Vasoactive peptides as biomarkers for the prediction of retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation. METHODS: Prospective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models. RESULTS: We included 224 infants born at median (IQR) 29.6 (27.1-30.8) weeks gestation and birth weight of 1160 (860-1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659-1564) pmol/L and 348 (300-382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210-502) pmol/L and 196 (156-268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score. CONCLUSIONS: MR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future. IMPACT: Plasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II. Both biomarkers have the potential to improve early prediction of retinopathy of prematurity. Vasoactive peptides might allow to reduce the proportion of screened infants substantially.

Oscillatory mechanics in very preterm infants on continuous positive airway pressure support: Reference values.

OBJECTIVE: To create reference values for respiratory system resistance (Rrs) and reactance (Xrs) measured by the forced oscillation technique (FOT) in nonintubated very preterm infants. DESIGN: Retrospective analysis of data collected as part of prospective observational studies in two centers. SETTING: Tertiary neonatal intensive care units. PATIENTS: Non-intubated infants below 32 weeks' gestation age who did not develop bronchopulmonary dysplasia. INTERVENTIONS: We applied FOT using a mechanical ventilator (Fabian HFOi; Vyaire) that superimposed small-amplitude oscillations (10 Hz) on a continuous positive airway pressure of 3 and 5 cmH2 O. Measurements were performed during regular tidal breathing using a face mask. MAIN OUTCOME MEASURES: We analyzed 198 measurements performed between 7 postnatal days and 40 weeks postmenstrual age (PMA) in 85 infants, with a median (Q1, Q3) gestational age of 30.43 (29.14, 31.18) weeks. Logarithmic transformations were applied to Rrs and Xrs, and the relationship between transformed impedance values and demographic factors was examined by backwards stepwise linear regression. RESULTS: In univariable analysis, transformed Xrs was significantly associated with PMA, postnatal age, weight, and length, while Rrs was not. The best multivariable regression model estimating transformed Xrs (cmH2 O*s/L) at continuous positive airway pressure (CPAP) = 5 cmH2 O was: Ln(50 - Xrs) = 4.536 - 0.009 x PMA - 0.014 x weight z-score. SEE = 0.053, R2 = 0.36. The mean (SD) Rrs at CPAP = 5 cmH2 O was 33.63 (5.28) cmH2 O*s/L. CONCLUSION: We have established reference values for Rrs and Xrs at 10 Hz in nonintubated preterm neonates on continuous positive airway pressure support.

Association of growth with neurodevelopment in extremely low gestational age infants: a population-based analysis.

To assess the association between postnatal growth and neurodevelopment at the age of 2 years in extremely low gestational age newborns (ELGAN, < 28 weeks' gestation). Retrospective population-based cohort study including all live born ELGAN in 2006-2012 in Switzerland. Growth parameters (weight, length, head circumference, body mass index) were assessed at birth, at hospital discharge home, and 2-year follow-up (FU2). Unadjusted and adjusted regression models assessed associations between growth (birth to hospital discharge and birth to FU2) and neurodevelopment at FU2. A total of 1244 infants (mean GA 26.5 ± 1.0 weeks, birth weight 853 ± 189 g) survived to hospital discharge and were included in the analyses. FU2 was documented for 1049 (84.3%) infants. The mean (± SD) mental and a psychomotor development index at 2FU were 88.9 (± 18.0) and 86.9 (± 17.7), respectively. Moderate or severe neurodevelopmental impairment was documented in 23.2% of patients. Changes of z-scores between birth and discharge and between birth and FU2 for weight were - 1.06 (± 0.85) and - 0.140 (± 1.15), for length - 1.36 (± 1.34), and - 0.40 (± 1.33), for head circumference - 0.61 (± 1.04) and - 0.76 (± 1.32) as well as for BMI 0.22 (± 3.36) and - 0.006 (± 1.45). Unadjusted and adjusted analyses showed that none of the four growth parameters was significantly associated with any of the three outcome parameters of neurodevelopment. This was consistent for both time intervals. CONCLUSION: In the present population-based cohort of ELGAN, neither growth between birth and hospital discharge nor between birth and FU2 were significantly associated with neurodevelopment at age of 2 years. WHAT IS KNOWN: • Studies assessing the association between growth and neurodevelopment in extremely low gestational age newborns (28 weeks' gestation) show conflicting results. WHAT IS NEW: • Neither growth between birth and hospital discharge nor between birth and corrected age of 2 years were significantly associated with neurodevelopment at age of 2 years. • The role of postnatal growth as a predictor of neurodevelopmental outcome during infancy might be smaller than previously assumed.

