Time intervals between pumping did not affect breastmilk protein produced by mothers of preterm infants.

AIM: Few studies investigate factors that might influence the content of expressed breastmilk. This study aims to investigate the influence of the intervals between breastmilk pumping and the time of the day on protein and fat concentration in breastmilk. METHODS: Mothers of very preterm infants in a neonatal ward who expressed more than 400 mL per day were included. Expressed breastmilk was obtained from each mother over 30 h who were pumping at strictly planned and varying intervals: 2, 3, 4 and 6 h. All samples were analysed using infrared transmission spectroscopy. RESULTS: Ten mothers participated at a median of 22 days postpartum. A total of 176 milk samples were analysed, and the average protein and fat concentrations in g/100 mL were 1.1 ± 0.23 and 4.2 ± 1.3, respectively. The time intervals between breast pumping sessions did not impact protein content, but fat content decreased by longer intervals (p < 0.01). The time of the day for milk pumping did not influence the protein or fat content. CONCLUSION: A single milk sample collected after any 2-6 h interval, at any time during the day, represents the protein content in the breastmilk, but not the fat content which decreased with longer intervals.

Preterm children born below 33-35 weeks of gestation have an increased risk of mathematical difficulties.

AIM: To investigate the association between gestational age (GA) and grade point averages by domains of language and mathematics at the end of lower secondary education. METHODS: A nationwide register-based study including all Danish children born in 1992-1997 who completed lower secondary education. Grades were evaluated by GA. Domain-specific differences in grades were investigated, and academic profiles were made. RESULTS: The study population comprised 319 796 children. For language, only minor differences in grades were observed. The grades in mathematics ranged from 7.02 (95% confidence interval [CI]: 7.00-7.04) at GA = 40 weeks to 5.86 (95% CI: 5.61-6.11) at GA <28 weeks. Grade differences showed lower grades in mathematics, compared to language, below GA 33-35 weeks. The academic profile of mathematical difficulties was more prevalent among GA <32 weeks. Average/high grades within both domains represented the predominant academic profile, constituting 68.8% at GA 39-41 weeks and 56.6% at GA <28 weeks. CONCLUSION: Only in mathematics decreasing GA was associated with lower grades. Increased mathematical difficulties were found below GA 33-35 weeks. The academic profile of mathematical difficulties was more prevalent among GA <32 weeks. However, the absolute differences in grades were small, and the predominant academic profile was average/high grades within both domains across all GA.

Children in Denmark with cerebral palsy rarely complete elementary school.

AIM: To investigate how children with cerebral palsy (CP) perform in the Danish school system and which factors are associated with school performance. METHOD: This was a population-based cohort study including 463 126 children born from 1997 to 2003. Data were extracted from seven national registries. The study encompassed 818 children with CP (483 [59.0%] males, 335 [41.0%] females) and 417 731 without CP (214 535 [51.4%] males, 203 196 [48.6%] females). We evaluated two primary outcomes: not completing 10 years of elementary school, defined as attending fewer than eight final mandatory exams; and grade point averages (GPAs). Mann-Whitney U tests were used to analyse differences in GPAs and logistic regressions were used to calculate odds ratios (ORs). RESULTS: Among children with and without CP, 62.6% and 12.4% did not complete elementary school respectively (OR = 11.85 [10.28-13.66]). Additionally, children with CP who attended all final exams achieved lower overall GPAs than children without CP (6.6 vs 7.3, p = 0.001). In children with CP, comorbidities, maternal education, severity of motor impairments, and intellectual deficits were associated with increased odds of not completing elementary school. Notably, one-third of children with CP with apparent normal intelligence did not complete school, despite special educational measures. INTERPRETATION: Danish children with CP rarely complete elementary school despite initiatives for a more supportive educational system. The complexity of individual needs in children with CP may be challenging for an inclusive school environment. WHAT THIS PAPER ADDS: Children with cerebral palsy (CP) have a high risk of not completing elementary school. Children with CP achieve lower overall grades than children without CP. Motor impairment, comorbidities, and maternal education are associated with poor school performance. Intellectual impairment is the most important predictor of poor school performance.

The effect of gestational age on major neurodevelopmental disorders in preterm infants.

