Normal neonatal hearing screening did not preclude sensorineural hearing loss in two-year-old very preterm infants.

AIM: Very preterm infants are at risk of neonatal hearing loss. However, it is unknown whether infants with a normal neonatal hearing screening result risk sensorineural hearing loss (SNHL) at a later age. METHODS: This cohort study was conducted at the Erasmus Medical University Center Rotterdam, the Netherlands, on 77 very preterm infants born between October 2005 and September 2008. All infants underwent auditory brainstem response audiometry during neonatal hearing screening and at two years of corrected age. The frequency of SNHL in infants with a normal neonatal hearing screening was analysed and the risk factors associated with newly diagnosed SNHL in these infants were examined. RESULTS: We found that 3.9% (3/77) of the very preterm infants showed permanent hearing loss during their neonatal hearing screening. In addition, a relatively high prevalence of newly diagnosed SNHL (4.3%) was found in three of the 70 infants followed up at the age of two. The total prevalence rate of permanent hearing loss in the cohort was approximately 8%. CONCLUSION: A normal outcome of neonatal hearing screening did not guarantee normal hearing at two years of age in this very preterm cohort and paediatricians should be alert to the possibility of late-onset SNHL.

Auditory brainstem maturation in normal-hearing infants born preterm: a meta-analysis.

AIM: Children born preterm often have neurodevelopmental problems later in life. Abnormal maturation of the auditory brainstem in the presence of normal hearing might be a marker for these problems. We conducted a meta-analysis of auditory brainstem response (ABR) latencies at term age to describe differences in auditory brainstem maturation between normal-hearing preterm and term-born infants. METHOD: Computerized databases were searched for studies published between 1995 and 2014 that reported ABR measurements at term age in infants born preterm in a case-control design. Five peaks reflect the conduction of a neural signal along the brainstem auditory pathway. We collected I to V interpeak latency data, and III to V interpeak latency data, which refers to the more central part of the pathway. RESULTS: Preterm-born infants' III to V interval is significantly longer compared to infants born at term (0.081ms, effect-size=0.974), which also reflects on the I to V interval. Moreover, significantly increased ABR interpeak latencies of infants born preterm are related to lower gestational age and the need for neonatal intensive care treatment. INTERPRETATION: The delayed conduction time towards and into the auditory brainstem at term age suggests atypical maturation of the brainstem in normal-hearing infants born preterm. Both the duration of gestation and the consequences of the preterm birth (intensive care needed) negatively affect maturation of the auditory brainstem, which may influence later development.

Observational outcome results following a randomized controlled trial of early amino acid administration in preterm infants.

OBJECTIVE: Several reports have investigated amino acid administration in premature infants during the early postnatal phase. Most of these previous studies, however, have only evaluated short-term in-hospital outcomes. Our aim was to describe long-term outcomes in premature infants previously subjected to different nutritional regimens in a randomized controlled trial. The primary outcome was survival without major disabilities, and the secondary outcomes included anthropometry and mental development. METHODS: Infants born <32 weeks' gestation and <1500 g were randomized to receive glucose (n = 69) or glucose with 2.4 g · kg(-1) · day(-1 amino acids) (n = 63) from birth. From postnatal day 3 onward, the nutritional intake was similar. At 2 years of corrected age, the surviving infants were assessed for neurodevelopmental outcome and anthropometry. RESULTS: Ninety-seven percent of the surviving infants were examined at follow-up, with no overall effect on survival without major disabilities. Boys, however, had a normal outcome significantly more often if amino acids were administered from birth onward (crude odds ratio 3.8, 95% confidence interval 1.3-11.4) and following adjustment for confounders (odds ratio 6.2, 95% confidence interval 1.0-38.0). The secondary outcomes exhibited no differences in anthropometric data. The mental developmental index was lower in the small number of girls who survived without major disabilities following the early administration of amino acids. CONCLUSIONS: In this hypothesis-generating outcome study, premature boys, but not girls, benefited from amino acid administration directly following birth. The observed lower mental developmental index in a subgroup of girls, however, warrants further studies.

Neonatal and parental predictors of executive function in very preterm children.