Respiratory morbidity in preterm infants predicted by natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1).

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants <32 weeks. We aimed to assess whether plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) predict respiratory morbidity. METHODS: This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated. RESULTS: Two hundred and twenty-nine infants <32 weeks were included (median gestational age [GA] 29.6 weeks [interquartile range 29.0-30.7], median birth weight 1150 g [IQR 840-1410]). MR-proANP and CT-proET-1 were associated with the duration of supplemental oxygen in univariable analysis (both p < 0.001) but not after adjusting for co-factors. Infants with BPD/death showed higher plasma levels of MR-proANP (623.50 pmol/L [IQR 458.50-881.38] vs. 308.35 pmol/L [IQR 216.72-538.10]; p < 0.001) and CT-proET-1 (255.40 pmol/L [IQR 202.60-311.15] vs. 198.30 pmol/L [IQR 154.70-297.95]; p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors. CONCLUSIONS: MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors. IMPACT: Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Volumetric Capnography at 36 Weeks Postmenstrual Age and Bronchopulmonary Dysplasia in Very Preterm Infants.

OBJECTIVES: To assess the feasibility of volumetric capnography in spontaneously breathing very preterm infants at 36 weeks postmenstrual age (PMA) and its association with clinical markers of lung disease including the duration of respiratory support and bronchopulmonary dysplasia (BPD). STUDY DESIGN: We obtained mainstream volumetric capnography measurements in 143 very preterm infants at 36 weeks PMA. BPD was categorized into no, mild, moderate, and severe according to the 2001 National Heart, Lung and Blood Institute workshop report. Normalized capnographic slopes of phase II (SnII) and phase III (SnIII) were calculated. We assessed the effect of BPD, duration of respiratory support, and duration of supplemental oxygen on capnographic slopes. RESULTS: SnIII was steeper in infants with moderate to severe BPD (76 ± 25/L) compared with mild (31 ± 20/L) or no BPD (26 ± 18/L) (P < .001). The association of SnIII with moderate to severe BPD persisted after adjusting for birth weight z-score, respiratory rate, and airway dead space to tidal volume ratio. The diagnostic usefulness of SnIII to discriminate between infants with and without moderate to severe BPD was high (area under the curve, 0.94; 95% CI, 0.89-0.99). CONCLUSIONS: Volumetric capnography is feasible in spontaneously breathing preterm infants at 36 weeks PMA and reflects the degree of lung disease. This promising bedside lung function technique may offer an objective, continuous physiological outcome measure for assessment of BPD severity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02083562.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

Forced oscillation measurements in the first week of life and pulmonary outcome in very preterm infants on noninvasive respiratory support.

BACKGROUND: We aimed at investigating whether early lung mechanics in non-intubated infants below 32 weeks of gestational age (GA) are associated with respiratory outcome. METHODS: Lung mechanics were assessed by the forced oscillation technique using a mechanical ventilator (Fabian HFOi, ACUTRONIC Medical Systems AG, Hirzel, Switzerland) that superimposed small-amplitude oscillations (10 Hz) on a continuous positive airway pressure. Measurements were performed during regular tidal breathing using a face mask on days 2, 4, and 7 of life. Respiratory system resistance (Rrs) and reactance (Xrs) were computed from flow and pressure. RESULTS: One hundred and seventy-seven measurements were successfully performed in 68 infants. Infants had a mean (range) GA of 29.3 (24.1-31.7) weeks and a birth weight of 1257 (670-2350)g. Xrs was associated with the duration of respiratory support (R2 = 0.39, p < 0.001). A multilevel regression model, including Xrs and GA, explained the duration of respiratory support better than GA alone (R2 = 0.51 vs. 0.45, p = 0.005, likelihood ratio test). CONCLUSION: Assessment of Xrs in the first week of life is feasible and improves prognostication of respiratory outcome in very preterm infants on noninvasive respiratory support.

Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury.

