AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 4
July 1991
DEVELOPMENTAL FOLLOW-UP OF VERY LOW BIRTHWEIGHT PREMATURE INFANTS WITH LOW FREE THYROXINE Padmani Kama, M.D.
If a low level of free thyroxine (T4) is predictive of the true hypothyroidism in sick premature infants, long-term developmental follow-up of these infants should reveal a direct correlation between the free thyroxine level early in life and developmental disability in later years. Half of the 16 infants who were followed had normal freeT4 (0.8 ng/dl or higher) and the remaining 8 infants had a low free T4 (0.38 ± 0.15 ng/dl) during the first 2 weeks of life. Infants with low free T4 were followed sequentially during their stay in the neonatal intensive care unit and all eight showed free T4 levels more than 0.8 ng/dl by 36 to 44 weeks postconceptional age without any thyroid replacement. At follow-up, all 16 infants were functioning within normal range by Stanford-Binet testing at mean age of 4.6 years. There was no significant difference between the two groups in their motor development, hearing, language, or physical growth. Despite the small sample size, it appears there is no correlation between the free T4 levels during the first 2 weeks of life in infants 33 weeks' or less gestation and their developmental outcome at mean age of 4.6 years.
The early diagnosis of congenital hypothyroidism, followed by adequate therapy, is essential for the normal mental development of human infants. In 1957, Smith et al1 demonstrated that none of the severely hypothyroid infants who received inadequate thyroid replacement achieved an intelligence quotient of 90 or higher. Since the clinical manifestations of congenital hypothyroidism are often subtle at birth, neonatal screening programs have been implemented to facilitate early identification of neonates with hypothyroidism. Current recommendations of the American Academy of Pediatrics specify that both term and preterm infants should be screened for congenital hypothyroidism, along with other metabolic disorders, during the first week of life.2 Even though there is no reason to believe that premature infants are at higher risk of developing hypothyroidism, screening of premature sick neonates during the first postnatal week by measuring thyroxine (T4) frequently reveals low T 4 levels.34 Wilson et al5 screened similar infants using free T 4 , an active component, and found normal values. Kanarek et al6 found that 16 sick premature infants weighing 1500 gm or less had free T 4 between 4 and 76 pmol/liter
(0.3 to 5.9 ng/dl) between 5 and 10 days of age. Both free T 4 and triiodothyronine (T3) concentrations are reduced in healthy as well as sick premature neonates compared with full-term neonates during the first 10 days of life.7 This limited and discrepant literature about free T 4 levels in low birthweight infants make it difficult to interpret. In addition, there are no published data that evaluate the relationship between screening values for thyroid disease during the first week and long-term outcome of premature infants. Some short-term follow-up data are available. A 1 year follow-up of premature infants using the Gesell test revealed no significant difference between the infants with low compared with normal total T 4 levels.3 In addition, very low birthweight infants with initial low T 4 levels treated with T 4 were found to be no different developmentally at 12 months of age when compared with an untreated group in the nursery.8 In both studies infants were identified only with a low total T 4 . Since developmental data at 1 year may not detect subtle brain dysfunction or even mild to moderate intellectual impairment, follow-up studies are necessary to resolve the question of long-
Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan Reprint requests: Dr. Kama, Department of Neonatology, Sparrow Hospital, P. O. Box 30480, 1215 E. Michigan Avenue, Lansing, MI 48909
288
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
ABSTRACT
EFFECT OF LOW FREE THYROXINE/Karna
METHODS Subjects
