Can the CHOP-INTEND be used as An Outcome Measure in the First Months of Age? Implications for Clinical Trials and Real World Data.

BACKGROUND: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. OBJECTIVE: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. METHODS: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. RESULTS: our study includes 61 assessments collected < 2 weeks, 25 at 2-4 weeks, 20 at 5-8 weeks, 25 at 9-12 weeks and 20 at 13-17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. CONCLUSIONS: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects.

Assessing floppy infants: a new module.

Our aim was to develop a new module for assessing the floppy infant, to describe the application of the module in a cohort of low-risk newborns and piloting the module in a cohort of floppy infants. The module was applied to a cohort of 143 low-risk newborns and piloted in in a cohort of 24 floppy infants. The new add-on module includes a neurological section and provides a section for recording information obtained by physical examination and antenatal history. For each item, column 1 reports abnormal findings, column 3 normal findings, and column 2 intermediate signs to be followed. Consistent with previous studies, in low-risk infants, none had definitely abnormal or mildly abnormal signs, with the exception of tendon reflexes that were not easily elicitable in 17.14% of term-born infants. CONCLUSION: Our study suggest that the module can be easily used in a clinical setting as an add-on to the regular neonatal neurological examination in newborns identified as hypotonic on routine examination. Larger cohorts are needed to establish the accuracy of the prognostic value of the module in the differential diagnosis of floppy infant. WHAT IS KNOWN: • Hypotonia is one of the key signs in newborns with neuromuscular disorders and can be associated with a wide range of other conditions (central nervous system involvement, genetic and metabolic diseases). • Weakness or/and contractures can identify infants with a neuromuscular disorder and help in the differential diagnosis of floppy infants. WHAT IS NEW: • To date, this is the first attempt to develop and apply a specific neurological module for the assessment of the floppy infant. • The module can be used in a routine clinical setting as an add-on to the regular neurological examination and has potential to differentiate the floppy infants from the low-risk infants.

Spyramicine and Trimethoprim-Sulfamethoxazole Combination to Prevent Mother-To-Fetus Transmission of Toxoplasma gondii Infection in Pregnant Women: A 28-Years Single-center Experience.

BACKGROUND: There is weak evidence on the best treatment of pregnant women with Toxoplasma gondii infection to prevent the vertical transmission to the fetus. METHODS: We conducted a 28-year retrospective study aiming to compare the efficacy of three therapeutic regimens [Spiramicyn alone (Spy) vs. Pyrimethamine-Sulfadiazine (P/S) vs. Spiramicyn with Trimethoprim-Sulfamethoxazole (Spy+TMP-SMX)] for the prevention of mother-to-fetus transmission of T. gondii infection. RESULTS: 170 women were included: 58 (34.1%) had certain congenital toxoplasmosis (CT), 61 (35.9%) a probable infection and 41 (24.1%) possible infection. In total 97 mothers (57.1%) were treated with the Spy+TMP-SMX combination, 64 mothers (37.6%) were treated with Spy only and 8 mothers (4.7%) with P/S. Infected infants were 20/170 (11.7%). However, 8.2% (8/97) of infants born to mothers treated with Spy+TMP-SMX were infected, 20% (11/55) of infants born to women treated with Spy and 12.5% (1/8) of infants born to mothers treated with P/S were infected. Logistic regression analysis demonstrated that Spy treatment alone was associated with an increased risk of CT compared to the Spy+TMP-SMX combination (OR, 2.78, 95% CI 1.04-7.41, P value 0.041). No difference was observed when the Spy+TMP-SMX was compared with the P/S combination (OR 1.59; 95% CI 0.17 - 14.58; P value 0.682). Results were confirmed when the analyses were corrected by trimester of infection and by type of maternal treatment (OR 7.72; 95% CI 3.40-17.53, P value <0.001). CONCLUSIONS: The combination of Spy+TMP-SMX may be more effective in reducing the risk of maternal-fetal transmission of Toxoplasmosis compared to Spy alone; furthermore, this combination is not inferior to P/S, the current international standard-of-care maternal treatment for the prevention of CT. A prospective trial comparing the combination Spy+TMP-SMX with P/S would be necessary to provide definitive evidence on the best regimen for pregnant women with T. gondii infection.

Long-Term Clinical, Audiological, Visual, Neurocognitive and Behavioral Outcome in Children With Symptomatic and Asymptomatic Congenital Cytomegalovirus Infection Treated With Valganciclovir.

Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. There are no enough data on long-term outcome of newborns with congenital CMV (cCMV) infection, particularly for those asymptomatic at birth. For this reason, we performed this study to evaluate long-term audiological, visual, neurocognitive, and behavioral outcome in patients with symptomatic and asymptomatic cCMV infection treated with oral Valganciclovir (VGC). Thirty-six newborns with confirmed cCMV infection were evaluated: 12 (33.3%) symptomatic at birth and 24 asymptomatic (66.7%). No one had cognitive impairment. Cognitive assessment scales resulted abnormal in 4/35 patients (11.4%). 11/21 patients (52.4%) achieved abnormal scores in neuropsychological tests. The language evaluation gave pathological results in 6/21 (28.5%) patients. 6/35 patients (17.1%) developed SNHL, all symptomatic at birth except one. None of the 34 patients evaluated developed CMV retinopathy. Our study shows that both symptomatic and asymptomatic newborns with cCMV infection develop long-term sequelae, particularly in the behavioral and communicative areas, independently from the trimester of maternal infection.

Correction to: Unexpected tracheal agenesis with prenatal diagnosis of aortic coarctation, lung hyperecogenicity and polyhydramnios: a case report.

An amendment to this paper has been published and can be accessed via the original article.

Unexpected tracheal agenesis with prenatal diagnosis of aortic coarctation, lung hyperecogenicity and polyhydramnios: a case report.

BACKGROUND: Tracheal agenesis (TA) is a rare disorder usually diagnosed prenatally when a congenital high airway obstruction syndrome (CHAOS) is identified. We present a case of unexpected TA in a neonate without prenatal diagnosis of airway obstruction, with a difficult management at birth. Moreover, we discuss about differential diagnosis, classification and treatment issues. CASE PRESENTATION: A 2280 g female neonate was born at 35 week gestational age (GA) with prenatal diagnosis of aortic coarctation, polyhydramnios and diffuse hyperechogenicity of the right lung. At birth, the neonate had no audible cry, no air entry to the lungs, and hypotonia. Tracheal intubation was unsuccessful, and no visualization of the trachea was obtained when tracheostomy was attempted. Post-mortem examination showed tracheal agenesis associated with tracheoesophageal fistula and revealed no cardiologic malformations. Aortic coarctation had been suspected prenatally because of the first portion of the descendent thoracic aorta being compressed by a fibrous band connecting the proximal and distal tracheal branches. CHAOS had not developed due to the tracheoesophageal fistula (TOF). CONCLUSIONS: TA is not always diagnosed in the fetus and it may present unexpectedly making the neonate's management at birth critical. An effective rescue temporary oxygenation may be obtained with mask ventilation or oesophageal intubation in those cases of TA associated with a TOF. We suggest to consider a fetal magnetic resonance imaging (MRI) when the association polyhydramnios/lung hyperechogenicity occurs, even in the absence of CHAOS or other malformations. Once a diagnosis is provided, the mother should be transferred to selected centres where an ex-utero intrapartum procedure (EXIT) can be attempted. Moreover, despite high mortality, different surgical management are described to improve survival.

Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature.

Neonatal Lupus Syndrome (NLS) is a distinct clinical entity caused by transplacental passage of maternal anti-SSA/Ro antibodies (Ab). Mothers may have systemic lupus erythematosus, Sjögren syndrome, or other connective tissue disease, or may be completely healthy at the time of giving birth. NLS includes several clinical manifestations: complete congenital heart block (CCHB) and cutaneous lupus are the most common, while hepatobiliary disease, hematological manifestations and central nervous system involvement may occur. Data from literature on the incidence of the different clinical manifestations of NLS are difficult to compare because they come mostly from retrospective studies or prospective studies, but up to date no systematic follow-up was carried out. We performed a large prospective single-center study with a systematic clinical and instrumental follow-up until 9months of life, in order to evaluate the incidence and the clinical impact of NLS features. From 2004 to 2014 all infants born in our center to mothers with anti-SSA/Ro Ab were enrolled in a specific diagnostic and follow-up (FU) program. At birth, 50 infants born to mothers with anti-SSA/Ro Ab were found positive for anti-SSA/Ro Ab. Infants were tested for anti SSA/Ro Ab at 3months of life, if positive they were re-tested at 6 and 9months. At 9months anti-SSA/Ro Ab were positive in 10% of children. In two cases (4%) a CCHB was identified during pregnancy and required pacemaker implantation at birth. In 10% of cases a transient ECG alterations was found during follow-up. Hematological NLS features (anemia, neutropenia, thrombocytopenia) were found at birth and during FU in several patients, in all cases without clinical manifestations and in most cases with complete normalization at 9months. Mild and transient elevation of aminotransferases between 3 and 6months of life were found in 56% and 40% of patient, respectively; non-specific ultrasound cerebral anomalies in absence of clinical neurological signs were found at birth in 9 patients (18%), subsequently normalized. Prenatal maternal screening is of primary importance in order to early detect CCHB, which requires maternal treatment and pacemaker implantation at birth. Infants born to mothers with anti-SSA/Ro Ab should be monitored for all NLS features at birth. However, during the first months of life, these infants seem to develop only mild, transient and self-limited clinical manifestations, which in most cases are completely solved at 9months of life. This consideration, together with the evidence that only 10% of infants had anti-SSA/Ro Ab persistent in blood at 9months, suggests that follow-up of these children can be performed until 6-9months of life with good clinical safety. Moreover, a clinical and laboratory monitoring at 3months of life, when the highest incidence of hematological features and liver tests alterations are observed, is strongly recommended. In the future, it would be clarified if a follow-up until adulthood would be indicated in cases with persistent anti SSA/Ro or in all infants born to mother with anti SSA/Ro.

