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Background Pulmonary disease is common in preterm infants, despite antenatal glucocorticoid therapy. The addition of antenatal thyrotropin-releasing hormone therapy has been reported to decrease pulmonary morbidity in these infants.
Methods We enrolled 996 women at 13 North American centers who were in preterm labor at <30 weeks' gestation in a double-blind, placebo-controlled, randomized trial of antenatal thyrotropin-releasing hormone, given intravenously in four doses of 400 µg each at eight-hour intervals. The primary outcome was chronic lung disease or death of the infant on or before the 28th day after delivery, and secondary outcomes were respiratory distress syndrome and chronic lung disease or death at 36 weeks' postmenstrual age. Complete data were available for 981 women and their 1134 live-born infants. The 769 infants born at <32 weeks' gestation were defined as the group at risk.
Results There were no significant differences between the at-risk treatment and placebo groups in mean (±SD) birth weight (1109±354 vs. 1097±355 g), gestational age (27.9±2.1 vs. 27.9±2.1 weeks), sex, or race. The frequencies of respiratory distress syndrome (66 percent vs. 65 percent), death at 28 days (11 percent vs. 11 percent), chronic lung disease or death at 28 days (45 percent vs. 42 percent) and at 36 weeks (32 percent vs. 34 percent), and other neonatal complications as well as the severity of lung disease were not significantly different in the at-risk treatment and placebo groups. Similarly, there were no differences in outcome between the treatment and placebo groups for the infants born at >32 weeks' gestation.
Conclusions In preterm infants at risk for lung disease, antenatal administration of thyrotropin-releasing hormone and glucocorticoid is no more beneficial than glucocorticoid alone.
Thyroid hormones stimulate fetal lung development in vitro and in animals,7,8 and the combination of thyroid hormone and glucocorticoid has synergistic effects.9,10,11,12,13,14,15,16,17 In humans, little thyroid hormone is transferred from mother to fetus, whereas fetal serum concentrations of thyroid hormone are increased by the administration of thyrotropin-releasing hormone to the mother. This hormone does cross the placenta and stimulates fetal secretion of thyrotropin, triiodothyronine, thyroxine, and prolactin.18,19,20,21
Antenatal glucocorticoid therapy reduces the incidence and severity of respiratory distress syndrome in premature infants but has no effect on the occurrence of chronic lung disease.4,6 In most but not all trials of antenatal thyrotropin-releasing hormone in combination with glucocorticoid, the incidence and severity of respiratory distress syndrome, chronic lung disease, or an adverse outcome, defined as chronic lung disease or death by 28 days' postnatal age, were reduced.22,23,24,25,26,27 However, one study was unblinded, most of the trials were relatively small, and most infants were not treated with surfactant. We undertook this randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of antenatal thyrotropin-releasing hormone in combination with glucocorticoid in infants born to women who had preterm labor at <30 weeks' gestation. Surfactant was administered when clinically indicated.
Methods
Patient Enrollment and Evaluation
Women in active labor with gestations of at least 24 but less than 30 weeks were recruited at 13 North American centers between October 1992 and December 1996. Women who had bleeding, infection, hypertension (blood pressure, >140/90 mm Hg), fetuses with hydrops or life-threatening anomalies, or one dead fetus in multiple pregnancies were not eligible for the study. The study protocol was approved by the institutional review board at each center, and informed consent was obtained from all the women.