BACKGROUND: Preterm infants have an increased risk of neurodevelopmental disorders. We established a direct quantitative comparison of the association between the degree of prematurity and three different neurodevelopmental disorders. METHODS: In this cohort study, we combined data from 995,498 children in the Danish Medical Birth Register, from birth years 1997-2013, with information on cerebral palsy, epilepsy, and special educational needs. We estimated the gestational week-specific prevalence and risk for each of the disorders. RESULTS: The risk ratio of cerebral palsy at gestational weeks 21-24, compared to term birth, was more than ten times higher than for the two other disorders. The prevalence of epilepsy and special educational needs declined almost parallel, with 9.2% (4.6%-13.5%) and 12.5% (11.2%-13.7%), respectively, per week of gestation toward term birth. Cerebral palsy did not decline similarly: from gestational weeks 21-24 until week 29 the prevalence declined insignificantly by 0.6% (-11.1%-11.0%) per week; whereas from week 29 until term, the prevalence declined markedly by 36.7% (25.9%-45.9%) per week. CONCLUSIONS: The prevalence and risk of cerebral palsy are affected differently by the degree of prematurity compared with epilepsy and special educational needs, possibly reflecting important differences in cerebral pathophysiology. IMPACT: For each week of gestation toward term birth, there was a clear log-linear decline in the prevalence of early childhood epilepsy and special educational needs. In contrast, the risk of cerebral palsy was high at the earliest gestational age, and the prevalence did not decline significantly until gestational week 29, from where it declined notably by nearly 40% for each week of gestation until term birth. Our results indicate important differences in the pathophysiological processes that associate preterm birth with these three neurodevelopmental disorders.

Prediction of ABO hemolytic disease of the newborn using pre- and perinatal quantification of maternal anti-A/anti-B IgG titer.

BACKGROUND: Hemolysis in fetus/newborns is often caused by maternal antibodies. There are currently no established screening procedures for maternal ABO antibodies harmful to fetus/newborn. We investigated the clinical significance, and predictive value of maternal anti-A/B titer for hyperbilirubinemia in ABO-incompatible newborns. METHODS: We conducted a case-control study of blood group O mothers and their ABO-compatible (O) vs. -incompatible (A/B) newborns receiving phototherapy, and of ABO-incompatible newborns receiving phototherapy vs. no phototherapy. Newborn data and treatment modalities were recorded, and total serum bilirubin and hemoglobin were measured. Maternal anti-A/B immunoglobulin-γ (IgG) titers were measured prenatally and perinatally, and negative and positive predictive values (NPV, PPV) were calculated to assess the risk of developing hyperbilirubinemia requiring phototherapy. RESULTS: We found a significantly higher maternal IgG antibody titer in the case group (p < 0.001). Maternal anti-A/B titers at first trimester had modest predictive values: NPV = 0.82 and PPV = 0.65 for neonatal hyperbilirubinemia; titers at birth improved the predictive values: NPV = 0.93 and PPV = 0.73. Newborn hemoglobin was significantly lower in incompatibles compared to compatibles (p = 0.034). Furthermore, increased anti-A/B IgG production during pregnancy was associated with hyperbilirubinemia and hemolysis in incompatible newborns. CONCLUSIONS: There was a significant association between maternal anti-A/B IgG titer and hyperbilirubinemia requiring treatment. IMPACT: Maternal anti-A/B IgG titer in the first trimester and at birth is predictive of hemolytic disease of the ABO-incompatible newborn. Increased IgG anti-A/B production throughout pregnancy in mothers to ABO-incompatible newborns developing hyperbilirubinemia contrasts a constant or reduced production in mothers to newborns not developing hyperbilirubinemia. Screening tools available in most immunohematology laboratories can identify clinically important IgG anti-A/B. Use of maternal samples taken at birth yielded NPV = 0.93 and PPV = 0.73.

upd(20)mat is a rare cause of the Silver-Russell-syndrome-like phenotype: Two unrelated cases and screening of large cohorts.

