Antenatal exposure to betamethasone: psychological functioning and hea
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《英国医生杂志》
1 Clinical Trials Research Unit, University of Auckland, Private Bag 92019, Auckland, New Zealand, 2 Department of Psychology, University of Auckland, 3 Liggins Institute, University of Auckland
Correspondence to: J E Harding j.harding@auckland.ac.nz
Objectives To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood.
Design Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.
Setting Tertiary obstetric hospital in Auckland, New Zealand.
Participants 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo).
Interventions Mothers received two doses of betamethasone or placebo 24 hours apart.
Main outcome measures Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey.
Results No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life.
Conclusions Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.
A single course of antenatal glucocorticoids is recommended in the management of preterm labour for the prevention of neonatal respiratory distress syndrome.1 The use of glucocorticoids results in considerable reduction in mortality and morbidity, as well as costs, in infants born preterm.1 2 Follow-up studies of development into childhood suggest that no adverse effects occur through early childhood.3 However, information about long term psychological functioning and health related quality of life into adulthood after antenatal glucocorticoids remains scarce.
Other perinatal exposure to glucocorticoids has been associated with adverse neurodevelopmental outcomes. Repeated antenatal courses of glucocorticoids cause decreased fetal brain growth and myelination in sheep.4 Non-randomised studies in humans have reported decreased neonatal head circumference after repeated courses of antenatal glucocorticoids,5 with increased risk of hyperactivity in childhood.6 Furthermore, school age children exposed to postnatal glucocorticoids for neonatal chronic lung disease have lower IQ scores.7 To date the data on psychological functioning in adulthood after exposure to antenatal glucocorticoids are limited to one small follow-up study of a randomised controlled trial. No difference in cognitive functioning or self report of psychoneuroticism was found between groups in 81 participants aged 20.8 Conversely, a non-randomised cohort of 130 children at age 14 suggested better cognitive functioning in those exposed to glucocorticoids.9
Given the above concerns, we followed a cohort of neonatal survivors from the first and largest randomised controlled trial of antenatal glucocorticoids (the Auckland steroid trial, conducted by Liggins and Howie10) to assess the long term effects on psychological functioning and health related quality of life in adulthood.
Methods
The Auckland steroid trial and childhood follow-up have been described previously.3 10 Briefly, between December 1969 and February 1974 all women expected to deliver between 24 and 36 weeks at the National Women's Hospital, Auckland, New Zealand, were eligible for enrolment unless immediate delivery was indicated. Women were randomised to an intramuscular injection of 6 mg short acting betamethasone phosphate and 6 mg long acting betamethasone acetate or an identical looking placebo of 6 mg cortisone acetate with a 70th of the glucocorticoid potency (trial 1). The allocated treatment was repeated 24 hours later if delivery had not occurred. If possible, labour was arrested with tocolytics for 48 hours. After the first 717 women had enrolled, the dose of betamethasone was doubled (trial 2). A total of 1142 women were enrolled and delivered 1218 babies. Primary endpoints were neonatal respiratory distress syndrome and perinatal death.
Follow-up in adulthood
Between February 2002 and December 2003 attempts were made to trace those "babies," now adults, who survived the neonatal period. Those located were invited to enter a follow-up study of adult cardiovascular and respiratory status,11 including collection of information about medical history and socioeconomic status. Between February 2003 and March 2004 we invited the subgroup of those who had participated in the cardiorespiratory follow-up who lived in the greater Auckland area to participate in the current study, which involved a structured assessment by a researcher in psychology (VKL). We obtained written informed consent from each participant.
Outcome measures and definitions
Cognitive functioning
We used the Wechsler abbreviated scale of intelligence to assess cognitive functioning.12 This comprises four subtests giving scales for full IQ, verbal IQ, and performance IQ.
Working memory and attention
We used the Benton visual retention test,13 the paced auditory serial addition test,14 and the Brown attention deficit disorder scale to assess working memory and attention.15 The Benton visual retention test assesses visual perception, visual memory, and visuoconstructive abilities by asking participants to copy from memory 10 increasingly difficult designs. Results are expressed as number of correct designs and a total error score.
