal exposure to labetalol in hypertensive disorders of pregnancy.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) affect foetal outcome. Labetalol is frequently used to lower maternal blood pressure and prolong pregnancy. Conflicting evidence exists for specific neonatal side effects described after maternal labetalol treatment. Our aim was to investigate neonatal effects of foetal exposure to labetalol on cerebral oxygenation and extraction. METHODS: In a prospective observational study, clinical characteristics, vital parameters and cerebral oxygen delivery and extraction were collected during the first 24 h of life in labetalol-exposed preterm neonates and compared with two control groups. RESULTS: Twenty-two infants with a mean gestational age of 28.9 weeks, born from labetalol-treated mothers with HDP were included and matched with 22 infants with non-labetalol-treated mothers with HDP and 22 infants without maternal HDP. No significant differences between groups were found neither in heart rate, blood pressure and inotropic support, nor in mean regional cerebral oxygen saturation and fractional tissue oxygen extraction. CONCLUSION: Foetal labetalol exposure associated effects on preterm heart rate, blood pressure, cerebral oxygenation and extraction are not demonstrated. Maternal disease severity seems to play a more important role in neonatal cerebral haemodynamics. Maternal labetalol treatment has no clinically important short term side effects in the preterm neonate.

Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates.

BACKGROUND: Currently, reliable reference values of regional cerebral oxygen saturation (rScO2) for different gestational age (GA) groups are lacking, which hampers the implementation of near-infrared spectroscopy (NIRS) alongside monitoring arterial oxygen saturation (SaO2) and blood pressure in neonatal intensive care. The aim of this study was to provide reference values for rScO2 and cerebral fractional tissue oxygen extraction (cFTOE; (SaO2 - rScO2)/SaO2) for small adult and neonatal NIRS sensors. METHODS: In this study, 999 infants born preterm (GA <32 wk) were monitored with NIRS during the first 72 h of life. Mixed modeling was used to generate reference curves grouped per 2 wk of GA. In addition, the influence of a hemodynamically significant patent ductus arteriosus, gender, and birth weight were explored. RESULTS: Average rScO2 was ~65% at admission, increased with GA (1% per week) and followed a parabolic curve in relation to postnatal age with a peak at ~36 h. The cFTOE showed similar but inverse effects. On average, the neonatal sensor measured 10% higher than the adult sensor. CONCLUSION: rScO2 and cFTOE reference curves are provided for the first 72 h of life in preterm infants, which might support the broader implementation of NIRS in neonatal intensive care.

Neonatal glucocorticoid treatment: long-term effects on the hypothalamus-pituitary-adrenal axis, immune system, and problem behavior in 14-17 year old adolescents.

Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX-treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7-10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided.

Comparing near-infrared spectroscopy devices and their sensors for monitoring regional cerebral oxygen saturation in the neonate.

BACKGROUND: Near-infrared spectroscopy (NIRS) is an upcoming clinical method for monitoring regional cerebral oxygen saturation (rScO2) in neonates. There is a growing market offering different devices and sensors. Even though this technique is increasingly clinically applied, little is known about the similarities and/or differences in rScO2 values between the different devices and sensors. The aim of this study was to compare the rScO2 values obtained in (preterm) neonates with all available sensors of three frequently used NIRS devices. METHODS: Fifty-five neonates admitted to our neonatal intensive care unit (NICU) were included in this study. rScO2 was simultaneously monitored bilaterally with two different NIRS sensors (left and right frontoparietal) for at least 1 h. Then, the sensors were switched, and measurements were collected for at least another hour. RESULTS: We detected a rather close correlation between all investigated sensors from the three different NIRS devices, but absolute rScO2 values showed substantial differences: Bland-Altman analysis showed average differences from 10 to 15%. CONCLUSION: Although the rScO2 values correlated well between different NIRS sensors, sometimes there were substantial differences between the absolute rScO2 values, which may complicate clinical application.

Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents.

