Serum concentrations of adrenal steroids and their precursors as a measure of maturity of adrenocortical function in very premature newborns.

BACKGROUND: Relative adrenocortical insufficiency is often seen in sick premature newborns. As the human fetal adrenal cortex does not express the 3ß-hydroxysteroid dehydrogenase (3ß-HSD) enzyme before about 23 weeks of gestation, we hypothesized that this enzymatic step may be rate limiting in cortisol synthesis in premature infants of less than 28 weeks postmenstrual age at birth. METHODS: We measured cord, first day (D0) and median fourth day (D4) serum 17-OH-pregnenolone (17-OHPreg), 17-OH-progesterone (17-OHProg), 11-deoxycortisol, cortisol (F) and dehydroepiandrosterone sulphate concentrations and calculated the substrate/product ratios in 67 infants with gestational age 23.6-33.1 weeks. RESULTS: The mean 17-OHPreg/17-OHProg ratio as a marker of 3ß-HSD activity did not differ between the gestational age groups (gestational age <28 vs. ≥28 weeks: 0.40 vs. 0.48, p = 0.52 for cord, 3.1 vs. 2.4, p = 0.25 for D0, and 1.6 vs. 1.9, p = 0.62 for D4). In addition, the 17-OHPreg/17-OHProg ratio did not differ between the infants in the lowest F tertile compared to those in the highest F tertile group, and the serum 17-OHPreg and 17-OHProg concentrations were parallel with the respective F concentrations. CONCLUSION: We did not find evidence of significant immaturity in adrenal 3ß-HSD activity in preterm infants between 24 and 28 weeks of gestation.

Early hypoadrenalism in premature infants at risk for bronchopulmonary dysplasia or death.

AIM: To study the relationship between serum cortisol and dehydroepiandrosterone sulphate (DHEAS) concentrations and death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age in preterm infants. METHODS: Prospective measurement of cord, day of birth (D0) and day 4 (D4) serum cortisol and DHEAS concentrations and performance of low-dose (LD) ACTH tests in 89 preterm infants with gestational age <34 weeks at birth and in need of mechanical ventilation. RESULTS: Serum DHEAS levels correlated negatively with gestational age. At all sampling times, basal serum cortisol levels correlated positively with gestation-adjusted DHEAS levels (r = 0.39-0.46, p = 0.0032-<0.0001). The mean cord, D0 basal and stimulated cortisol, and cord and D0 DHEAS adjusted for gestational age were lower in the poor than good outcome infants (p < 0.02 for all). In the multiple logistic regression analyses, gestational age was the most significant factor affecting outcome, but low cord and D0 basal and stimulated cortisol and gestation-adjusted DHEAS levels also predicted poor outcome (OR 5.7-22; p = 0.049-0.014). CONCLUSIONS: Low cord and first day serum cortisol and DHEAS levels associated with poor outcome in preterm infants, which suggests general relative adrenocortical insufficiency in some premature newborns.

Circulating glucocorticoid bioactivity and serum cortisol concentrations in premature infants: the influence of exogenous glucocorticoids and clinical factors.

OBJECTIVE: Glucocorticoids are widely used before preterm delivery and in preterm infants may bear serious adverse effects. Better knowledge about the circulating glucocorticoid milieu after glucocorticoid treatment could improve treatment modalities. Therefore, we investigated the influence of exogenous glucocorticoids and clinical factors on serum cortisol (F) levels and circulating glucocorticoid bioactivity (GBA) in preterm infants. DESIGN: Eighty-nine infants (gestational age (GA) 23.6-33.1 weeks at birth) were enrolled in a prospective cohort study in two tertiary neonatal centres. METHODS: Cord, day of birth (D0), fourth day (D4) and 36 weeks postmenstrual age serum F and GBA levels were measured. RESULTS: The cord GBA was 5.8-fold and D0 GBA 2.3-fold higher in the infants exposed to antenatal steroids within 12 h before birth when compared with those unexposed or exposed >7 days before birth (95% CI 3.8-8.6; P<0.0001, and 1.8-3.0; P<0.0001 respectively). In the infants treated with early postnatal dexamethasone, D4 GBA was 1.7-fold (1.3-2.2; P<0.0005) higher when compared with levels in the infants without this treatment. Clinical factors indicating perinatal distress, such as Apgar scores <7 and low GA, were associated with higher cord, D0 and D4 serum F levels. CONCLUSIONS: Both ante- and postnatally administered glucocorticoids increase circulating GBA not attributable to endogenous F. Perinatal distress and preceding glucocorticoid treatment need to be taken into account when circulating glucocorticoid milieu is evaluated in preterm infants. The GBA assay may prove to be a useful instrument in the development of new glucocorticoid treatment strategies.

