Normal Preterm Infants Research Articles

INTESTINAL MOTILITY DURING ONTOGENY AND INTESTINAL PSEUDO-OBSTRUCTION IN CHILDREN

From the fragmentary studies performed to date of both functional obstruction and the ontogeny of intestinal motility, several conclusions can be drawn. The development of motor activity that is primarily dependent on neuronal activity, such as sucking, swallow-induced peristalsis of the esophagus, and cyclic fasting small intestinal motor activity, occurs according to a timetable that is similar in all species studies is gestationally dependent, but its timing during gestation is species specific. Postprandial events, including gastric emptying and continuous postprandial motor activity in the small intestine, in contrast seem to be dependent on the nature of the humoral response to food, provided that the musculature of the gut and enteric nerves are able to respond to it. Although these activities are primarily determined by neuronal development, there is a limited amount of information to suggest that their appearance may be pharmacologically manipulated to advance the timing and rate of development. It is commonplace now for cortisol to be used to induce the production of surfactant in mothers of babies who are at risk of hyaline membrane disease. A limited amount of information suggests that cortisol may have similar effects in inducing duodenal motor activity, and, thus, it may be possible to advance the timing and rate of development of intestinal motility in the very preterm infant by its use. There are, however, no studies to date to prove this. It is now clear that intestinal pseudo-obstruction is a heterogeneous disorder associated with various pathologies, some of which are intrinsic to the gut, whereas others are multisystem diseases affecting the intestine. In addition, although intestinal pseudo-obstruction was originally thought to involve the small intestine, it is now realized that it may not affect only one region, as in achalasia or Hirschsprung's disease, but also it may present diffusely throughout the gut. The motility changes caused by the disease processes are nonspecific, although neuropathic and myopathic changes are distinct and due to the destruction of the particular motor control system involved. The mechanisms of the ontogenic and disease changes described in this article are, however, almost totally unexplored. The recent upsurge of interest in the area with the development of advances in cellular and molecular biology, at least the early events, is now beginning to unravel. At the present time, the stage is being set for probably the most exciting phase of understanding of the nature of the ontogeny of intestinal motor activity, which the author expects will enable us to manipulate motor activity in normal preterm infants and, it is hoped, congenital dysmotile states.

Longitudinal head growth in developmentally normal preterm infants.

To determine growth in head circumference from birth to 18 months of age in normal infants with low birth weight. Healthy, appropriate-for-gestational-age, singleton, white infants weighing less than or equal to 2500 g at birth and with normal development at 18 months of age were included in this study. Serial measurements of head circumference (corrected for gestational age) from 450 eligible infants were compared with reference data for head circumference. Longitudinal measurements of head circumference for infants weighing more than 1000 g at birth were similar to reference data for term infants. Head measurements for infants weighing less than or equal to 1000 g at birth were notably smaller than the measurements in the reference data. A cubic spline curve drawn through the head circumference measurements between birth and age 18 months (corrected for gestational age) for infants weighing less than or equal to 1000 g at birth was significantly (P < .001) below the curve for infants weighing more than 1000 g at birth. At age 18 months, the mean difference in head circumference between the group weighing less than or equal to 1000 g at birth and the weights in the reference data was 1.6 cm (P < .01). (Data were analyzed with Wilcoxon's signed rank test.) These data show that head circumference grids are appropriate for observing head growth in infants with a birth weight more than 1000 g. However, head circumference growth for normal infants with birth weight less than or equal to 1000 g does not "catch up" with that of larger premature infants or term infants.

Sleep state organization in premature infants of less than 35 weeks' gestational age.