The paced auditory serial addition test assesses sustained attention by asking participants to add 61 consecutive digits. As each digit is presented, the participant must sum that digit with the digit presented beforehand. The test is repeated with decreasing intervals between digits: 2.4 seconds, 2.0 seconds, 1.6 seconds, and 1.2 seconds. Results are expressed as a score of correct digits at each time interval. The Brown attention deficit disorder scale is a 40 item self completed questionnaire that measures symptoms of attention deficit disorder, with a total score out of 120. We defined probable attention deficit disorder as a score of > 39.
Psychiatric morbidity
We used the Beck depression inventory II,16 the trait portion of the state-trait anxiety inventory,17 and the schizotypy traits questionnaire to assess psychiatric morbidity.18 The Beck depression inventory II is a 21 item self completed questionnaire that measures presence and severity of depression symptoms as listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. We defined probable depression as a score of > 13. The trait portion of the state-trait anxiety inventory is a 20 item self completed questionnaire that measures individual differences in proneness to anxiety. We defined probable anxiety as a score above the 80th centile. The schizotypy traits questionnaire is a 37 item self completed questionnaire that measures the minor manifestations of a psychotic disorder. Results are expressed as a total score and three subscales—magical ideation, unusual perceptual experiences, and paranoid ideation and suspiciousness.
Handedness
We used the Edinburgh handedness inventory to assess handedness.19 This is a 10 item self completed questionnaire that measures hand preference for 10 everyday activities. Results are expressed as a laterality quotient, where right handedness is +30 to +100, ambidextrous is -30 to +30, and left handedness is -100 to -30.
Health related quality of life
We assessed health related quality of life by using the Australasian version of the short form 36 health survey (SF-36), which has been validated in 7862 New Zealanders.20 This is a 36 item self completed questionnaire that measures eight multi-item domains of perceived health related quality of life. Scores range from 0 (worst) to 100 (best) for all domains. Five domains (physical functioning, role limitation due to physical problems, bodily pain, social functioning, role limitation due to emotional problems) define health status by absence of disability, and the maximum score is achieved when no disability is reported. Three domains (general health perception, vitality, and mental health) define both positive and negative health status, and a score of 50 indicates neither positive nor negative status. We also asked participants questions to determine the presence of visual, hearing, and speech abnormalities.
Assignment
The chief pharmacist used random number tables to generate randomisation and held the randomisation key. The study drug was supplied in identical numbered ampoules.
Masking
Staff who enrolled mothers and who cared for and assessed participants in the neonatal period were blind to study group allocation. Adult participants and all members of the study team involved in tracing, recruitment, assessment and analysis were also unaware of the participants' in utero exposure.
Participant flow and follow-up
Of the 988 neonatal survivors from the Auckland steroid trial, 713 (72%) were successfully traced at 30 years. Of these, 534 completed the cardiorespiratory follow-up—56% of those presumed to be alive and 80% of those traced and known to be alive.11 Of these, 280 were eligible for the current study (that is, lived in the greater Auckland area), of whom 192 (69%) participated (figure).
Participant flow to psychological follow-up in adulthood. *Details published elsewhere.11 Non-participants presumed to be alive at age 30. Traced but declined participation in cardiorespiratory adult follow-up or residing overseas and not returning to New Zealand within timeframe of study
Analyses
We used SAS version 8.02 (SAS Institute, Cary, NC) to analyse data on an intention to treat basis. We compared continuous variables with unpaired t tests or Mann-Whitney tests and categorical data with 2 tests as appropriate. We log transformed variables with skewed distributions. If the distribution remained skewed, we present data as medians. Primary analyses were unadjusted. Secondary analyses used multiple linear regression to adjust for confounding by sex, birth weight, gestational age, and socioeconomic status decided a priori. We explored further confounders by using the change in estimates technique at the 10% level.21 We created birth weight standard deviation (z) scores by using data from all New Zealand deliveries in 1990-1. We assigned New Zealand socioeconomic index scores from occupational data.11
Eighty seven participants exposed to betamethasone and 105 participants exposed to placebo took part (66% v 71% of those eligible; P = 0.36). Mean (SD) age at follow-up was 31.2 (1.1) and 31.1 (1.1) years in the two groups.