AIM: To examine neonatal and parental predictors of executive function in very preterm (gestational age ≤30 weeks) children aged 4.0-12.0 years. METHODS: Two-hundred very preterm (mean age 8.2 ± 2.5 years) children without severe disabilities, born between 1996 and 2004, were assessed with measures of executive function including working memory, verbal fluency, planning and inhibitory control. Neonatal predictors were obtained from clinical records. Parental predictors included parental education, which was derived from questionnaires. Multiple linear regression analyses identified associations between neonatal and parental predictors and executive function in very preterm children. RESULTS: Better postnatal growth at 6 weeks of corrected age-predicted better spatial span (R² = 0.03, ß = 0.17, p = 0.02) and planning (R² = 0.03, ß = 0.16, p = 0.04). A higher level of parental education predicted better verbal fluency (R² = 0.02, ß = 0.12, p = 0.02). Verbal working memory was not predicted by neonatal risk factors or by parental education (ß(s ) < 0.09, p(s ) > 0.20). CONCLUSIONS: Executive function in very preterm children is associated with early postnatal growth and level of parental education but not with neonatal complications.

The profile of executive function in very preterm children at 4 to 12 years.

AIM: To examine executive functioning in very preterm (gestational age ≤30 wks) children at 4 to 12 years of age. METHOD: Two-hundred very preterm (106 males, 94 females; mean gestational age 28.1wks, SD 1.4; mean age 8y 2mo, SD 2y 6mo) and 230 term children (106 males, 124 females; mean gestational age 39.9wks, SD 1.2; mean age 8y 4mo, SD 2y 3mo) without severe disabilities, born between 1996 and 2004, were assessed on an executive function battery comprising response inhibition, interference control, switching, verbal fluency, verbal and spatial working memory, and planning. Multiple regression analyses examined group differences while adjusting for effects of parental education, age, sex, and speed indices. RESULTS: Relative to children born at term, very preterm children had significant (p(s) <0.02; where p(s) represents p-values) deficits in verbal fluency (0.5 standardized mean differences [SMD]), response inhibition (0.4 SMD), planning (0.4 SMD), and verbal and spatial working memory (0.3 SMD), independent of slow and highly fluctuating processing speed. A significant group by age interaction indicated that group differences for response inhibition decreased between 4 and 12 years. INTERPRETATION: Very preterm birth is associated with a profile of affected and non-affected executive functions independent of impaired speed. Deficits are of small to moderate magnitude and persist over time, except for response inhibition for which very preterm children catch up with peers.

Development of preschool and academic skills in children born very preterm.

OBJECTIVE: To examine performance in preschool and academic skills in very preterm (gestational age ≤ 30 weeks) and term-born comparison children aged 4 to 12 years. STUDY DESIGN: Very preterm children (n = 200; mean age, 8.2 ± 2.5 years) born between 1996 and 2004 were compared with 230 term-born children (mean age, 8.3 ± 2.3). The Dutch National Pupil Monitoring System was used to measure preschool numerical reasoning and early linguistics, and primary school simple and complex word reading, reading comprehension, spelling, and mathematics/arithmetic. With univariate analyses of variance, we assessed the effects of preterm birth on performance across grades and on grade retention. RESULTS: In preschool, very preterm children performed comparably with term-born children in early linguistics, but perform more poorly (0.7 standard deviation [SD]) in numerical reasoning skills. In primary school, very preterm children scored 0.3 SD lower in complex word reading and 0.6 SD lower in mathematics/arithmetic, but performed comparably with peers in reading comprehension and spelling. They had a higher grade repeat rate (25.5%), although grade repeat did not improve their academic skills. CONCLUSIONS: Very preterm children do well in early linguistics, reading comprehension, and spelling, but have clinically significant deficits in numerical reasoning skills and mathematics/arithmetic, which persist with time.

Validity of an early parent-report questionnaire for language disorder in very preterm children from 2 to 10 years of age.

BACKGROUND: Language problems at an early age in very preterm (VP) children can have a detrimental effect on other developmental domains and often persist throughout childhood. The aim of this study was to examine the concurrent and predictive validity of an early language parent-report questionnaire for language disorder in VP children from 2 to 10 years of age. MATERIALS AND METHODS: In 80 VP children (<32 weeks' gestation) without major disabilities, a parent-questionnaire and formal language assessment, both normed for the general population, were administered at 2 years corrected age (CA). Of these infants, 62 were seen for follow-up formal language assessment at age 4 and 61 were seen at age 10. Sensitivity and specificity values were calculated. RESULTS: The Lexi-list showed acceptable concurrent validity for word production scores obtained at age 2 CA. The predictive validity was good for sentence production and acceptable for word production scores obtained at age 4, and low for language production scores obtained at age 10. A Lexi-list cut-off score of <85 (i.e., <-1 SD) was found optimal. INTERPRETATION: A norm-referenced parent-report questionnaire is a useful, first screening tool in a neonatal follow-up. It not only detected early language disorder at age 2 CA but also proved to be a good predictor for language disorder at age 4. However, it did not predict language disorder at age 10. Formal language assessment at age 4 would therefore be recommended for children with an abnormal parent-report language score at age 2 CA.