Silver-Russell syndrome (SRS) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly, feeding difficulties and body asymmetry. Recently, upd(20)mat has been identified in few patients with SRS-like features, suggestive of a new imprinting disorder characterized by prenatal and postnatal growth failure. Here, we describe two male patients with upd(20) and feeding difficulties, prenatal and postnatal growth retardation and normal cognitive development. During pregnancy, confined placental mosaicism for trisomy 20 was detected in one of the patients but was not investigated further until identification of upd(20)mat in the neonatal period. To evaluate whether upd(20)mat should be part of the first trier genetic diagnostic in patients with growth retardation, we screened a large cohort of patients (n = 673) referred to our laboratories for SRS-testing without detecting any upd(20). Our results, along with the existing evidence, indicate that upd(20)mat is a very rare cause of growth retardation, but should be followed up when confined placental mosaicism for trisomy 20 mosaicism is observed during pregnancy.

The impact of hemoglobin on the efficacy of phototherapy in hyperbilirubinemic infants.

BackgroundPhototherapy is the routine treatment for neonatal hyperbilirubinemia. Absorption of light in the skin transforms the native Z,Z-bilirubin to photobilirubins. This study investigates whether the hemoglobin concentration has an impact on efficacy of phototherapy, expressed by the decline of total serum bilirubin concentration (TsB).MethodsA trial was conducted on 93 infants, gestational age ≥33 weeks, with uncomplicated hyperbilirubinemia. The infants were treated with conventional phototherapy using LED light for 24 h. The median light irradiance was 66.8 µW/cm2/nm.ResultsThe median decrease in TsB after 24 h was 121 (57-199) µmol/l; the median hemoglobin was 12.0 (7.0-14.7) mmol/l. There was a significant effect of hemoglobin concentration on the decrease in TsB of -3.61 µmol/mmol hemoglobin (P=0.022), after adjusting for initial TsB and postnatal age. That is, assuming the same initial TsB and postnatal age, for each mmol/l increase in hemoglobin, the decrease in TsB was 3.61 µmol/l smaller. In our hemoglobin range, the decrease in TsB is reduced by 28 µmol/l (23%).ConclusionIncreasing hemoglobin levels led to a decrease in the efficacy of phototherapy. Our data provide additional support for the conclusion that the transformation of bilirubin to photobilirubins takes place mainly in the superficial capillaries of the skin.

From neonatal lung function to lung function and respiratory morbidity at 6-year follow-up.

BACKGROUND: Lung function is traceable from infancy to adulthood. Only a few studies have examined lung function from birth to childhood longitudinally in children born moderate to late preterm. We aimed to investigate how prematurity and lung function in the neonatal period are related to lung function and respiratory morbidity at age 6 in former moderate to late preterm children compared with children born at term. METHODS: Lung function was measured in a cohort of moderately to late preterm (n = 48) and term-born (n = 53) infants in the neonatal period by FeNO, and tidal breathing flow-volume loops (TBFVL) and at age 6 (n = 52) by spirometry, whole-body plethysmograph and impulse oscillation combined with a respiratory symptom questionnaire. RESULTS: Moderate to late preterm children had a higher TPEF /TE ratio neonatally (42.6% vs. 33.7%, p = 0.02) and a lower % predicted orced expiratory volume in the first second at age 6 (94.4% vs. 101.9%, p = 0.01) compared to term-born children. We found a significant association between the variability of neonatal tidal volume and effective airway resistance at age 6 (ß = -0.34, p = 0.03). No association between neonatal FeNO or TBFVL and respiratory morbidity at 6-year follow-up was shown. CONCLUSION: Children born moderate to late preterm had lower lung function at age 6 than term-born children. We did not find evidence for the use of neonatal tidal breathing parameters as a predictor for subsequent respiratory morbidity or lung function, however sample size was small.

Blood-Biomarkers for Glucose Metabolism in Preterm Infants.

