608 Correspondence

was and is presently individualized to maintain these levels. Because of the variables noted by De Lia and Emery, fixed dosage regimens are undesirable during pregnancy. We recognized and acknowledged that the 1987 report represented circumstantial evidence. We subsequently have reported in this JO URf\:AL fetal digoxin measurements obtained before, during, and after maternal digoxin therapy.' We have additional experience with two other cases (unpublished data). In all three cases there was no incremental change in the fetal digoxin level during prolonged maternal digitalization . And in each case, there was no response by the fetus to maternal digitalization. A group from Guys Hospital in London reported a similar experience at the Fifth International Fetal Medicine and Surgery Society Meeting held in Bonn, Germany, June, 1988. Each of the fetuses at our institution who failed to respond to maternal digitalization subsequently responded rapidly to either direct fetal or neonata l digitalization. Thus the weight of current evidence (both biologic and pharmacologic) does not support transplacental digitalization . Evaluation of maternal kinetics is further compromised by the assumption that fetal kinetics are similar. We have, now on multiple occasions~ demonstrated that the fetal elimination half-life of digoxin is < 15 hours. We have also shown that digoxin-like immunoreactive substance behaves as a stress hormone correlating with epinephrine, norepinephrine, and fetal respiratory blood gas values.' Drs. De Lia and Emery's letter raises an important issue-the need for treatment of fetal supraventricular tachycardia in the absence of cardiac failure. We are unaware of any study that approaches the natural history of fetal supraventricular tachycardia. Though fetal supraventricular tachycardia is potentially lifethreatening, it is not in most instances associated with cardiac failure, and spontaneous conversion to sinus rhythm is likely common. We summarized our thoughts on this subject in 1988.' Presently, we perform sonographic follow-up of these fetuses for evidence of congestive heart failure . Should this be noted , either direct fetal digitalization or transplacental treatment with another appropriate antiarrythmic agent is begun . The problems of a randomized trial are not quite as cumbersome as Drs. De Lia and Emery suggest. The target maternal level should be based on pharmacologic levels in the absence of interfering substances associateq with an evaluation of the biologic effect. The end points are straightforward-fetal biologic effect and demonstration of incremental increase in fetal digoxin concentrations. The safety of cordocentesis in experienced hands (loss < 1/300) renders this an acceptable study. The lack of a biologic effect, associated with a lack of an incremental change in fetal digoxin measurements during adequate maternal digitalization , would confirm our suspected lack of efficacy. In summary, though Drs. De Lia and Emery believe digoxin to be effective therapy for supraventricular

Februarv 1990 Am J Obstet , ;} newl

tachycardia, many fetuses (and their exact number is unknown) fail to alter their ventricular rate despite adequate maternal concentrations of digoxin assuming (as they do) a 1 : 1 passage of digoxin. Second, direct measurements of fetal blood before a nd during prolonged maternal administration and after cessation of digoxin administration fail to reveal any change in the fetal digoxin concentration as measured by immunoassay. Third , fetuses who fail to respond to maternal transplacental digitalization often respond rapidly when given digoxin directly. Fourth, the level of digoxin-like immunoreactive substance is elevated in fetuses with similar illnesses and the elevation correlates with the fetal catecholamine concentration. Fifth, digoxin-like immunoreactive substance is not measured by the Abbott Laboratories assay in healthy fetuses. Sixth, healthy fetuses delivered of mothers who receive digoxin do indeed have elevated digoxin measurements. Thus digoxin crosses the placenta of the otherwise healthy fetus. The only conclusion possible at this time is that maternally administered digoxin fails to cross the placenta of sick fetuses in an amount adequate to render an effect. Drs. De Lia and Emery are unwilling to abandon transplacental digitalization. Certainly, this is their prerogative. However, we would point out the following. Maternal digitalization carries a finite risk. In the absence of being able to elucidate the natural history of supraventricular tachycardia and thus the true risk to the fetus, in the absence of being able to document directly transplacental passage of digoxin, and in the absence of a randomized trial supporting the efficacy of maternal digitalization , is this small risk (and expense) to the mother necessary? OUf experience to date suggests that reported successes of transplacental digitalization are compatible with serendipity. We thank Drs. De Lia and Emery fOf the opportunity to expand on this fascinating subject. Carl P. Wemer, MD Department of Obstetrics and Gynecology University of Iowa Hospitals and Clinics Iowa City, IA 52242 REFERENCES