No improvement in outcome of nationwide extremely low birth weight infant populations between 1996-1997 and 1999-2000.

OBJECTIVE: Our goal was to investigate whether outcome in extremely low birth weight infants changes over time in Finland. PATIENTS AND METHODS: All infants with a birth weight <1000 g born in Finland in 1996-1997 and 1999-2000 were included in the study. Perinatal and follow-up data were collected in a national extremely low birth weight infant research register. Data concerning cerebral palsy and visual impairment were obtained from hospitals, the national discharge, and visual impairment registers. RESULTS: A total of 529 and 511 extremely low birth weight infants were born during 1996-1997 and 1999-2000. No changes were detected in prenatal, perinatal, neonatal, and postneonatal mortality rates between the periods. The survival rates including stillborn infants were 40% and 44%. The incidence of respiratory distress syndrome and septicemia increased from 1996-1997 to 1999-2000 (75% vs 83% and 23% vs 31%). The overall incidence of intraventricular hemorrhage increased (29% vs 37%), but the incidence of intraventricular hemorrhage grades 3 through 4 did not (16% vs 17%). The rates of oxygen dependency at the age corresponding with 36 gestational weeks, retinopathy of prematurity stages 3 to 5, cerebral palsy, and severe visual impairment did not change. Mortality remained higher in 1 university hospital area during both periods compared with the other 4 areas, but no regional differences in morbidity were detected during the later period. CONCLUSIONS: No significant changes were detected in birth or mortality rate in extremely low birth weight infants born in Finland during the late 1990s, but some neonatal morbidities seemed to increase. Regional differences in mortality were detected in both cohorts. Repeated long-term follow-up studies on geographically defined very preterm infant cohorts are needed for establishing reliable outcome data of current perinatal care. Regional differences warrant thorough audits to assess causalities.

Intraventricular haemorrhage in very-low-birthweight preterm infants: association with low prothrombin activity at birth.

AIM: To determine the occurrence of intraventricular haemorrhage (IVH) and its association with coagulation factors at birth in preterm neonates born before 30 wk gestation. METHODS: 38 neonates (median gestational age 27 wk, range 24-29 wk; median birthweight (BW) 933 g, range 515-1760 g) admitted to the neonatal intensive care unit were studied. Blood samples for coagulation factors were taken within 2 h after birth. The first cranial ultrasonographic examination was performed within the first 3 d. The occurrence of IVH was tested statistically by the Mann-Whitney U-test for association with the activity of coagulation factors and clinical variables. RESULTS: Thirteen IVHs occurred within the first 3 d of life. IVH was associated with BW <1000 g (p=0.012), low mean blood pressure within the first 2 d (p=0.026), gestational age <27 wk (p=0.054), low Apgar scores (<7) at 1 min (p=0.078) and intrauterine growth restriction (p=0.072). At birth (samples drawn with a median of first 36 min of life), infants with subsequent IVH had statistically significantly lower prothrombin (factor II) activity (p=0.024) than infants without IVH. CONCLUSION: The measured low prothrombin may have been affected by a prior bleeding event. Nevertheless, preterm infants with low prothrombin activity may be susceptible to IVH, or to the progression of it, if left undiagnosed.

Focus on neonatal resuscitation--NOW.