To assess sleep organization in premature infants of < 35 wk gestational age (w GA), we performed polygraphic recordings in 24 neurologically normal neonates (eight per group): artificially ventilated 27-30 and 31-34 w GA infants and nonventilated 31-34 w GA infants. Sleep states were defined by concordance of EEG and rapid eye movement criteria. Uninterrupted active sleep periods of > 13 min and quiet sleep periods of > 5 min were observed in all babies, except in one 33 w GA ventilated infant. Intervals from the beginning of recording to the 1st quiet sleep period varied from 0 to 63 min and intervals to the beginning of the longest sleep cycle varied from 5 to 84 min. Nonventilated 31-34 w GA infants had longer sleep cycles (p < 0.02), principally because of longer active sleep periods. However, percentages of different states in the cycles were similar in all groups. When body movements were required for state definition, amounts of active and quiet sleep diminished and the percentage of indeterminate sleep was augmented significantly. In conclusion, our study demonstrated that 1) sleep state differentiation is present as soon as 27 w GA; and 2) artificial ventilation, performed in a highly specialized neonatal intensive care unit, does not modify sleep organization of neurologically normal premature infants. We hypothesize that this "earlier" sleep state differentiation, compared with previous data, may be related to improvements in neonatal intensive care over recent years.

Maturation and effect of stimulus rate on brainstem auditory evoked potentials

Brainstem auditory evoked potentials (BAEPs) at three stimulus rates (20, 41.3 and 61.3 c/s) were recorded in 104 normal preterm infants, distributed in four age groups between 32 and 39 weeks (conceptional age), and in 20 normal adults. The latency shifts between 61.3 c/s and 20 c/s, and between 41.3 c/s and 20 c/s, were calculated for each wave, and studied as a function of age. A significant effect of conceptional age was shown on the ‘61.3–20 c/s’ and the ‘41.3–20 c/s’ wave V latency shifts, and a significant difference between adults and newborns was noted for the wave V and wave III latency shifts. No significant difference was obtained for the wave I latency shifts. This suggests that the changes of auditory adaptation with maturation may be predominantly at a central level, i.e. on central synapses.

Effect of maturation on the extrathoracic airway stability of infants.

The influence of maturation on extrathoracic airway (ETA) stability during quiet sleep was determined in 13 normal preterm infants of 1.41 +/- 0.14 (SD) kg birth weight and 32 +/- 2 wk estimated gestational age. Studies began in the first week of life and were performed three times at weekly intervals. A drop in intraluminal pressure within the ETA was produced by external inspiratory flow-resistive loading (60 cmH2O.l-1 x s at 1 l/min); an increase in intrinsic resistance, indicating airway narrowing, was sought as a measure of ETA instability. Baseline total pulmonary resistance was not significantly different between weeks 1, 2, and 3 (88 +/- 35, 65 +/- 24, and 61 +/- 17 cmH2O.l-1 x s, respectively) but increased markedly above baseline with loading to 144 +/- 45 cmH2O.l-1.s during week 1 (P < 0.001), 89 +/- 28 cmH2O.l-1 x s at week 2 (P < 0.01), and 74 +/- 25 cmH2O.l-1 x s at week 3 (n = 10). The increment with loading was significantly greater during week 1 than during weeks 2 or 3 (P < 0.02). Similar studies were also done in seven full-term infants in the first week of life to evaluate the influence of gestational maturity on ETA stability. Despite a relatively greater drop in intraluminal pressure within the ETA of term vs. preterm infants with loading (P < 0.001), total pulmonary resistance failed to increase (68 +/- 21 to 71 +/- 32 cmH2O.l-1.s). These data reveal that ETA instability is present in preterm infants at birth and decreases with increasing postnatal age. Full-term neonates, by comparison, display markedly greater ETA stability in the immediate neonatal period.

Tactile-kinesthetic stimulation effects on sympathetic and adrenocortical function in preterm infants