Background characteristics
Those who participated in this study were more likely to have had respiratory distress syndrome but had otherwise similar perinatal characteristics to the entire cohort of non-participants presumed to be alive at age 30 (table 1). Those who participated were less likely to have been from a multiple pregnancy, to have obtained fewer than four years of high school education, or to be in the lowest socioeconomic group but had otherwise similar perinatal and adult characteristics to those who were eligible for this study (lived in the Auckland area) but declined participation (table 1). No significant differences in perinatal or adult characteristics existed between the betamethasone and placebo exposed participants who took part (table 2).
Table 1 Characteristics of infants who participated in this study compared with those who were eligible but declined participation and with all non-participants presumed to be alive at age 30. Values are numbers (percentages) unless stated otherwise
Table 2 Characteristics of participants exposed to betamethasone and placebo. Values are numbers (percentages) unless stated otherwise
Previous psychiatric diagnosis
A previous psychiatric diagnosis was reported by six (7%) betamethasone exposed and six (6%) placebo exposed participants (relative risk 1.2, 95% confidence interval 0.40 to 3.6; P = 0.74). One placebo exposed participant had schizophrenia. The other diagnoses were affective and anxiety conditions.
Psychological functioning
No difference existed between groups in measures of cognitive functioning, working memory and attention, depression, anxiety, schizotypy, or handedness (table 3). Adjustment for previous psychiatric diagnosis did not change the depression, anxiety, or schizotypy results.
Table 3 Psychological functioning and health related quality of life outcomes in groups exposed to betamethasone and placebo
Health related quality of life
We found no difference between groups in the eight domains of the SF-36 (table 3). No difference existed between groups in the numbers reporting visual or hearing difficulties. However, betamethasone exposed participants reported significantly fewer speech difficulties. All participants with speech difficulties reported a mild impairment, in that they were partially understood when speaking to strangers but completely understood when speaking to those who knew them well.
Multivariate analysis
Adjustment for sex, birth weight, gestational age, and socioeconomic status did not change the results.
Discussion
National Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 1994;12(2): 1-24.
Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev 2000;(2): CD000065.
MacArthur BA, Howie RN, Dezoete JA, Elkins J. School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 1982;70: 99-105.
Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001;19: 415-25.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180: 114-21.
French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190: 588-95.
Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350: 1304-13.
Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000;105: E77.
Doyle LW, Ford GW, Rickards AL, Kelly EA, Davis NM, Callanan C, et al. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams. Pediatrics 2000;106: E2.
Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50: 515-25.
Dalziel SR, Walker NK, Parag V, Mantell CH, Rea HH, Rodgers A, et al. Cardiovascular risk factors after exposure to antenatal betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005;365: 1856-62.
Wechsler D. Wechsler abbreviated scale of intelligence. San Antonio, TX: Psychological Corporation, 1999.
Sivan AB. Benton visual retention test. 5th ed. San Antonio, TX: Psychological Corporation, 1992.
Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977;44: 367-73.
Brown TE. Brown attention deficit disorder scales. San Antonio, TX: Psychological Corporation, 1996.
Beck AT. Beck depression inventory-II (BDI-II). San Antonio, TX: Psychological Corporation, 1996.
Spielberger CD. State-trait anxiety inventory (form Y). Redwood City, CA: Mind Garden, 1983.
Claridge G, Broks P. Schizotypy and hemisphere function: I. Theoretical considerations and the measurement of schizotypy. Pers Indiv Dif 1984;5: 633-48.
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9: 97-113.
Scott KM, Tobias MI, Sarfati D, Haslett SJ. SF-36 health survey reliability, validity and norms for New Zealand. Aust N Z J Public Health 1999;23: 401-6.
Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health 1989;79: 340-9.
Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984;104: 259-67.
Castro L, Yolton K, Haberman B, Roberto N, Hansen NI, Ambalavanan N, et al. Bias in reported neurodevelopmental outcomes among extremely low birth weight survivors. Pediarics 2004;114: 404-10.