Neonatal neurological examination of late preterm babies.

BACKGROUNDS: Healthy late-preterm (LP) infants examined at term equivalent age showed wider median and range of neurological scores than full-term infants; differences between infants born at 34 and those born at 35-36 weeks were also observed. AIMS: The aim of this study is to establish the range and frequency distribution of neonatal neurological scores in a cohort of low risk LP infants assessed during the first 3 days from birth. STUDY DESIGN AND SUBJECTS: 118 low-risk infants born between 34 and 36 weeks of gestational age (GA) were assessed between 48 and 72 h from birth. OUTCOME MEASURES: The full version of the Hammersmith Neonatal Neurologic Assessment and the screening proforma were used to assess all the infants. The raw scores obtained were compared to those of full-term infants using the same examination. RESULTS: The distribution of neurological scores was similar among the 3 GAs for 26 items, with different median scores among LP infants born at 36 weeks and those born at 34 and 35 in only 2 items. LP infants showed a wider range of findings for each item than that of full term infants assessed soon after birth. Using the screening proforma, in our cohort, for each item the findings falling outside the 90% level were identical to those found in term-born and very preterm infants assessed at term age. CONCLUSIONS: The neurological scores obtained in our cohort could help as reference data when examining LP infants at birth compared to age matched low risk infants.

Is growth-discordance in twins a substantial risk factor in adverse neonatal outcomes?

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.

Neonatal outcome in hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders in pregnancy account for increased perinatal morbidity and mortality when compared to uneventful gestations. AIMS: To analyze perinatal outcome of pregnancies complicated by different kinds of hypertension to uncomplicated pregnancies in a series of Italian women and to compare our data with series from other countries. STUDY DESIGN: The sample was divided into four groups of hypertensive women: chronic hypertension (CH), gestational hypertension (GH), preeclampsia (PE), and chronic hypertension complicated by preeclampsia (CHPE). One thousand normal pregnancies served as controls. SUBJECTS: Neonatal features of the offspring of 965 Italian women with hypertension in pregnancy were evaluated. MEASURES: Gestational age, birthweight and the rate of small for gestational age were the outcomes. Perinatal asphyxia and mortality were also assessed. RESULTS: Gestational age, the mean of birth weight and birth percentile were significantly lower in all groups with hypertensive complications when compared with controls. The rate of very early preterm delivery (<32 weeks) was 7.8% in CH, 5.9% in GH, 21.2% in PE and 37.2% in CHPE while it was to 1.2% in the control group. The rate of SGA was globally 16.2% in CH, 22.8% in GH, 50.7% in PE, 37.2% in CHPE and 5% in controls. The rate of SGA in PE was much higher than reported in series from other countries. CONCLUSION: Comparing our data with those reported from other countries, it is evident that the rate of fetal growth restriction in PE we found in our center, is significantly higher even in the presence of a global lower incidence of PE.

Visual, motor and perceptual abilities at school age in children with isolated mild antenatal ventricular dilatation.

BACKGROUND: The detection of prenatal ventriculomegaly raises anxiety about possible neurological sequelae. A few studies have investigated possible neurodevelopmental sequelae in the first years after birth but no systematic assessment has been performed at school age. AIMS: The aim of this study was to assess minor neurological signs, perceptual and visual function in a cohort of children with isolated mild antenatal ventricular dilatation examined at school age. STUDY DESIGN: Seventeen children with evidence of mild antenatal ventriculomegaly in the second and third trimester of pregnancy were included in the study. OUTCOME MEASURES: Children were assessed at school age (range 5 years 3 months-11 years, 11 months) using a structured neurological examination for minor neurological signs and age specific tests assessing perceptual motor abilities (Developmental Test of Visual-Motor Integration; Movement Assessment Battery for Children). RESULTS: Only one of the 17 children had abnormal results. The remaining 16 had normal results on all the tests, irrespective of the magnitude and the symmetry of the dilatation or of its evolution on neonatal scan. CONCLUSIONS: Our results suggest that children who had mild isolated prenatal ventricular dilatation are unlikely to develop even minor motor or perceptual difficulties at school age.