UNLABELLED: The paper by Saugstad et al. in this issue of Acta Paediatrica presents new and provocative data on the development of the child's physiological status during the first minutes of life. The data were extracted from the database of the Resair 2 study designed to investigate the outcome of resuscitation with air or 100% oxygen. The potential of these variables to predict the outcome of asphyxiated infants was evaluated. CONCLUSION: The data--in spite of some technical limitations and lack of representative reference measurements--point out the potential value of sequential physiological observations in the early identification of newborn infants at risk of poor outcome, challenge the routine habit of giving ample oxygen to depressed neonates, and call for further studies.

Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.

OBJECTIVES: To investigate the effect of hydrocortisone treatment on survival without bronchopulmonary dysplasia (BPD) and to study whether serum cortisol concentrations predict the response. STUDY DESIGN: We performed a randomized, placebo-controlled trial on infants with gestation < or =30 weeks, body weight of 501 to 1250 g, and respiratory failure. Hydrocortisone was started before 36 hours of age and given for 10 days at doses from 2.0 to 0.75 mg/kg per day. Shortly before hydrocortisone treatment, basal and stimulated (ACTH, 0.1 microg/kg) serum cortisols were measured. RESULTS: The study was discontinued early, because of gastrointestinal perforations in the hydrocortisone group (4/25 vs 0/26, P = .05); 3 of the 4 had received indomethacin/ibuprofen. The incidence of BPD (28% vs placebo 42%, P = 0.28) tended to be lower, and patent ductus arteriosus (36% vs 73%, P = .01) was lower in the hydrocortisone group. The hydrocortisone-treated infants with serum cortisol concentrations above the median had a high risk of gastrointestinal perforation. In infants with cortisol values below the median, hydrocortisone treatment increased survival without BPD. CONCLUSIONS: Serum cortisol concentrations measured shortly after birth may identify those very high-risk infants who may benefit from hydrocortisone supplementation.

Early neonatal dexamethasone treatment for prevention of bronchopulmonary dysplasia. Randomised trial and meta-analysis evaluating the duration of dexamethasone therapy.

UNLABELLED: The aim of the aborted trial was to determine whether the short early dexamethasone (DX) given after the birth improves the early outcome. We also reviewed the evidence (meta-analysis) to determine whether the duration of early DX treatment influences the early outcome, particularly in terms of bronchopulmonary dysplasia (BPD). The participants of the randomised multicentre, double-blinded placebo-controlled trial had a birth weight 500-999 g, gestation < or = 31.0 weeks, and respiratory failure by the age of 4 h. The infants received either four doses of DX (0.25 mg/kg at 12 h intervals) or placebo. The meta-analysis was performed to determine the beneficial and adverse effects of early short (<96 h duration) versus early prolonged (>96 h) DX treatment. The trial was discontinued after 109 infants had been enrolled. There was a non-significant improvement in the outcome (survival without BPD, severe intracranial haemorrhage or periventricular leukomalacia; RR 1.27; 95% CI 0.87-1.85). The risks for gastrointestinal perforation and hyperglycaemia tended to increase. A total of 15 trials were included in the meta-analysis: 10 involved prolonged (i.e. >96 h; 1594 infants) and five short interventions (1069 infants). Early prolonged DX decreased the RR for BPD to 0.72 (95% CI 0.61-0.87), whereas early short DX course did not significantly decrease the risk (RR 0.82; 95% CI 0.64-1.05). Gastrointestinal haemorrhages and perforations were significantly increased only in the early prolonged DX group. CONCLUSION: The dosage and duration of early corticosteroid given to small premature infants influences the risk of the side-effects and the early outcome.

Development of selected coagulation factors and anticoagulants in preterm infants by the age of six months.

