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Preemies on Steroids:  A New Iatrogenic Disaster? by Helen Harrison

Published in Birth March 2001, Vol.28, No. 1, pp.57-59.

At the Hot Topics in Neonatology conference last December, Dr. Barbara Schmidt referred to the year 2000 as "Annus Terribilis" for her profession.1  Large studies from the NICHD2  in the US  and the EPICure group3 in the UK had revealed unexpectedly grim outcome statistics for extremely low birthweight and short gestation babies --  a 50% rate of disability serious enough to be diagnosed by two to three years of age .  Because follow up at such early ages reveals only a fraction of the impairments diagnosed by mid to late childhood,4  the eventual toll in disability promises to be considerably higher.3  Premature birth, it was also reported, permanently disorganizes and reduces the size of the brain, adversely affecting cognition and behavior.5, 6  The more premature the infant, the smaller and more abnormal the brain.5   Adult cardiovascular disease, underdeveloped kidneys and diabetes were further linked to low birth weight. 7   It had become increasingly apparent that improved survival among extremely preterm infants was producing greater numbers of children with  permanent health  impairments and handicaps.8  Further, some of this disability was linked to iatrogenic causes,2 a result of the continued haphazard use of poorly evaluated therapies in perinatal and neonatal care. 9,  10

Improved survival  among extremely premature infants  has been credited in part to the use of  steroid drugs 11, 12 currently administered to nearly half of mothers before extremely preterm delivery and to half of all extremely preterm infants after birth.13  In perhaps the most disturbing revelation of the year 2000, steroids were implicated as  "neurotoxic" substances 2 that  further reduce the size of the premature brain14 and increase rates of cerebral palsy,15, 16, 1 7 cognitive  deficits, 2, 15  and severe retinopathy.18, 19  Two large randomized controlled trials of postnatal steroids were halted prematurely because of serious short term complications such as intestinal perforations, growth retardation, periventricular leukomalalcia, hyperglycemia, hypertension, and infection. 20, 21 In addition, animal and human studies of steroids in the perinatal and neonatal period  have suggested that steroids contribute to long-term cardiovascular disease, 22, 23 immune system disorders and autoimmune diseases such as multiple sclerosis, 24 renal calcification, 25 abnormal lung development,26 and neurological and behavioral deficits.27, 28  

Prenatal steroids -- used in single two-injection doses -- have been accepted as safe and effective in reducing neonatal mortality and morbidity,  however, many obstetricians treat  high risk pregnant women with multiple courses of steroids29 on the theory that if a little bit is good, more is better.  New research  now implicates multiple doses  of prenatal steroids with impaired head growth,30 impaired brain development and behavior problems; 31, 32  increased mortality and lung disease; 26  gastroesophageal reflux;33  and severe retinopathy.34  A consensus statement from NIH, issued in August 2000, now discourages their use.29

Postnatal steroids became  widespread in neonatal care by the 1990s having been  introduced into the nursery without properly conducted clinical trials for safety and efficacy  10 and despite warnings from researchers (beginning in the 1970s) of serious potential dangers.35, 36 ,37 Steroids were accepted enthusiastically because they produced dramatic short term improvements in the respiratory status of premature infants (long term benefits were less apparent).38   Dr. William Silverman, who has written extensively on previous iatrogenic mishaps in neonatology, 39,40 estimates that tens of thousands of infants have  now been treated with these drugs, in what he suspects will be "one of the worst iatrogenic disasters in modern history, exceeded only by the DES fiasco." 41

Neonatologist Alan Jobe  recently criticized his profession's embrace of poorly tested and potentially dangerous steroid treatment by quoting Tom Lehrer's bitter lyrics on the misuse of scientific technology: "Once the rockets are up, who cares where they come down?  That's not my department says  Wernher von Braun."38   Dr. Jobe further writes: "Adverse neurodevelopmental outcomes [from the use of steroids] no doubt  result from the effects of these potent agents on the developing nervous system and should come as no surprise."38 Except, of course , to parents and  the public.

