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[Associated anomalies in lip-maxillopalatal clefts].

BACKGROUND: Retrospective studies of cleft lip and palate patients suggest a multifactorial aetiology for this condition. Many patients exhibit multiple defects, often removed from the orofacial region. The frequency and location of such coexistent abnormalities vary between studies. PATIENTS: A retrospective case-note study of 1,737 individuals with orofacial cleft, treated between 1974 and 1998 at our centre, was undertaken to assess the frequency of associated malformations and syndromes. RESULTS: Associated malformations were found to be present in 33% of all cases investigated. In nearly one half of these individuals (48%), defects could be attributed to recognisable syndromes. Patients with isolated palatal clefts (45.6%) and those with bilateral clefts of the lip and palate (35.3%) were particularly well-represented. The following problems were observed relatively frequently: Cerebral anomalies (16%), facial anomalies (14%), heart malformations (15%), anomalies of the extremities (9%) and urogenital tract abnormalities (8%). In contrast, endocrine aberrations were identified sporadically (0.5%). A partial situs inversus was found only in one case. CONCLUSION: As clefts of the lip and palate are frequently associated with additional malformations, the importance of thorough interdisciplinary neonatal screening cannot be over emphasised.

Abnormalities, Multiple↗

Prediction of permanent hearing loss in high-risk preterm infants at term age.

UNLABELLED: The aim of this series was to assess hearing screenings; auditory brainstem responses (ABR), transient evoked otoacoustic emissions (TEOAE) and free field auditory responses (FF) for the prediction of permanent bilateral hearing loss in high-risk preterm infants at term post-conceptional age. A total of 51 preterm infants (gestational age < 34 weeks, birth weight < 1500 g) underwent examinations at term and hearing, speech and neurological development were followed up until a corrected age of 18 months. Significant hearing defects were verified by broader ABR examinations under sedation and by clinical ward observation including responsiveness to sounds and enhancement of hearing using an amplification device. Seven bilateral fails in ABR were found, together with nine bilateral fails in TEOAE and four fails in FF screening at term age. Six preterm infants were later confirmed to have a significant permanent bilateral hearing loss, four of whom had also cerebral palsy. Bilateral failure in ABR screening predicted hearing loss with a sensitivity of 100% and a specificity of 98%, TEOAE with a sensitivity of 50% and a specificity of 84% and in the FF examination at the levels of 50% and 98%, respectively. CONCLUSION: Transient evoked otoacoustic emissions alone seem not to be so applicable to the neonatal screening of hearing in high-risk preterm infants as shown earlier in full-term infants, possibly because a hearing defect may be due to retrocochlear damage. Consequently, auditory brainstem response screening seems to be more suitable for very low birth weight preterm infants.

Deafness↗

Congenital hypothyroidism in Turkey: a retrospective evaluation of 1000 cases.

In this retrospective investigation, 1000 cases of congenital hypothyroidism followed-up in the Pediatric Endocrinology Unit at Hacettepe University Children's Hospital between 1964-1989 were evaluated with respect to age at diagnosis, main complaints, symptoms and physical findings. The mean age at diagnosis was 49.22 months, with 55.4 percent of patients diagnosed after two years of age and only 3.1 percent during the neonatal period. The main complaints of the patients were growth failure (26.7%), inability to speak (21.4%), and inability to walk (18.1%). The physical signs and symptoms most commonly detected by the physician were hypotonia (72%), constipation (66.8%), cretinoid face (64.6%), and macroglossia (64.6%). These results emphasize the necessity for routine neonatal screening programs to be established in Turkey, with the aim of detecting congenital hypothyroidism.

Age Factors↗

Modifying an enzyme immunoassay of immunoreactive trypsinogen to use time-resolved fluorescence.

A coated microtiter-well, enzyme-linked immunometric assay for quantifying immunoreactive trypsinogen in dried blood spots was modified to use time-resolved fluorescence of europium in place of end-point enzymatic color development as the quantification step. The streptavidin-horseradish peroxidase and color development solutions supplied as packaged reagents were replaced by europium-labeled avidin, and the signal was developed with commercially available enhancement solution and read by time-resolved fluorescence. The change of label from enzyme to europium increased the dynamic range of the assay by about 5-fold, reduced the detection limit 10-fold, and halved the intra- and interassay imprecision. The improved analytical precision and stability of the modified assay resulted in a more precise description of the population distribution of immunoreactive trypsinogen values in newborns, showing less variance in the upper centiles. This effect is of paramount importance when using this assay for neonatal screening for cystic fibrosis.