Background: Neurofilament light chain (NfL) is a highly promising biomarker of neuroaxonal injury that has mainly been studied in adult neurodegenerative disease. Its involvement in neonatal disease remains largely unknown. Our aim was to establish NfL plasma concentrations in preterm and term infants in the first week of life. Methods: Plasma NfL was measured by single molecule array immunoassay in two neonatal cohorts: cohort 1 contained 203 term and preterm infants, median gestational age (GA) 37.9 weeks (interquartile range [IQR] 31.9-39.4), in whom venous and arterial umbilical cord blood was sampled at birth and venous blood at day of life (DOL) 3; cohort 2 contained 98 preterm infants, median GA 29.3 weeks (IQR 26.9-30.6), in whom venous blood was sampled at DOL 7. Results: Median NfL concentrations in venous blood increased significantly from birth (18.2 pg/mL [IQR 12.8-30.8, cohort 1]) to DOL 3 (50.9 pg/mL [41.3-100, cohort 1]) and DOL 7 (126 pg/mL [78.8-225, cohort 2]) (p < 0.001). In both cohorts NfL correlated inversely with birth weight (BW, Spearman's rho -0.403, p < 0.001, cohort 1; R -0.525, p < 0.001, cohort 2) and GA (R -0.271, p < 0.001, cohort 1; R -0.487, p < 0.001, cohort 2). Additional significant correlations were found for maternal age at delivery, preeclampsia, delivery mode, 5-min Apgar, duration of oxygen supplementation, sepsis, and brain damage (intraventricular hemorrhage or periventricular leukomalacia). Multivariable logistic regression analysis identified the independent predictors of NfL in cohort 1 as BW (beta = -0.297, p = 0.003), delivery mode (beta = 0.237, p = 0.001) and preeclampsia (beta = 0.183, p = 0.022) and in cohort 2 as BW (beta = -0.385, p = 0.001) and brain damage (beta = 0.222, p = 0.015). Conclusion: Neonatal NfL levels correlate inversely with maturity and BW, increase during the first days of life, and relate to brain injury factors such as intraventricular hemorrhage and periventricular leukomalacia, and also to vaginal delivery.

Nasal microbiota and symptom persistence in acute respiratory tract infections in infants.

Acute respiratory tract infections (ARI) in infancy have been implicated in the development of chronic respiratory disease, but the complex interplay between viruses, bacteria and host is not completely understood. We aimed to prospectively determine whether nasal microbiota changes occur between the onset of the first symptomatic ARI in the first year of life and 3 weeks later, and to explore possible associations with the duration of respiratory symptoms, as well as with host, environmental and viral factors. Nasal microbiota of 167 infants were determined at both time-points by 16S ribosomal RNA-encoding gene PCR amplification and subsequent pyrosequencing. Infants were clustered based on their nasal microbiota using hierarchical clustering methods at both time-points. We identified five dominant infant clusters with distinct microbiota at the onset of ARI but only three clusters after 3 weeks. In these three clusters, symptom persistence was overrepresented in the Streptococcaceae-dominated cluster and underrepresented in the cluster dominated by "Others" (p<0.001). Duration of symptoms was not associated with the type of respiratory virus. Infants with prolonged respiratory symptoms after their first ARI tend to exhibit distinct microbial compositions, indicating close microbiota-host interactions that seem to be of importance for symptom persistence and recovery.

Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants.

BACKGROUND: Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. OBJECTIVES: To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. SELECTION CRITERIA: We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP.Meta-analysis of three trials (N = 366) suggested beneficial effects of oral beta-blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I² = 0%; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.01; I² = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD -0.09, 95% CI -0.16 to -0.02; I² = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I² = 0%; typical RD -0.15, 95% CI -0.28 to -0.02; I² = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta-blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment. AUTHORS' CONCLUSIONS: Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events.

Influence of respiratory dead space on lung clearance index in preterm infants.

Lung clearance index (LCI), a marker of ventilation inhomogeneity derived from multiple breath washout (MBW), is used for clinical monitoring and as a key outcome of clinical trials in infants and children with cystic fibrosis. Utility of LCI is controversial in preterm infants with bronchopulmonary dysplasia (BPD) who tend to have high dead space to tidal volume ratio (VD/VT). We investigated the effect of VD/VT on LCI in a cohort of preterm infants with and without BPD and term healthy controls. We analyzed MBW data from 455 infants at a mean (SD) of 43.4 (3.5) w postmenstrual age. VD was estimated from the molar mass signal of an ultrasonic flowmeter (VD,MM). LCI was associated with VD,MM/VT (r(2)=0.13, p<0.001) but was not associated with BPD. Adjusting for VD,MM/VT did not reveal an association between LCI and BPD. We conclude that VD,MM/VT is a relevant factor when interpreting LCI in this population but the effect size of this association is moderate.