The development of the coagulation and anticoagulation system in preterm infants was assessed, with special emphasis on extremely low birth weight (ELBW) infants and haemorrhagic or other complications after birth. Coagulation factors II (prothrombin), V (FV), VII (FVII) and X (FX) were analysed at birth and at a corrected age of six months. In addition, antithrombin (AT), protein C (PC) and protein S (PS) were measured at six months, and DNA samples were tested for Factor V Leiden (R506Q). Eighty-two infants, with a median gestational age (GA) of 32 weeks (range 24-36) and a median birth weight of 1562 g (range 695-3520), were studied. Fifteen of these were ELBW infants (range 695-1000g). Prothrombin, FV, FVII and FX reached healthy term six-month-old infant activity levels. Prothrombin and FX did not reach adult values; median activity levels remained at 82% and 78%, respectively. During the follow up, the FV and FVII levels of the ELBW infants (GA 24-27 weeks) increased more than those of the preterm infants born with higher GA (p < 0.001). At birth, prothrombin correlated significantly with FV, FVII and FX (p < 0.001). FVII at birth and at six months correlated significantly with PC (p = 0.021 and p = 0.009, respectively). These findings indicate that the gain in the coagulation factor concentrations in infancy is greatest in infants with the lowest GA at birth. Interesting new inter-relations of coagulation factor and physiological anticoagulant levels may indicate that there are still unrecognised pathways in the function of newborn haemostasis.

Cloacal anomaly simulating megalocystis in the first trimester.

We present a case of cloacal anomaly that simulated megalocystis in the first trimester of gestation of a female fetus. During the second trimester, repeated paracentesis was necessary to treat increasing ascites, oligohydramnios, and hydronephrosis. Our data support findings that ascites presenting with a multiloculated cystic structure on sonography during the second trimester may be typical for cloacal anomalies. Active treatment of the fetal ascites is recommended to improve the child's prospects for survival.

Pre- and post-discharge feeding of very preterm infants: impact on growth and bone mineralization.

In this prospective study we examined (1) how the nutritional status of very preterm infants, judged by growth measures and biochemical values, evolved during the initial hospitalization; (2) the effect of feeding on growth after discharge from hospital; and (3) the risk factors associated with low lumbar bone mineral content (BMC) later in infancy. Sixty-four former preterm infants had their lumbar spine (L2-L4) BMC assessed by dual energy X-ray absorptiometry when they weighed between 5 and 7 kg. Predicted BMC values were calculated based on our previously reported reference lumbar BMC data. These values were used to convert the preterm infants' BMC values into percentages. The extremely preterm group (gestational age < or =28 weeks) had significantly more respiratory morbidity and longer duration of hospital stay than the more mature infants. Both groups developed growth retardation and malnutrition during the hospital stay. Exclusive breastfeeding after discharge from hospital supported linear catch-up growth and weight gain but was associated with a 7.0 (1.2-41.7)-fold risk of having low BMC values. The other factors associated with the risk of having low BMC values later in infancy were low serum phosphate levels at 6 weeks, with a 7.8 (1.6-37.0)-fold risk, and male gender, with a 4.3 (1.2-16.1)-fold risk. Appropriately designed interventional studies are needed to improve the growth and nutrition of these infants during initial hospitalization. In order to improve the postdischarge nutrition, we suggest that the amount and duration of multicomponent human milk fortification should be studied further to provide individualized nutrition throughout the catch-up growth period until the end of the first year of life.

Dexamethasone pretreatment attenuates cerebral vasodilative responses to hypercapnia and augments vasoconstrictive responses to hyperventilation in newborn pigs.