I . Weiner CPo Thompson MIB . Direct fetal treatment of supraventricular tach ycardia a fter failed transplacental therapy. AM J OBSTET Gy~I:.COL 19H8; 15H: 570-3. 2. Weiner CP, Robillard .fE. Atrial natriuretic factor, digoxinlike immunoreactive substance, norepinephrine. epinephrine. and plasma renin activity in human fetuses and their alteration by fetal disease. A~I J OilS rET GY:-"ECOL 19HH; 159 :1353-60.

Feedback mechanism of human chorionic gonadotropin secretion To Ihe Editors: The article of Ahmed and Murphy dealing with the effects of various hormones on human chorionic go-


Volume 162 I'umber 2

nadotropin (hCG) production in early and late placental explant cultlll'e~ that was recentlv published in this JOUR]\;J\L (Ahmed NA. Murphy BEP. The effects of \'arious hormones on human chorionic gonadotropin production in early and late placental explant cultures. AM J 0BS n O'r GY!'\ECOL 1988; 159: 1220-7) is an important contribution to the understanding of the feedback mechanism of hCG production and release. The authors found that testosterone inhibited and cortisol or dehydroepiandrosterone sulfate stimulated the production of hCG under the experimental conditions chosen for the study. These results. as we would like to point out. contradict pl'evious work I'eported by Haning et aI., I which indicated that fetal adrenal steroids seem to inhibit and not to stimulate hCG secretion. The sel'um hCG levels in pregnant women with a male fetus are known to be significantly lower than in those with a female fetus but only in the last trimester of pregn ancy." If this distinction is caused by testosterone secreted by the fetal testes, the hCG decrease occurring in both sexes after the tenth week of pregnancy has to be governed by factors other than testosterone alone. Ahmed a nd Murphy also postulated that the high output of hCG in early pregnancy as compared with that in late pregnancy could be due to differences in the half-life of hCG. The half-life of hCG has been shown by Wide and Hobson·; to be longer in early preg-


nancy than in late pregnancy. Although such a difference in the clearance rate may affect the semm level of hCG to a certain degree, it is probably of minor significance as compared to the enormous secretory capacity of the relatively small trophoblastic mass in early pregnancy. J. S. E. Der·icks-Tan, PhD H.-D . Taubert, MD Abt. fur Gyn. Endokrinologie Universitats-Frauenklinik Theodor-Stern-Kai 7 6000 Frankfurt, Federal Republic of Germany

REFERENCES I . Haning RV, Choi L. Curet LB. et al. Interrelationships among human chorionic gonadotropin (hCG). 1713estradiol. progesterone. and estriol in maternal serum: evidence for an inhibitory effect of the fetal adrenal on secretion ofhCG. J Clin Endocrinol Metab 1983;56: 1188-94. 2. Danzer H. Braunstein GO. Raso r J. et al. Maternal serum human chorionic gonadotropin concentrations and fetal sex prediction. Fertil Steril 1980;34:336-40. 3. Wide L. Hobson B. Some qualitative differences of heG in serum from early and late pregnancies and trophoblastic diseases. Acta Endocrinol 1987; 116:465,72.

Response declined

Feedback mechanism of human chorionic gonadotropin secretion.

608 Correspondence was and is presently individualized to maintain these levels. Because of the variables noted by De Lia and Emery, fixed dosage reg...
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