Fall 2007 Newsletter

CARES Foundation, Inc.

Adverse Effects Of Prenatal Dexamethasone:
The Evidence Is Inconclusive

Submitted by Heino F. L. Meyer-Bahlburg, Dr. rer. nat., NYS Psychiatric Institute & Columbia University, and Maria I. New, Mt. Sinai School of Medicine, New York, NY. E-mail: meyerb@childpsych.columbia.edu

Through the phrasing of their paper title and conclusions, Hirvikoski et al. (1) posit as definitive that “prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia [adversely] affects cognitive functions”. We certainly welcome that the Swedish team has provided follow-up data on cognitive function in this under-researched area, but the data do not justify their conclusions.

In the absence of randomized clinical trials, the best investigative approach would be a prospective case-control study involving blinded assessments and comparing separately short-term and long-term prenatal dexamethasone treated children to demographically similar non-treated children of the same sex and condition (CAH-affected versus -unaffected), and with comparable participation-refusal rates, all factors to which behavioral outcome data are much more sensitive than endocrinological data. The present study, however, did not use blinded assessments, had no CAH-affected children among the controls, and only 3 long-term treated children, i.e., CAH girls, in the treated group who could not be analyzed by themselves and are grouped with the short-term treated CAH boys (plus one CAH girl who could not be tested because of “low intellectual performance” and only entered group comparisons involving parent-report data). Moreover, the controls came from two different sources and differed markedly from the dexamethasone-treated group in urban-rural background and in participation-refusal rates. Breaking down the treatment sample into even smaller subsamples is likely to create additional disparities, which should be checked and reported. All of this raises unanswerable questions of sample comparability.

In addition, given the recent publication of a Scandinavian study (2) on impaired intelligence in CAH children, the question arises whether the data showing marginally (p<.08) impaired full-scale IQ in the dexamethasone-exposed group reflected CAH effects rather than dexamethasone effects, which in turn might account for some of the significant effects on specific neuropsychological tests. Another problem is that several of the effects were significant for the comparison of CAH-unaffected short-term dexamethasone-treated children to controls, but not for the CAH-affected dexamethasone-treated children, although the latter combined the short-term treated CAH boys with the long-term treated CAH girls. This is not only a question of statistical power. For instance, anxiety means for treated unaffected children were shown to be above the means of controls on all 4 scales while the anxiety means for affected children were below those of controls on 3 of the 4 scales. Thus, short-term exposure to dexamethasone during a very early phase of brain differentiation has adverse effects, but long-term exposure from very early through late fetal development is not adverse or even beneficial? This interpretation seems less plausible than confounding effects from inadvertent differences between comparison groups in demographic, sex, and/or disease characteristics. (Unfortunately, the data for the other tests are not reported by subgroup so that one cannot check on the consistency of those findings.)

It would therefore seem premature to make this Swedish study the basis for depriving CAH girls of a prenatal treatment that has very beneficial effects on their genital development and reduces or abolishes the need for genital surgery.

References

1. Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Wedell A, Lajic S 2006 Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia affects cognitive functions. J Clin Endocrinol Metab: doi:10.1210/ jc.2006-1340

2. Johannsen TH, Ripa CPL, Reinisch JM, Schwartz M, Mortensen EL, Main KM 2006 Impaired cognitive function in women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 91(4):1376-1381.

Reprinted with permission from Journal of Clinical Endocrinology and Metabolism (2007).