Altered maturation in brainstem neural conduction in very premature babies with fetal growth restriction.

BACKGROUND: Using maximum length sequence brainstem auditory evoked response (MLS BAER) to study brainstem neural conduction and maturation in fetal growth restriction (FGR) babies born very prematurely and assess the effect of FGR on brainstem neural maturation. METHODS: MLS BAER was recorded and analyzed at a mean 40 week postmenstrual age in babies born at 27-32 week gestation without other major perinatal conditions or problems. The data were compared between babies with FGR (n = 30) and age-matched babies without FGR (n = 34) to define any differences. RESULTS: A notable difference in MLS BAER was found in interpeak intervals between the babies with FGR and those without FGR. The FGR babies manifested significantly shortened I-III interval, moderately prolonged III-V interval, and significantly decreased III-V/I-III interval ratio. The slope of the I-III interval-rate function in FGR babies was moderately decreased, relative to that in the babies without FGR. CONCLUSION: FGR babies born very prematurely are associated with accelerated or precocial neural maturation at caudal brainstem regions, but moderately delayed maturation at rostral brainstem regions. The altered brainstem neural maturation is different from previously reported mildly delayed maturation in FGR babies born less prematurely, and may have important implication for neurodevelopmental outcome. IMPACT: This first MLS BAER study in FGR found that brainstem neural maturation in very premature FGR babies differed from age-matched non-FGR babies. Neural maturation in very premature FGR babies is accelerated or precocial at caudal brainstem regions but moderately delayed at rostral brainstem regions. The altered maturation is different from previously reported mild delay in brainstem neural maturation in FGR babies born less prematurely. FGR exerts a major and differential effect on brainstem neural maturation in babies born very prematurely. This alteration in very premature FGR babies may have important implication for their neurodevelopment.

Brainstem auditory pathway function at four months of corrected postnatal age in preterm infants born below 30 week gestation.

OBJECTIVE: Functional status of the brainstem auditory pathway was examined at four months of corrected postnatal age in infants born below 30 week gestation to assess the effect of very or extremely preterm birth on postnatal development of the pathway. METHODS: Thirty-four preterm infants born at 24-29 week gestation (GA24-29w) were studied at four months of corrected postnatal age. Normal controls were 38 postnatal age-matched term infants. Maximum length sequence brainstem auditory evoked response (MLS BAER) were recorded and analysed with 60 dB nHL clicks. RESULTS: Compared with term control group, GA24-29w group manifested higher BAER threshold (p < 0.05), longer MLS BAER wave latencies at all click rates 91-910/s (p < 0.01-0.001), and lower wave amplitudes at most click rates (p < 0.05-0.01). No significant differences were found between the two groups in I-V interval at any click rates. I-III interval was shorter while III-V interval was longer in GA24-29w group than in term group at higher rates (all p < 0.05). III-V/I-III interval ratio in GA24-29w group was greater at 455 and 910/s clicks (p < 0.05 and 0.01). These interval variables showed similar changes when 4 GA24-29w infants with threshold elevation were excluded. CONCLUSIONS: At four months of corrected postnatal age, infants born below 30 week gestation manifested elevated BAER threshold, increased wave latencies, and reduced amplitude. They also manifested a small decrease in I-III interval but a small increase in III-V interval at high rates. Very or extremely preterm birth exerts a mild or moderate effect on postnatal development of the brainstem auditory pathway.

Pregnancy induced hypertension and outcomes in early and moderate preterm infants.