OBJECTIVE: To reduce the risk of bronchopulmonary dysplasia, preterm infants receive neonatal treatment with glucocorticoids, mostly dexamethasone (DEX). Compared to current protocols, treatment regimens of the late 1980s - early 1990s prescribed high doses of DEX for an extensive period up to 6 weeks. Worldwide at least one million children have been treated with this dose regimen. Previous studies have shown adverse effects of neonatal treatment with the glucocorticoid dexamethasone (DEX) on outcome in children aged 7-10 years. On the other hand, treatment with another glucocorticoid, hydrocortisone (HC), was not related to adverse effects in childhood. In the current study we determined the consequences of early life intervention with DEX or HC in adolescents (age 14-17 years). Besides motor function and intellectual capacities, we also examined fundamental neuropsychological functions which have so far received little attention. METHODS: In an observational cohort study we compared 14-17 year-old adolescents who received DEX (.5 mg/kg/day tapering off to .1 mg/kg/day over 21 days, n=63), or HC (5 mg/kg/day tapering off to 1 mg/kg/day over 22 days, n=67), or did not receive neonatal glucocorticoids (untreated, n=71) after premature birth (gestational age<32 weeks). Because gestational age was shorter and duration of ventilation was longer in the DEX-treated group, all analyses were corrected for these potential confounders. Motor function, IQ, and neuropsychological functions were assessed. RESULTS: DEX-treated group participants scored lower on gross motor skill tasks than their HC-treated and untreated counterparts. A higher proportion of DEX-treated girls needed special education compared to the other groups. DEX-treated adolescents performed poorer on neuropsychological tasks measuring alertness, visuomotor coordination, and emotion recognition. The HC-treated group did not differ from the untreated group. CONCLUSIONS: Even after 14-17 years, neonatal treatment with .5 mg/kg/day DEX was associated with adverse effects on motor function, school level, and neuropsychological functions, whereas treatment with the clinically equally effective dose of 5 mg/kg/day HC was not. Potential physiological mechanisms underlying the differences in dexamethasone and hydrocortisone effects are discussed. Based on the current findings, we recommend early identification of neuropsychological deficits after DEX treatment in order to specify extra educational needs.

Effect of antihypotensive treatment on cerebral oxygenation of preterm infants without PDA.

BACKGROUND: Preterm infants with hypotension (mean arterial blood pressure [MABP] < gestational age [GA]) are treated with volume expansion and/or dopamine to ensure adequate cerebral perfusion/oxygenation. We used near-infrared spectroscopy to analyze the effects of volume expansion and dopamine on cerebral oxygenation in hypotensive preterm infants without patent ductus arteriosus (PDA). PATIENTS AND METHODS: Among 390 infants, 71 (GA < 32 weeks) were hypotensive and eligible for inclusion. Thirty-three infants received volume expansion only (NaCl 0.9%; 20 mL/kg), and 38 received additional dopamine (5 µg/kg per minute). Nine and 11 infants initially treated with dopamine subsequently needed 7.5 and 10 µg/kg per minute, respectively. Seventy-one infants without hypotension were individually matched to serve as controls. MABP, regional cerebral oxygen saturation (rSco(2)), fractional tissue oxygen extraction (cFTOE), and arterial saturation (Sao(2)) were monitored 15 minutes before and 30 and 60 minutes after volume or dopamine and at comparable postnatal ages in controls. RESULTS: No changes in MABP, rSco(2), or cFTOE were found 30 minutes after volume expansion. MABP increased 60 minutes after 5 µg/kg per minute dopamine (median [range]: 28 [19-32] vs 33 [23-46] mm Hg; P < .001). There was a small increase and decrease, respectively, in rSco(2) (63 [43-84] vs 66 [46-87]%; P < .05) and cFTOE (0.33 [0.14-0.56] vs 0.31 [0.07-0.54]1/1; P < .05). However, no differences were found at any time point between controls and infants treated with volume or additional dopamine (5, 7.5, and 10 µg/kg per minute) for rSco(2) or cFTOE. CONCLUSIONS: Volume expansion and additional dopamine do not cause any significant change in rSco(2) or cFTOE in hypotensive preterm infants without PDA. We speculate that very preterm infants with hypotension but without signs of a compromised cerebral oxygenation and systemic perfusion might not be in need of antihypotensive therapy.

Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins.

BACKGROUND: Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years. METHODS: This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner. FINDINGS: Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5-38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0-1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin. CONCLUSIONS: There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.

Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age.

OBJECTIVE: The goal was to investigate cardiovascular responses to a psychosocial stressor in school-aged, formerly premature boys and girls who had been treated neonatally with dexamethasone or hydrocortisone because of chronic lung disease. METHODS: We compared corticosteroid-treated, formerly preterm infants with formerly preterm infants who had not been treated neonatally with corticosteroids (reference group). Children performed the Trier Social Stress Test for Children, which includes a public speaking task and a mental arithmetic task. Blood pressure was recorded continuously before, during, and after the stress test. Plasma norepinephrine levels were determined before the test, directly after the stress task, and after recovery. RESULTS: Overall, in response to stress, girls had significantly larger changes in systolic blood pressure and mean arterial pressure and in stroke volume and cardiac output, compared with boys. Boys exhibited larger total peripheral resistance responses, compared with girls. The hydrocortisone group did not differ significantly from the reference group in any of the outcome measures. However, dexamethasone-treated children had smaller stress-induced increases in systolic and mean arterial blood pressure than did hydrocortisone-treated children. In addition, the dexamethasone group showed smaller increases in stroke volume and blunted norepinephrine responses to stress, compared with children in the reference group. Correction for gender did not affect these results. CONCLUSIONS: The differences in cardiovascular stress responses between girls and boys are consistent with known gender differences in adult cardiovascular stress responses. Our data demonstrate that neonatal treatment with dexamethasone has long-term consequences for the cardiovascular and noradrenergic stress responses; at school age, the cardiovascular stress response was blunted in dexamethasone-treated children. Hydrocortisone-treated children did not differ from the reference group, which suggests that hydrocortisone might be a safe alternative to dexamethasone for treating chronic lung disease of prematurity.

Cardiovascular follow-up at school age after perinatal glucocorticoid exposure in prematurely born children: perinatal glucocorticoid therapy and cardiovascular follow-up.

OBJECTIVE: To study whether antenatal or neonatal glucocorticoid therapy to reduce the incidence and severity of chronic lung disease in preterm infants is associated with long-term adverse cardiac effects and hypertension. DESIGN: Retrospective matched-cohort study. SETTING: Outpatient clinic of a tertiary care hospital. PARTICIPANTS: One hundred ninety-three children aged 7 to 10 years who had been born prematurely between December 2, 1993, and September 15, 1997. Main Exposure Neonatal treatment with dexamethasone disodium phosphate(n = 48) or the clinically equally effective glucocorticoid hydrocortisone (n = 51), or only antenatal treatment with betamethasone disodium phosphate and betamethasone acetate (n = 51). These 3 groups were compared with a reference group of prematurely born children who had not been exposed to perinatal glucocorticoid therapy (n = 43). MAIN OUTCOME MEASURES: General hemodynamic data (heart rate and blood pressure), cardiovascular function as assessed at echocardiography, intima-media thickness of the carotid arteries, and cardiac biochemical features as early markers of expansion and volume overload of the cardiac left ventricle (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide). RESULTS: No significant group differences were found for heart rate, blood pressure, biochemical features, intima-media thickness, or systolic or diastolic left ventricular function. CONCLUSIONS: Although no differences were found in blood pressure and cardiovascular function at school age in children antenatally or neonatally treated with glucocorticoids, further cardiovascular follow-up may be advisable because cardiovascular dysfunction may become apparent only later in life.

Neonatal dexamethasone treatment for chronic lung disease of prematurity alters the hypothalamus-pituitary-adrenal axis and immune system activity at school age.

