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PEDIATRICS Vol. 110 No. 2 August 2002, pp. 249-253

Neurodevelopmental Outcome of Children Treated With Antenatal Thyrotropin-Releasing Hormone

Judy M. Briët, PhD*, Loekie van Sonderen, MD*, Maarten Buimer, MD{ddagger}, Kees Boer, MD, PhD{ddagger} and Joke H. Kok, MD, PhD*

* Departments of Neonatology
{ddagger} Obstetrics and Gynecology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. To evaluate neurodevelopmental outcome until 2 years of age in children who participated in a multicenter antenatal thyrotropin-releasing hormone (TRH) trial to improve respiratory outcome and to lower mortality.

Methods. Neurodevelopmental outcome was studied in infants whose mothers were admitted to the Academic Medical Center and enrolled in the European Antenatal TRH trial. Mothers were treated for imminent preterm delivery (before 30 weeks) with corticosteroids plus either placebo (placebo-group) or TRH (TRH-group). TRH treatment consisted of 400 µg every 8 hours up to 4 doses. Assessments included neurologic development at 12 months and psychomotor development at 12 and 24 months using the Bayley developmental scales.

Results. Sixty-two infants were included, 10 of whom died. Of the surviving infants, 24 received TRH and 28 received placebo. Ten infants were lost to follow-up. Each group consisted of 21 infants. Both groups were comparable regarding gestational age, birth weight, and time interval between trial medication and birth. However, in the TRH group, more respiratory problems, ventilator days, and chronic lung disease were found. Neurologic and motor outcome did not differ between the groups, but lower mental developmental index scores were found in the TRH group at both ages.

Conclusions. Antenatal TRH treatment is associated with a delay in mental development. This study demonstrates the importance of long-term follow-up of perinatal intervention trials with possible consequences for neurodevelopmental outcome of the infant.

Key Words: developmental outcome/outcome studies • follow-up • thyrotropin-releasing hormone

Abbreviations: TRH, thyrotropin-releasing hormone • RDS, respiratory distress syndrome • MDI, Mental Developmental Indexes • PDI, Psychomotor Developmental Indexes • T3, triiodothyronine • T4, thyroxine


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
From 1989 to 1997, 10 clinical trials were conducted to study whether combined treatment of antenatal thyrotropin-releasing hormone (TRH) and glucocorticoids in imminent preterm delivery would prevent respiratory disorders and decrease the risk of neonatal death in preterm infants.1–11 Although short-term clinical effects were the principle outcome measure, indirect positive effects of the combined treatment on neurodevelopmental outcome might also occur because infants with respiratory distress syndrome (RDS) and bronchopulmonary disease have a higher risk for developmental problems.12,13 However, TRH crosses the placenta readily and stimulates the fetal pituitary gland to produce thyroid hormones, thereby causing intrauterine hyperthyroidism, and subsequently can aggravate transient hypothyroxinemia in premature infants.14,15 Thyroid hormones are essential for normal development of the central nervous system.16 Imbalances in thyroid hormone supply during rapid brain growth could have consequences for the developmental outcome of the infants; hyperthyroidism as well as hypothyroidism has been associated with developmental problems.17,18 Thus, antenatal TRH treatment might affect neurodevelopmental outcome in a positive as well as in a negative way.