Avidin↗

Cystic fibrosis newborn screening: impact of early screening results on parenting stress.

Newborn screening for cystic fibrosis (CF) is currently available through dried blood analysis for immunoreactive trypsinogen (IRT). The possible parenting stress associated with false-positive results or the early diagnosis of an asymptomatic infant has yet to be systematically addressed. This exploratory study examined levels of parenting stress among mothers of these infants. Results indicated significantly less total parenting stress but greater defensiveness in responding among families of false-positive screened children relative to their healthy comparison families. Parents of children diagnosed with CF through newborn screening did not show significantly higher stress scores than their healthy or "traditionally-diagnosed" CF comparison families. They did however have high frequencies of "at-risk scores" warranting referral based on clinical cut-off levels for Total Parenting Stress scores (45%) and Child Demandingness subscale score (50%). As the possibility for expanding CF neonatal screening to other states is considered, the need for further exploration of psychosocial sequelae affecting parenting will be increasingly important.

Adult↗

[Pre- and postpartum ultrasound examinations for diagnosis of urogenital abnormalities].

BACKGROUND: The aim of the study was to evaluate prenatal and postpartal sonographic investigations to diagnose congenital uropathies. PATIENTS/METHODS: The Mainz birth defect monitoring system, the "Mainzer Model", was launched in 1990. Over a period of five years (1/90 to 1/95) 19,028 newborns underwent postpartal sonographic examination. Anamnestic data including prepartal sonographic examination were collected. According to a defined ultrasound criteria list, ultrasound findings were considered normal in 94.8% of the neonates, 4.4% were defined as requiring a follow-up examination and 0.8% were pathological. In the current study we analyzed patients with pathological findings with their pre- and postpartal sonographic investigations as well as their clinical data (urinary tract infections, operative procedures). RESULTS: In the study group prenatal ultrasonography showed evidence of severe anomalies only in 51 fetuses (32.9%). Surgical correction was required in 39 cases. 20 (51%) have been diagnosed prenatally. 28 patients presented with urinary tract infections. Out of this group only 11 patients have been detected by prenatal ultrasound. CONCLUSION: In conclusion, postnatal ultrasound is more effective to diagnose anomalies of the urinary tract. To prevent complications i.e. urinary tract infections a neonatal screening program would be valuable.

Female↗

Biotinidase deficiency: two cases of very early presentation.

Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks) are described. On admission, both children had severe neurological symptoms. In the first patient, magnetic resonance imaging (MRI) of the brain showed frontal and temporal atrophy, and in the second patient, CT of the brain showed diffuse periventricular hypodensities, particularly in the frontal region. Oral treatment with biotin (15mg and 10mg per day respectively) made all symptoms disappear within a few weeks. On follow-up 13 and 16 months later, both children were still asymptomatic on this treatment. Their psychomotor development was normal. MRI and CT of the brain had normalized. Later, a moderate hearing loss was detected in the first patient. In biotinidase deficiency, early diagnosis and treatment with oral biotin are essential in order to prevent irreversible damage to the central nervous system and early death from metabolic acidosis. Neonatal screening for biotinidase deficiency would fulfil this goal.

Amidohydrolases↗

Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols.

We compare two protocols for newborn screening for cystic fibrosis (CF). The first uses the immunoreactive trypsinogen (IRT) assay with a cutoff of > or = 180 ng/ml and a sweat test to identify CF patients. The second uses the IRT assay with a 100 ng/ml cutoff in conjunction with direct analysis for the delta F508 CF transmembrane conductance regulator (CFTR) mutation in a two-tiered (i.e., IRT/DNA) protocol, followed by a sweat test. We screened 220,865 newborns from Wisconsin for CF, using the IRT protocol identifying 369 infants with an elevated IRT, of whom 46 were found to have CF. Another 7 CF patients were identified who had a false-negative IRT level. The CF incidence in the white population was 1 in 3,431 (carrier incidence of 1 in 30). The IRT protocol had a sensitivity of 87% and a positive predictive value of 12.5%. We subsequently used the IRT/DNA protocol to screen 21,258 infants. Of 518 infants with an IRT level > or = 100 ng/ml, 24 carried at least one copy of the delta F508 CFTR mutation, and 4 of these infants were found to have CF, yielding a positive predictive value for this protocol of 16.7%. Direct comparison of the positive predictive value of the two protocols is not valid, because of the different populations screened. However, had the IRT protocol been used on the IRT/DNA cohort, 50 infants, including the 4 with CF, would have received sweat tests, yielding a positive predictive value of 8%. Because of the small sample size, this positive predictive value is not significantly different from that obtained for the IRT/DNA test. However, from a practical point of view the IRT/DNA approach does decrease considerably the number of sweat tests that must be undertaken. The number of false positives for the IRT protocol (46 in 21,258) is increased significantly compared with that for the IRT/DNA approach (20 in 21,258; P < .001). The incidence of delta F508 carriers detected in cohorts with an elevated IRT level was increased compared with the incidence in the general population. The direct costs for the IRT/DNA approach (100 ng/ml) were $11,374 per CF patient detected, compared with $10,187 per CF patient detected for the IRT protocol. Therefore, we conclude that the IRT/DNA approach to CF newborn screening decreases the number of false-positive subjects contacted, without a significant increase in cost.

