Objective-Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.Methods-Infants born very preterm (n=86, 24-32 weeks gestational age) were followed prospectively from birth, and studied with MRI, 3D MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI): scan 1 early in life (median 32.1 weeks) and scan 2 at termequivalent age (median 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/ choline), lactate to choline ratios, average diffusivity (D AV ) and white matter fractional anisotropy (FA) from up to seven white and four subcortical grey matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analysed using generalized estimating equation modelling adjusting for clinical confounders such as illness severity, morphine exposure, brain-injury and surgery.Results-After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β= −0.0002, p=0.028) and reduced subcortical grey matter NAA/choline (β= −0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.Interpretation-Early procedural pain in very preterm infants may contribute to impaired brain development.

No abstract

A woman 45 years of age or older is considered to be of very advanced maternal age. In Australia, 0.1% of parturients are in this category at present. The investigators undertook a retrospective cohort study of women aged 45 or above at the time of delivery, all of whom delivered at 20 or more weeks of gestation. In the 108,818 women reviewed, 76 women of very advanced maternal age had 77 pregnancies (incidence ϭ 0.7 per 1000 births). The mean age was 46 years. Sixteen women in the study were primiparous. In multiparas, a mean of 8.8 years had passed since the last live birth. More than half the women had had at least one miscarriage and 13 (17% of the total) reported having 3 or more. Only 14% of women required assisted reproduction. The most frequent medical problems were depression, present in 9 women, and uterine leiomyomas in 4. No chromosomal abnormalities were found in the 53% of pregnancies that were evaluated.Two thirds of pregnancies were free of complications. Ten women had pregnancy-related hypertensive disorders compared with 10% of women 20 to 29 years of age. Two women were delivered before term because of preeclampsia. Gestational diabetes was diagnosed in 8% of pregnancies; only one woman received insulin. Labor began spontaneously in 36% of pregnancies and was induced in 17%, most often "electively" or because of postdate status or spontaneous rupture of membranes at term. The rate of cesarean section was 49% compared with 23% in the younger women. Four women required manual removal of the placenta because of bleeding, and 3 had postsection wound infections.Eight of 78 live-born infants were small-for-gestational age, whereas 6 were large-for-gestational age. Seven singleton births and both sets of twins were born prematurely for a variety of reasons, the most common being premature rupture of membranes. Thirteen infants, 17% of the total, were admitted to the special care nursery; prematurity and respiratory distress syndrome accounted for 6 and 4 admissions, respectively. The overall rate of special care was 16.5%. Five infants in the study group (6%) had congenital abnormalities.The findings in this large-scale study of women aged 45 or above are, in general, reassuring for older women who are in good health and who have a chromosomally normal fetus.

WHAT'S KNOWN ON THIS SUBJECT: Greater numbers of invasive procedures from birth to term-equivalent age, adjusted for clinical confounders, are associated with altered brain microstructure during neonatal care and poorer cognitive outcome at 18 months' corrected age in children born very preterm.WHAT THIS STUDY ADDS: Altered myelination at school age is associated with greater numbers of invasive procedures during hospitalization in very preterm children without severe brain injury or neurosensory impairment. Greater numbers of invasive procedures and altered brain microstructure interact to predict lower IQ. abstract BACKGROUND: Very preterm infants (born 24-32 weeks' gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS:Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5-7.7). T 1 -and T 2 -weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children-IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS:Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS:Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ. Pediatrics 2014;133:412-421