Meanwhile, a systematic review has been published concluding that there is no evidence that neonatal death significantly decreased or that respiratory disorders are prevented by antenatal TRH treatment.19 Until now, only 1 study (using a low-dosage scheme of 4 x 200 µg in 1367 infants) reported on developmental outcome using a parental questionnaire at 12 months of age.20 They found an association between antenatal TRH and a delay in major milestone achievements at 1 year of age, such as motor delay, social delay, and sensory impairment. The credibility of this follow-up study has been questioned because the authors did not use a validated questionnaire.21 We participated in the European TRH trial.11 Developmental outcome of infants who were enrolled in our hospital was evaluated using standardized assessment methods.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The European TRH trial consisted of 2 concurrent, multicenter, double-blind, randomized, placebo-controlled trials with a common core data set (the Dutch Thyroneth Trial, coordinated in Amsterdam, and the Antenatal TRH trial, coordinated in Oxford). Because of imminent preterm delivery (<30 weeks), pregnant women received up to 4 doses of 400 µg of TRH or placebo (2 uL of normal saline) every 8 hours during a 24-hour period. All women received also at least 1 dose of antenatal corticosteroids. In the original trial, the primary outcome was defined as the combined outcome of death or oxygen dependency at 28 days after birth. Detecting a reduction of 30% (significant at a 5% confidence level with 90% power) of the primary outcome required a sample size of 3600 women. However, the trial was stopped before the due date because of evidence that arose from outside the trial.1,4 Details of this trial have been published elsewhere.11 Finally, 225 women and 275 infants were enrolled in the European trial. In the Academic Medical Center in Amsterdam (1 of the participating centers), 62 infants were included between March 1996 and July 1997 (23% of the total inclusion of infants in the European trial). Fifty-three of the 62 infants were discharged from the hospital. In the placebo group, 2 infants died antepartum, 1 infant died intrapartum, and 4 infants died in the neonatal period. In the TRH group, 2 infants died in the neonatal period. After discharge home, 1 infant in the TRH group died. At the age of 1 year, 52 infants were available for follow-up. Twenty-four surviving infants were exposed to TRH, and 28 were exposed to placebo. This follow-up study was approved by the Committee of Medical Ethics of the Academic Medical Center in Amsterdam.

Neurodevelopmental Assessment
At the corrected age of 12 months, a neurologic examination was done according to the method of Touwen22 by a pediatrician (L.v.S.). Neurologic outcome was classified as normal, suspect, or abnormal. Abnormality was defined as severe abnormality of tone, posture, and movement leading to functional impairment or delay in motor development. A suspect outcome was defined as moderate functional impairment or developmental delay.

At 12 and 24 months (corrected ages), mental and motor outcomes were assessed by a developmental psychologist (J.M.B.) using the Dutch version of the Bayley Scales of Infant Development.23 Mental Developmental Indexes (MDI) and Psychomotor Developmental Indexes (PDI) were determined in relation to Dutch norms (mean score of 100, standard deviation of 16). Both examiners were not involved in the original study, and the mothers were not informed about the nature of the trial medication (placebo or TRH).

Statistics
Univariate analyses were conducted to study differences in baseline characteristics, clinical data, and neurodevelopmental outcome between the 2 study groups. Categorical data were analyzed with the {chi}2 test for 2 x 2 tables. Continuous data were analyzed using Student t test. Multiple regression analyses were done to study the effect of antenatal TRH administration on neurodevelopmental outcome. Predefined confounding variables at randomization were included in the model: trial assignment, gestational age at entry in trial, gender of the infant, educational level of the mother, ethnic background, number of doses TRH (≤2 vs ≥3), and time interval between first dose and delivery. Post hoc analyses were conducted to study whether clinical characteristics that occurred after TRH administration affected outcome. Multiple regression analyses included clinical characteristics (eg, gestational age at delivery, birth weight ratio, surfactant and postnatal steroids), background characteristics (eg, gender of the infant, ethnic background and educational level of the mother), variables at randomization (number of doses TRH [≤2 vs ≥3] and time interval between first dose and delivery) and trial assignment. Statistics were done using SPSS (version 9.0; SPSS Inc, Chicago, IL); P ≤ .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifty-two surviving infants were eligible for follow-up (Table 1). In the TRH group, 2 infants, both boys, were lost to follow-up; 1 was born at term age with a birth weight of 4545 g, and the other was born after 26 weeks’ gestational age and had a birth weight of 890 g; he did not need surfactant or mechanical ventilation, and he developed RDS but no bronchopulmonary dysplasia and did not have brain damage. In the placebo group, 8 infants were lost to follow-up, 5 of whom were boys. The infants were born after 26 weeks, 28 (n = 2), 29, 30 (n = 2), 37, and 40 weeks’ gestational age, respectively. Birth weights ranged from 1035 g to 4140 g. One infant needed surfactant and developed RDS, 3 infants were mechanically ventilated but none of them received postnatal corticosteroids, 4 infants developed bronchopulmonary dysplasia and 1 infant was still on oxygen at 36 weeks, and 2 infants experienced cerebral damage. No differences were found between the children who participated in the follow-up study and the children who were lost to follow-up with respect to background variables, randomization variables, or clinical characteristics (data not shown). In each study group, 21 infants (TRH: 21 [91%] of 23; placebo: 21 [72%] of 29) were examined at least once. At 1 year of age, neurologic examination was done in 20 TRH-treated infants and 19 placebo infants. Mental and motor outcomes were studied in 16 TRH-treated infants at 1 and 2 years, in 3 infants only at the age of 1 year, and in 2 infants only at the age of 2 years. In the placebo group, mental and motor outcomes were examined in 19 infants at both ages and in 2 infants only at the age of 2 years.