Between July and November 1983, 78 infants 33 weeks' or less gestational age were screened for hypothyroidism during the first week of life using T 4 and thyroid stimulating hormone (TSH) from filter paper specimens. Eighty percent of these infants were on the ventilator for respiratory support and were sick premature infants. T 4 and TSH were measured by the radioimmunoassay. Thirty-three of the 78 (42%) infants had a low total T 4 (less than 6|xg/dl) and normal TSH (2 to 20 |xU/ml) levels during the first week of life. Free T 4 was measured during the second week of life in the infants with low total T 4 and normal TSH. Free T 4 determination was done by Smith and Kline Laboratory using the Amersham competitive protein binding assay. Twenty-one infants (67.8%) showed a low free T 4 (0.38 ± 0.13 ng/ dl). The remaining 12 infants with low total T 4 had a normal free T 4 of 0.8 ng/dl or higher. T 4 binding globulin (TBG) in the low free T 4 group was 23.2(18 to 33) |xg/dl. All surviving infants with low free T 4 were followed sequentially during their stay in the neonatal intensive care unit and showed free T 4 levels 0.8 ng/dl or higher between 36 and 44 weeks postconceptional age without any thyroid replacement. Follow-up of all premature infants with low total T 4 is shown in Table 1. All 33 infants required ventilator assistance for 5 or more days. Seven infants were excluded from follow-up due to large intraventricular hemorrhages (grade III or higher by Papil's classification). Four infants died and six could not be located for the follow-up assessment. The remaining 16 infants (eight infants with free T 4 less than 0.8 ng/dl and eight with more than 0.8 ng/dl) were evaluated in our follow-up clinic once a year through a mean age of 4.6 years. FOLLOW-UP MEASURES
Parameters measured include physical growth, developmental quotient, motor development, language, and hearing. Their development is reported
between 4 and 5 years of age. Physical growth (head circumference, length, and weight) was measured by a nurse and were plotted over time on a National Center for Health Statistics percentiles growth chart.9 For the purpose of this study, growth curves were divided into these three categories: (1) Catch up growth, that is, the growth curves showed an increased rate of growth; (2) consistent growth, that is, growth followed a particular percentile line; and (3) poor growth, that is, growth showed a decreasing rate of growth. Stanford-Bind testing10 was done by an experienced child psychologist to evaluate developmental quotient and language. Motor evaluation was performed by a pediatric physical therapist utilizing a modified Peabody test11 and the St. Anne Dargassies battery.12 Hearing was evaluated by an audiologist using both behavioral audiograms and tympanograms. Gross and fine motor skills, language, and hearing were divided in two groups, either normal or below the level expected for age. The Student t test (one tail) was used in the analysis to determine if statistically significant differences existed between the two groups of children for Stanford-Binet, gestational age, birthweight, and days in the hospital. The Fisher's exact test was done for the rest of the variables. P < 0.05 was considered significant. RESULTS
The 16 infants with low total T 4 were followed in the Developmental Assessment Clinic for an average of 4.6 ± 0.45 years of age. Table 2 shows infants with normal free T 4 (0.8 ng/dl or higher) were larger at birth and were discharged earlier from the hospital. Even though gestational age and days on the mechanical ventilator were not statistically different, infants with lower free T 4 level were younger and required mechanical ventilation for a longer duration of time. DEVELOPMENTAL FOLLOW-UP Physical Growth
The majority (11 of 16,fivefrom low free T 4 and six from normal free T 4 group) of infants showed catch-up growth in all three measurements of weight, height, and head circumference. One infant from the low free T 4 group showed poor or decreased growth. The rest of the infants were following their
July 1991
DEVELOPMENTAL FOLLOW-UP OF VERY LOW BIRTHWEIGHT PREMATURE INFANTS WITH LOW FREE THYROXINE Padmani Kama, M.D.
If a low level of free thyroxine (T4) is predictive of the true hypothyroidism in sick premature infants, long-term developmental follow-up of these infants should reveal a direct correlation between the free thyroxine level early in life and developmental disability in later years. Half of the 16 infants who were followed had normal freeT4 (0.8 ng/dl or higher) and the remaining 8 infants had a low free T4 (0.38 ± 0.15 ng/dl) during the first 2 weeks of life. Infants with low free T4 were followed sequentially during their stay in the neonatal intensive care unit and all eight showed free T4 levels more than 0.8 ng/dl by 36 to 44 weeks postconceptional age without any thyroid replacement. At follow-up, all 16 infants were functioning within normal range by Stanford-Binet testing at mean age of 4.6 years. There was no significant difference between the two groups in their motor development, hearing, language, or physical growth. Despite the small sample size, it appears there is no correlation between the free T4 levels during the first 2 weeks of life in infants 33 weeks' or less gestation and their developmental outcome at mean age of 4.6 years.