As the rockets began landing last year, the explosions occurred out of public and parental sight.   Disturbing studies and commentaries on steroids were presented  (quietly) in neonatal journals and conferences. However the  media, for the most part,  seems to have missed this iatrogenic disaster-in-the-making. Perhaps there have simply been no press releases from the medical journals and  researchers.  As neonatologist Mildred Stahlman once remarked, "We have allowed the media to publicize our successes widely, and have minimized our failures to the public"42

I participate in several Internet listservs for parents of premature infants.  The parents with whom I correspond uniformly report that they were never informed of the known and suspected risks of multiple prenatal or postnatal steroids.  A few parents say they were told the drugs might "slow growth," but complications involving the brain, eyes and other organs and systems were never mentioned.  When I  give parents the studies and commentaries referenced in this article they become angry that they were never given this information, though much of it has been available to neonatologists for decades.  They are devastated to discover that many of the illnesses and disabilities their children now suffer may have resulted from, or have been complicated by, the use of steroids. In addition, high risk pregnant women report they continue to be treated with multiple doses of antenatal steroids without being informed of the risks.

The steroid  issue is being discussed by physicians on the Internet, as well.  A recent poll 43 of 259 neonatologists conducted by Dr. Richard Scott Taylor revealed that steroids are still commonly used and that neonatologists' practices vary widely concerning when and how they use these drugs.  Less than 10% of the respondents reported involving parents in formal informed consent procedures for the use of steroids. Dr.  Taylor comments: "It.does not make sense to me that as physicians, we get informed consent for standard procedures with clear risk benefit balance such as immunizations and blood transfusions yet are not necessarily expected to get consent for PNCS [post-natal corticosteroids] where there is no standard for use, and significant potential for harm..But perhaps we should. "

I strongly agree!  Given the current widespread use of poorly evaluated therapies in neonatal care and the dismal outcomes (with and without steroids)  I must also agree with neonatologist Jeffrey Maisels that care for very low birthweight infants is currently  "a vast and uncontrolled experiment undertaken without informed consent and with possibly undesirable results."44 

The time has come for parents --  who, with their children,  must suffer the outcomes -- and for the public --  who ultimately pay for this care and its consequences -- to be  honestly informed about the "experimental" nature of neonatal treatment for very preterm infants and its unfortunate results.  It is also time for parents and the public to demand that steroids and, in fact,  all poorly evaluated neonatal treatments be used only in the context of formal clinical trials. Furthermore, the time has come, in the wake of this "annus terribilis" to assert the right of parents to give, or to withhold, their fully informed consent to the experimental, arduous, and dangerous treatment of their extremely premature infants.9

References

Schmidt B. Prevention of IVH and BPD: International Randomized Placebo-Controlled Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP).  Presented at Hot Topics in Neonatology, December 5, 2000, Washington, DC.

2.      Vohr BR, Wright LL, Dusick AM,.et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994,  Pediatrics 2000;105:1216-26.

3.       Wood NS, Marlow N, Costeloe K, et al.  Neurologic and developmental disability          after extremely preterm birth. N Engl J Med 2000;343:378-84.

4.      McGrath MM, Sullivan MC, Lester BM, and Oh W. "Longitudinal neurological follow-up in neonatal intensive care unit survivors with various neonatal morbidities. Pediatrics 2000;106:1397-1405.

5.       Peterson BS, Vohr B, Staib, LH et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000;284:1939-1947.

6.      Hack M, Taylor HG. Perinatal brain injury in preterm infants and later neurobehavioral function. JAMA 2000;284:1973-1974.

7.      Eriksson J,  Forsen T, Tuomilehto J, et al. Fetal and childhood growth and hypertension in adult life. Hypertension 2000;36 (5):790.

8.      Jobe  A. Overview for prevention of IVH -Why are <1 kg infants normal? Presented at Hot Topics in Neonatology December 5, 2000, Washington, D.C.

9.      Harrison H. The principles for family-centered neonatal care.  Pediatrics 1993;92:643-650.

10.   Finer NN, Craft A, Vaucher YE et al. Postnatal steroids: Short-term gain, long-term pain? J Pediatr 2000;137:9-13.

11.  Lorenz JM. Survival of the extremely preterm infant in North American in the 1990s. Clin Perinatol 2000;27:255-262.

12.  Halliday HL.  Clinical trials of postnatal corticosteroids: Inhaled and systemic. Biol Neonate 1999;76:29-40.

13.  Vermont Oxford Network 1998 Database Summary.  Burlington, Vermont: Vermont Oxford Network;1999.

14.   Murphy BP, Inder TE, Huppi PS, et al.  Quantitative brain growth following treatment with dexamethasone for neonatal chronic lung disease [abstract]. Pediatr Res 2000;47:419A.

15.  Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethsone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal and Neonatal Ed 2000;83:F177-F181.