Tin W, Fritz S, Wariyar U, Hey E. Outcome of very preterm birth: children reviewed with ease at 2 years differ from those followed up with difficulty. Arch Dis Child Fetal Neonatal Ed 1998;79: F83-7.(Stuart R Dalziel, research fellow1, Vane)
Correspondence to: J E Harding j.harding@auckland.ac.nz
Objectives To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood.
Design Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.
Setting Tertiary obstetric hospital in Auckland, New Zealand.
Participants 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo).
Interventions Mothers received two doses of betamethasone or placebo 24 hours apart.
Main outcome measures Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey.
Results No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life.
Conclusions Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.
A single course of antenatal glucocorticoids is recommended in the management of preterm labour for the prevention of neonatal respiratory distress syndrome.1 The use of glucocorticoids results in considerable reduction in mortality and morbidity, as well as costs, in infants born preterm.1 2 Follow-up studies of development into childhood suggest that no adverse effects occur through early childhood.3 However, information about long term psychological functioning and health related quality of life into adulthood after antenatal glucocorticoids remains scarce.
Other perinatal exposure to glucocorticoids has been associated with adverse neurodevelopmental outcomes. Repeated antenatal courses of glucocorticoids cause decreased fetal brain growth and myelination in sheep.4 Non-randomised studies in humans have reported decreased neonatal head circumference after repeated courses of antenatal glucocorticoids,5 with increased risk of hyperactivity in childhood.6 Furthermore, school age children exposed to postnatal glucocorticoids for neonatal chronic lung disease have lower IQ scores.7 To date the data on psychological functioning in adulthood after exposure to antenatal glucocorticoids are limited to one small follow-up study of a randomised controlled trial. No difference in cognitive functioning or self report of psychoneuroticism was found between groups in 81 participants aged 20.8 Conversely, a non-randomised cohort of 130 children at age 14 suggested better cognitive functioning in those exposed to glucocorticoids.9
Given the above concerns, we followed a cohort of neonatal survivors from the first and largest randomised controlled trial of antenatal glucocorticoids (the Auckland steroid trial, conducted by Liggins and Howie10) to assess the long term effects on psychological functioning and health related quality of life in adulthood.
Methods
The Auckland steroid trial and childhood follow-up have been described previously.3 10 Briefly, between December 1969 and February 1974 all women expected to deliver between 24 and 36 weeks at the National Women's Hospital, Auckland, New Zealand, were eligible for enrolment unless immediate delivery was indicated. Women were randomised to an intramuscular injection of 6 mg short acting betamethasone phosphate and 6 mg long acting betamethasone acetate or an identical looking placebo of 6 mg cortisone acetate with a 70th of the glucocorticoid potency (trial 1). The allocated treatment was repeated 24 hours later if delivery had not occurred. If possible, labour was arrested with tocolytics for 48 hours. After the first 717 women had enrolled, the dose of betamethasone was doubled (trial 2). A total of 1142 women were enrolled and delivered 1218 babies. Primary endpoints were neonatal respiratory distress syndrome and perinatal death.
Follow-up in adulthood
Between February 2002 and December 2003 attempts were made to trace those "babies," now adults, who survived the neonatal period. Those located were invited to enter a follow-up study of adult cardiovascular and respiratory status,11 including collection of information about medical history and socioeconomic status. Between February 2003 and March 2004 we invited the subgroup of those who had participated in the cardiorespiratory follow-up who lived in the greater Auckland area to participate in the current study, which involved a structured assessment by a researcher in psychology (VKL). We obtained written informed consent from each participant.
Outcome measures and definitions
Cognitive functioning
We used the Wechsler abbreviated scale of intelligence to assess cognitive functioning.12 This comprises four subtests giving scales for full IQ, verbal IQ, and performance IQ.
Working memory and attention
We used the Benton visual retention test,13 the paced auditory serial addition test,14 and the Brown attention deficit disorder scale to assess working memory and attention.15 The Benton visual retention test assesses visual perception, visual memory, and visuoconstructive abilities by asking participants to copy from memory 10 increasingly difficult designs. Results are expressed as number of correct designs and a total error score.