The early diagnosis of congenital hypothyroidism, followed by adequate therapy, is essential for the normal mental development of human infants. In 1957, Smith et al1 demonstrated that none of the severely hypothyroid infants who received inadequate thyroid replacement achieved an intelligence quotient of 90 or higher. Since the clinical manifestations of congenital hypothyroidism are often subtle at birth, neonatal screening programs have been implemented to facilitate early identification of neonates with hypothyroidism. Current recommendations of the American Academy of Pediatrics specify that both term and preterm infants should be screened for congenital hypothyroidism, along with other metabolic disorders, during the first week of life.2 Even though there is no reason to believe that premature infants are at higher risk of developing hypothyroidism, screening of premature sick neonates during the first postnatal week by measuring thyroxine (T4) frequently reveals low T 4 levels.34 Wilson et al5 screened similar infants using free T 4 , an active component, and found normal values. Kanarek et al6 found that 16 sick premature infants weighing 1500 gm or less had free T 4 between 4 and 76 pmol/liter
(0.3 to 5.9 ng/dl) between 5 and 10 days of age. Both free T 4 and triiodothyronine (T3) concentrations are reduced in healthy as well as sick premature neonates compared with full-term neonates during the first 10 days of life.7 This limited and discrepant literature about free T 4 levels in low birthweight infants make it difficult to interpret. In addition, there are no published data that evaluate the relationship between screening values for thyroid disease during the first week and long-term outcome of premature infants. Some short-term follow-up data are available. A 1 year follow-up of premature infants using the Gesell test revealed no significant difference between the infants with low compared with normal total T 4 levels.3 In addition, very low birthweight infants with initial low T 4 levels treated with T 4 were found to be no different developmentally at 12 months of age when compared with an untreated group in the nursery.8 In both studies infants were identified only with a low total T 4 . Since developmental data at 1 year may not detect subtle brain dysfunction or even mild to moderate intellectual impairment, follow-up studies are necessary to resolve the question of long-
Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan Reprint requests: Dr. Kama, Department of Neonatology, Sparrow Hospital, P. O. Box 30480, 1215 E. Michigan Avenue, Lansing, MI 48909
288
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
ABSTRACT
EFFECT OF LOW FREE THYROXINE/Karna
METHODS Subjects
Between July and November 1983, 78 infants 33 weeks' or less gestational age were screened for hypothyroidism during the first week of life using T 4 and thyroid stimulating hormone (TSH) from filter paper specimens. Eighty percent of these infants were on the ventilator for respiratory support and were sick premature infants. T 4 and TSH were measured by the radioimmunoassay. Thirty-three of the 78 (42%) infants had a low total T 4 (less than 6|xg/dl) and normal TSH (2 to 20 |xU/ml) levels during the first week of life. Free T 4 was measured during the second week of life in the infants with low total T 4 and normal TSH. Free T 4 determination was done by Smith and Kline Laboratory using the Amersham competitive protein binding assay. Twenty-one infants (67.8%) showed a low free T 4 (0.38 ± 0.13 ng/ dl). The remaining 12 infants with low total T 4 had a normal free T 4 of 0.8 ng/dl or higher. T 4 binding globulin (TBG) in the low free T 4 group was 23.2(18 to 33) |xg/dl. All surviving infants with low free T 4 were followed sequentially during their stay in the neonatal intensive care unit and showed free T 4 levels 0.8 ng/dl or higher between 36 and 44 weeks postconceptional age without any thyroid replacement. Follow-up of all premature infants with low total T 4 is shown in Table 1. All 33 infants required ventilator assistance for 5 or more days. Seven infants were excluded from follow-up due to large intraventricular hemorrhages (grade III or higher by Papil's classification). Four infants died and six could not be located for the follow-up assessment. The remaining 16 infants (eight infants with free T 4 less than 0.8 ng/dl and eight with more than 0.8 ng/dl) were evaluated in our follow-up clinic once a year through a mean age of 4.6 years. FOLLOW-UP MEASURES
Parameters measured include physical growth, developmental quotient, motor development, language, and hearing. Their development is reported
between 4 and 5 years of age. Physical growth (head circumference, length, and weight) was measured by a nurse and were plotted over time on a National Center for Health Statistics percentiles growth chart.9 For the purpose of this study, growth curves were divided into these three categories: (1) Catch up growth, that is, the growth curves showed an increased rate of growth; (2) consistent growth, that is, growth followed a particular percentile line; and (3) poor growth, that is, growth showed a decreasing rate of growth. Stanford-Bind testing10 was done by an experienced child psychologist to evaluate developmental quotient and language. Motor evaluation was performed by a pediatric physical therapist utilizing a modified Peabody test11 and the St. Anne Dargassies battery.12 Hearing was evaluated by an audiologist using both behavioral audiograms and tympanograms. Gross and fine motor skills, language, and hearing were divided in two groups, either normal or below the level expected for age. The Student t test (one tail) was used in the analysis to determine if statistically significant differences existed between the two groups of children for Stanford-Binet, gestational age, birthweight, and days in the hospital. The Fisher's exact test was done for the rest of the variables. P < 0.05 was considered significant. RESULTS
The 16 infants with low total T 4 were followed in the Developmental Assessment Clinic for an average of 4.6 ± 0.45 years of age. Table 2 shows infants with normal free T 4 (0.8 ng/dl or higher) were larger at birth and were discharged earlier from the hospital. Even though gestational age and days on the mechanical ventilator were not statistically different, infants with lower free T 4 level were younger and required mechanical ventilation for a longer duration of time. DEVELOPMENTAL FOLLOW-UP Physical Growth
The majority (11 of 16,fivefrom low free T 4 and six from normal free T 4 group) of infants showed catch-up growth in all three measurements of weight, height, and head circumference. One infant from the low free T 4 group showed poor or decreased growth. The rest of the infants were following their
