Walter C. Allan

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the childs neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Maternal thyroid deficiency and pregnancy complications: implications for population screening

Objective To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. Methods TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. Results Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9–9.5). Other pregnancy complications did not occur more frequently Conclusion From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age.

OBJECTIVES. Our goals were to compare cognitive, language, behavioral, and educational outcomes of preterm children to term controls and to evaluate the impact of neonatal brain injury, indomethacin, and environmental risk factors on intellectual function at 12 years of age. METHODS. A total of 375 children born in 1989–1992 with birth weights of 600 to 1250 g enrolled in the Indomethacin Intraventricular Hemorrhage Prevention Trial and 111 controls were evaluated. Neuropsychometric testing, neurologic examination, and interviews on educational needs were completed. Severe brain injury was defined as the presence of grade 3 to 4 indomethacin intraventricular hemorrhage, periventricular leukomalacia, or severe ventriculomegaly on cranial ultrasound. RESULTS. On the Wechsler Scales of Intelligence for Children, the preterm cohort obtained a full-scale IQ of 87.9 ± 18.3, verbal IQ of 90.8 ± 18.9, and performance IQ of 86.8 ± 17.9. Preterm children obtained scores 6 to 14 points lower than term controls on all psychometric tests after adjustment for sociodemographic factors. On the Clinical Evaluation of Language Fundamentals (test of basic language skills), 22% to 24% of preterm children scored in the abnormal ranges (<70) as opposed to 2% to 4% of controls. Preterm children with and without brain injury required more school services (76% and 44% vs 16%), and support in reading (44% and 28% vs 9%), writing (44% and 20% vs 4%), and mathematics (47% and 30% vs 6%) compared with controls. Preterm children also displayed more behavior problems than their term counterparts. Severe neonatal brain injury was the strongest predictor of poor intelligence. Antenatal steroids, higher maternal education, and 2-parent family were associated with better cognition, whereas minority status incurred a disadvantage. Indomethacin did not affect intellectual function among preterm children. CONCLUSIONS. Preterm children born in the early 1990s, especially those with severe brain injury, demonstrate serious deficits in their neuropsychological profile, which translates into increased use of school services at 12 years.

Maternal obesity and markers of inflammation in pregnancy.

OBJECTIVES To evaluate whether obesity is associated with changes in pro-inflammatory and immunomodulatory cytokines in pregnancy. METHODS We performed a cross-sectional study using maternal serum from the early second trimester to examine biomarkers associated with inflammation in relation to maternal body mass index (n=80 total). RESULTS Leptin and high sensitivity C-reactive protein were significantly different between groups and increased with increasing body mass index. MCP-1 was significantly increased in the morbidly obese mothers. Interleukin-2 exhibited a U-shaped relationship with body mass index; transforming growth factor-beta1 demonstrated a nonsignificant negative trend with body mass index; and the levels of hepatocyte growth factor and tumor necrosis factor-alpha did not differ appreciably between groups. CONCLUSIONS Maternal obesity in pregnancy is associated with changes in cytokines, protein hormones and acute phase proteins in the second trimester, with an increase in MCP-1 in the morbid obesity category, and an increase in Leptin and hsCRP with increasing BMI category.

Executive and Memory Function in Adolescents Born Very Preterm

BACKGROUND: Many preterm children display school difficulties, which may be mediated by impairment in executive function and memory. OBJECTIVE: To evaluate executive and memory function among adolescents born preterm compared with term controls at 16 years. METHODS: A total of 337 of 437 (77%) adolescents born in 1989 to 1992 with a birth weight < 1250 g and 102 term controls were assessed with a battery of executive function and memory tasks. Multiple regression analyses were used to compare groups and to identify associations between selected factors and outcomes among preterm subjects. RESULTS: Adolescents born preterm, compared with term controls, showed deficits in executive function in the order of 0.4 to 0.6 SD on tasks of verbal fluency, inhibition, cognitive flexibility, planning/organization, and working memory as well as verbal and visuospatial memory. After exclusion of adolescents with neurosensory disabilities and full-scale IQ < 70, significant group differences persisted on most tests. Preterm subjects, compared with term controls, were at increased risk of exhibiting problems related to executive dysfunction, as measured with the Behavior Rating Inventory of Executive Function, on the Metacognition Index (odds ratio [OR]: 2.5 [95% confidence interval (CI): 1.2–5.1]) and the Global Executive Composite (OR: 4.2 [95% CI: 1.6–10.9]), but not on the Behavioral Regulation index (OR: 1.5 [95% CI: 0.7–3.5]). Among adolescents born preterm, severe brain injury on neonatal ultrasound and lower maternal education were the most consistent factors associated with poor outcomes. CONCLUSIONS: Even after exclusion of preterm subjects with significant disabilities, adolescents born preterm in the early 1990s were at increased risk of deficits in executive function and memory.

Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial.

We enrolled 61 neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that indomethacin (0.1 mg/kg given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would prevent extension of intraventricular hemorrhage. Twenty-seven infants were assigned to receive indomethacin; 34 infants received saline placebo. There were no significant differences between the two groups in birth weight, gestational age, sex, Apgar scores, percentage of infants treated with surfactant, or distribution of hemorrhages at the time of the first cranial sonogram (echo-encephalogram). Within the first 5 days, 9 of 27 indomethacin-treated and 12 of 34 saline solution-treated infants had extension of their initial intraventricular hemorrhage (p = 1.00). Four indomethacin-treated and three saline solution-treated infants had parenchymal extension of the hemorrhage. Indomethacin was associated with closure of a patent ductus arteriosus by the fifth day of life (p = 0.003). There were no differences in adverse events attributed to indomethacin. We conclude that in very low birth weight infants with low grade intraventricular hemorrhage within the first 6 postnatal hours, prophylactic indomethacin therapy promotes closure of the patent ductus arteriosus and is not associated with adverse events, but does not affect the cascade of events leading to parenchymal involvement of intracranial hemorrhage.