This was an exploratory, prospective, longitudinal, cohort study that aimed to establish "healthy" reference levels related to growth parameters and glucose metabolites in preterm infants. This was conducted to further investigate growth and metabolic disturbances potentially related to neonatal illness. The study sample consisted of 108 preterm infants born before 32 weeks in 2018-2019 in the Capital Region of Denmark. Repetitive blood samples were acquired at the neonatal wards, while clinical data were obtained from the regional hospital medical record system. Thirty-four "healthy" preterm infants (31%) were identified. The "ill" infants were divided into four subgroups dependent on gestational age and small for gestational age. Reference levels for the growth parameters and metabolic biomarkers glucose, albumin, and adiponectin, and two glucose control indicators, glycated albumin and fructosamine, were determined for the "healthy" and "ill" subgroups. The "ill" extremely preterm infants had increased glucose levels (mean difference 0.71 mmol/L, 95% CI 0.23; 1.18 mmol/L) and glycated albumin (corrected; %) (mean difference 0.92 mmol/L, 95% CI 0.38 mmol/L;1.47 mmol/L) compared to the "healthy" infants. In "ill" extremely preterm infants and "ill" very preterm infants born small for gestational age, levels of biomarkers containing proteins were decreased. In the "Ill" extremely preterm infants and infants born small for gestational age, postnatal growth was continuously decreased throughout the postconceptional period. The short-term glucose-control indicator, glycated albumin (corrected; %), reflected well the high glucose levels due to its correction for the depleted plasma-protein pool.

Anxiety in adolescents born preterm or with very low birthweight: a meta-analysis of case-control studies.

AIM: To determine if adolescents who are born very preterm (<32 wks; of gestation) and/or with very low birthweight (VLBW; <1500 g) have a higher risk of experiencing clinically significant anxiety problems. METHOD: We used a systematic review and meta-analysis. We searched the databases ISI Web of Knowledge, PubMed, PsycNET, Educational Resources Information Center (ERIC), Latin American and Caribbean Literature on the Health Sciences (LILACS), and Virtual Health Library (VHL) with equivalent search expressions (from the databases' inception to June 2011). Also, we screened reference lists of identified articles. We selected case-control studies of adolescents 11 to 20 years old who were very preterm/VLBW and had a matched reference group born at term with normal birthweight that reported a validated anxiety outcome measure. For data extraction, two authors independently reviewed titles, abstracts, and full articles identified through the searches. Subsequently two authors independently extracted data. RESULTS: We included six studies with 1519 adolescents (787 very preterm/VLBW, 732 comparisons). The general risk of developing clinically significant anxiety problems was nearly doubled (p<0.05) in the very preterm/VLBW population (OR 2.27, 95% confidence interval 1.15-4.47). The overall prevalences were 9.9% in the very preterm/VLBW group and 5.5% in the comparison group. INTERPRETATION: Those born very preterm/VLBW have an increased risk of developing clinically significant anxiety problems in adolescence.

Socio-economic achievements of individuals born very preterm at the age of 27 to 29 years: a nationwide cohort study.

AIM: To describe the socio economic achievement of individuals born very preterm (VPT) at the age of 27 to 29 years. METHOD: Demographic and social data were extracted from national registers for all individuals born between 1974 and 1976 in Denmark (n=208 656). Of these, 203 283 individuals were alive in 2006. We compared VPT individuals (gestational age <33wks, n=1422; 51.8% males, n=736) with individuals born at term (>36wks, n=192 223; 51.1% males, n=98 240), of whom 4.08% (n=58) of the VPT and 0.19% (n=373) of the term individuals had a diagnosis of cerebral palsy (CP). RESULTS: Overall results in the two groups were similar, but significant differences appeared. The VPT group had a lower educational level than the term group: 23.9% versus 16.3% had a basic education (corresponding to attendance at basic school for 9y or less; odds ratio [OR] =1.61, 95% confidence interval [CI] 1.42-1.82). Similarly, 31.9% versus 37.6% had a tertiary education (corresponding to different levels of professional education; OR=0.77, CI 0.69-0.86). Net income was 11% lower in the VPT group and 10.8% versus 5.3% were receiving welfare support (OR=2.14, CI 1.81-2.55). In the VPT group 59% versus 52% did not have children (p<0.001) and there were more individuals living alone without children (28.8% vs 21.8%; OR=1.45, CI 1.29-1.63). INTERPRETATION: VPT birth in the 1970s in Denmark is associated with a highly statistically significant educational and social disadvantage persisting into young adulthood. CP increased the relative risk of social disadvantage in VPT individuals. However, the majority of the survivors are well integrated in society.

Personality in Adults Who Were Born Very Preterm.