In the perinatal period, glucocorticoids are frequently administered to enhance pulmonary maturity or prevent chronic lung disease of prematurity. Recently, it has been suggested that the perinatal exposure to glucocorticoids can be associated with unfavorable neurologic development. We studied the hypothesis that 24-h pretreatment with glucocorticoid might modify cerebrovascular responses to high and low partial arterial CO(2) tension in newborn animals in vivo. A closed cranial window was implanted over the left parietal cortex of 20 anesthetized ventilated newborn (<3 d old) pigs. The actual experiments were carried out in 15 pigs: eight pretreated with a total dose of 6 mg/kg of dexamethasone and seven controls. Five pigs were used for preliminary experiments as described in the text. Pial arteriolar diameters were measured during 1) baseline conditions (normocapnia), 2) hypercapnia induced by ventilating the animals with a gas mixture containing 10% CO(2), or 3) hyperventilation with resultant hypocapnia. Under these conditions, the concentrations of 6-keto-PGF(1alpha) in the CSF were measured in five experimental animals and six controls. In summary, the dexamethasone pretreatment 1) attenuated the hypercapnia-induced dilator responses of pial arterioles and prevented the hypercapnia-associated fall in mean arterial blood pressure; 2) caused moderate, although not statistically significant, diminution in 6-keto-PGF(1alpha) levels in the CSF during baseline; 3) blocked hypercapnia-induced elevation of 6-keto-PGF(1alpha); and 4) enhanced vasoconstrictive arteriolar responses to hyperventilation. We speculate that in the clinical setting, the dexamethasone effects may compromise the adjustments of global or regional cerebral blood flow to changing physiologic states in neonates.

Lumbar bone mineral content and density measured using a Lunar DPX densitometer in healthy full-term infants during the first year of life.

This cross-sectional study provides values for lumbar spine bone mineral content (BMC) and density (BMD) in 41 healthy full-term born Finnish infants, 19 boys and 22 girls, during the first year of life measured by dual energy X-ray absorptiometry (DXA) using the Lunar DPX densitometer. Lumbar BMC correlated with the weight (r=0.733; P=0.000), length (r=0.677; P=0.000), standardized length (r=0.315; r=0.045) and age at examination (r=0.314; P=0.045), and with the bone area (r=0.736; P=0.000). Infants with < or =-1 SD scores for lengths at examination had significantly lower BMC values [mean (SD); 1.79 (0.66) g] than infants with SD scores above -1 SD [2.27 (0.46) g] (P=0.011). Exclusive breast feeding did not correlate with the lumbar BMC values (r=-0.039; P=0.811). No differences were found in lumbar spine BMC (P=0.097), BMD (P=0.254) and bone area (P=0.094) values between boys and girls. In order to determine the predictive value of the anthropometric measurements on lumbar BMC, stepwise multiple regression analysis were performed, bone area and present weight were the only independent variables which explained 67.6% of the variance in the BMC values. The present cross-sectional data imply that, in healthy term infants, patterns of relative linear growth during the first year of life are related to the lumbar BMC values. In future, careful longitudinal measurements of linear growth are needed to study connections between growth patterns and bone mineral status in infancy.

Determinants of bronchial responsiveness to methacholine at school age in twin pairs.

The methacholine inhalation challenge test (MIC) was used to evaluate bronchial responsiveness in 67 children who were the products of multiple pregnancies when they were 7-15 years old. At birth, 30 (45%) infants had intrauterine growth retardation (IUGR; birth weight <2 SD below normal birth weight, or birth weight difference >1.3 SD between twin-pairs), and 59 (88%) were born before 37 weeks of gestation. None of the children had doctor-diagnosed asthma. The provocative dose of methacholine causing a 20% fall in Wright's peak expiratory flow (WPEF) (PD20) was below 1,000 microg in 10 (15%) children, and they were classified as MIC responders. There were no differences in perinatal or neonatal factors between MIC responders and nonresponders; in particular, MIC responses did not differ between IUGR infants, and children with appropriate growth for gestational age (AGA) at birth. There were seven discordant pairs in which one child was a MIC responder and the other was not; 5 responders were IUGR, and 2 were AGA children (ns). Respiratory tract infections after the neonatal period were equally common in IUGR and AGA children. However, these infections were associated with later bronchial hyperresponsiveness. Doctor-diagnosed respiratory infections, numbers of antibiotic courses, episodes of otitis media, and the need for adenoidectomy, tonsillectomy, and tympanostomy were more common in MIC responders than in nonresponders. We conclude that IUGR was not associated with subsequent bronchial hyperresponsiveness in twin pairs assessed by the MIC test. A significant relationship was seen between bronchial hyperresponsiveness and infections after the neonatal period.