The women were randomly assigned within centers to the treatment or placebo group in permuted blocks of four. The study was double-blinded, and only the pharmacies at the participating centers had the randomization schedule. The women were each given four doses of 400 µg of thyrotropin-releasing hormone (Thypinone, Abbott Laboratories, Abbott Park, Ill., or Thyrel, Ferring Laboratories, Tarrytown, N.Y.) intravenously in 50 ml of normal saline or were given normal saline alone over a period of 20 minutes at 8-hour intervals. All the women received two 12-mg doses of intramuscular betamethasone 24 hours apart, or four 6-mg doses of intramuscular dexamethasone at 12-hour intervals, starting within 72 hours of the time of the first dose of thyrotropin-releasing hormone. According to the trial design, only one course of thyrotropin-releasing hormone was given; however, additional courses of glucocorticoid and tocolytic-drug therapy were given at the discretion of the physician. Tocolytic drugs were given to 85 percent of the women in the treatment group and 83 percent of the women in the placebo group, and there were no differences between the two groups in the use of 
-adrenergic agonists (mean for both groups, 57 percent), magnesium sulfate (70 percent), prostaglandin-synthesis inhibitors (24 percent), or calcium-channel blockers (9 percent).
The women's pulse rates and blood pressures were monitored closely during and after the infusions, and assessments were made for indications of fetal distress. Gestational age was assigned at the time of the mother's enrollment on the basis of an ultrasound examination, if performed at less than 20 weeks' gestation, and on the basis of menstrual dates if appropriate ultrasound results were not available.
In accordance with the protocol, infants weighing <800 g were treated at birth with surfactant (Exosurf, Glaxo Wellcome, Research Triangle Park, N.C., or Survanta, Abbott Laboratories), and those weighing more than 800 g were treated after birth (rescue treatment) with surfactant as needed for respiratory distress. The infants received standard neonatal intensive care at the discretion of their physicians. Respiratory distress syndrome was defined as the need for oxygen and either the need for assisted ventilation for more than 48 hours after birth or radiologic findings consistent with respiratory distress syndrome.
The primary outcome was infant death on or before the 28th day after delivery or chronic lung disease, defined as the need for oxygen therapy for 21 of the first 28 days of life, including day 28. These end points were evaluated both for the entire group of infants and for the group of infants who were born at <32 weeks' gestation (defined as the group at risk for lung disease).
Secondary outcome measures were the incidence of chronic lung disease or death at <36 weeks' postmenstrual age (an age at which most infants should be ready for discharge home), calculated from the first day of the last menstrual period, and the occurrence of other complications of prematurity, including patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity.
Cord-blood samples were obtained at nine centers to determine the fetal response to thyrotropin-releasing hormone. Plasma thyrotropin and triiodothyronine were measured by immunoassay (Nichols Institute, San Juan Capistrano, Calif.) in those samples.
Statistical Analysis
A sample consisting of 1090 live births was required to detect a decrease of 40 percent in the incidence of chronic lung disease in the group treated with thyrotropin-releasing hormone as compared with the placebo group, with 80 percent power, allowing for two interim analyses.28 The stopping boundaries were not crossed at the time of these two analyses, and therefore the study was completed.
The characteristics of the mothers and infants and the outcomes in the two groups were compared with the use of Fisher's exact test or its extension to tables larger than two-by-two tables. Continuous characteristics, such as gestational age and birth weight, were compared with the use of Student's t-test.
Odds ratios and confidence intervals were calculated for all outcomes of the group at risk and the group not at risk. The infants who died before reaching 28 days of life or 36 weeks' postmenstrual age were considered to have chronic lung disease in between-group comparisons. Secondary analysis in the group at risk examined outcomes according to gestational age and other complications seen in the preterm infant.
All analyses were based on the intention-to-treat principle, and all statistical tests were two-sided.
Results
Between October 1992 and December 1996, 2209 women were screened, of whom 1516 (69 percent) were eligible for the study; 996 of those eligible (66 percent) were enrolled. Complete data were available for 981 of these women and their 1134 live-born infants. There were no significant differences in age, race, marital status, prenatal care, or pregnancy history between the mothers in the two groups, nor were there differences in their fetuses' mean (±SD) gestational ages at the time of randomization (Table 1).