AIM: To investigate the personality in very preterm individuals (VPT; gestational age, GA, <32 weeks) at adult age in two cohorts born in 1974-76 and 1980-82, respectively, and to illuminate the effect of increased survival rates and the clinical implications of deviations in personality. METHOD: Demographic data were extracted for all individuals born in Denmark in 1974-76 and 1980-82. From each period one index-group each comprising 150 individuals with the lowest gestational age was selected. Thereafter two control groups born at term were matched by gender, age and residential area. Personality was assessed with the short version of NEO PI-R, and psychiatric diagnoses were obtained from the Danish Psychiatric Central Research Register. RESULTS: Of all the individuals born <32 weeks of gestation in 1980-82 67% were alive in 2006 vs. 43% of those born in 1974-76 (p<0.0001). A total of 433 individuals participated in the study, 76% of the VPT groups (n = 227, mean GA = 27.9) and 69% of the control groups (n = 206). There were no significant differences on personality scores between the two VPT groups. Compared to the control groups, the combined VPT groups scored higher on neuroticism (p = 0.005) and agreeableness (p = 0.012), but lower on extraversion (p = 0.002). Psychiatric disorder was strongly associated with higher scores on neuroticism and lower scores on extraversion. INTERPRETATION: Improved survival of VPT infants was not associated with increased deviances in the personality as adults. The personality traits in VPT individuals differ moderately from those of term born controls. High scores in neuroticism and low scores in extraversion were associated with increased risk psychiatric disorders. VPT adults also showed signs of positive adaptation in the form of an agreeable and confident attitude towards others. WHAT THIS PAPER ADDS: The much improved survival rate in very preterm infants during the early years of active neonatology was not associated with increased risk of personality deviation. There are signs of positive adaptation in the form of increased agreeableness in young adults born very preterm.

Gestational age and basic school achievements: a national follow-up study in Denmark.

OBJECTIVE: Children born at <32 weeks' gestation are at increased risk of intellectual impairment. Few studies have focused on the majority of preterm children born at 32 to 36 weeks' gestation. We aimed to investigate the association between the full range of gestational ages at birth and the risk of not completing basic school. METHODS: This longitudinal, register-based study included all live-born infants in Denmark from 1988 to 1989. Data were obtained from national registers. School achievements were evaluated by using the examination marks. The association between gestational age and not completing basic school was estimated, taking into account the effect of their parents' educational level, being small for gestational age, plurality, and cerebral palsy. RESULTS: The cohort constituted 120,585 infants, of whom 118,281 (98.6%) were alive in 2007. Of these infants, 5.01% (n = 5.928) were born before 37 weeks' gestation. Of the subjects born before 37 weeks' gestation, 11.5% (95% confidence interval: 10.7-12.4) did not complete basic school compared with 7.5% (95% confidence interval: 7.3-7.6) of those born at term. The percentage of subjects who did not complete basic school increased with decreasing gestational age. The increase was steeper at <31 weeks (4.2% per week) than at 31 to 36 weeks' gestation (0.5% per week). CONCLUSIONS: The risk of not completing basic school increased with decreasing gestational age. The risk was moderate at ≥31 weeks' gestation and increased steeply at <31 weeks' gestation. The increase at <31 weeks' gestation was only partly explained by cerebral palsy.

Early nasal continuous positive airway pressure in a cohort of the smallest infants in Denmark: neurodevelopmental outcome at five years of age.

AIM: To evaluate neurodevelopmental outcome at age 5 y of age in a cohort of preterm children treated mainly with nasal continuous positive airway pressure (CPAP) in the neonatal period. METHODS: A national prospective observational study was conducted in Denmark which included all 269 surviving children with a birthweight below 1000 g or a gestational age below 28 wk born in Denmark in between 1994 and 1995. A total of 164 children (61%) had been treated with nasal CPAP only in the neonatal period. A reference group (n = 76) of term children was studied in parallel. RESULTS: Of the 269 surviving children, 252 (94%) were examined. Twenty-four children (10%) had cerebral palsy, and three children were blind. No case of hearing impairment was detected. Nineteen percent of the index children had an IQ score <-- 2 SD and 42% had an IQ score <-- 1 SD of the mean score of the reference group. CONCLUSIONS: The intellectual development of children in this cohort treated with early nasal CPAP did not suggest a higher proportion of adverse effects on the brain compared to the published follow-up studies of preterm children treated with mechanical ventilation. In our population-based cohort, however, the survival rate for infants below 25 wk of gestation was relatively low and this may indicate a limit for the use of early nasal CPAP.