Analysis of Variance↗

Bilateral otoacoustic emissions pass in a baby with Mondini deformity and subsequently confirmed profound bilateral hearing loss.

Evoked otoacoustic emissions are well established as a hearing screening technique and are used extensively in paediatric audiology. They are believed to originate from the outer hair cells and can be detected in almost 100% of normally hearing ears; even a mild hearing loss has been shown to abolish otoacoustic emissions. Results are presented of a baby boy born at 29 weeks' gestation requiring 77 days of neonatal care, but experiencing no complications following discharge from the neonatal unit. This child had clear bilateral evoked otoacoustic emissions at almost four months of age, but was subsequently found to have a profound bilateral hearing impairment and absent otoacoustic emissions. Radiological investigations revealed bilateral Mondini dysplasia, and this child has now been implanted with a multi-channel MXM Digisonic cochlear implant. He is progressing well and shows awareness of sound. Approximately 10 previous cases of otoacoustic emissions occurring in profoundly deaf ears have been reported in the literature. Although it is likely that this child's hearing loss was progressive in nature, the authors believe that this is the first reported case of otoacoustic emissions being recorded in the presence of Mondini dysplasia. This raises concerns about the use of neonatal screening in isolation without adequate mechanisms for later identification of hearing impairment, although it is acknowledged that it represents a rare situation.

Child, Preschool↗

Cost analysis: concepts and application.

Public health nurses are increasingly called upon to justify the cost of care or to decide which of two alternative programs is more cost-effective. Cost studies can be complex and difficult to conduct, but an understanding of the basic techniques allows nurses to fully participate in planning, implementing, and evaluating programs that greatly impact the health of the community. This article defines some of the basic terms used in health economics, discusses standard methods of cost analysis, and provides an example of neonatal screening to illustrate methods of describing, measuring, and assigning a value to cost items.

Adrenal Hyperplasia, Congenital↗

Failure to diagnose critical heart malformations in newborns before discharge--an increasing problem?

AIM: To determine what proportion of newborns with critical heart defects are discharged undiagnosed from the maternity ward. METHODS: Data were retrieved retrospectively for infants born in our referral area from 1993 to 2001 and undergoing surgical or catheter-based intervention before 2 mo of age because of critical heart defects. RESULTS: 259 full-term infants had critical heart defects. Duct-dependent systemic circulation was present in 129, duct-dependent pulmonary circulation in 106, and 24 infants were not duct dependent but critically ill. In 51 infants (20%) the heart defect was not suspected before discharge from the maternity ward. Such late detection occurred more often in infants with duct-dependent systemic circulation (30%) and in children with defects that were not duct dependent (38%) than in children with duct-dependent pulmonary circulation (4%) (p<0.001). The proportion detected after discharge from the maternity ward increased from 13% in 1993-1995 and 21% in 1996-1998 to 26% in 1999-2001 (p<0.05). CONCLUSION: Many infants with critical congenital heart defects are not diagnosed before discharge from the neonatal maternity ward. The proportion discharged undiagnosed has increased. Neonatal screening fails mainly in children with duct-dependent systemic circulation.

Diagnostic Errors↗

Assessment of pancreatic function in screened infants with cystic fibrosis.

