PEDIATRICS Vol. 107 No. 4 April 2001, pp. 804

Prenatal Treatment of Congenital Adrenal Hyperplasia: Author Differs With Technical Report

To the Editor.

In the recent report from the American Academy of Pediatrics on congenital adrenal hyperplasia,¹ the authors make an inappropriate conclusion about prenatal treatment of congenital adrenal hyperplasia (CAH) with dexamethasone, namely that "spontaneous abortion, fetal demise during late pregnancy, intrauterine growth retardation, liver steatosis, hydrocephalus, agenesis of the corpus callosum, and hypospadias with unilateral cryptorchidism occur occasionally." In fact, these are rare events mostly in isolated cases. The reason for these unwarranted conclusions is that they are based on an incomplete review of the literature. Indeed, large studies have shown that the frequency of spontaneous abortion and fetal demise is no different in prenatally treated and untreated groups.^2-4 Furthermore, in 1 report the occurrence of liver steatosis in the study by Lajic and co-workers² in 1 unaffected girl who did not receive full-term treatment with dexamethasone was attributed by the author to an adenovirus. In the same study, hydrocephalus and agenesis of the corpus callosum occurred in 1 male infant treated for only 7 weeks, and hypospadias and cryptorchidism occurred in 1 boy treated for only 7 weeks. In the Scandinavian study reporting these events, the authors stated that they could not attribute with certainty these complications to dexamethasone treatment. There have been only 3 incidences of intrauterine growth retardation, all of which had recovery in postnatal life.^5,6 Haan's case report⁶ of a successful prenatal treatment states that the relationship between growth retardation in his patient and dexamethasone treatment remains uncertain. Also, Forest⁵ notes in her study of 43 treated pregnancies that in the 2 instances of intrauterine growth retardation, the mothers were small in size and received doses of dexamethasone much higher than currently recommended. In a 1998 review Forest³ states, "There is a general consensus on the fact that children born from dexamethasone-treated pregnancies have no obvious ill effects." Additionally, the European experience reported by Forest⁷ affirms that "postnatal growth and development are considered normal in all girls treated to term." There has been only 1 occurrence of hydrocephalus in the largest studies,⁸ and recent reports have concluded that the birth weight, birth length, and head circumference are not different in offspring of dexamethasone-treated pregnancies.^2,4,8

Studies before 1993 must be viewed with caution, as it was common practice to stop dexamethasone treatment to obtain hormone values in amniotic fluid and because protocols varied among institutions. In more recent studies (after 1993) that comprise 495 pregnancies,^2-4 except for weight gain, all maternal complications including striae, hypertension, edema, and gestational diabetes were not increased in the pregnancies treated with dexamethasone compared with those not treated. Since 1993, 106 female fetuses have been treated until term. No fetal complications could be attributed with certainty to the dexamethasone treatment.

In the report by the American Academy of Pediatrics, the section on page 1513 entitled "Maternal Complications of Prenatal Treatment" begins with the statement, "Maternal adverse effects of dexamethasone may be serious and long-lasting," a statement that is misleading, unwarranted, and instills fears when prenatal treatment may be warranted. Furthermore, the results of prenatal treatment studies are described inappropriately, ie, "In long-term follow-up of most infants treated throughout the pregnancy or treated until mid-gestation, development seems to be normal ... " In fact, the studies of long-term effects by Lajic,² Forest,³ and Trautman⁹ all demonstrate that growth and development is normal in prenatally treated children.

The wrong reference for Trautman is quoted on page 1512 in the section entitled "Fetal Outcome," paragraph 3. The reference quoted refers only to maternal psychiatric study, not to the follow-up of children treated prenatally with dexamethasone. The correct reference for the psychiatric study on prenatally treated children is that of Trautman et al.⁹

Because the abstract of the Ad Hoc Writing Committee states that "the reference list is designed to allow physicians who wish more information to research the topic more thoroughly," it is unfortunate that the authors fail to cite the most recent, and the largest, study on prenatal diagnosis and treatment.⁴ They also neglect to cite a thorough review by Forest,³ a leader in prenatal diagnosis and treatment in Europe. The oversight of these references makes the Technical Report an inadequate review of the current thinking in prenatal diagnosis and treatment of CAH, and it should be amended.

Prenatal treatment with dexamethasone is effective in reducing genital virilization so that genitoplasty is unnecessary. Based on recent large studies including 106 genetic females with CAH, properly conducted prenatal diagnosis and treatment are safe for both fetuses and mothers.

