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Objective: The aim of the study was to assess the developmental outcome of neonatal survivors of hemolytic disease of the neonate treated with modern intrauterine transfusion techniques. Study Design: In this prospective, observational study, auditory evoked-response tests were performed in the nursery. Neurodevelopmental evaluation with the Gesell Developmental Schedules was performed between 9 and 18 months of corrected age to assess motor skills, language development, comprehension capacity, and social skills. The McCarthy Scales of Children's Abilities were administered between 36 and 62 months. Results: Forty children who survived severe fetal hemolytic disease were followed up until 62 months old. Demographic data included gestational age at first intrauterine transfusion (26.4 ± 3.7 weeks), median number of intrauterine transfusions (4, range 1-8), lowest fetal hematocrit (20.2%± 7.8%), peak fetal bilirubin (7.1 ± 2.1 mg/dL), incidence of hydrops fetalis (45%),and mean gestational age at delivery (35.6 ± 2.2 weeks). One case of severe bilateral deafness and 1 case of right spastic hemiplegia were diagnosed. The Gesell Developmental Schedules score was assessed between 9 and 18 months of corrected age in 22 infants. The global developmental quotient was 101.9 ± 9.5 (mean for normal population is 100). Regression analysis revealed no correlation between the global developmental quotient and gestational age at the first intrauterine transfusion, gestational age at birth, or the severity of the fetal hemolytic disease (fetal hematocrit, fetal bilirubin, presence of hydrops fetalis, total number of intrauterine transfusions, duration of neonatal phototherapy, and number of neonatal exchange transfusions). Eleven of the 40 children were followed up until they were 62 months old, and the McCarthy Scales of Children's Abilities were administered. The mean cognitive index was 107.6 ± 9.4 (90-109 is considered average). Conclusion: Despite severe fetal hemolytic disease, normal developmental outcome can be expected for children treated with intrauterine transfusions. (Am J Obstet Gynecol 1998;179:858-63.)

Objective: We sought to evaluate the growth status of twins at birth using individualized growth assessment methods and to compare this assessment with that obtained with conventional methods. Study design: Twenty twin pregnancies were studied longitudinally with ultrasound. Measurements of the head and abdominal cubes (A, B), head circumference (HC), abdominal circumference (AC), thigh circumference (ThC), and femur diaphysis length (FDL) made in the 2nd trimester were used to specify Rossavik growth models for each parameter in each fetus. These models were used to predict weight (WT), HC, AC, ThC, and crown–head length (CHL) at birth. Actual birth measurements made within 24 hours of delivery were compared to predicted values, the latter corrected using singleton [corrects for both technical problems (TP)] or twin [corrects for both technical problems (TP) and decreased soft-tissue deposition (DSTD)] correction factors where appropriate. Two sets of growth potential realization index (GPRI) values and their corresponding neonatal growth assessment scores (NGAS) were calculated and compared to previously established normal values. Birth measurements were compared with appropriate population age-specific size curves. These data were used to characterize and classify the growth status of each twin neonate. Results: Individualized growth assessment identified five primary types of growth outcomes: normal (Group I, 45%); primarily DSTD (Group II, 22.5%); IUGR (Group III, 15%); above average soft-tissue deposition (Group IV, 5%); and growth acceleration (Group V, 7.5%). Within Group I was a subgroup with evidence of DSTD (Group Ib, 33.3% of Group I). Group II could be divided into two subgroups, one with only DSTD (Group IIa, 44.4% of Group II) and one with both DSTD and other growth abnormalities (Group IIb, 55.6% of Group II). Group III had multiple growth abnormalities which were more severe than those seen in Group II. All normal neonates were AGA and had virtually all anatomic parameters within their respective normal ranges. Of the neonates with definite evidence of IUGR (Groups IIb and III), only 4 of 11 (36.4%) were SGA and only 6 of 11 (54.5%) had any of the five anatomic parameters below their respective normal ranges. Only 1 of 3 (33.3%) of neonates with growth acceleration was LGA and none (0%) of the five anatomic parameters were above their respective normal ranges. Conclusions: Individualized growth assessment methods provide a more comprehensive assessment of growth outcome in twins and detect a decrease in soft-tissue deposition not identifiable with conventional growth assessment procedures. The latter procedures are also less sensitive in the detection of both IUGR and growth acceleration. © 1995 John Wiley & Sons, Inc.