Phonological development in very-low-birthweight children: an exploratory study.

AIM: Very-low-birthweight (VLBW; birthweight<1500 g and/or gestational age <32 wks) children are at risk for speech problems. However, there are few studies on speech development in VLBW children at an early age. The aim of this study was to investigate phonological development in 2-year-old VLBW children. METHOD: Twenty VLBW children without major neurosensory impairment (7 males, 13 females; mean birthweight 971 g, SD 315; mean gestational age 28 wks, SD 1.81) and 20 term children (7 males, 13 females; mean birthweight 3503 g, SD 416; mean gestational age 40 wks, SD 1.26) were compared on measures of phonological development derived from 20-minute spontaneous speech samples of standardized mother-child play interaction as well as on standardized tests of cognitive and psychomotor development, language, and behaviour. RESULTS: VLBW children had significantly fewer acquired consonants (median 9, p=0.02) and a significantly lower phonological mean length of utterance (pMLU; median 4.1, p<0.01) than term children (median acquired consonants 10, median pMLU 5.0). INTERPRETATION: This study provides evidence for poor phonological development in even healthy VLBW children, compared with term-matched children, independent of their cognitive, psychomotor, and language development, and their behavioural functioning.

Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial.

Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 µg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective: This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 µg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants.

Prenatal and Postnatal Exposure to Persistent Organic Pollutants and Infant Growth: A Pooled Analysis of Seven European Birth Cohorts.

BACKGROUND: Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. OBJECTIVES: We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). METHODS: We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. RESULTS: We found a significant increase in growth associated with p,p'-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted ß = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (ß = -0.10; 95% CI: -0.19, -0.01). CONCLUSION: To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p'-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels.

Prenatal exposure to PCB-153, p,p'-DDE and birth outcomes in 9000 mother-child pairs: exposure-response relationship and effect modifiers.

Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p'-DDE) can impair fetal growth; however, the exposure-response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure-response relationship between PCB-153 and p-p'-DDE and birth outcomes; to evaluate whether any no exposure-effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother-child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure-response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194g (95% CI -314, -74) per 1µg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure-response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association.

Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age.

Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic compounds that may modulate sex steroid hormones. Steroid hormones play a mediating role in brain development and may influence behaviors that show sex differences, such as childhood play behavior. In this study we evaluated the effects of perinatal exposure to environmental levels of PCBs and dioxins on childhood play behavior and whether the effects showed sex differences. As part of the follow-up to the Dutch PCB/dioxin study at school age, we used the Pre-School Activity Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n = 207). The PSAI assesses masculine or feminine play behavior scored on three subscales: masculine, feminine, and composite. Prenatal exposure to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord plasma and breast milk. For breast milk we measured additional PCBs as well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5 years +/- 0.4). Effects of prenatal exposure to PCBs, measured in maternal and cord plasma, on the masculine and composite scales were different for boys and girls (p <.05). In boys, higher prenatal PCB levels were related with less masculinized play, assessed by the masculine scale (p(maternal) =.042; p(cord) =.001) and composite scale (p(cord) =.011), whereas in girls higher PCB levels were associated with more masculinized play, assessed by the composite scale (p(PCBmilk) =.028). Higher prenatal dioxin levels were associated with more feminized play in boys as well as girls, assessed by the feminine scale (p =.048). These effects suggest prenatal steroid hormone imbalances caused by prenatal exposure to environmental levels of PCBs, dioxins, and other related organochlorine compounds.

Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies.

Effects of perinatal exposure to PCBs on neuropsychological functions in the Rotterdam cohort at 9 years of age.

PCBs are known for their neurotoxic properties, especially on the developing brain. To increase insight into the neurotoxic effects of PCB exposure, the authors studied the effects of perinatal exposure to environmental levels of these compounds on different neuropsychological domains. In 9-year-old children of the Rotterdam PCB--dioxin cohort, higher prenatal PCB levels were associated with longer response times (RTs), more variation in RTs, and lower scores on the Tower of London (TOL; Shallice, 1982). A longer breast-feeding duration was associated with lower TOL scores and with better spatial organizational skills. There was some evidence of negative effects of lactational exposure to PCBs on scores on the TOL.

Immunological effects of environmental exposure to polychlorinated biphenyls and dioxins in Dutch school children.

