[Show abstract][Hide abstract] ABSTRACT: AimTo evaluate to what extent extremely preterm children (<28 weeks’ gestational age) of overweight (BMI 25-29) or obese (BMI ≥ 30) women are at increased risk of adverse development at 2 years measured with the Bayley Scales of Infant Development II in a multi-center prospective cohort study.Methods
Heights and pre-pregnancy weights of the mothers of 852 preterm born children were collected and included in multinomial logistic regression models.ResultsCompared to newborns born to mothers with normal BMIs, newborns of obese mothers, but not those of overweight mothers, were more likely to have Bayley Scales indices more than 3 standard deviations below the reference mean (mental: OR = 2.1; 95% CI: 1.3, 3.5) (motor: OR = 1.7; 95% CI: 1.1, 2.7). These associations were even more prominent in children who did not have the intermittent or sustained systemic inflammation profile previously shown to be associated with severely impaired development (mental: OR = 4.6; 95% CI: 1.6, 14) (motor: OR = 3.7; 95% CI: 1.5, 8.9).Conclusion
Maternal obesity is associated with an increased risk of impaired offspring development. Some of this impaired development cannot be attributed to confounding due to immaturity, socio-economic correlates, or neonatal systemic inflammation.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background
Very little is known about the prevalence, antecedents and correlates of impaired visual fixation in former very preterm newborns.
In the multi-center ELGAN Study sample of 1057 infants born before the 28th week of gestation who had a developmental assessment at 2 years corrected age, we identified 73 who were unable to follow an object across the midline. We compared them to the 984 infants who could follow an object across the midline.
In this sample of very preterm newborns, those who had impaired visual fixation were much more likely than those without impaired visual fixation to have been born after the shortest of gestations (odds ratio = 3.2; 99% confidence interval =1.4, 7.5) and exposed to maternal aspirin (OR: 5.2; 99% CI: 2.2, 12). They were also more likely than their peers to have had prethreshold ROP (OR: 4.1; 99% CI: 1.8, 9.0). At age 2 years, the children with impaired fixation were more likely than others to be unable to walk (even with assistance) (OR: 7.5; 99% CI: 2.2, 26) and have a Mental Development Index more than 3 standard deviations below the mean of a normative sample (OR:3.6; 99% CI: 1.4, 8.2).
Risk factors for brain and retinal damage, such as very low gestational age, appear to be risk factors for impaired visual fixation. This inference is further supported by the co-occurrence at age 2 years of impaired visual fixation, inability to walk, and a very low Mental Development Index
[Show abstract][Hide abstract] ABSTRACT: Purpose
To explain why very preterm newborns who develop retinopathy of prematurity (ROP) appear to be at increased risk of abnormalities of both brain structure and function.
A total of 1,085 children born at <28 weeks' gestation had clinically indicated retinal examinations and had a developmental assessment at 2 years corrected age. Relationships between ROP categories and brain abnormalities were explored using logistic regression models with adjustment for potential confounders.
The 173 children who had severe ROP, defined as prethreshold ROP (n = 146) or worse (n = 27) were somewhat more likely than their peers without ROP to have brain ultrasound lesions or cerebral palsy. They were approximately twice as likely to have very low Bayley Scales scores. After adjusting for risk factors common to both ROP and brain disorders, infants who developed severe ROP were at increased risk of low Bayley Scales only. Among children with prethreshold ROP, exposure to anesthesia was not associated with low Bayley Scales.
Some but not all of the association of ROP with brain disorders can be explained by common risk factors. Most of the increased risks of very low Bayley Scales associated with ROP are probably not a consequence of exposure to anesthetic agents.
Journal of American Association for Pediatric Ophthalmology and Strabismus 06/2014; 18(3):241–247. DOI:10.1016/j.jaapos.2014.01.014 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The offspring of obese women are at increased risk for systemic inflammation. Blood concentrations of inflammatory proteins in preterm newborns of obese women have not been reported.
To compare blood concentrations in the highest quartile for gestational age of inflammatory proteins and day of blood specimen collection on two days at least one week apart of newborns of overweight (i.e., BMI 25-29) and obese women (i.e., BMI≥30) with newborns of women with lower BMIs. Because deliveries for spontaneous indications are more likely than those for other indications to be associated with inflammation, we evaluated spontaneous indication deliveries separately from maternal or fetal indications.
Prospective cohort study.
We measured from 939 children born before the 28th week of gestation 25 inflammation-related proteins in blood obtained on postnatal day 1 (range 1-3), day 7 (range 5-8) and day 14 (range 12-15).
Among infants delivered for spontaneous indications, maternal BMI was not related to elevated concentrations of any protein. Among infants delivered for maternal (i.e., preeclampsia) or fetal indications, those whose mother was overweight or obese were more likely than others to have elevated concentrations of inflammation proteins.