OBJECTIVE: To identify the effect of pregnancy induced hypertension on neonatal outcomes in early and moderate preterm infants of gestational age less than 34 weeks. STUDY DESIGN: Prospectively collected data in 773 premature deliveries less than 34 weeks from 10 centers in China between July 2014 and July 2016 were analyzed in this cohort study. Univariate and Multivariate regression analyses were conducted to exam the effect of pregnancy induced hypertension on neonatal outcomes, including mortality to discharge, intrauterine growth restriction, severe brain injury, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, early onset of sepsis and retinopathy of prematurity. RESULTS: The incidence of PIH in this cohort was 18.4%. Women with PIH tended to have a higher cesarean delivery rate (78.2% vs 40.9%, P < 0.001). More tocolytics and magnesium sulfate were used in PIH women (72.5% vs 48.7%, P < 0.001; 59.2% vs 34.7%, P < 0.001). Mean birth weight was lower in infants of PIH mothers than infants of non-PIH mothers (1522.1 ±â€¯348.8 g vs 1683.4 ±â€¯345.3, P < 0.001). In multivariate regression models, PIH was associated with increased risk of IUGR (OR 8.402; 95% CI 4.350-16.227) and lower odds of NRDS (OR 0.526; 95% CI 0.332-0.853). CONCLUSION: Preterm infants less than 34 weeks born to PIH women had a higher risk of intrauterine growth restriction and lower birth weight. PIH warrants more intensive interventions to prevent relevant infant morbidities.

Reduced wave amplitudes of brainstem auditory response in high-risk babies born at 28-32week gestation.

OBJECTIVE: To examine brainstem auditory electrophysiology in high-risk babies born at 28-32week gestation by analysing the amplitudes of wave components in maximum length sequence brainstem auditory evoked response (MLS BAER). METHODS: 94 preterm babies, ranging in gestation 28-32weeks, with perinatal problems (high-risk) were recruited. The amplitudes of MLS BAER wave components were studied at term age (37-42weeks postconceptional age). RESULTS: Compared with normal term controls, the amplitude in the high-risk preterm babies was significantly smaller at the highest click rate 910/s for wave I (p<0.01), at all 91-910/s for wave III (all p<0.01) and at 455 and 910/s (p<0.05 and 0.01) for wave V. Compared with age-matched low-risk preterm controls, the amplitude was significantly smaller at 455 and 910/s for wave I (p<0.05 and 0.05), 91-910/s for wave III (p<0.05-0.001), and 227-910/s (p<0.05 and 0.01) for wave V. No differences in the V/I and V/III amplitude ratios were found between the high-risk preterm babies and the controls. CONCLUSIONS: The amplitudes of MLS BAER wave components, mainly more central components, were reduced in the high-risk preterm babies born at 28-32week gestation. Electrophysiological activity of the brainstem auditory neuron in such babies is depressed, mainly attributed to or related to the associated perinatal problems.

Cordblood-Based High-Throughput Screening for Deafness Gene of 646 Newborns in Jinan Area of China.

OBJECTIVES: Infants with slight/mild or late-onset hearing impairment might be missed in universal newborn hearing screening (UNHS). We identified the mutation hot spot of common deaf gene in the newborns in Jinan area population by screening the mutation spot with neonate cord blood, in order to make clear whether the neonate cord blood for screening is feasible. METHODS: Six hundred and forty-six newborns were subjected to both UNHS and genetic screening for deafness by using neonate cord blood. The newborn genetic screening targeted four deafness-associated genes, which were commonly found in the Chinese population including gap junction beta-2 protein (GJB2), gap junction beta-3 protein (GJB3), solute carrier family 26 member 4 (SLC26A4), and mtDNA 12S rRNA. The most common 20 spot mutations in 4 deaf genes were detected by MassARRAY iPLEX platform and mitochondrial 12S rRNA A1555G and C1494T mutations were sequenced using Sanger sequencing. RESULTS: Among the 646 newborns, 635 cases passed the UNHS and the other 11 cases (1.7%) did not. Of the 11 failures, two cases were found to carry homozygous GJB2 p.R143W pathogenic mutation, one case was found to have heterozygous GJB2 235delC mutation, and another one case carried heterozygous GJB3 p.R180X pathogenic mutation. Six hundred and thirty-five babies passed the newborn hearing screening, in which 25 babies were identified to carry pathogenic mutations, including 12 heterozygotes (1.9%) for GJB2 235delC, eight heterozygotes (1.3%) for SLC26A4 IVS7-2A>G, one heterozygote (0.2%) for p.R409H, two homozygotes (0.3%) for m.1494C>T, and two homozygotes (0.3%) for m.1555A>G. CONCLUSION: Newborn genetic screening through the umbilical cord blood for common deafness-associated mutations may identify carriers sensitive to aminoglycoside antibiotic, and can effectively prevent or delay hearing loss occurs.

