Thuy Mai Luu

Determinants of developmental outcomes in a very preterm Canadian cohort

Objectives Identify determinants of neurodevelopmental outcome in preterm children. Methods Prospective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death. Results Of the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38%–51%) had a NDI, 17% (11%–23%) had a sNDI, 6.4% (3.1%–8.6%) had CP, 2.6% (2.5%–13.3%) had hearing aids or cochlear implants and 1.6% (0%–3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3–4.3, 0.04–3.5 and 0.12–1.96, respectively. Conclusion Most preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes.

Preterm Birth and Hypertension Risk: The Oxidative Stress Paradigm

The majority of epidemiological studies in developmental programming have explored the influence of low birth weight (irrespective of gestational age) on long-term chronic disease in individuals born during the first half of the 20th century.1,2 Low birth weight neonates may represent infants born at term with intrauterine growth restriction (IUGR) or born preterm with or without IUGR. As such, there is emerging interest in the effects of preterm birth alone (beyond birth weight and IUGR) on specific aspects of human development and long-term health. Approximately 10% of all births worldwide are preterm (before 37 completed weeks of gestation).3 Besides being of low birth weight, preterm neonates are suddenly and prematurely exposed to the extrauterine environment at a time when organogenesis is incomplete. Exposure postnatally to factors such as high oxygen concentrations,4 medications5 (including glucocorticoids),6 and inadequate nutrition7 likely adversely influence postnatal growth and ongoing organ development. In addition to possible genetic and epigenetic factors that may contribute to hypertension risk (including hypertension-related complications of pregnancy), a multitude of aspects related to both intrauterine and extrauterine growth, as well as the postnatal environment, may all play an important role in the programming of hypertension in individuals born preterm. In this review, we will highlight, in particular, the potential effect of oxidative stress associated with preterm birth on neonatal development and future disease risk. The survival of neonates born at low and very low gestational ages is recent in the history of medicine and has increased remarkably over the last few decades. The first generations of survivors of very preterm birth are currently just reaching adulthood and as such are providing emerging evidence of chronic health conditions, such as hypertension. The link between preterm birth and hypertension risk (independent of birth weight) has been …

Concurrent validity of ages and stages questionnaires in preterm infants.

BACKGROUND: Although preterm infants born at 29 to 36 gestational weeks (GW) are at risk for developmental delay, they do not always benefit from systematic follow-up. Primary care physicians are then responsible for their developmental surveillance and need effective screening tests. This study aimed to determine whether the Ages and Stages Questionnaires (ASQ) at 12 and 24 months’ corrected age (CA) identify developmental delay in preterm infants. METHODS: With a cross-sectional design involving 2 observations at 12 and 24 months’ CA, 124 and 112 preterm infants were assessed. Infants were born between May 2004 and April 2006 at 29 to 36 GW. The ASQ and the Bayley Scales of Infant Development were used. Concurrent validity was calculated by using κ coefficient, sensitivity, and specificity. RESULTS: At 12 months’ CA, the ASQ did not perform well in identifying infants with mental delay (κ = 0.08–0.19; sensitivity = 0.20–0.60; specificity = 0.68–0.88). Agreement (κ = 0.28–0.44) and specificity (0.90–0.97) were better for the psychomotor scale, but the sensitivity remained insufficient (0.25–0.52). At 24 months, the ASQ had good sensitivity (0.75–0.92) and specificity (0.55–0.78) for detecting mental delays (κ = 0.45). Results remained unsatisfactory for detecting motor delays (sensitivity = 0.31–0.50; specificity = 0.73–0.92). CONCLUSIONS: Preterm infants with developmental delays at 12 months’ CA are not adequately identified with the ASQ. At 24 months’ CA, the ASQ identifies mental delays but not psychomotor delays. Additional measures should be used to increase yield of detecting at-risk preterm infants.

Endothelial Progenitor Cells as Prognostic Markers of Preterm Birth-Associated Complications

Preterm birth is associated with alteration of the vascular tree that can result in disease states such as bronchopulmonary dysplasia and retinopathy of prematurity during the neonatal period and emphysema and hypertension in adulthood. Studies have suggested a potential role for endothelial progenitor cells in the pathophysiology of prematurity‐related complications involving blood vessels; however, this knowledge has never been synthesized. We conducted a systematic review of the published data to examine the characteristics of endothelial progenitor cells in relation to preterm birth in humans. Preterm infants compared with term controls displayed similar or increased circulating/cord blood endothelial progenitor cell counts. However, the preterm endothelial progenitor cells were more vulnerable to exogenous factors such as oxidative stress. A reduced number, in particular of endothelial colony‐forming cells, was associated with bronchopulmonary dysplasia. No studies have examined endothelial progenitor cells beyond the neonatal period. These findings could prove useful in the identification of biomarkers for prognostication or therapeutic strategies for vascular‐related diseases in preterm‐born individuals. Stem Cells Translational Medicine 2017;6:7–13

Preterm Birth and Hypertension: Is There a Link?

Factors in perinatal life have recently been recognized as determinants of later life health and diseases, especially hypertension. The detection of higher values of blood pressure in preterm-born individuals reaching adulthood has turned the attention to preterm birth-related complications and deleterious conditions as factors triggering early cardiovascular alterations, which may increase hypertension risk and associated complications in this population. Further, preterm birth is frequently associated with pregnancy complications such as lower placental perfusion, increased blood pressure in the mother and preeclampsia, often resulting in intrauterine growth restriction. These conditions further impact the risk of hypertension in the offspring whether through inherited genetic factors or perpetuated pathophysiology leading to preeclampsia, preterm delivery, and chronic hypertension. In this review, we will highlight evidence of developmental cardiovascular alterations and potential mechanisms linking preterm birth to the risk of hypertension and cardiovascular diseases into adulthood.