In a previous study, birth weight projections obtained with Rossavik growth models were systematically greater than actual birth weights in triplets but not in singletons. To investigate the cause of this overestimation, average mean percent deviations for head circumference (HC), abdominal circumference (AC), thigh circumference (ThC), and weight (WT) at different times in the third trimester were studied in 13 normal triplet and 20 normal singleton fetuses using individual growth curve standards. Average mean percent deviation values for HC in both singletons and triplets were close to zero throughout the third trimester. Average mean percent deviation values for AC in both singletons and triplets were similar, and remained relatively constant. Average mean percent deviation values for ThC in triplets decreased toward the end of the third trimester, but those for singletons increased. Average mean percent deviation values for estimated weight did not change during the third trimester in singletons whereas those in triplets decreased. The difference in average mean percent deviation values for estimated weight between singletons and triplets in the 32- to 36-week interval was statistically significant. There were no significant differences between actual and predicted measurements for HC in both singletons and triplets at birth. However, actual birth measurements were systematically less than predicted birth measurements for AC and ThC in singletons, and for AC, ThC, and WT for triplets. These systematic differences were significantly larger in triplets for ThC and WT. Nutrition Score values, direct measures of subcutaneous tissue, were significantly lower in triplets compared to singletons. These results suggest that the deposition of soft tissue seen in normal singletons during the third trimester occurs to a much lesser extent in normal triplets.

In groups of normally growing singletons (20), twins (20), and triplets (13), predicted femur diaphysis length (FDL) values at birth were obtained using Rossavik growth models specified from second-trimester ultrasound studies of fetal growth. Six previously published functions were utilized to obtain predicted crown-heel length (CHL) values from predicted FDL values. These values were compared to the actual CHL values and the percent differences calculated. Based on their systematic (mean percent difference) and random (standard deviation of percent difference) prediction errors, the functions of Vintzileos (singletons), Hadlock (twins), and Brown (triplets) were found to give optimal results (no systematic error; random error: +/- 6%). Using predicted CHL values obtained with these optimal functions, growth potential realization index values for CHL (GPRICHL) were determined for singletons, twins, and triplets. In all three groups, the mean GPRICHL value was 100% with a range of approximately 95% to 105%. These results indicate that the CHL can be predicted from second-trimester growth patterns and evaluated using individualized growth assessment methods.

A new growth classification system for triplets based on individual growth curve standards provides new information on the growth status of triplets at birth. OBJECTIVES. The objectives of this study were to characterize growth outcome at birth in triplet pregnancies using Individualized Growth Assessment methods, and to compare these results to conventional methods of growth outcome evaluation. STUDY DESIGN. Rossavik growth models derived from second-trimester ultrasound measurements were used to predict the birth characteristics of 21 triplet neonates. Actual measurements of weight, head, abdominal, and thigh circumferences at birth were compared to population standards and to predicted values, the latter by calculation of Growth Potential Realization Index (GPRI) values. GPRI values were calculated using singleton (measurement procedure correction) and triplet (measurement procedure correction+decreased soft tissue deposition) correction factors (SCF, TCF). Neonatal Growth Assessment Scores (NGAS) were calculated using both sets of GPRI values. RESULTS. Three types of triplet neonates were identified. Group I (33.3%) were normal with both types of NGAS values, had very few abnormal GPRI values or anatomic measurements, and were all appropriate for gestational age. Group III (14.3%) were abnormal with both types of NGAS values, most GPRI values were abnormal, and all were small for gestational age. Group II (52.4%) had abnormal NGAS values when calculated from GPRI values determined with SCF and normal NGAS values when calculated from GPRI values determined with TCF. All but one was AGA. Almost all GPRIWT and GPRIThC values were abnormal using SCF and normal using TCF. CONCLUSION. Although growth outcome in triplet neonates can be normal (Group I) or intrauterine growth retarded (Group III), the majority are in an intermediate group (Group II) characterized by a decrease in soft tissue mass, which may or may not be pathological.