The paced auditory serial addition test assesses sustained attention by asking participants to add 61 consecutive digits. As each digit is presented, the participant must sum that digit with the digit presented beforehand. The test is repeated with decreasing intervals between digits: 2.4 seconds, 2.0 seconds, 1.6 seconds, and 1.2 seconds. Results are expressed as a score of correct digits at each time interval. The Brown attention deficit disorder scale is a 40 item self completed questionnaire that measures symptoms of attention deficit disorder, with a total score out of 120. We defined probable attention deficit disorder as a score of > 39.
Psychiatric morbidity
We used the Beck depression inventory II,16 the trait portion of the state-trait anxiety inventory,17 and the schizotypy traits questionnaire to assess psychiatric morbidity.18 The Beck depression inventory II is a 21 item self completed questionnaire that measures presence and severity of depression symptoms as listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. We defined probable depression as a score of > 13. The trait portion of the state-trait anxiety inventory is a 20 item self completed questionnaire that measures individual differences in proneness to anxiety. We defined probable anxiety as a score above the 80th centile. The schizotypy traits questionnaire is a 37 item self completed questionnaire that measures the minor manifestations of a psychotic disorder. Results are expressed as a total score and three subscales—magical ideation, unusual perceptual experiences, and paranoid ideation and suspiciousness.
Handedness
We used the Edinburgh handedness inventory to assess handedness.19 This is a 10 item self completed questionnaire that measures hand preference for 10 everyday activities. Results are expressed as a laterality quotient, where right handedness is +30 to +100, ambidextrous is -30 to +30, and left handedness is -100 to -30.
Health related quality of life
We assessed health related quality of life by using the Australasian version of the short form 36 health survey (SF-36), which has been validated in 7862 New Zealanders.20 This is a 36 item self completed questionnaire that measures eight multi-item domains of perceived health related quality of life. Scores range from 0 (worst) to 100 (best) for all domains. Five domains (physical functioning, role limitation due to physical problems, bodily pain, social functioning, role limitation due to emotional problems) define health status by absence of disability, and the maximum score is achieved when no disability is reported. Three domains (general health perception, vitality, and mental health) define both positive and negative health status, and a score of 50 indicates neither positive nor negative status. We also asked participants questions to determine the presence of visual, hearing, and speech abnormalities.
Assignment
The chief pharmacist used random number tables to generate randomisation and held the randomisation key. The study drug was supplied in identical numbered ampoules.
Masking
Staff who enrolled mothers and who cared for and assessed participants in the neonatal period were blind to study group allocation. Adult participants and all members of the study team involved in tracing, recruitment, assessment and analysis were also unaware of the participants' in utero exposure.
Participant flow and follow-up
Of the 988 neonatal survivors from the Auckland steroid trial, 713 (72%) were successfully traced at 30 years. Of these, 534 completed the cardiorespiratory follow-up—56% of those presumed to be alive and 80% of those traced and known to be alive.11 Of these, 280 were eligible for the current study (that is, lived in the greater Auckland area), of whom 192 (69%) participated (figure).
Participant flow to psychological follow-up in adulthood. *Details published elsewhere.11 Non-participants presumed to be alive at age 30. Traced but declined participation in cardiorespiratory adult follow-up or residing overseas and not returning to New Zealand within timeframe of study
Analyses
We used SAS version 8.02 (SAS Institute, Cary, NC) to analyse data on an intention to treat basis. We compared continuous variables with unpaired t tests or Mann-Whitney tests and categorical data with 2 tests as appropriate. We log transformed variables with skewed distributions. If the distribution remained skewed, we present data as medians. Primary analyses were unadjusted. Secondary analyses used multiple linear regression to adjust for confounding by sex, birth weight, gestational age, and socioeconomic status decided a priori. We explored further confounders by using the change in estimates technique at the 10% level.21 We created birth weight standard deviation (z) scores by using data from all New Zealand deliveries in 1990-1. We assigned New Zealand socioeconomic index scores from occupational data.11
Eighty seven participants exposed to betamethasone and 105 participants exposed to placebo took part (66% v 71% of those eligible; P = 0.36). Mean (SD) age at follow-up was 31.2 (1.1) and 31.1 (1.1) years in the two groups.