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  		TABLE 1. Number of Children After Discharge Home and Eligible for Follow-up

 
Table 2 presents background and clinical characteristics of all infants born from mothers included in our hospital (n = 62), of the infants who were eligible for follow-up (n = 52), and of the infants whose developmental outcome was assessed (n = 42). There were no differences between the 2 groups regarding gestational age, birth weight or time interval of trial medication to birth. Also, no differences in ethnic background, gender of the infant, and maternal education were found. However, more ventilation days and more chronic lung disease were found in the total TRH group as well as in the TRH groups eligible for follow-up and participating in the follow-up study when compared with the comparable placebo groups.


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  		TABLE 2. Characteristics of the Total Group, the Group Eligible for Follow-up, and the Group of Children Who Actually Participated in the Follow-up study

 
Univariate as well as multiple regression analyses were conducted to study the effect of TRH administration on neurodevelopmental outcome (Table 3). Confounding variables in the regression model were trial assignment, gestational age at entry in trial, gender of the infant, educational level of the mother, ethnic background, number of doses of TRH (≤2 vs ≥3), and time interval between first dose and delivery. Neurologic outcome did not differ between the 2 groups, although 3 infants in the TRH group versus 0 infants in the placebo group were diagnosed as neurologically abnormal. MDI and PDI scores were normally distributed. At the corrected age of 12 months, the TRH group scored 14 points less on the mental scale than the placebo group (ß: 17.4; standard error: 7.0; t value: 2.5; adjusted P = .03). Four infants in the TRH group obtained a score below 1 standard deviation of the norm versus none in the placebo group (P = .03). After correction for confounding variables, this difference was no longer significant. Mean PDI was also lower in the TRH infants, but the 10-point difference was not statistically significant (P = .08).


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  		TABLE 3. Neurodevelopmental Outcome at 1 and 2 Years of Age

 
Also at the corrected age of 2 years, mean MDI was again significantly lower in the TRH group (ß: 15.2; standard error: 7.5; t value: 2.0; adjusted P = .01). The difference in mean PDI diminished to 5 points (P = .27) but was still against the TRH infants.

Effect of Clinical Characteristics After TRH Administration on Neurodevelopmental Outcome
More respiratory problems were found in the TRH group than in the placebo group. These are known to be associated with developmental outcome. Therefore, post hoc analyses were conducted to study whether clinical characteristics after TRH administration affected outcome at 2 years of age. Confounding variables that were entered in the multiple regression model were trial assignment, gestational age at delivery, birth weight ratio, surfactant and postnatal steroids, gender of the infant, ethnic background and educational level of the mother, number of doses of TRH (≤ 2 vs ≥3), and time interval between first dose and delivery. These analyses showed that male gender (ß: 16.4; standard error: 7.3; t value: 2.2; adjusted P = .05), low maternal education (ß: 17.1; standard error: 5.8; t value: 2.9; adjusted P = .007), and TRH administration (ß: 12.5; standard error: 8.1; t value: 1.6; adjusted P = .05) were associated with lower MDI scores at 2 years of age.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This follow-up study shows that antenatal TRH administration in addition to corticosteroids to pregnant women who were at risk for preterm delivery is associated with a delay in mental development of their children at the (corrected) age of 1 and 2 years.