The purpose of our study was to investigate the neuroendocrine response in preterm infants to a pattern of tactile-kinesthetic stimulation that facilitates their growth and development. Preterm infants (mean gestational age 30 weeks, mean birth weight 1176 gm) received normal nursery care or tactile-kinesthetic stimulation for three 15-minute periods at the start of three consecutive hours each day for 10 days. On day 1 and day 10 of the study, a 24-hour urine sample was collected for norepinephrine, epinephrine, dopamine, cortisol, and creatinine assay and a blood sample was taken by heel stick for cortisol and growth hormone assay. Urine norepinephrine and epinephrine values increased significantly only in the stimulated babies. Urine dopamine and cortisol values increased in both groups, and serum growth hormone decreased in both groups. Individual differences in urine norepinephrine, epinephrine, dopamine, and cortisol values were highly stable across the 10 days despite a 10-fold range of values among the infants. The results of this study suggest that tactile-kinesthetic stimulation of preterm infants has fairly specific effects on maturation and/or activity of the sympathetic nervous system. In addition, this study has defined catecholamine and cortisol secretion across gestational age in normal preterm infants. Finally, these data suggest that highly stable individual levels of catecholamine and cortisol secretion are established by birth in humans.

Anemia in the newborn: a diagnostic approach and challenge.

T he normal mean hemoglobin at birth is 16.5 g/dL with a range of 13 to 21 g/dL. Intrauterine growth retardation, maternal diabetes, post maturity and maternal cigarette smoking, are all associated with higher levels of hemoglobin, probably as a consequence of hypoxia or stress. Because of significant capillary hemoconcentration in the first few days of life, a venous specimen is essential for accuracy. Although a hemoglobin level of less than 13 g/dL is, by itself, indicative of significant anemia, values at the lower end of the range may be seen with a variety of pathological states and must be evaluated in concert with physical signs, reticulocyte count, and bilirubin levels. The differential diagnosis of anemia in the newborn infant is more extensive than in later life because there may be both maternal as well as infant causes. However, the approach to the anemic neonate does not differ substantially from the diagnostic approach that is used in later life. Essential information in evaluation of the anemic neonate includes a family history and a description of the pregnancy, including the mother’s health and medications, and the circumstances of the birth. Basic initial laboratory studies include a complete blood count (including RBC) red cell indices, reticulocyte count, an evaluation of red cell morphology, a direct Coombs’ test, and serum bilirubin. Table 1 lists hematologic values for normal term and premature (32 week) infants. After it is ascertained that the newborn is anemic, a stepwise approach to diagnosis is outlined on Fig 1. As in the older patient, there are only two fundamental mechanisms for anemia in the

Magnetic resonance imaging in preterm infants

Magnetic resonance imaging was performed in 9 preterm infants at 37–43 weeks postmenstrual age. They all were born at 26–35 weeks gestation. Myelination was graded according to its most cephalic location. Myelination pattern 2 (myelination observed in the posterior limb of the internal capsule and adjacent structures of the thalamus and lenticular nucleus) was demonstrated in 2 infants, pattern 3 (myelination of the corona radiata) in 3 infants, and pattern 4 (myelination of the centrum semiovale) in 4 infants. Bilateral low intensity areas were found on T 1-weighted images in 7 infants and a ribbon-like, high intensity was observed in 5. These findings revealed a wide variety of magnetic resonance imaging appearance in apparently normal preterm infants. Caution is needed in interpreting the pathologic nature of such features in preterm infants during the perinatal period.

11 FIBRINOLYSIS IN THE CSF FOLLOWING INTRAVENTRICULAR HAEMORHAGE

Current therapies for posthaemorrhagic hydrocephalus (PHH) such as surgical shunting, repeated tapping and acetazolamide all have major problems and so we are exploring the possibilities of lysis of the obstructing clots. X oligomers, as indicators of fibrinolysis, were measured in CSF from 5 normal preterm infants (mean 102 ng/ml), 6 preterm infants with IVH but no PHH ( mean 315 ng/ ml) and 8 infants with progressive PHH (mean >500 ng/ ml). Serial CSF samples from one infant with IVH showed a peak X oligomer level over 1,000 ng/ml after 15 days.4 infants were treated with repeated intraventricular injections of urokinase or streptokinase (2,500 or 5,000 units). CSF taken 2-3 days post-injection showed no change in the levels of X oligomers (already very high). Repeated doses were not associated with bleeding problems but hydrocephalus resolved in only one infant.Conclusions: There is considerable natural fibrinolytic activity in the CSF after IVH. Single intraventricular injections of modest doses of fibrinolytic agents do not have a sustained effect on CSF fibrinolysis or hydrocephalus. Larger doses by infusion look more premising.