OBJECTIVE: To compare long-term effects of neonatal treatment with dexamethasone or hydrocortisone for chronic lung disease of prematurity on the hypothalamus-pituitary-adrenal axis and the immune response in children at school age. PATIENTS AND METHODS: A total of 156 prematurely born children were included in this retrospective matched cohort study. Children treated with dexamethasone (n = 52) or hydrocortisone (n = 52) were matched for gestational age, birth weight, grade of infant respiratory distress syndrome, grade of periventricular or intraventricular hemorrhage, gender, and year of birth. A reference group of 52 children not treated with corticosteroids was included for comparison. Plasma adrenocorticotropic hormone and cortisol in response to a social stress task were determined. Cytokine production was analyzed after in vitro stimulation of whole-blood cultures. RESULTS: The Trier Social Stress Test adapted for children induced an adrenocorticotropic hormone and cortisol response in all of the groups. The adrenocorticotropic hormone response was blunted in the dexamethasone group. The overall cortisol level was lower in the dexamethasone than in the hydrocortisone and reference group. Cortisol and adrenocorticotropic hormone in the hydrocortisone and reference groups were similar. The ratio of T-cell mitogen-induced interferon-gamma/interleukin-4 secretion was significantly higher in the dexamethasone group than in the hydrocortisone group. Interferon-gamma production and the ratios of interferon-gamma/interleukin-4 and interferon-gamma/ interleukin-10 were significantly higher in the dexamethasone group than the reference group. However, production of these cytokines did not differ between the hydrocortisone and the reference groups. CONCLUSION: Neonatal treatment of prematurely born children with dexamethasone but not with hydrocortisone resulted in long-lasting programming effects on hypothalamus-pituitary-adrenal axis and on the T-helper 1/T-helper 2 cytokine balance. Follow-up of these children is required to investigate long-term clinical consequences. We recommend that authors of previously performed randomized, controlled trials on neonatal glucocorticoid treatment include immune and neuroendocrine analyses in prolonged follow-up of these children.

Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone.

Neonatal dexamethasone (DEX) for chronic lung disease is associated with adverse outcome. We compared behavioral and motor development at school age of children who neonatally received DEX to children neonatally treated with hydrocortisone (HC) in a retrospective matched cohort study. DEX- and HC-treated groups matched for gestational age, birth weight and year, gender, and severity of respiratory distress syndrome were compared with a reference group (REF) and a group treated only antenatally with betamethasone (BMETH). REF and BMETH groups had a higher gestational age and less severe respiratory distress syndrome. From 192 children (DEX, n = 46; HC, n = 52; REF, n = 43; BMETH, n = 51), the Child Behavioral Checklists from parents and teachers (Teacher's Report Form) and the Movement Assessment Battery for Children to assess neuromotor function were analyzed. DEX girls had a poorer performance on nearly all behavioral scales of the Teacher's Report Form compared with HC girls. DEX boys did not differ from HC boys. The HC boys or girls did not differ from the REF or BMETH groups. Neuromotor development was poorer in DEX than the BMETH and REF groups. The HC group did not differ from REF and BMETH groups. We suggest that neonatal HC may be a "safer" alternative for DEX for the treatment of CLD.

Long-term and short-term outcome after delayed-interval delivery in multi-fetal pregnancies.

OBJECTIVE: To assess a possible difference in the short- and long-term outcome between infants born from a delayed-interval delivery. STUDY DESIGN: We included all neonates that were either born between November 1991 and December 2000 from a delayed-interval delivery in the Isala Clinics, Zwolle, The Netherlands, or admitted to our clinic after birth. Gestational age, time of delay, birth weight, mortality, morbidity, long-term development and adverse outcome were compared between groups. Moreover, the 'delayed infants' group was compared to a reference group. The following statistical tests were used: prevalence ratio, the Wilcoxon test and the t-test. RESULTS: Twenty-nine delivery-delaying procedures were successfully performed in our hospital. We included 17 sets of twins and 3 sets of triplets. The mean delay of 19.6 days accounted for a significant increase in birth weight and neonatal survival as well as a decrease in adverse outcome and presence of a number of disease; a negative effect on long-term development could not be shown. The reference group showed less sepsis than the delayed infants group. No serious maternal complications were observed. CONCLUSION: Delaying the delivery of a second or third infant has a positive effect on short-term outcome. Long-term outcome is comparable to children with the same gestational age.