Maternal pre-pregnancy overweight and obesity appear to contribute to a pro-inflammatory state in very preterm newborns delivered for maternal or fetal indications. Our failure to see a similar pattern among newborns delivered for spontaneous indications, which often have inflammatory characteristics, might reflect competing risks.
Early human development 09/2013; 89(12). DOI:10.1016/j.earlhumdev.2013.09.014 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Isolated periventricular leukomalacia, defined as periventricular leukomalacia unaccompanied by intraventricular hemorrhage, is reportedly increased in newborns with systemic hypotension and in infants who received treatment for systemic hypotension or a patent ductus arteriosus.
This study sought to determine if the risk profile of one or more hypoechoic lesions unaccompanied by intraventricular hemorrhage, our surrogate for isolated periventricular leukomalacia, differs from that of one or more hypoechoic lesions preceded or accompanied by intraventricular hemorrhage. We compared extremely preterm infants (i.e., gestation 23-27 weeks) with each of these entities to 885 extremely preterm infants who had neither an isolated hypoechoic lesion nor a hypoechoic lesion preceded or accompanied by intraventricular hemorrhage.
The risk of a hypoechoic lesion with intraventricular hemorrhage (N = 61) was associated with gestation <25 weeks, high Score for Acute Neonatal Physiology, early recurrent or prolonged acidemia, analgesic exposure, and mechanical ventilation 1 week after birth.
In this large, multicenter sample of extremely low gestational age newborns, the risk profile of a hypoechoic lesion unaccompanied by intraventricular hemorrhage differed from that of a hypoechoic lesion with intraventricular hemorrhage. This suggests that hypoechoic lesions accompanied or preceded by intraventricular hemorrhage (our surrogate for periventricular hemorrhagic infarction) may have a different causal pathway than hypoechoic lesions without intraventricular hemorrhage, our surrogate for periventricular leukomalacia.
[Show abstract][Hide abstract] ABSTRACT: Background
We sought to disentangle the contributions of perinatal systemic inflammation and small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at age 2 years.
We measured the concentration of 25 inflammation-related proteins in blood obtained during the first 2 postnatal weeks from 805 infants who were born before the 28th week of gestation and who had MDI measurements at age 2 years and were able to walk independently.
SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on 2 days a week apart) were at greater risk of an MDI < 55, but not 55–69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of IL-1beta, TNF-alpha, or IL-8 during the first two postnatal weeks were at even higher risk of an MDI < 55 than their SGA peers without systemic inflammation and of their non-SGA peers with systemic inflammation.
SGA appears to place very preterm newborns at increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk.
Pediatric Research 12/2012; 73(3). DOI:10.1038/pr.2012.188 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to evaluate the association between maternal medication use during pregnancy and cerebral white matter damage and cerebral palsy (CP) among very preterm infants.
This analysis of data from the Extremely Low Gestational Age Newborns (ELGAN) Study included 877 infants born <28 weeks' gestation. Mothers were interviewed, charts were reviewed, placentas were cultured and assessed histologically, and children were evaluated at 24 months corrected age. A diagnostic algorithm classified neurologic findings as quadriparetic CP, diparetic CP, hemiparetic CP, or no CP.
After adjustment for the potential confounding of disorders for which medications might have been indicated, the risk of quadriparetic CP remained elevated among the infants of mothers who consumed aspirin (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3-6.9) and nonsteroidal antiinflammatory drugs (NSAIDs) (OR, 2.4; 95% CI, 1.04-5.8). The risk of diparetic CP was also associated with maternal consumption of an NSAID, but only if the consumption was not approved by a physician (OR, 3.5; 95% CI 1.1-11.0).
The possibility that aspirin and NSAID use in pregnancy could lead to perinatal brain damage cannot be excluded.
American journal of obstetrics and gynecology 09/2012; 207(3):192.e1-9. DOI:10.1016/j.ajog.2012.06.059 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether concentrations of inflammation-related proteins are elevated in the blood of preterm newborns who develop cerebral white matter damage.
We measured 25 proteins in blood collected on days 1, 7, and 14 from 939 infants born before the 28th week of gestation. Brain ultrasound scans were read by at least two sonologists, who agreed on the presence or absence of lesions. A protein concentration was considered elevated if it was in the highest quartile for gestational age and the day on which the specimen was collected.
In time-oriented models, elevated concentrations of vascular endothelial growth factor receptor 1, serum amyloid A, and macrophage inflammatory protein 1β on day 1 and interleukin-8 on day 7 were associated with increased risk of ventriculomegaly. Elevated concentrations of macrophage inflammatory protein 1β on day 1 and intercellular adhesion molecule 1 on day 7 were associated with increased risk of an echolucent lesion. Infants with elevated concentrations of inflammation-related proteins on two separate days were at significantly increased risk for ventriculomegaly, but at only modestly increased risk for an echolucent lesion.