Interburst interval measurements in the EEGs of premature infants with normal neurological outcome

Interburst intervals (IBIs) are quiescent of cerebral activity, which normally occur in the electroencephalograms (EEGs) of premature infants. Although it is generally felt that the duration of these intervals shorten with increasing conceptional age (CA), no systemic studies of IBIs have been done in a large group of normal premature infants with long-term follow-up and using multichannel routine EEGs. In this study, we measured the IBIs, using defined criteria, in 36 premature infants who were normal at 3 years. The IBIs were measured in 104 EEGs, obtained from these infants, using standard recording techniques. Mean and the maximum IBIs were calculated. IBI duration decreased with increasing CA, although this trend was not very prominent when very restrictive criteria for measurement of IBI length were used. Less restrictive criteria for defining an IBI led to trends which are similar to those of previous studies. Various clinical factors, such as mild encephalopathies, small intraventricular/ subependymal hemorrhages, mild bronchopulmonary dysplasia, or patent arteriosus did not significantly alter IBI durations. Comparison with other techniques of IBI measurement and recording are discussed. The longest period of continuous activity during a routine recording was also measured and was found to increase with increasing CA.

Gross and fine motor development of preterm infants at eight and 12 months of age.

Forty-five neurologically normal preterm infants were allocated to one of two groups according to their gestational age at birth (less than 32 weeks; 32 to 36 weeks). Their gross and fine motor development was assessed at eight and 12 months chronological age and eight and 12 months adjusted age. At eight months chronological age the two groups differed significantly in both gross and fine motor development, but at eight and 12 months adjusted age and 12 months chronological age they differed significantly only in fine motor development.

Heparin cofactor II in adults and infants with thrombosis and DIC

Heparin cofactor II (HC II) was measured by a chromogenic activity assay in normal preterm infants (gestational age, 28-36 weeks; n = 17; 29% +/- 11.5 [mean +/- 1 SD], range 11-51), normal full-term infants (n = 18; 49% +/- 6.6 [mean +/- 1 SD], range 36-58), and normal adults (n = 38; 101% +/- 14 [mean +/- 1 SD], range 73-130). Normal children attained adult levels at approximately 5 to 7 months of age. The lower values in preterm and term infants most likely reflect immature liver function. Neither adults and children with a history of thrombosis with prior negative evaluation (n = 74), patients with documented protein C and protein S deficiency (n = 4), nor sick infants without evidence of consumptive coagulopathy (n = 15) had significantly lower levels of HC II activity. Infants with disseminated intravascular coagulation (n = 2) had strikingly lower levels of HC II activity.

Phosphorus metabolites and intracellular pH in the brains of normal and small for gestational age infants investigated by magnetic resonance spectroscopy.

The brains of 30 normal preterm and term infants whose birth wt were appropriate for gestational age and 13 who were small for gestational age but healthy were studied by phosphorus magnetic resonance spectroscopy to determine values for metabolite concentration ratios and intracellular pH. In the AGA infants, phosphocreatine/inorganic orthophosphate increased between 28 and 42 wk of gestational plus postnatal age, suggesting a rise in the phosphorylation potential of brain tissue. At the same time, the concentration of phosphomonoester (mainly phosphoethanolamine) fell and that of phosphodiester (including phosphatidylethanolamine and phosphatidylcholine) increased. These changes reflected myelination and proliferation of membranes. Intracellular pH was approximately 7.1 and did not change with brain maturation. No differences were detected in these variables between the infants who were small for gestational age and those who were appropriate for gestational age.

Development of sleep states in normal premature and full-term newborns.