[Effect of pulmonary surfactant on Th1/Th2 balance in neonates with respiratory distress syndrome].

OBJECTIVE: To investigate the effect of pulmonary surfactant (PS) on the Th1/Th2 balance and serum levels of interleukin-4 (IL-4), interferon-γ (IFN-γ) and IgE in neonates with respiratory distress syndrome (RDS). METHODS: A total of 58 neonates with RDS were divided into control (n=20) and PS treatment groups (n=38). The control group underwent mechanical ventilation and other conventional treatment, while the PS treatment group received with bovine PS treatment within 1 hour of being admitted to the hospital together with mechanical ventilation and other conventional treatment. Enzyme-linked immunosorbent assay was used to measure serum levels of IL-4, IFN-γ and IgE before treatment and 24, 48 and 72 hours after treatment. Simultaneously, arterial blood gas, respiratory system compliance, and other ventilator parameters were recorded. RESULTS: Compared with the control group, the PS treatment group showed significantly shorter duration of mechanical ventilation and oxygen exposure time (P<0.05), significantly better respiratory system compliance and significantly lower oxygenation index 24, 48 and 72 hours after treatment (P<0.05). At 48 and 72 hours after treatment, serum levels of IFN-γ were significantly lower in the PS treatment group than in the control group (120±46 ng/L vs 229±59 ng/L, P<0.05; 141±40 ng/L vs 282±44 ng/L, P<0.05), and serum levels of IL-4 were significantly higher in the PS treatment group than in the control group (263±48 pg/mL vs 152±45 pg/mL, P<0.05; 417±49 pg/mL vs 201±46 pg/mL, P<0.05). At 72 hours after treatment, serum level of IgE was significantly lower in the PS treatment group than in the control group (115±44 pg/mL vs 199±43 ng/mL; P<0.05). CONCLUSIONS: PS treatment can shorten the duration of mechanical ventilation and oxygen exposure time, regulate serum levels of IFN-γ, IL-4 and IgE, and influence Th1/Th2 balance in neonates with RDS, thus inhibiting lung inflammatory response and reducing lung injury.

[Clinical features and genotype-phenotype studies of 89 Chinese patients with X-linked adrenoleukodystrophy].

OBJECTIVE: X-linked adrenoleukodystrophy (X-ALD) is the most common inherited disorder of peroxisomal metabolism which is characterized by demyelination of central nervous system, impaired adrenal cortex and abnormal accumulation of very long chain fatty acids in body fluid and tissues. In this study, the clinical features and the genotype-phenotype relationship were investigated so as to help early diagnosis. METHODS: Clinical data of 89 Chinese patients with X-ALD were analyzed and mutation spectrums in 53 of the patients were investigated by polymerase chain reaction and DNA sequencing. RESULTS: Of the 89 cases, 60 (67.4%) had childhood cerebral ALD (CCALD, mean age of onset was 6.5 years, range 2 - 10 years), 18 (20.2%) had adolescent cerebral ALD (ACALD, mean age of onset 12.1 years, range 11 - 19 years), 7 (7.9%) had adrenomyeloneuropathy (AMN, mean age of onset 23 years, range 6 - 39.5 years), and two cases were asymptomatic and another 2 had simple Addison's disease only. CCALD was the most common and severe phenotype, visual impairment was the most common initial symptom in CCALD and ACALD patients. Twenty four cases (63%) in whom hydrocortisone and ACTH were measured showed adrenal insufficiency. Forty five different mutations were identified in 53 patients. Missense mutations were the most common. No hotspot mutation was found in these patients and 1415delAG, the most frequent mutation found worldwide seemed not to be the real "hotspot" in these Chinese patients. The same phenotype may be due to diverse genomic mutations. A single mutation may result in different phenotypes even within a family. CONCLUSION: The phenotype distribution, initial symptom and gene mutation spectrum of Chinese patients may not be completely consistent with those in other countries. The clinical phenotype of the disease had no definite relationship with the nature of gene mutations.