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There were 11 stillbirths and 1134 live births, with 844 singleton and 290 multiple births. Seven hundred sixty-nine (68 percent) of the infants were born at <32 weeks and were considered the at-risk group. There were no significant differences between the treatment and placebo groups in the incidence of respiratory distress syndrome, death, or chronic lung disease 28 days after delivery or at 36 postmenstrual weeks in either the group at risk or the group not at risk (Table 2). There were also no significant differences in these outcomes between treatment and placebo groups consisting of singleton infants and singleton infants plus one randomly selected infant from each mother with multiple births.
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Discussion
This trial was undertaken in 1992 to assess the efficacy and safety of antenatal administration of thyrotropin-releasing hormone to improve pulmonary outcomes in preterm infants. Thyrotropin-releasing hormone appeared to be beneficial in all previous studies22,23,24,25 except an Australian trial27 in which a lower dose (200 µg, as opposed to 400 µg) and different schedule (every 12 hours, as opposed to every 8 hours) were used. Changes in neonatal care during the past decade, in particular the routine use of surfactant, and improved survival of very-low-birth-weight infants also contributed to the rationale for conducting this trial. Finally, findings of low plasma concentrations of thyroid hormone at birth in a subgroup of infants treated with thyrotropin-releasing hormone21 aroused concern about possible effects on the function of the hypothalamic–pituitary–thyroid axis after birth.
In our study, antenatal administration of thyrotropin-releasing hormone had no effect on pulmonary outcomes in either the group of infants who were delivered at <32 weeks or those considered not at risk (delivered at >32 weeks). The incidences of respiratory distress syndrome and chronic lung disease decreased with advancing gestational age in both the treatment and placebo groups, in a manner consistent with the recognized role of lung immaturity in the pathogenesis of these disorders. There was no indication that thyrotropin-releasing hormone improved pulmonary outcome in any subgroup of infants defined by gestational age or treatment interval. There was also no evidence of either beneficial or adverse effects of thyrotropin-releasing hormone on the occurrence of patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, or retinopathy of prematurity. The wide ranges in the incidence of both chronic lung disease and death at the various centers, without apparent benefit from thyrotropin-releasing hormone, could be due to differences among the centers in the ethnic composition of the study groups, the severity of the initial illness, or clinical practices.
We did find that administration of thyrotropin-releasing hormone had the expected transient side effects of nausea and vomiting, headache, and flushing in the mother, but the majority of women had no side effects. These side effects usually did not recur with subsequent infusions, and few women withdrew from the study even after having one of these problems. Virtually all the women were receiving at least one tocolytic drug each, but there was no difference in outcome based on the type of tocolytic drug given.
Our finding that thyrotropin-releasing hormone did not lessen respiratory morbidity in premature infants agrees with the results of the Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone27 and a recent study by Maturana et al.29 A comparison of these three negative trials and the four earlier trials suggesting efficacy reveals several differences. The earlier trials involved smaller numbers of women with fewer infants in the group at risk, one trial was not blinded,22 and one was published only as an abstract.24 These limitations may have produced inaccurate conclusions. It is also possible, however, that changes in the management of preterm birth during the past five years, particularly more aggressive respiratory care, and improved survival of infants with less than 26 weeks' gestation have influenced the response to thyrotropin-releasing hormone. In very small infants, immaturity of the lungs may have a more dominant role in the disease process than surfactant deficiency, and therefore these infants could be less responsive to thyrotropin-releasing hormone. We also found no evidence that antenatal thyrotropin-releasing hormone decreased the need for surfactant. In contrast to the earlier trials, which enrolled women with gestations of <32 weeks, we enrolled only women with gestations of less than 30 weeks. If thyrotropin-releasing hormone is effective primarily in more mature fetuses, delivered within 10 days after treatment, this benefit might have been missed in our study.
The plasma concentrations of thyrotropin and triiodothyronine at birth in infants delivered less than six hours after the last dose of thyrotropin-releasing hormone or placebo were similar to those in another study of somewhat older infants.21 This suggests that the lack of efficacy of thyrotropin-releasing hormone in this trial did not result from reduced placental transfer of the hormone or from unresponsiveness of the fetal pituitary–thyroid axis.