Simple rapid procedures based on salt-solvent pairs have been developed for the isolation of drugs and drug metabolites from urine, plasma, and breast milk. The best overall recovery of drugs (84-104%) was obtained by using ammonium carbonate—ethyl acetate extraction. Internal standards were added to the biological samples before the isolation procedure was begun; standards labeled with stable isotopes were preferred. The isolated drugs were quantitated by selective ion detection, with use of an LKB 9000-PDP 12 in electron impact mode, a Finnigan 1015-PDP 8/1 in chemical ionization mode, and an atmospheric pressure ionization mass spectrometer. Sensitivity of detection was in the nanogram to picogram range.

To characterize the growth of the thigh circumference (ThC) in individual fetuses, longitudinal studies of ThC growth were carried out in 20 fetuses between 19 (+/- 1.8) and 38 (+/- 1.5) weeks, menstrual age. Because of measurement uncertainties, analysis of growth patterns was limited to the data collected after 22 weeks. The Rossavik growth model fit the data well [R2: 95.8(+/- 2.9 SD)%], but considerable coefficient variability was seen, particularly for the coefficient k. Use of the coefficient k-value (1.138) derived from a cross-sectional data set reduced the variability of the coefficient c by 95% and made the results of the longitudinal and cross-sectional studies consistent with each other. This k-value was taken as the appropriate one for ThC growth curves. Studies of ThC growth in individual fetuses revealed considerable variability in growth curve shape, although the majority of curves could be approximated by a straight line. No differences between growth curves for males and females could be detected. The average longitudinal ThC growth curve was found to be very similar to the growth curve obtained in a cross-sectional study of ThC growth. ThC growth after 26.1 weeks could be predicted with an accuracy of +/- 15% from growth models derived from the data obtained before 26.1 weeks. These results indicate that ThC growth after 22 weeks (as with other parameters) can be followed in individual fetuses. However, because of the greater inherent variability in growth patterns, using each fetus as its own control may be more important.

The ability of Rossavik growth models, determined from measurements obtained before 24 weeks, to predict third-trimester growth and birth characteristics in normally growing twins has been investigated. Third-trimester values for head circumference, abdominal circumference, and femur diaphysis length were predicted with an accuracy of +/- 6% to 9% (95% to 98% of percent deviations). For thigh circumference and estimated weight, the comparable values were +/- 15% and +/- 16%, respectively. The head circumference at birth was predicted without bias; the random error was approximately +/- 5% (94% of percent differences). Weight, abdominal circumference, and thigh circumference were systematically overestimated (3.1%, 14.9%, and 11.3%, respectively) as a result of differences in prenatal and postnatal measurement procedures. After correction for systematic errors, these parameters could be predicted with random errors of -11.5% to 7.2% (weight), -12.8% to 5.4% (abdominal circumference), and -15.3% to 10.0% (thigh circumference). Growth Potential Realization Index values were found to have means of approximately 100% and ranges from 91% to 118%. These results are similar to those for singletons and indicate that individual assessment of growth in twins can be carried out with the same methods used for singletons.

Certain drugs in urine, plasma, breast milk, and amniotic fluid have been quantitatively analyzed in the picogram to nanogram range by selective ion detection with two gas chromatograph—mass spectrometer—computer systems: an LKB 9000/PDP 12 operated in the electron impact mode and a Finnigan 1015/PDP 8/I operated in the chemical ionization mode. With the latter system, it is possible to monitor several drugs and drug metabolites and an internal standard in a single temperature-programmed analysis. Internal standards labeled with stable isotopes are preferred for selective ion detection. Diphenylhydantoin-2,4,5-13C has been used to quantify diphenylhydantoin, and pentobarbital-2,4(6) ,5-13C has been used to quantify amobarbital, secobarbital, caffeine, meperidine ("Demerol"), and phenobarbital in 50-200 µl samples of plasma and breast milk.

Procedures have been developed for obtaining urinary steroid profiles for newborn human infants. The GLC profiles contain five steroids which have been identified previously, and numerous steroids which are not yet identified. The method chosen for general use was the separation of the TMSi ethers of steroids obtained by enzymic hydrolysis, or by the Fotherby-Roy method, using a 12 ft 1% SE-30 or OV-1 column. Qualitative and quantitative comparisons can be made for normal infants, for the same infant with increasing age, and for infants with profiles altered by placental transfer of drugs.