[Prenatal diagnosis of X-linked adrenoleukodystrophy].

OBJECTIVE: To make prenatal dignosis of X-linked adrenoleukodystrophy (ALD) for the prevention of the disease. METHODS: Eighteen amniocenteses were performed on 17 suspected carriers of X-ALD during 18-30 gestation weeks. The very long chain fatty acids (VLCFAs) levels of cultured amniocytes were tested by gas chromatography-mass spectrometry (GC/MS). The plasma VLCFAs levels were measured in 8 of the 18 prenatal diagnosed children when they were born or after abortion. ABCD1 gene mutation analysis was carried out in 8 cases by PCR and sequencing. ALDP of amniocytes was tested by Western blotting in 2 cases from a family, one female, another male, and the VLCFAs of cultured amniocytes were increased in both of them. RESULTS: Among the 18 fetuses, 10 were males and 8 were females. The VLCFAs levels of the cultured amniocytes were increased in 3 males and 4 females. The postnatal plasma VLCFAs were normal in 5 cases with normal VLCFAs levels of amniocytes, and increased in 3 cases with high VLCFAs levels of amniocytes. ABCD1 gene mutations were found in 4 cases with high VLCFAs levels of amniocytes, no mutation was found in other 4 cases with normal VLCFAs levels of amniocytes. ALDP of amniocytes could be detected in the female with high VLCFAs levels of amniocytes, and it could not be detected in the male with high VLCFAs levels of amniocytes. Three male fetuses with high VLCFAs levels of amniocytes were aborted. The others who were born were normal clinically so far. CONCLUSION: The prenatal diagnosis is very important for the prevention of ALD. Amniocyte VLCFAs level analysis combined with ABCD1 gene mutation analysis and ALDP test could make a proper prenatal diagnosis.

The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy (X-ALD).

OBJECTIVE: To elucidate the phenotype and the genotype-phenotype correlations in Chinese patients with X-linked adrenoleukodystrophy (X-ALD). METHODS: Clinical features of 40 Chinese patients with X-ALD were studied and mutation spectrums were investigated by polymerase chain reaction (PCR) and sequencing. RESULTS: Among these patients, four were siblings from two unrelated families, the others were unrelated. There were 31 cases with childhood cerebral (CCALD), 8 cases with adolescent cerebral (ACALD) and 1 case with adrenomyeloneuropathy (AMN). Visual impairment, which presented in 12 cases (30%), was the most common initial symptom. Nine (69%) of 13 cases who had hydrocortisone and ACTH measured showed adrenal insufficiency. By follow-up date, 19 cases (47.5%) were dead. The interval from onset to death varied from 1 to 6 years and the average were 3.3 years. The mean age at death was 10.5 years. Eleven cases (27.5%) were in vegetable state. The mean interval from onset to apparently vegetable state was 2.8 years (range from 1 to 6 years). Four cases had progressive neurological disability. Four cases were lost follow-up. One case with CCALD and one case with ACALD progressed slowly. The courses of the disease of these two patients were 5 years and 15 years respectively. Thirty five mutations were identified in 40 cases. Most were located within exon 1-3 (40%, 16/40) and exon 6-8 (42%, 17/40). There is a distinct clustering of missense mutations in exon 6 (17%, 7/40). Five types of mutations were associated with CCALD, three with ACALD and a missense mutation was identified in the patients with AMN. The two patients with long disease courses had a missense mutation c.1559 T>A and a nonsense mutation c.1785 G>A respectively. The siblings with similar manifestations and onset age were observed in two families, whose mutations were c.887 A>G and c.1028 G>T. CONCLUSION: The phenotypes, disease severity and rate of neurodegeneration could not be predicted by the nature of mutations.