Concentrations of inflammation-related proteins in the circulation in the first days after preterm birth provide information about the risk of sonographic white matter damage. The inflammatory process might begin in utero.
The Journal of pediatrics 06/2011; 158(6):897-903.e1-5. DOI:10.1016/j.jpeds.2010.11.059 · 3.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up.
The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders.
Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis.
The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.
Journal of perinatology: official journal of the California Perinatal Association 01/2011; 31(8):524-34. DOI:10.1038/jp.2010.201 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate reader variability of white matter lesions seen on cranial sonographic scans of extreme low gestational age neonates (ELGANs).
In 1,452 ELGANs, cranial sonographic scans were obtained in the first and second postnatal weeks, and between the third postnatal week and term. All sets of scans were read independently by two sonologists. We reviewed the use of four diagnostic labels: early periventricular leucomalacia, cystic periventricular leucomalacia, periventricular hemorrhagic infarction (PVHI), and other white matter diagnosis, by 16 sonologists at 14 institutions. We evaluated the association of these labels with location and laterality of hyperechoic and hypoechoic lesions, location of intraventricular hemorrhage, and characteristics of ventricular enlargement.
Experienced sonologists differed substantially in their application of the diagnostic labels. Three readers applied early periventricular leucomalacia to more than one fourth of all the scans they read, whereas eight applied this label to ≤5% of scans. Five applied PVHI to ≥10% of scans, while three applied this label to ≤5% of scans. More than one third of scans labeled cystic periventricular leucomalacia had unilateral hypoechoic lesions. White matter abnormalities in PVHI were more extensive than in periventricular leucomalacia and were more anteriorly located. Hypoechoic lesions on late scans tended to be in the same locations, regardless of the diagnostic label applied.
Experienced sonologists differ considerably in their tendency to apply diagnostic labels for white matter lesions. This is due to lack of universally agreed-upon definitions. We recommend reducing this variability to improve the validity of large multicenter studies.
[Show abstract][Hide abstract] ABSTRACT: We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation.
We measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology.
Within the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed. CONCLUSIONS/INFERENCES: Regardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age.
[Show abstract][Hide abstract] ABSTRACT: We sought to identify risk factors for congenital microcephaly in extremely low gestational age newborns.
Demographic, clinical, and placental characteristics of 1445 infants born before the 28th week were gathered and evaluated for their relationship with congenital microcephaly.
Almost 10% of newborns (n = 138), rather than the expected 2.2%, had microcephaly defined as a head circumference >2 SD below the median. In multivariable models, microcephaly was associated with nonwhite race, severe intrauterine growth restriction, delivery for preeclampsia, placental infarction, and being female. The risk factors for a head circumference between <1 and >2 SD below the median were similar to those of microcephaly.
Characteristics associated with fetal growth restriction and preeclampsia are among the strongest correlates of microcephaly among children born at extremely low gestational ages. The elevated risk of a small head among nonwhites and females might reflect the lack of appropriate head circumference standards.
American journal of obstetrics and gynecology 08/2010; 203(2):138.e1-8. DOI:10.1016/j.ajog.2010.05.006 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Little is known about the antecedents of microcephaly in early childhood among children born at extremely low gestational age.
To identify some of the antecedents of microcephaly at age two years among children born before the 28th week of gestation.
Observational cohort study.
1004 infants born before the 28th week of gestation.
Head circumference Z-scores of <-2 and >or=-2, <-1.
Risk of microcephaly and a less severely restricted head circumference decreased monotonically with increasing gestational age. After adjusting for gestational age and other potential confounders, the risk of microcephaly at age 2 years was increased if microcephaly was present at birth [odds ratio: 8.8 ((95% confidence interval: 3.7, 21)], alpha hemolytic Streptococci were recovered from the placenta parenchyma [2.9 (1.2, 6.9)], the child was a boy [2.8 (1.6, 4.9)], and the child's mother was not married [2.5 (1.5, 4.3)]. Antecedents associated not with microcephaly, but with a less extreme reduction in head circumference were recovery of Propionibacterium sp from the placenta parenchyma [2.9 (1.5, 5.5)], tobacco exposure [2.0 (1.4, 3.0)], and increased syncytial knots in the placenta [2.0 (1.2, 3.2)].
Although microcephaly at birth predicts a small head circumference at 2 years among children born much before term, pregnancy and maternal characteristics provide supplemental information about the risk of a small head circumference years later. Two findings appear to be novel. Tobacco exposure during pregnancy, and organisms recovered from the placenta predict reduced head circumference at age two years.