The metabolism of 5, 5-diphenylhydantoin was studied in the newborn human in two instances; one involved direct administration of the drug, and the other was by placental transfer of the drug from the mother. 5-(3,4-Dihydroxy-1, 5-cyclohexadien-1-yl)-5-phenylhydantoin was found to be a major metabolite. The GC and GC-MS methods employed here are well suited to the problem of studying drug metabolism in the newborn.

Pharmacokinetic studies involving plasma, urine, breast milk, saliva and liver homogenates have been carried out by selective ion detection with a gas chromatographic-mass spectrometric-computer system operated in the chemical ionization mode. Stable isotope labeled drugs were used as internal standards for quantification. The half-lives, the concentration at zero time, the slope (regression coefficient), the maximum velocity of the reaction and the apparent Michaelis constant of the reaction were determined by regression analysis, and also by graphic means.

Since drugs administered to gravid females are rapidly transferred to the fetus, transplacentally acquired drugs and drug metabolities should be excreted by the fetus into amniotic fluid. Analyses have been carried out on amniotic fluid obtained at the time of delivery using a gas chromatograph-mass spectrometer-computer system. The drugs that have been identified are caffeine, secobarbital and phenobarbital. Theobromine (3,7-dimethylxanthine) and smaller amounts of 1,7- and 1,3-dimethylxanthine, three metabolites of caffeine, were also found in amniotic fluid, but metabolites of secobarbital and phenobarbital were not detected. It is known that human fetal tissues have active enzyme systems for metabolizing drugs, but these results suggest that this may be a selective rather than general occurence.

This investigation has evaluated the ability of Rossavik growth models (derived from data obtained before 26 weeks) to predict birth characteristics in normal fetuses (assuming no growth after 38 weeks). Both weight and head circumference were predicted without systematic errors and the ranges of the random errors were approximately +/- 10% and +/- 5%, respectively. A range of approximately +/- 10% for the random error was also found for the abdominal and thigh circumferences, but both parameters were systematically overestimated (17.3% and 6.4%, respectively). No evidence of a relationship between the percent deviation and age at delivery (up to 41 weeks) was found for any of the parameters studied. As indicators of pregnancy outcome, Growth Potential Realization Index (GPRI) values were calculated for each parameter (predicted values corrected for systematic errors were used for the abdominal and thigh circumferences). Mean GPRI values were not significantly different from 100% and the ranges were approximately 90% to 110% except for the head circumference (range: 95% to 105%). These results indicate that GPRI values can be used to characterize the outcome of prenatal growth processes on an individual basis, with each fetus acting as its own control.

To provide a more detailed assessment of the growth of twins, the individual second trimester growth patterns of six fetal parameters [HC, AC, FDL, ThC, head cube (A) and abdominal cube (B)] were studied in fourteen sets of normal twins (six monozygotic and eight dizygotic) and sixteen normal singletons using the Rossavik growth model [P = c(t)(k + s(t)]. Comparisons of start points and coefficient c values indicated no statistically significant differences in the growth processes of twins and singletons in early pregnancy and no detectable effect of zygocity. Comparisons of second trimester growth within sets of twins and randomly paired singletons revealed the presence of differences in feto-placental support. A significant effect of differences in genetic growth potential or maternal support could not be demonstrated, however. These results suggest that with respect to growth, normal twins in the second trimester can be treated as two singletons in the same mother.

Internal reference compounds labeled with stable isotopes have been used to quantify drugs and drug metabolites in urine, plasma and breast milk. [2,4,5-13C3]Diphenylhydantoin, [2,4,5-13C3]phenobarbital and [1-C2H3]valium have been used to quantify diphenylhydantoin, phenobarbital and valium, respectively; [2,4,5-13C3]pentobarbital has been used to quantify amobarbital, secobarbital, butabarbital and pentobarbital. Analyses have been carried out in the picogram to nanogram range by selective ion detection with two gas chromatograph—mass spectrometer—computer systems. Instrumental measurements with picogram samples have also been made using an atmospheric pressure ionization mass spectrometer.