Influence of gestational age on dead space and alveolar ventilation in preterm infants ventilated with volume guarantee.

BACKGROUND: Ventilated preterm infant lungs are vulnerable to overdistension and underinflation. The optimal ventilator-delivered tidal volume (VT) in these infants is unknown and may depend on the extent of alveolarisation at birth. OBJECTIVES: We aimed to calculate respiratory dead space (VD) from the molar mass (MM) signal of an ultrasonic flowmeter (VD,MM) in very preterm infants on volume-targeted ventilation (VT target, 4-5 ml/kg) and to study the association between gestational age (GA) and VD,MM-to-VT ratio (VD,MM/VT), alveolar tidal volume (VA) and alveolar minute volume (AMV). METHODS: This was a single-centre, prospective, observational, cohort study in a neonatal intensive care unit. Tidal breathing analysis was performed in ventilated very preterm infants (GA range 23-32 weeks) on day 1 of life. RESULTS: Valid measurements were obtained in 43/51 (87%) infants. Tidal breathing variables were analysed using multivariable linear regression. VD,MM/VT was negatively associated with GA after adjusting for birth weight Z score (p < 0.001, R(2) = 0.26). This association was primarily influenced by the appliance dead space. Despite similar VT/kg and VA/kg across all studied infants, respiratory rate and AMV/kg increased with GA. CONCLUSIONS: VD,app rather than anatomical VD is the major factor influencing increased VD,MM/VT at a younger GA. A volume guarantee setting of 4-5 ml/kg in the Dräger Babylog® 8000 plus ventilator may be inappropriate as a universal target across the GA range of 23-32 weeks. Differences between measured and set VT and the dependence of this difference on GA require further investigation.

The neonatal lung--physiology and ventilation.

This review article focuses on neonatal respiratory physiology, mechanical ventilation of the neonate and changes induced by anesthesia and surgery. Optimal ventilation techniques for preterm and term neonates are discussed. In summary, neonates are at high risk for respiratory complications during anesthesia, which can be explained by their characteristic respiratory physiology. Especially the delicate balance between closing volume and functional residual capacity can be easily disturbed by anesthetic and surgical interventions resulting in respiratory deterioration. Ventilatory strategies should ideally include application of an 'open lung strategy' as well avoidance of inappropriately high VT and excessive oxygen administration. In critically ill and unstable neonates, for example, extremely low-birthweight infants surgery in the neonatal intensive care unit might be an appropriate alternative to the operating theater. Best respiratory management of neonates during anesthesia is a team effort that should involve a joint multidisciplinary approach of anesthetists, pediatric surgeons, cardiologists, and neonatologists to reduce complications and optimize outcomes in this vulnerable population.

[Follow up care of the preterm infant]. / Nachsorge des frühgeborenen Kindes.

The birthrate of preterm infants in Switzerland has remained stable over the last few years with 7.3 % of all live births in 2011. Although outcome and survival have significantly improved in the last decades, morbidity and mortality of preterm infants are still challenging the health care system. Important sequelae especially of extreme preterm birth are bronchopulmonary dysplasia (BPD), impaired growth and neurodevelopmental delay. Respiratory problems following discharge are more common among preterm infants and include an increased risk of cough, wheeze and airway hyperresponsiveness leading to a higher re-hospitalization rate in the first year of life compared to term infants. Routine vaccinations should be administered according to the chronological age. For very preterm infants an accelerated vaccination schedule is recommended. Respiratory-Syncytial-Virus (RSV) immunoglobulin is available for infants with moderate and severe BPD. Growth and neurodevelopment of preterm infants should be closely monitored. In the first 24 months of life, interpretation of the findings should take the preterm birth into account and gestational age should be corrected accordingly. Preterm infants are at risk for neurodevelopmental impairment including vision and hearing. Early detection of neurodevelopmental problems and implementation of appropriate interventions can improve outcome.