Since the earlier reports, thyrotropin-releasing hormone has been used in a number of centers throughout the United States on the assumption that it was both effective and safe. Although it does appear safe, we found no evidence of efficacy. Furthermore, initial follow-up data from the Australian trial30,31 suggest that antenatal thyrotropin-releasing hormone may be associated with delays in early developmental milestones. We conclude that antenatal administration of thyrotropin-releasing hormone is not indicated for women who are at risk for delivering a premature infant.
Supported by grants (RO1-HD29201, MO1-RR00040, MO1-RR000425, MO1-RR01271, and P50-HL56401) from the National Institutes of Health and by Perinatal Associates, Inc., Hospital for Sick Children, Toronto, and the Children's Hospital of Eastern Ontario Research Institution.
We are indebted to Brian Strom, M.D., for critical help and encouragement with study design; to Christine Coburn, R.N., the project director, for her outstanding coordination and effective leadership; to Mr. Chris Boardman for biostatistical support; to all the obstetrical and neonatal nurses, residents, fellows, respiratory therapists, and pharmacists who made this study possible; to Ms. Peggy McDonald for preparing the manuscript; to Ms. Barbara Erwins for administrative support; to Ferring Laboratories and Abbott Laboratories for providing thyrotropin-releasing hormone; and to Glaxo Wellcome for providing surfactant (Exosurf) at selected sites.
Source Information
From the Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia (R.A.B., P.L.B., A.C.) and the University of Pennsylvania School of Nursing (J.P.-M.), Philadelphia; Children's Hospital of Eastern Ontario, Ottawa, Ont., Canada (D.J.D); Harbor–UCLA Medical Center, Torrance, Calif. (J.F.P.); University of California, San Francisco (R.H.P., J.T.P.); St. Joseph's Hospital, Phoenix, Ariz. (M.C.H.); University of California, San Diego (F.L.M.); and Good Samaritan Hospital, Phoenix, Ariz. (S.K.S.).
Address reprint requests to Dr. Roberta A. Ballard at the Division of Neonatology, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
References
-agonist on surfactant, pulmonary mechanics, and -receptor binding in fetal lamb lung. Pediatr Res 1988;24:166-170. [Medline]
In addition to the authors, the following members of the North American Thyrotropin-Releasing Hormone Study Group participated in this study: B. Planer, B. Banks, M. McCarthy, and E. Escobar, Children's Hospital of Philadelphia, Philadelphia; M. Morgan, E. Anday, K. Mooney, M. Johnson, and J. Merrill, Hospital of the University of Pennsylvania, Philadelphia; N. Newton and J. Milar, University of California, San Francisco, Medical Center, San Francisco; M. Ross, D. Polk, and S. Harrington, Harbor–UCLA Medical Center, Torrance, Calif.; K. Ash and J. Frank, Ottawa General Hospital, Ottawa, Ont., Canada; E. Tyrala and L. Chan, Temple University Hospital, Philadelphia; J. Lioy and R. Librizzi, West Jersey Hospital, Voorhees, N.J.; J. Garbaciak and E. Ramthun, St. Joseph's Hospital, Phoenix, Ariz.; C. Carballo, Good Samaritan Hospital, Phoenix, Ariz.; T. Moore and E. Milan, University of California, San Diego, Medical Center, San Diego; H. Schneider and D. Block, Kaiser Permanente Medical Center, San Diego, Calif.; J. Keith and M. Rivera-Alsina; Naval Medical Center, San Diego, Calif.; N. Ragavan and N. Dunn, Abington Memorial Hospital, Philadelphia; V. Bhutani, S. Weiner, and M. Grous, Pennsylvania Hospital, Philadelphia. The members of the Data Safety and Monitoring Committee were M. Bracken, Yale University, New Haven, Conn.; R. Goldenberg, University of Alabama at Birmingham, Birmingham; R. Soll, University of Vermont, Burlington; and L. Wright, National Institute of Child Health and Human Development (ad hoc).
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