Benzyloxime-trimethylsilyl (BO-TMSi) derivatives of infant urinary steroids have been prepared and studied by GC and GC-MS techniques. These derivatives were used in a “metabolic profile” procedure which provides a urinary steroid profile in which the hydroxy (H-series) steroids and those containing a reactive ketone group (K-series) are well separated. Distinctive profiles may be obtained in this way. Comparisons may be made for normal infants, for the same infant with increasing age, and for pathologic circumstances.

Quantitative steroid profiles were obtained in fifty-three newborn infants. The excretion of steroids (mg/24 h) did not correlate with birth weight, sex or gestational age. The steroid profiles of individual infants were followed for four months. During this period the profiles changed completely from a profile in which neonatal steroids predominate to a profile composed of metabolites of adrenocortical steroids.

Using microdensitometry, the depletion course of glycogen from the corneal epithelium was measured for periods of oxygen deprivation of up to five hours. Within 30 minutes, glycogen depletion was found to be proceeding at its maximum rate, coming to a minimum stable level, equivalent to diastase depletion, by four hours. Concurrent swelling of the epithelium proceeded more regularly, ie, with less initial acceleration, stabilizing at four hours also.

The mental achievement of 32 infants manifesting IM at birth without evidence of chromosome abnormalities or intrauterine infection have been compared to 13 well nourished (WN) infants. All infants came from a middle to a high socioeconomic background. Selection of patients was made in 1963 so the Colorado Intrauterine Growth Grid was not available. Retrospective plotting of infant weights showed that 41% of the IM infants fell above the 10th percentile. Knobloch-Pasamanick modification of the Gesell test demonstrated statistically lower scores in fine motor ability in the IM infant at 9 months of age. By 3 years of age all subtest scores were statistically lower in the IM infant except gross motor skills. The WPPSI, WISC, & WISC-R phychometric tests were used at older ages. The following findings were observed in the IM infant compared to the WN infant. Full scale IQ 120 7%/38%; educatable mental retardate 19%/0; learning disabilities 34%/15%; non-compensated learning disability 18%/0; specific learning disability 28%/15%; special education 19%/0; seizures beyond the newborn period 13%/8%; language problems 16%/0; significant visual problems 3%/0; medical Rx for hyperactivity 9%/0. Evidence of IM in infants at birth may serve as an important clinical marker for potential learning disability in the infant at an older age. - Work supported by the MacDonald & the Doris Hebbard Knapp Fund

Neural oscillations mediate the coordination of activity within and between brain networks, supporting cognition and behaviour. How these processes develop throughout childhood is not only an important neuroscientific question but could also shed light on the mechanisms underlying neurological and psychiatric disorders. However, measuring the neurodevelopmental trajectory of oscillations has been hampered by confounds from instrumentation. In this paper, we investigate the suitability of a disruptive new imaging platform - Optically Pumped Magnetometer-based magnetoencephalography (OPM-MEG) - to study oscillations during brain development. We show how a unique 192-channel OPM-MEG device, which is adaptable to head size and robust to participant movement, can be used to collect high-fidelity electrophysiological data in individuals aged between 2 and 34 years. Data were collected during a somatosensory task, and we measured both stimulus-induced modulation of beta oscillations in sensory cortex, and whole-brain connectivity, showing that both modulate significantly with age. Moreover, we show that pan-spectral bursts of electrophysiological activity drive task-induced beta modulation, and that their probability of occurrence and spectral content change with age. Our results offer new insights into the developmental trajectory of beta oscillations and provide clear evidence that OPM-MEG is an ideal platform for studying electrophysiology in neurodevelopment., Competing Interests: CONFLICTS OF INTEREST V.S. is the founding director of QuSpin, a commercial entity selling OPM magnetometers. J.O. and C.D. are employees of QuSpin. E.B. and M.J.B. are directors of Cerca Magnetics Limited, a spin-out company whose aim is to commercialise aspects of OPM-MEG technology. E.B., M.J.B., R.B., N.H. and R.H. hold founding equity in Cerca Magnetics Limited. HS, FW, and TH are employees of Cerca Magnetics Limited.