A severe case of intracranial hemorrhage due to alloimmune thrombocytopenia.

Alloimmune thrombocytopenia (AIT) is an important cause of intrauterine hemorrhagic lesions that result from platelet-antigen incompatibility between mother and foetus. Foetal platelets are destroyed by cross-reactive maternal antibodies that cross the placenta. The most serious complication of AIT is foetal intracranial bleeding that may eventually result in intrauterine death or severe neurological impairments.

Neurological examination of preterm infants at term equivalent age.

BACKGROUND: We previously reported the neurological findings of the Dubowitz neonatal examination in a cohort of 157 low-risk preterms born between 25 and 33 weeks gestational age (GA) and examined at term equivalent age (TEA). Median and range of scores were wider than those found in term-born infants and preterms showed a different neurological behaviour in specific items. However, the cohort number was too small to draw any definitive conclusion about the distribution of findings. AIMS: We provide normative data from a low-risk cohort of 380 preterm infants; we also assess the findings and their relationship to motor outcome in preterms with major cranial ultrasound (US) abnormality. STUDY DESIGN: We assessed, at TEA, 380 low-risk preterms born <35 weeks gestation (range 25-34.9, median 29) with normal 2 year motor outcome and 85 preterm infants with major US abnormality. RESULTS: At TEA low-risk preterms had less flexor limb tone, poorer head control but better visual following than term-born infants. For 28/34 of the neurological items the range and median scores were similar across gestational ages. In infants with major US lesions the range and median scores differed from low-risk preterms in 20/34 items; 40% of infants developing a diplegia and 80% developing a tetraplegia had >7 items outside the 90th centile; all infants with >12 items outside the 90th centile developed a tetraplegia. CONCLUSIONS: We provide reference values for the neurological examination of low-risk preterms at TEA. In infants with major US abnormality the number of items outside the 90th centile was an indicator of outcome severity.

Infants born to mothers with anti-SSA/Ro autoantibodies: neonatal outcome and follow-up.

Neonatal lupus syndrome is considered a model of passively acquired autoimmune disease. The first 10 newborns born to mothers with connective tissue disease and positive for anti-SSA/Ro antibodies enrolled in a follow-up program to evaluate the incidence of cardiac, hepatobiliary, hematologic, echoencephalographic, and cutaneous manifestations until 9 months of age are described in this study. No congenital heart block was observed, but only transient rhythm alterations were observed. In all, 1 infant showed typical neonatal lupus syndrome skin lesions at 3 months of age. During the neonatal period, echoencephalographic alterations were found more frequently, whereas at follow-up, hepatic and hematologic alterations were more often observed. In all, 1 baby showed persistent neutropenia. A standard program that enrolls all infants born to mothers with anti-SSA/Ro autoantibodies, who are at risk of developing neonatal lupus syndrome, should also include tests performed some time after birth, as a number of clinical manifestations might appear at a late stage.

Visual development in infants with prenatal post-haemorrhagic ventricular dilatation.

OBJECTIVE: The aim of this study was to assess visual function in 13 infants with evidence of prenatal post haemorrhagic ventricular dilatation. DESIGN: Infants were assessed at 5, 12 and 24 months using a battery of tests specifically designed to assess various aspects of visual function in infancy. Visual findings were correlated with several variables, including extent of the lesion and presence of epilepsy. RESULTS AND CONCLUSIONS: Abnormalities of visual function were frequent (over 60%) in our cohort at age 2 years, ranging from isolated abnormal ocular movements to severe abnormalities of all the aspects of visual function assessed. The most severe and persistent abnormalities of visual function were found in infants with grade IV intraventricular haemorrhage and shunted hydrocephalus who also had epilepsy in the first year.

Thalamic atrophy in infants with PVL and cerebral visual impairment.