All infants in the follow-up study were enrolled in the Academic Medical Center in Amsterdam, 1 of the participating centers of the European antenatal TRH trial. This trial was stopped prematurely in 1997.11 At that time, 225 women were recruited and 275 infants were delivered. Selection bias could have occurred in studying the developmental outcome of a small group of children (23% of the original cohort) from only 1 of the participating centers while recruitment was stopped before the due date. The risk of finding results by chance is increased because of this. However, block randomization in each participating center was applied to ensure comparability between women allocated to the 2 treatment groups. Selection bias also could have occurred by the relatively large number of infants (n = 10) who were lost to follow-up; 8 of them originated from the placebo group, 2 of whom had brain damage. Because of this, none of the placebo children who participated in the follow-up study had brain damage versus 2 children in the TRH group. Missing the follow-up data of 8 children might have positively affected outcome of the placebo group.

Although block randomization ensures comparability of the 2 study groups, the finding that respiratory problems were found more often in infants who received antenatal TRH to prevent respiratory distress problems still might be caused by chance. Results from the original group did not show an increased risk of respiratory problems in TRH infants.11 The present finding also cannot readily be explained by a skewed distribution of the proportions of infants born in each time window of the treatment. The optimal time window is ≥24 hours to ≤10 days after the first treatment dose. Forty-eight percent of the TRH infants and 43% of the placebo infants were born in the optimal time window. However, the finding of more ventilation days in the TRH group is in accordance with results from the Cochrane meta-analyses19 that showed the need of ventilation to be increased in infants who were exposed to antenatal TRH. In infants who were born >10 days after trial entry, the need for oxygen therapy or death at 28 days and RDS were even more common in infants who were exposed to antenatal TRH than in infants who received placebo. In our follow-up group, only 24% of the infants in the TRH group versus 43% in the placebo group were born >10 days after trial entry.

Respiratory problems are known to be associated with poor developmental outcome12,13 and thus also could explain the difference found in MDI besides TRH treatment. In analyzing the effect of TRH on outcome, it is not allowed to correct for phenomena that occurred after randomization because they could be the result of the intervention. Therefore, we investigated the effect of clinical characteristics after TRH administration on outcome. Our findings show that respiratory problems were not associated with a delay in mental development at 2 years of age, but male gender, low maternal education, and TRH administration were. Male gender and low maternal education are known risk factors for developmental problems.24,25 The adverse effect of TRH could be the result of a temporary disturbance in the fetal and neonatal thyroid hormone levels during a crucial period of brain development. Unfortunately, neonatal thyroid hormone levels of the infants were not collected in the European Antenatal TRH trial. TRH crosses the placenta readily and evokes secretion of fetal thyrotropin, triiodothyronine (T3), and thyroxine (T4), as was found in cord blood of infants born shortly after TRH administration.14,15,26 High levels are subsequently followed by suppressed levels as a result of the negative feedback system in infants who received >1 dose,14 and suppressed levels of T4 but not of T3 were found after a single dose.15 However, the suppressive effect on T3 and thyrotropin was resolved before day 3 of life.26 In 13 infants included in an antenatal TRH trial with an abnormal TRH test at 28 days, no deleterious effects on developmental outcome were seen.27 Although T3 is the biologically active hormone, brain cells are dependent on T4 for intracellular use. Transient hypothyroxinemia has been described in prematurely born infants and is associated with developmental problems.17,28 Adverse effects after TRH administration have also been found in the only other follow-up study20 that used an even lower treatment dose.

It is not likely that antenatal TRH treatment will be used anymore in clinical practice because from the meta-analysis,19 it is concluded that antenatal TRH to women at risk of very preterm birth cannot be recommended. However, in the past, TRH was already used in clinical practice.29 Results of the present study emphasize the importance not only of randomized controlled trials but also of long-term follow-up of clinical intervention trials in the perinatal period with a possible interference of neurodevelopment of the newborn infant.


   ACKNOWLEDGMENTS
 
We thank the children and their parents for cooperation.


   FOOTNOTES
 
Received for publication Jun 11, 2001; Accepted Mar 26, 2002.

Reprint requests to (J.M.B.) Academic Medical Center, Department of Neonatology, H3N, University of Amsterdam, Box 22700, 1100 DE Amsterdam, the Netherlands. E-mail: j.m.briet{at}amc.uva.nl


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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