Previously we have reported that 37% of infants with cystic fibrosis diagnosed by neonatal screening with the dried blood spot immunoreactive trypsin assay have pancreatic sufficiency. However, 34 of the 78 infants had pancreatic function tests an average 2.3 years after diagnosis, thus it was possible that the percentage with neonatal pancreatic sufficiency was underestimated, due to the loss of pancreatic function with time in some infants. To assess this hypothesis we have assessed pancreatic function at the time of diagnosis in a further 20 infants since the completion of the previous study. Results of fecal fat determinations and/or pancreatic stimulation tests indicate that 10 (50%) of these infants have pancreatic sufficiency. Combining these results with those of the previous study, 31 of 64 patients (48%) have pancreatic sufficiency at this early age. We have also monitored the progression of pancreatic disease in the 39 patients with pancreatic sufficiency recognized to date. Eleven have developed pancreatic insufficiency and require enzyme replacement therapy. Five others have shown further improvement of colipase secretion with age. We conclude that the dried blood immunoreactive trypsin screening program for cystic fibrosis does recognize patients with pancreatic sufficiency, and at diagnosis nearly half the patients are in this category. To date, 28% of patients with pancreatic sufficiency have demonstrated a variable decline in pancreatic function with age.

Cystic Fibrosis↗

Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles.

Metabolic profiling of amino acids and acylcarnitines from blood spots by automated electrospray tandem mass spectrometry (ESI-MS/MS) is a powerful diagnostic tool for inborn errors of metabolism. New approaches to sample preparation and data interpretation have helped establish the methodology as a robust, high-throughput neonatal screening method. We introduce an efficient 96-well-microplate batch process for blood-spot sample preparation, with which we can obtain high-quality profiles from 500-1000 samples per day per instrument. A computer-assisted metabolic profiling algorithm automatically flags abnormal profiles. We selected diagnostic parameters for the algorithm by comparing profiles from patients with known metabolic disorders and those from normal newborns. Reference range and cutoff values for the diagnostic parameters were established by measuring either metabolite concentrations or peak ratios of certain metabolite pairs. Rigorous testing of the algorithm demonstrates its outstanding clinical sensitivity in flagging abnormal profiles and its high cumulative specificity.

Algorithms↗

Effect of gender, birth weight and gestational age on serum 17-hydroxyprogesterone concentration and distribution among neonates in Saudi Arabia.

Blood samples from 813 newborns were spotted on to filter paper and the 17-hydroxyprogesterone concentration was measured using the Delfia (R) fluorometric immunoassay. The median, mean, and standard deviation (SD) for the total population were 20, 21 and (11) nmol/L respectively. Males had significantly higher levels than females with median, mean and (SD) of 22, 22 and (12) nmol/L. Similarly, low birth weight babies were found to have significantly higher levels than normal birth weight babies with median, mean and (SD) of 21, 24 (12) nmol/L. Preterm babies were also found to have significantly higher levels than full term babies, with median, mean and (SD) of 25, 29 (16) nmol/L. As experienced elsewhere, those factors should be taken into consideration when considering a cut-off point in any neonatal screening program for congenital adrenal hyperplasia.

17-alpha-Hydroxyprogesterone↗

Transient iodine organification defect in infants with ectopic thyroid glands.

BACKGROUND: Thyroid gland ectopy is the most common cause in infants with congenital hypothyroidism (CH). Its association with iodine organification defect, as suggested by positive perchlorate discharge test (PDT) has been reported. However, whether such an association represents a true or transient defect has not yet been determined. This finding has an important clinical, epidemiological, and genetic implications. OBJECTIVE: To determine the natural history of iodine organification defect in patients with CH caused by thyroid ectopy detected by neonatal screening. DESIGN: Prospective longitudinal study. SETTING: King Khalid University Hospital, Riyadh, Saudi Arabia. PATIENTS AND METHODS: PDT was performed, at the time of diagnosis and follow-up, in infants who showed an enlarged ectopic thyroid gland with a Tc-99m pertechnetate uptake of 2% or more. RESULTS: Of 115 neonates with ectopic thyroid glands, 19 showed an enlarged gland with Tc-99m uptake ranging from 2 to 3.2%. Perchlorate discharge test was performed in 13 of these and was consistent with iodine organification defect in nine. Repeated PDT in seven patients showed normal values. CONCLUSION: The results of the authors' study indicate the transient nature of the iodine organification defect and suggest that a delay in the developmental of synthetic mechanisms occur in the dysgenetic glands.

Choristoma↗

[Complications during the neonatal period can cause visual impairment later in life. Only few of the children were born prematurely--a surprising result of the study].