Perinatal exposure to PCBs and dioxins is associated with immune changes in healthy Dutch preschool children. To examine whether such effects persist into later childhood, we here report on the immunological effects of perinatal exposure to PCBs and dioxins in 167 Dutch children at school age. A higher postnatal PCB exposure was associated with a higher prevalence of recurrent middle ear infections and a higher prenatal PCB exposure with less shortness of breath with wheeze, as assessed by parent questionnaire. Our data indicate that, at environmental levels of these man made chemicals, subtle health effects may occur.

Executive function and IQ predict mathematical and attention problems in very preterm children.

Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processing speed indices and IQ. Interactions with group (very preterm versus term birth status) were examined. Analyses were conducted separately for two subsamples: children in preschool and children in primary school. Very preterm children performed poorer on tests for mathematics and had more parent and teacher rated attention problems than term controls (ß(s)>.11, P(s)<.01). IQ contributed unique variance to mathematics in preschool and in primary school (ß(s)>.16, P(s)<.007). A significant interaction of group with IQ (ß = -. 24, P = .02) showed that IQ contributed unique variance to attention problems as rated by teachers, but that effects were stronger for very preterm than for term infants. Over and above IQ, EF contributed unique variance to mathematics in primary school (ß = .13, P<.001), to parent rated inattention in preschool and in primary school (ß(s)>-.16, P(s)<.04), and to teacher rated inattention in primary school (ß = -.19; ß = .19, P(s)<.009). In conclusion, impaired EF is, over and above impaired IQ, an important predictor for poor mathematics and attention problems following very preterm birth.

Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 µg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

Mortality, neonatal morbidity and two year follow-up of extremely preterm infants born in The Netherlands in 2007.

BACKGROUND: Extremely preterm infants are at high risk of neonatal mortality and adverse outcome. Survival rates are slowly improving, but increased survival may come at the expense of more handicaps. METHODOLOGY/PRINCIPAL FINDINGS: Prospective population-based cohort study of all infants born at 23 to 27 weeks of gestation in The Netherlands in 2007. 276 of 345 (80%) infants were born alive. Early neonatal death occurred in 96 (34.8%) live born infants, including 61 cases of delivery room death. 29 (10.5%) infants died during the late neonatal period. Survival rates for live born infants at 23, 24, 25 and 26 weeks of gestation were 0%, 6.7%, 57.9% and 71% respectively. 43.1% of 144 surviving infants developed severe neonatal morbidity (retinopathy of prematurity grade ≥3, bronchopulmonary dysplasia and/or severe brain injury). At two years of age 70.6% of the children had no disability, 17.6% was mild disabled and 11.8% had a moderate-to-severe disability. Severe brain injury (p = 0.028), retinopathy of prematurity grade ≥3 (p = 0.024), low gestational age (p = 0.019) and non-Dutch nationality of the mother (p = 0.004) increased the risk of disability. CONCLUSIONS/SIGNIFICANCE: 52% of extremely preterm infants born in The Netherlands in 2007 survived. Surviving infants had less severe neonatal morbidity compared to previous studies. At two years of age less than 30% of the infants were disabled. Disability was associated with gestational age and neonatal morbidity.

Language functions in preterm-born children: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Preterm-born children (<37 weeks' gestation) have higher rates of language function problems compared with term-born children. It is unknown whether these problems decrease, deteriorate, or remain stable over time. The goal of this research was to determine the developmental course of language functions in preterm-born children from 3 to 12 years of age. METHODS: Computerized databases Embase, PubMed, Web of Knowledge, and PsycInfo were searched for studies published between January 1995 and March 2011 reporting language functions in preterm-born children. Outcome measures were simple language function assessed by using the Peabody Picture Vocabulary Test and complex language function assessed by using the Clinical Evaluation of Language Fundamentals. Pooled effect sizes (in terms of Cohen's d) and 95% confidence intervals (CI) for simple and complex language functions were calculated by using random-effects models. Meta-regression was conducted with mean difference of effect size as the outcome variable and assessment age as the explanatory variable. RESULTS: Preterm-born children scored significantly lower compared with term-born children on simple (d = -0.45 [95% CI: -0.59 to -0.30]; P < .001) and on complex (d = -0.62 [95% CI: -0.82 to -0.43]; P < .001) language function tests, even in the absence of major disabilities and independent of social economic status. For complex language function (but not for simple language function), group differences between preterm- and term-born children increased significantly from 3 to 12 years of age (slope = -0.05; P = .03). CONCLUSIONS: While growing up, preterm-born children have increasing difficulties with complex language function.

Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial.

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.