Risk factors for early intraventricular hemorrhage in low birth weight infants

Because earlier studies suggested that preterm infants with germinal matrix hemorrhage or intraventricular hemorrhage or both (GMH/IVH) present within the first 12 postnatal hours are at greatest risk for the development of high-grade hemorrhage and neurodevelopmental disability, we examined the risk factors for this insult among 229 neonates of 600 to 1250 gm birth weight in a multicenter study. All had echoencephalography (ECHO) within the first 11 hours and serially for the next 20 days; risk factor data were collected prospectively. Forty-three infants had GMH/IVH within the first 5 to 11 hours (mean age at ECHO 7.7 hours): 18 GMH and 21 grade II, 1 grade III, and 3 grade IV IVH. One hundred eighty-six infants did not have GMH/IVH at a mean age of 7.9 hours. Both groups of infants were similar in birth weight, gestational age, maternal risk factors, cord pH values, and surfactant therapy before ECHO. The group with early IVH had more vertex presentations than the group without early IVH (79% vs 55%, p = 0.043), less maternal tocolytic use (42% vs 60%, p = 0.029), and more vaginal deliveries (67% vs 44%, p = 0.005). In the first 21 days, severe IVH developed in 12 infants with early IVH and in 6 infants without early IVH (p < 0.001). There were more neonatal deaths (16% vs 6%, p = 0.035) and more deaths at any time during the primary hospitalization (23% vs 9%, p = 0.010) among the early IVH group than among the group without early IVH. Multivariate analysis indicated that the mode of delivery, fetal presentation, and birth weight were important and independent prognostic indicators of IVH.

Evidence for Catch-up in Cognition and Receptive Vocabulary Among Adolescents Born Very Preterm

BACKGROUND: Very preterm adolescents display persistent deficits in neuropsychological functions. OBJECTIVE: To compare cognitive and language outcomes at 16 years and cognitive and receptive vocabulary trajectories throughout school years between very preterm and term children and to determine child and family factors associated with better developmental trajectories. DESIGN AND METHODS: At 8, 12, and 16 years, 322 very preterm children with birth weights of 1250 g or less and 41 term children had cognitive and language testing. Hierarchical growth-curve modeling was used to delineate the differences in cognitive and receptive vocabulary development between participants. Cluster analyses allowed for the characterization of very preterm children with different patterns of cognitive and receptive vocabulary development. RESULTS: At 16 years, very preterm adolescents had deficits in general cognition and higher-order language skills (phonological awareness and phonemic decoding) compared with term peers. Although the between-group difference in cognitive scores remained stable from 8 to 16 years, very preterm children demonstrated catch-up gains in receptive vocabulary during the same period. Moreover, subgroups of very preterm children displayed developmental trajectories in cognition similar to term children (55% on the vocabulary and 46% on the block-design subtests). These children had lower rates of neurosensory impairment and mothers with higher education and were from an ethnic nonminority. CONCLUSIONS: Significant catch-up in receptive vocabulary is observed by the age of 16 years among very preterm children compared to term peers. The absence of neurosensory impairment and residing in a favorable socioeconomic milieu are associated with the most optimal developmental trajectories.

Trajectories of Receptive Language Development From 3 to 12 Years of Age for Very Preterm Children

OBJECTIVES: The goal was to examine whether indomethacin use, gender, neonatal, and sociodemographic factors predict patterns of receptive language development from 3 to 12 years of age in preterm children. METHODS: A total of 355 children born in 1989–1992 with birth weights of 600 to 1250 g were evaluated at 3, 4.5, 6, 8, and 12 years with the Peabody Picture Vocabulary Test-Revised. Hierarchical growth modeling was used to explore differences in language trajectories. RESULTS: From 3 to 12 years, preterm children displayed catch-up gains on the Peabody Picture Vocabulary Test-Revised. Preterm children started with an average standardized score of 84.1 at 3 years and gained 1.2 points per year across the age period studied. Growth-curve analyses of Peabody Picture Vocabulary Test-Revised raw scores revealed an indomethacin-gender effect on initial scores at 3 years, with preterm boys assigned randomly to receive indomethacin scoring, on average, 4.2 points higher than placebo-treated boys. However, the velocity of receptive vocabulary development from 3 to 12 years did not differ for the treatment groups. Children with severe brain injury demonstrated slower gains in skills over time, compared with those who did not suffer severe brain injury. Significant differences in language trajectories were predicted by maternal education and minority status. CONCLUSION: Although indomethacin yielded an initial benefit for preterm boys, this intervention did not alter the developmental trajectory of receptive language scores. Severe brain injury leads to long-term sequelae in language development, whereas a socioeconomically advantaged environment supports better language development among preterm children.

Mid-Gestational Maternal Free Thyroxine Concentration and Offspring Neurocognitive Development at Age Two Years

CONTEXT Lower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy. OBJECTIVE The objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy. DESIGN This was an observational, nested case-control study. SETTING The study was conducted at physician offices and prenatal clinics throughout Maine. STUDY SUBJECTS Between May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T(4) was measured in stored second-trimester sera from euthyroid women (TSH 0.1-3.5 mIU/ml; n = 5560). Women with free T(4) at the third centile or less (n = 99) were matched with women whose free T(4) was at the 10th to the 90th centile (n = 99). INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURE Bayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables. RESULTS Unadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the childs age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14). CONCLUSIONS Isolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.