Background characteristics
Those who participated in this study were more likely to have had respiratory distress syndrome but had otherwise similar perinatal characteristics to the entire cohort of non-participants presumed to be alive at age 30 (table 1). Those who participated were less likely to have been from a multiple pregnancy, to have obtained fewer than four years of high school education, or to be in the lowest socioeconomic group but had otherwise similar perinatal and adult characteristics to those who were eligible for this study (lived in the Auckland area) but declined participation (table 1). No significant differences in perinatal or adult characteristics existed between the betamethasone and placebo exposed participants who took part (table 2).
Table 1 Characteristics of infants who participated in this study compared with those who were eligible but declined participation and with all non-participants presumed to be alive at age 30. Values are numbers (percentages) unless stated otherwise
Table 2 Characteristics of participants exposed to betamethasone and placebo. Values are numbers (percentages) unless stated otherwise
Previous psychiatric diagnosis
A previous psychiatric diagnosis was reported by six (7%) betamethasone exposed and six (6%) placebo exposed participants (relative risk 1.2, 95% confidence interval 0.40 to 3.6; P = 0.74). One placebo exposed participant had schizophrenia. The other diagnoses were affective and anxiety conditions.
Psychological functioning
No difference existed between groups in measures of cognitive functioning, working memory and attention, depression, anxiety, schizotypy, or handedness (table 3). Adjustment for previous psychiatric diagnosis did not change the depression, anxiety, or schizotypy results.
Table 3 Psychological functioning and health related quality of life outcomes in groups exposed to betamethasone and placebo
Health related quality of life
We found no difference between groups in the eight domains of the SF-36 (table 3). No difference existed between groups in the numbers reporting visual or hearing difficulties. However, betamethasone exposed participants reported significantly fewer speech difficulties. All participants with speech difficulties reported a mild impairment, in that they were partially understood when speaking to strangers but completely understood when speaking to those who knew them well.
Multivariate analysis
Adjustment for sex, birth weight, gestational age, and socioeconomic status did not change the results.
Discussion
National Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 1994;12(2): 1-24.
Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev 2000;(2): CD000065.
MacArthur BA, Howie RN, Dezoete JA, Elkins J. School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 1982;70: 99-105.
Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001;19: 415-25.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180: 114-21.
French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190: 588-95.
Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350: 1304-13.
Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000;105: E77.
Doyle LW, Ford GW, Rickards AL, Kelly EA, Davis NM, Callanan C, et al. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams. Pediatrics 2000;106: E2.
Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50: 515-25.
Dalziel SR, Walker NK, Parag V, Mantell CH, Rea HH, Rodgers A, et al. Cardiovascular risk factors after exposure to antenatal betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005;365: 1856-62.
Wechsler D. Wechsler abbreviated scale of intelligence. San Antonio, TX: Psychological Corporation, 1999.
Sivan AB. Benton visual retention test. 5th ed. San Antonio, TX: Psychological Corporation, 1992.
Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977;44: 367-73.
Brown TE. Brown attention deficit disorder scales. San Antonio, TX: Psychological Corporation, 1996.
Beck AT. Beck depression inventory-II (BDI-II). San Antonio, TX: Psychological Corporation, 1996.
Spielberger CD. State-trait anxiety inventory (form Y). Redwood City, CA: Mind Garden, 1983.
Claridge G, Broks P. Schizotypy and hemisphere function: I. Theoretical considerations and the measurement of schizotypy. Pers Indiv Dif 1984;5: 633-48.
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9: 97-113.
Scott KM, Tobias MI, Sarfati D, Haslett SJ. SF-36 health survey reliability, validity and norms for New Zealand. Aust N Z J Public Health 1999;23: 401-6.
Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health 1989;79: 340-9.
Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984;104: 259-67.
Castro L, Yolton K, Haberman B, Roberto N, Hansen NI, Ambalavanan N, et al. Bias in reported neurodevelopmental outcomes among extremely low birth weight survivors. Pediarics 2004;114: 404-10.
Tin W, Fritz S, Wariyar U, Hey E. Outcome of very preterm birth: children reviewed with ease at 2 years differ from those followed up with difficulty. Arch Dis Child Fetal Neonatal Ed 1998;79: F83-7.(Stuart R Dalziel, research fellow1, Vane)