The aim of this retrospective study was to establish the presence and severity of cerebral visual impairment in preterm infants with PVL. We also wished to establish whether abnormalities of visual function are related to brain MRI findings and more specifically not only to the involvement of optic radiations and occipital cortex but also to changes in the thalami, that are often affected in infants with PVL. Twelve infants with cystic PVL were assessed at 1 year (+2) corrected age with a battery of tests specifically designed to assess various aspects of visual function in infancy, such as ocular movements, visual acuity, visual fields and fixation shift. All infants also had a brain MRI. Eleven of the 12 had involvement of the optic radiations: all had some abnormalities of visual function and visual impairment was more severe in infants with more extensive involvement of the optic radiations. The child with normal optic radiations had normal visual function. Six of the 12 infants also had obvious signs of atrophy of the thalami and all had severe and wide-ranging abnormalities of visual function in all testing domains. Two children had equivocal atrophy of the thalami, both had some abnormalities of visual function. Four children had normal thalami and had normal visual function or only minor abnormalities on one of the visual tests. Our results suggest that the atrophy of the thalami may play an additional role in the abnormal development of visual function in infants with PVL and abnormal optic radiations.

Prognostic value of EEG performed at term age in preterm infants.

RATIONALE: Electroencephalography (EEG) was performed at term age on 32 infants born prematurely (25-32 weeks). EEG was assessed looking for overall background activity and transients. METHODS: A quantitative analysis was performed, selecting 5-min epochs of "tracé alternant" free of artefacts during quiet sleep. EEG findings were compared with cranial ultrasound (US) findings at term age and with neurodevelopmental outcome at 2 years (Student's t-test). RESULTS: The overall EEG background activity was not always related to the outcome or to the severity of cranial US. Infants with normal US and normal outcome had longer synchrony percentage of bursts, longer maximum duration of bursts and shorter mean of abnormal transients per interbursts than children with major lesions and abnormal outcome. Infants with minor lesions, who all had normal outcome, also had better results than those with major lesions and abnormal outcome, but the range of the EEG findings was more variable. CONCLUSION: Our results suggest that the EEG performed at term age does not provide additional prognostic information compared to cranial US.

Neurologic examination of preterm infants at term age: comparison with term infants.

OBJECTIVES: The aim was to establish the range of neurologic findings in preterm infants reaching term age, their relation to gestational age at birth, and the possible differences with healthy term newborns tested during the first days of life. STUDY DESIGN: The Dubowitz neonatal neurologic examination was performed at term age in 157 low-risk preterm infants born between 25 and 34 weeks' gestation who had cranial ultrasonograms that were normal or showed minor abnormalities. Infants were subdivided in 3 groups according to their gestational age at birth. RESULTS: Within the preterm cohort, the range of scores for the 3 gestational age subgroups was different from each other for 21 of the 34 items, although the median scores were different only in 10 of the 34 items. The range of scores and their median in preterm infants however was wider than that found in term infants. Preterm infants examined at term were also more hyperexcitable and tended to have less flexor tone in the limbs and less extensor tone in the neck in the sitting posture. CONCLUSIONS: The distribution of scores provides useful guidelines when a preterm infant is examined at term.

Controlled trial of early dexamethasone treatment for the prevention of chronic lung disease in preterm infants: a 3-year follow-up.

OBJECTIVE: There is increasing concern in regard to the possible long-term adverse effects of postnatal dexamethasone treatment in preterm infants. The purpose of this study was to assess growth and neurodevelopmental outcome in preterm infants at high risk of chronic lung disease (CLD), treated with early (<96 hours) postnatal dexamethasone. DESIGN: Three-year follow-up data of physical growth and neurodevelopmental outcome of preterm infants enrolled in a controlled trial to study the effectiveness of early postnatal dexamethasone administration for the prevention of CLD were reviewed. The original trial included 25 treated neonates who received dexamethasone intravenously from the fourth day of life for 7 days (0.5 mg/kg/d for the first 3 days, 0.25 mg/kg/d the next 3 days, and 0.125 mg/kg/d on the seventh day), and 25 untreated neonates as controls. Forty-five surviving infants (22 untreated and 23 treated) completed the 3-year follow-up. RESULTS: At the end of follow-up, infants pertaining to both study groups had similar values for body weight, height, and head circumference, and a similar incidence of infants with anthropometrics data below the third percentile. Moreover, no differences were detected between the groups in regard to incidence of major cranial ultrasound abnormalities, cerebral palsy, major neurosensory impairment or IQ scores, and distribution. CONCLUSIONS: Early (<96 hours) postnatal dexamethasone administration at the doses employed in this study did not impair physical or neurodevelopmental outcome in preterm infants at high risk of CLD. However, the small sample size of our study was not tailored to look for long-term outcomes and our results are not in agreement with those of larger trials and systematic reviews. The real risks of postnatal dexamethasone administration could be definitely assessed only when more well-designed trials using long-term neurodevelopmental assessment as the primary outcome will be reported.