Forty per cent of children known at our low vision centre at the Department of Ophthalmology, University Hospital, Linköping, Sweden, had been treated in a neonatal ward after birth. Only few of them were born prematurely. Half of the children had an additional neurological handicap. The present neonatal screening program detects most cases of congenital cataract and all cases with retinopathy of prematurity.

Adolescent↗

Screening and diagnosis of beta-ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine.

Dihydropyrimidine dehydrogenase (DHPDase), dihydropyrimidinase (DHPase) and beta-ureidopropionase (betaUPase) are the enzymes that catalyze the first, second, and third steps of the degradation of pyrimidines, respectively. beta-Ureidopropionate (betaUP) and beta-ureidoisobutyrate (betaUIB) are increased in the urine of patients with betaUPase deficiency. The original case in which betaUPase deficiency was discovered by NMR spectroscopy was an 11-month-old patient who presented with hypotonia and dystonic movement. We detected a second but asymptomatic case during a pilot study of neonatal screening with filter-paper urine, urease pretreatment and gas chromatography/mass spectrometry (GC/MS). The urease pretreatment of urine without fractionation resulted in a high recovery of these polar ureide compounds and allowed the highly sensitive GC/MS detection and diagnosis of betaUPase deficiency. betaUP and betaUIB were identified using GC/MS techniques. In the urine of the neonate with betaUPase deficiency, betaUP and betaUIB were persistently increased. Thymine, 5,6-dihydrothymine and 5,6-dihydrouracil were increased only moderately but significantly. It is known that thymine and uracil increase markedly in DHPDase deficiency, and 5,6-dihydrothymine and 5,6-dihydrouracil increase in DHPase deficiency. Therefore, betaUPase deficiency can be differentially diagnosed from the first and second enzyme deficiencies. Application of this specific and sensitive diagnostic procedure will lead to an understanding of the clinical heterogeneity of betaUPase deficiency. Furthermore, the identification of patients with defects in pyrimidine metabolism will enable doctors to avoid cancer chemotherapy with pyrimidine analogues such as 5-fluorouracil, which could be dangerous for these patients.

Amidohydrolases↗

Identification of neonatal hearing impairment: ear-canal measurements of acoustic admittance and reflectance in neonates.

OBJECTIVES: 1) To describe broad bandwidth measurements of acoustic admittance (Y) and energy reflectance (R) in the ear canals of neonates. 2) To describe a means for evaluating when a YR response is valid. 3) To describe the relations between these YR measurements and age, gender, left/right ear, and selected risk factors. DESIGN: YR responses were obtained at four test sites in well babies without risk indicators, well babies with at least one risk indicator, and graduates of neonatal intensive care units. YR responses were measured using a chirp stimulus at moderate levels over a frequency range from 250 to 8000 Hz. The system was calibrated based on measurements in a set of cylindrical tubes. The probe assembly was inserted in the ear canal of the neonate, and customized software was used for data acquisition. RESULTS: YR responses were measured in over 4000 ears, and half of the responses were used in exploratory data analyses. The particular YR variables chosen for analysis were energy reflectance, equivalent volume and acoustic conductance. Based on the view that unduly large negative equivalent volumes at low frequencies were physically impossible, it was concluded that approximately 13% of the YR responses showed evidence of improper probe seal in the ear canal. To test how these outliers influenced the overall pattern of YR responses, analyses were conducted both on the full data set (N = 2081) and the data set excluding outliers (N = 1825). The YR responses averaged over frequency varied with conceptional age (conception to date of test), gender, left/right ear, and selected risk factors; in all cases, significant effects were observed more frequently in the data set excluding outliers. After excluding outliers and controlling for conceptional age effects, the dichotomous risk factors accounting for the greatest variance in the YR responses were, in rank order, cleft lip and palate, aminoglycoside therapy, low birth weight, history of ventilation, and low APGAR scores. In separate analyses, YR responses varied in the first few days after birth. An analysis showed that the use of a YR test criterion to assess the quality of probe seal may help control the false-positive rate in evoked otoacoustic emission testing. CONCLUSIONS: This is the first report of wideband YR responses in neonates. Data were acquired in a few seconds, but the responses are highly sensitive to whether the probe is fully sealed in the ear canal. A real-time acoustic test of probe fit is proposed to better address the probe seal problem. The YR responses provide information on middle-ear status that varies over the neonatal age range and that is sensitive to the presence or absence of risk factors, ear, and gender differences. Thus, a YR test may have potential for use in neonatal screening tests for hearing loss.

Acoustics↗