Preterm birth: risk factor for early-onset chronic diseases.

Preterm births (< 37 weeks’ gestation) are increasing worldwide and account for 8% of Canadian births.[1][1] With advances in perinatal care over the last 20–30 years, more than 90% of preterm infants survive and enter adulthood.[2][2] The “Barker hypothesis” of fetal origins of adult

In extremely preterm infants, do the Movement Assessment of Infants and the Alberta Infant Motor Scale predict 18-month outcomes using the Bayley-III?

BACKGROUND Extremely preterm infants are at high-risk for neurodevelopmental disabilities. The Movement Assessment of Infants (MAI) and the Alberta Infant Motor Scale (AIMS) have been designed to predict outcome with modest accuracy with the Bayley-I or Bayley-II. AIMS To examine and compare the predictive validity of the MAI and AIMS in determining neurodevelopmental outcome with the Bayley-III. DESIGN Retrospective cohort study of 160 infants born at ≤ 28 weeks gestation. METHOD At their corrected age, infants underwent the MAI at 4 months, the AIMS at 4 and 10-12 months, and the Bayley-III and neurological examination at 18 months. Sensitivity and specificity were calculated. RESULTS Infants had a mean gestation of 26.3 ± 1.4 weeks and birth weight of 906 ± 207 g. A high-risk score (≥ 14) for adverse outcome was obtained by 57% of infants on the MAI. On the AIMS, a high-risk score (<5th percentile) was obtained by 56% at 4 months and 30% at 10-12 months. At 18 months, infants with low-risk scores on either the MAI or AIMS had higher cognitive, language, and motor Bayley-III scores than those with high-risk scores. They were less likely to have severe neurodevelopmental impairment. To predict Bayley-III scores <70, sensitivity and specificity were 91% and 49%, respectively, for the MAI and 78% and 48%, respectively, for the AIMS. CONCLUSIONS Extremely preterm infants with low-risk MAI at 4 months or AIMS scores at 4 or 10-12 months had better outcomes than those with high-risk scores. However, both tests lack specificity to predict individual neurodevelopmental status at 18 months.

Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the CYBB gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A Mycobacterium avium lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.

Parental Perspectives Regarding Outcomes of Very Preterm Infants: Toward a Balanced Approach

Objectives To explore parental perspectives regarding their preterm child at 18 months corrected age and to investigate whether reported answers correlate with level of neurodevelopmental impairment (NDI) as defined by clinicians. We hypothesized that parents would report more negative concerns with increasing level of NDI. Study design This study included 190 infants born <29 weeks of gestational age in 2009‐2012 at 1 tertiary university health center. Infants underwent detailed developmental assessment at 18 months corrected age, and were classified into either absence or presence of mild to moderate or severe NDI. Parents were asked 2 open‐ended questions: “What concerns you most about your child?” and “Please describe the best things about your child.” Open‐ended questions were analyzed using qualitative methodology. Results In this cohort, 49%, 43%, and 8% of participants had no, mild to moderate, and severe NDI. The majority of parents (72.8%) had both positive and negative aspects to report; 26.8% only had positive ones. The main positive themes invoked by parents included their childs personality (61%), happiness (40%), developmental outcome/progress (40%), and physical health (11%). The main themes regarding parental concerns included neurodevelopment (56%), notably language and behavior, and physical health (24%), particularly growth/nutrition and physical fragility. There was no association between positive themes and categories of NDI, but parents of children with mild to moderate NDI reported more concerns about development. Conclusions Neonatal outcome research would benefit from incorporating parental perspectives regarding their child, including negative and positive aspects, enabling physicians to provide complete and balanced information to parents of all preterm infants.

Pulmonary magnetic resonance imaging biomarkers of lung structure and function in adult survivors of bronchopulmonary dysplasia with COPD

Abstract Bronchopulmonary dysplasia (BPD) is an emerging risk factor for chronic obstructive pulmonary disease. For BPD survivors, there are no guidelines for the management of lung disease that is often misdiagnosed as asthma. Pulmonary magnetic resonsance imaging (MRI) provides clinically-relevant lung biomarkers of ventilation abnormalities and emphysema. Here our objective was to quantify lung MRI biomarkers in adults with BPD to understand the underlying pathophysiologies responsible for their symptoms and abnormal pulmonary-function. We hypothesized that MRI measurements would be abnormal and reflect emphysema, not airways disease. Patients aged 20–29 year and born ≤32 weeks gestational age were included and those with MRI contraindications were excluded. A 25-year-old female never-smoker born <28 weeks gestation (S1) and a 27-year-old male ex-smoker born ~30 weeks gestation (S2) provided written-informed-consent and underwent pulmonary-function-tests and MRI. Lung abnormalities were quantified using ventilation defect percent (VDP), apparent diffusion coefficients (ADC) and mean linear intercept (Lm). Forced expiratory volume-in 1 sec (S1 = 46%pred/S2 = 33%pred), residual-volume (S1 = 192%pred/S2 = 267%pred) and diffusing-capacity-of-the-lung-for-carbon-monoxide (S1 = 73%pred/S2 = 72%pred) were abnormal. Chest–X-ray and computed tomography (CT) revealed mild structural abnormalities, while MRI VDP (S1 = 6%/S2 = 10%), ADC (S1 = 0.36 cm2/s/S2 = 0.37 cm2/s) and Lm (S1 = 400 μm/S2 = 430 μm) were markedly abnormal with ventilation defects spatially concordant with regions of low MRI signal-intensity and greater Lm, reflecting emphysema and/or gas-trapping. In BPD survivors, MRI biomarkers have the potential to serve as intermediate endpoints and help evaluate therapy.