Early human development 08/2010; 86(8):515-21. DOI:10.1016/j.earlhumdev.2010.07.001 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a 2002-2004 prospective cohort study of deliveries of infants at <28 weeks at 14 US centers, the authors sought the antecedents of white matter damage evident in newborn cranial ultrasound scans (ventriculomegaly and an echolucent lesion) and of cerebral palsy diagnoses at age 2 years. Of the 1,455 infants enrolled, those whose mothers received an antenatal steroid tended to have lower risks of ventriculomegaly and an echolucent lesion than their peers (10% vs. 23%, P < 0.001 and 7% vs. 11%, P = 0.06, respectively). Risk of ventriculomegaly was increased for infants delivered because of preterm labor (adjusted odds ratio (OR) = 2.3, 95% confidence interval (CI): 1.1, 4.9), preterm premature rupture of fetal membranes (OR = 3.6, 95% CI: 1.5, 8.7), and cervical insufficiency (OR = 2.8, 95% CI: 1.4, 5.5) when compared with infants delivered because of preeclampsia. Risk of an echolucent lesion was increased for infants delivered because of preterm labor (OR = 2.7, 95% CI: 1.2, 5.7) and intrauterine growth retardation (OR = 3.3, 95% CI: 1.2, 9.4). The doubling of diparesis risk associated with preterm labor and with preterm premature rupture of fetal membranes did not achieve statistical significance, nor did the doubling of quadriparesis risk and the tripling of diparesis risk associated with cervical insufficiency.
American journal of epidemiology 09/2009; 170(7):819-28. DOI:10.1093/aje/kwp206 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extremely low gestational age newborns (ELGANs) are at increased risk of chronic lung disease (CLD) and of developmental delay. Some studies have suggested that CLD contributes to developmental delay.
We examined data collected prospectively on 915 infants born before the 28th week of gestation in 2002-2004 who were assessed at 24 months of age with the Bayley Scales of Infant Development-2nd Edition or the Vineland Adaptive Behavior Scales. We excluded infants who were not able to walk independently (Gross Motor Function Classification System score < 1) and, therefore, more likely to have functionally important fine motor impairments. We defined CLD as receipt of oxygen at 36 weeks' postmenstrual age and classified infants as either not receiving mechanical ventilation (MV) (CLD without MV) or receiving MV (CLD with MV).
Forty-nine percent of ELGANs had CLD; of these, 14% were receiving MV at 36 weeks' postmenstrual age. ELGANs without CLD had the lowest risk of a Mental Developmental Index (MDI) or a Psychomotor Developmental Index (PDI) of <55, followed by ELGANs with CLD not receiving MV, and ELGANs with CLD receiving MV (9%, 12%, and 18% for the MDI and 7%, 10%, and 20% for the PDI, respectively). In time-oriented multivariate models, the risk of an MDI of <55 was associated with the following variables: gestational age of <25 weeks; single mother; late bacteremia; pneumothorax; and necrotizing enterocolitis. The risk of a PDI of <55 was associated with variables such as single mother, a complete course of antenatal corticosteroids, early and persistent pulmonary dysfunction, pulmonary deterioration during the second postnatal week, pneumothorax, and pulmonary interstitial emphysema. CLD, without or with MV, was not associated with the risk of either a low MDI or a low PDI. However, CLD with MV approached, but did not achieve, nominal statistical significance (odds ratio: 1.9 [95% confidence interval: 0.97-3.9]) for the association with a PDI of <55.
Among children without severe gross motor delays, risk factors for CLD account for the association between CLD and developmental delay. Once those factors are considered in time-oriented risk models, CLD does not seem to increase the risk of either a low MDI or a low PDI. However, severe CLD might increase the risk of a low PDI.
[Show abstract][Hide abstract] ABSTRACT: Neurosonography can assist clinicians and can provide researchers with documentation of brain lesions. Unfortunately, we know little about the reliability of sonographically derived diagnoses.
We sought to evaluate observer variability among experienced neurosonologists.
We collected all protocol US scans of 1,450 infants born before the 28th postmenstrual week. Each set of scans was read by two independent sonologists for the presence of intraventricular hemorrhage (IVH) and moderate/severe ventriculomegaly, as well as hyperechoic and hypoechoic lesions in the cerebral white matter. Scans read discordantly for any of these four characteristics were sent to a tie-breaking third sonologist.
Ventriculomegaly, hypoechoic lesions and IVH had similar rates of positive agreement (68-76%), negative agreement (92-97%), and kappa values (0.62 to 0.68). Hyperechoic lesions, however, had considerably lower values of positive agreement (48%), negative agreement (84%), and kappa (0.32). No sonologist identified all abnormalities more or less often than his/her peers. Approximately 40% of the time, the tie-breaking reader agreed with the reader who identified IVH, ventriculomegaly, or a hypoechoic lesion in the white matter. Only about 25% of the time did the third party agree with the reader who reported a white matter hyperechoic lesion.
Obtaining concordance seems to be an acceptable way to assure reasonably high-quality of images needed for clinical research.