1) to answer the question "Do sleep states exist in normal premature infants;" 2) to analyze the development of sleep cycle and sleep state characteristics in premature and full-term newborns. Polygraph recordings were done on 38 normal, appropriate for gestational age newborns, born at 30 to 41 weeks (w) of gestation. All infants fell asleep in active sleep (AS). Postwaking AS was significantly shorter than the next AS. Mean sleep cycle duration increased from approximately 46 min at 31-34 w of conceptional age (CA) to 70 min. at 35-36 w CA. In all infants we observed stable, greater than 5 min AS and quiet sleep (QS) periods, as defined by EEG and REM criteria. Indeterminate sleep was about 30% of the total sleep cycle at 31-34 w; it decreased to 12% at 35-36 w. Both duration and percentage of AS and QS significantly increased at 35-36 w and remained stable up to 39-41 w CA. Values of QS were significantly reduced when defined by additional criteria (respiratory rate, tonic chin EMG or motility). Concordance of QS criteria was not significantly better in older versus younger groups of infants. At all ages, AS values were insensitive to changes in the criteria chosen to define them. The contrast, starting from 31-34 w CA, between AS and QS as defined by EEG and REM criteria could account for state differences in the control of many physiological variables in prematures.

PREDICTION IN VERY PRETERM INFANTS OF SATISFACTORY NEURODEVELOPMENTAL PROGRESS AT 12 MONTHS

This study was performed to find out how well ultrasound brain-scanning and neurological examination of very preterm infants, together and separately, predicted normal neurodevelopmental progress at 12 months corrected age. 111 infants born at less than 33 weeks gestation were scanned at discharge from the neonatal unit, and neurological examinations were performed at a gestation-equivalent age at or near term. During the first year of life repeated neurological and developmental testing was carried out. At 12 months a diagnosis of normal progress or of major or minor neurodevelopmental disorders was made. 56 (50 per cent) infants with both a favourable ultrasound scan and normal neurological findings had a 98 per cent (90 to 99 per cent) probability of normal progress at 12 months, and a 100 per cent (93 to 100 per cent) probability of having no major disorder. Separately, ultrasound scanning and neurological examination were not such good predictors of normal outcome, although they selected larger groups of infants with high probabilities of progressing normally. Ultrasound brain-scanning and neurological examination can be used in combination to identify potentially normal preterm infants when they are discharged to their homes.

Effect of sleep state on chest wall movements and gas exchange in infants with resolving bronchopulmonary dysplasia.

During active sleep, neonates exhibit asynchronous chest wall movements, which have been associated with a small but significant decrease in oxygenation. To determine the effects of maturation and residual chronic lung disease on both these phenomena, we studied 11 preterm infants with resolving bronchopulmonary dysplasia (BPD) and compared these infants to ten healthy preterm infants all at time of discharge. Synchrony of chest wall (upper rib cage and abdominal) movements, sleep state, O2 saturation, and transcutaneous CO2 (TcPCO2) were recorded during both active (AS) and quiet sleep (QS). Sleep state was determined by electroencephalographic and behavioral criteria. Normal preterm infants displayed asynchronous chest wall movements only in AS, whereas, in infants with BPD, asynchrony predominated in both sleep states, although O2 saturation and TcPCO2 did not differ between sleep states in either group. The O2 saturation during AS was lower in the BPD group than in the group of normal infants (92% vs 96%; P less than 0.02), whereas TcPCO2 was higher in the BPD group unrelated to sleep state. We conclude that infants with resolving BPD exhibit asynchronous chest wall movements in both AS and QS, and that change in sleep state from QS to AS is not associated with a detrimental fall in oxygenation in these infants.

ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS IN PRETERM FEMALES

Precocious puberty was observed in a preterm ( 27 wks post-conceptional age - PCA) female. At 41 wks PCA, estradiol (E2) levels were elevated (282 pg/ml). By 13 months PCA, E2 decreased spontaneously (18 pg/ml) and pubertal changes regressed. However, pelvic ultrasonography revealed the development of ovarian cysts. In order to interpret these findings and determine their significance, we studied 6 normal preterm female infants (PCA ≤34 wks) during the first month of postnatal life. We measured: a) E2 - max > 30,000 pg/ml on day of birth (DOB), b) LH - max 196 mIu/ml on DOB, c) FSH - max 125.2 mIu/ml 3 wks after birth, d) 17-hydroxyprogesterone - max 4320 ng/dl on DOB, and e) DHEA-S - max 429 μg/dl on DOB. As in full term infants, E2 was highest on the DOB and decreased to prepubertal values within 1 month. In contrast, gonadotropin levels were variable but remained elevated throughout this period.Conclusions: Although in most preterm females elevated gonadotropin levels persist for at least 1 month, the same is not true for E2. These data suggest that the HPG axis is activated in premature female infants prior to their would be term delivery. The index case differed in that elevated E2 levels persisted and ovarian cysts developed.

Transcutaneous blood gases and sleep apnea profile in healthy preterm infants during early infancy.

Studying the development of transcutaneous blood gas levels (tcpO2 and tcpCO2) and the sleep apnea profile in relation to sleep states in normal preterm infants between 36 and 52 weeks postconceptual age we found a dynamic increase in tcpO2 during regular breathing (without apnea) and a steady decrease in tcpCO2 during both regular and periodic breathing. The mean tcpO2 of periodic breathing, however, persistently remained well below the corresponding level found during regular breathing. It is suggested that in normal preterm infants there is a continued maturational adjustment of autonomic respiratory control up to 3 months post term and, furthermore, that periodic breathing may persistently be associated with a relative hypoxemia.

Use and Abuse of the Apgar Score

The Apgar score, devised in 1952 by Dr Virginia Apgar, is a quick method of assessing the state of the newborn infant.1,2 The ease of scoring has led to its use in many studies of outcome. However, its misuse, as in current International Classification of Diseases, revision 9, coding, has led to an erroneous definition of asphyxia.* Although the Apgar score continues to provide a convenient shorthand for reporting the state of the baby and the effectiveness of resuscitation, the purpose of this statement is to place the Apgar score in its proper perspective as a tool for assessing asphyxia and for prognostication of future neurologic deficit. The Apgar score is comprised of five components: heart rate, respiratory effort, tone, reflex irritability, and color, each of which can be given a score of 0, 1, or 2 (Table). FACTORS THAT MAY AFFECT THE APGAR SCORE Although rarely stated, it is important to recognize that elements of the score such as tone, color, and reflex irritability are partially dependent on the physiologic maturity of the infant. The normal premature infant may thus receive a low score purely because of immaturity with no evidence of anoxic insult or cerebral depression. Maternal sedation or analgesia may decrease tone and responsiveness. Neurologic conditions such as muscle disease or cerebral malformations may decrease tone and interfere with respiration. Cardiorespiratory conditions may interfere with heart rate, respiration, and tone. Thus, to equate the presence of a low Apgar score solely with asphyxia represents a misuse of the score.

Auditory brainstem responses and behavioural responses in pre-term infants.

Auditory brainstem responses (ABRs) and behavioural thresholds were studied in 25 pre-term infants with post-conceptional ages of approximately 40 weeks to ascertain whether there were differences in the ABR between normal preterm and full-term new born infants to compare behavioural thresholds around 40 weeks of post-conceptional age and to follow changes of their behavioural thresholds in the first year of life. ABR thresholds, peak latencies of Waves I and V and the I-V peak interwave latency were measured. Behavioural audiometric thresholds to pure tones were determined through behavioural observation audiometry and conditioned orientation-reflex audiometry. The ABR thresholds of the pre-term infants, whether they were small for date (SFD) or appropriate for date (AFD), were in the normal ranges of the controls. Moreover, there were no significant differences between either the SFD or the AFD group and controls, as far as Wave I or V latency or I-V interval are concerned. Thus, the ABR was apparently unaffected by the infant being small-for dates. Behavioural audiometry disclosed that all normal full-term infants responded to pure tone stimuli, with mean thresholds of 85 dB, while only 42% of AFD and 30% of SFD would respond to pure tone stimuli at 90 dB or less. Behavioural thresholds caught up with the normal range by 12 months of age, except for a few infants.