Maria I. New
New York Presbyterian HospitalWeill Medical College of Cornell University
Department of Pediatrics (Endocrinology)
New York, NY 10021

REFERENCES

1. American Academy of Pediatrics, Ad Hoc Writing Committee, Section on Endocrinology and Committee on Genetics Technical report: congenital adrenal hyperplasia. Pediatrics. 2000; 106:1511-1518 [Abstract/Free Full Text]
2. Lajic S, Wedell A, Bui T, Ritzen E, Holst M Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1998; 83:3872-3880 [Abstract/Free Full Text]
3. Forest MG Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Curr Opin Endocrinol Diab. 1998; 4:209-217
4. Carlson AD, Obeid JS, Kanellopoulou N, Wilson RC, New MI Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment, Xth International Congress on Hormonal Steroids, Quebec, Canada. In: J Ster Biochem Mol Biol. 1999; 69:19-29 [CrossRef][Medline]
5. Forest MG, Betuel H, David M Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update 88 of the French multicentric study. Endocr Res. 1989; 15:277-301 [Medline]
6. Haan EA, Sergeantson SW, Norman R, Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency. Med J Aust. 1992; 156:132-135 [Medline]
7. Forest MG, Morel Y, David M Prenatal treatment of congenital adrenal hyperplasia. Trends Endocrinol Metab. 1998; 9:284-289 [Medline]
8. Forest MG, David M, Morel Y. Prenatal diagnosis and treatment of 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 1993;45:75-82. Review
9. Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology. 1995; 20:439-449 [CrossRef][Medline]

In Reply.

We thank Dr New for her comments regarding the AAP Technical Report on congenital adrenal hyperplasia (CAH) and for calling our attention to the incorrect Trautman citation.

Dr New is correct in pointing out that there is controversy concerning the possible fetal and maternal side effects of prenatal dexamethasone therapy. Each single instance of a reported complication is subject to multiple interpretations. We believe that just as it is inappropriate to stigmatize prenatal therapy before all the data are in, it is equally inappropriate to assume it is safe until proven harmful. Much the same can be said for the issue of maternal side effects. Although Dr New's latest report,¹ which appeared after the completion of the Committee's work, suggests no maternal complications other than excessive weight gain, she and others have previously reported significant, sometimes severe, maternal side effects.^2,3 The bulk of the published experience with prenatal therapy comes from the 2 groups that have pioneered its use, have advocated its use, and defended its safety. These issues will become clear only with long-term multicenter trials.

In comparison to the general approach to drug safety and efficacy studies required for the approval of new agents (or new indications for old agents), the number of treated pregnancies remains small, the length of follow-up short, and the depth of the follow-up data remains modest. Teratogenic agents may have no safe "threshold dose"; in human studies it is often not responsible to establish a dose-response curve.⁴ Therefore, if an agent is associated with fetal side effects in small numbers of individuals (or animals) treated with a higher dose, it remains the physician's ethical obligation to remain very cautious, even if using lower doses. The fact that only 1 in 8 treated pregnancies may benefit from the therapy confounds this equation even further.

There is much information on the effect of glucocorticoids on the brain.^5,6 Data continue to accumulate that indicate that high-dose glucocorticoid therapy is harmful for the developing (prenatal and postnatal) brain.^7-9 Further, Dr New herself coauthored a paper reporting increased frequency of white matter abnormalities and temporal lobe atrophy on magnetic resonance imaging in patients with CAH. Although cause and effect remain to be established, one must consider that glucocorticoid therapy may have played a role in causing these abnormalities.¹⁰

The maxim of "first do no harm" requires a cautious, long-term approach,^11-13 which is why the Academy Committee unanimously agrees that prenatal glucocorticoid therapy for CAH should be confined to centers doing controlled prospective, long-term studies. The memory of the tragedies associated with prenatal use of dexamethasone and thalidomide demands no less.

Jaime Frias
Lenore S. Levine
Sharon E. Oberfield
Sonya Pang
Janet Silverstein
For the AAP Ad Hoc Writing Committee

REFERENCES

1. Carlson AD, Obeid JS, Kanellopoulou N, Wilson RC, New MI Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol. 1999; 69:19-29
2. Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI Mothers' reaction to prenatal diagnostic procedures and dexamethasone treatment of congenital adrenal hyperplasia. J Psychosom Obstet Gynaecol. 1996; 17:175-181 [Medline]
3. Lajic S, Wedell A, Bui TH, Ritzen EM, Holst M Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1998; 83:3872-3880
4. Shephard TH "Proof" of human teratogenicity. Teratology. 1994; 50:97-98 [CrossRef][Medline]
5. Sapolsky RM, Romero LM, Munck AU How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000; 21:55-89 [Abstract/Free Full Text]
6. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998; 19:269-301 [Abstract/Free Full Text]
7. Stark AR, Waldemar AC, Tyson JE, Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N Engl J Med. 2001; 344:95-101 [Abstract/Free Full Text]
8. Ahlbom E, Gogvadze V, Chen M, Celsi G, Ceccatelli S Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death. Proc Natl Acad Sci U S A. 2000; 97:14726-14730 [Abstract/Free Full Text]
9. Uno H, Lohmiller L, Thieme C, Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macquues. I. Hippocampus. Dev Brain Res. 1990; 53:157 [Medline]
10. Nass R, Heier L, Moshang T, Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol. 1997; 12:181-186 [Medline]
11. Miller WL Dexamethasone treatment of congenital adrenal hyperplasia in utero: an experimental therapy of uproven safety. J Urol. 1999; 162:537-540 [CrossRef][Medline]
12. Speiser PW Prenatal treatment of congenital adrenal hyperplasia. J Urol. 1999; 162:534-536 [CrossRef][Medline]
13. Brook CGD Antenatal treatment of a mother bearing a fetus with congenital adrenal hyperplasia. Arch Dis Child Fetal Neonatal Ed. 2000; 82:F176-F181 [Free Full Text]