16.  Yeh TF, Yin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 1998;101:E71-78.

17.  O'Shea T, Kothadia J, Klinepeter K, et al.  Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999;104:15-21.

18.   Vohr BR, Phelps D, Wright LL, et al. Effects of neonatal interventions on retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) survivors <1000 grams [abstract]. Pediatr Res 2000;47:327-A

19.   Halliday HL, Ehrenkranz RA Delayed (>3weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev  2000:CD001145.

20.   Stark AR, Carlo W, Bauer C, et al. Complications of early steroid therapy in a randomized controlled trial [abstract]. Pediatrics Supplement 1999;104:739-A.

21.   Soll RF for the Vermont Oxford Network Steroid Study Group.  Early postnatal dexamethasone therapy for the prevention of chronic lung disease [abstract]. Pediatr Res 1999;45:226A.

22.  Ortiz LA, Quan A, Weinberg A, et al. Prenatal dexamethasone causes reduced glomerular number and hypertension in adult rats [abstract]. Pediatr Res 200;47:450-A.

23.  Doyle LW. Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci 2000;98:137-142.

24.   Bakker JM, Kavelaars A, Kampuis PJ et al. Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune disease in adults. J Immunol 2000;165:5932-7.

25.  Kamisuka MD, Williams MA, Nyberg DA et al. Renal calicification:  A complication of dexamethasone therapy in preterm infants with bronchopulmonary dysplasia. J Perinatol 1995;15:359-63.

26.  Banks BA, Merrill JD, Cnaan A, et al.  Multiple courses of antenatal corticosteroids (ANCS): Association with increased mortality and early severe lung disease (ESLD) in preterm neonates. Pediatrics 1999;104 (3) part 3:739.

27.  Kamphuis PJGH, Coiset G, Bakker JM, et al. Neonatal treatment with dexamethasone selectively reduces pituitary-adrenal responsiveness of rats to novelty stress in adulthood [abstract]. Pediatr Res 2000;47:71-A.

28.  Benesova O, Pavlik A. Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain. Neuropharmacology 1989;28:89-97.

29.  Antenatal corticosteroids revisited: Repeat courses.  NIH Consens Statement 2000 August 17-18;17:1-10.

30.   French NP, Hagan R, Evans SF, et al. Repeated antenatal corticosteroids: Size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114-21.

31.  French NP, Hagan R, Evans S, et al. Repeated antenatal corticosteroids (CS): Behavior outcomes in a regional population of very preterm (VP, <33w) infants. [abstract] Pediatr Res 1998:43:214-A.

32.   Kay HH, Bird IM, Coe CL, et al. Antenatal steroid treatment and adverse fetal effects: What is the evidence? J Soc Gynecol Investig 2000;7:269-278.

 33.  Bhandari V, Brodsky NL.  Repetitive doses of antenatal steroids (ANS) are associated with increased gastroesophageal reflux (GER) [abstract]. Pediatr Res 1999;45:186-A.

34.   del Moral T, Claure S, VanBuskirk S et al. Antenatal steroids and incidence of ROP in ELBW infants [abstract]. Pediatr Res 2000;47:395-A.

35.  Taeusch HW. Glucocorticoid prophylaxis for respiratory distress syndrome: A review of potential toxicity. J Pediatr 1975:87:617-623.

36.  Weichsel ME. The therapeutic use of glucocorticoid hormones in the neonatal period: Potential neurological hazards. Ann Neurol 1977;2:364-366.

37.  Frank L. The use of dexamethasone in premature infants at risk for bronchopulmonary dysplasia or who already have developed chronic lung disease: A cautionary note [letter]. Pediatrics 1991;88:413-414.

38.   Jobe A. Glucocorticoids in perinatal care: Misguided rockets? J Pediatr 2000;137:1-3.

39.  Silverman WA. Where's the Evidence? Debates in Modern Medicine.  New York: Oxford University Press, 1998.

40.  Silverman WA. Retrolental Fibroplasia: A Modern Parable. New York: Grune & Stratton, 1980.

41.   Silverman WA. Personal communication. November 7, 2000.

42.   Stahlman MT. Ethical issues in the nursery: Priorities versus limits. J Pediatr 1990;116:167-170.

43.  Taylor RS.  Postnatal steroid use among neonatologists: Survey results December 2000. http://www.cheo.on.ca/rtaylor/PNSteroid-r.htm

44.   Maisels J. as quoted by S J Brown.  Neonatal intensive care: Life at what cost? Pediatric News January 1993:1,26

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