1632 Correspondence

incidence in the fetus when the maternal blood ethanol concentration decreased to < 10 mg / dl; this is indicative of ethanol withdrawal in the fetus.

The authors speculate that their findings with regard to fetal breathing activity may have resulted from a transient metabolic acidosis or increased central ner­vous system levels of carbon dioxide in the fetus as a consequence of the acute ethanol intoxication. We have examined the effect of maternal administration of acute, high-dose ethanol on maternal and fetal arterial blood gases and acid-base balance in the near-term pregnant sheep.3 There were no measurable changes in maternal and fetal blood gases and acid-base balance even at maternal and fetal arterial blood ethanol con­centrations of 374 mg/dl and 382 mg/dl, respectively. On the basis of these data, it appears unlikely that a fetal acidosis occurred in the case reported by Castillo et al. Furthermore, to speculate that a transient fetal metabolic acidosis or increased central nervous system levels of carbon dioxide may have existed as a result of the metabolism of acetaldehyde, the proximate metab­olite of ethanol, is scientifically incorrect. Acetaldehyde oxidation, catalyzed primarily by hepatic aldehyde de­hydrogenase, leads to the formation of acetate. In­creased reducing equivalents in the liver (i.e., nicotin­amide adenine dinucleotide phosphate) and conse­quent reduction of pyruvate to lactate would have to occur to produce metabolic acidosis, and acetate would have to be oxidized by means of intermediary metab­olism (i.e., tricarboxylic acid cycle) to produce carbon dioxide. Also, it has been well established that although maternal and fetal blood ethanol concentrations are virtually identical, the maternal and fetal blood acetal­dehyde concentrations are about lOOO-fold less than the respective ethanol concentrations, and the acetal­dehyde concentration in fetal blood is less than that in maternal blood'" 5 These pharmacokinetic data indicate that acetaldehyde has a minor role at best in the effects of maternal ethanol ingestion on the fetus.

These comments are intended to complement, not to detract from, the findings of this very interesting case report and especially the final conclusion drawn by the authors-that it is important to document ma­ternal ethanol consumption when fetal biophysical ac­tivities are to be evaluated.

Graeme N. Smith, PhD John Patrick, MD

Department of Obstetrics and Gynaecology Department of Physiology The University of Western Ontario 268 Grosvenor London, Ontario, Canada N6A 4V2

James F. Brien, PhD Department of Pharmacology and Toxicology Queen's University Kingston, Ontario, Canada

REFERENCES 1. McLeod W, Brien ]F, Loomis C, Carmichael L, Probert C,

Patrick]. Effects of maternal ethanol ingestion on fetal breathing movements, gross body movements, and heart

June 1990 Am J Obstet Gynecol

rate at 37 to 40 weeks' gestational age. AM] OBSTET Gy­

NECOL 1983;145:251-7. 2. Smith GN, Brien]F, Carmichael L, Homan], Clarke DW,

Patrick J. Development of tolerance to ethanol-induced suppression of breathing movements and brain activity in the near-term fetal sheep during short-term maternal ad­ministration of ethanol.] Dev Physiol 1989; 11 :66-75.

3. Smith GN, Brien ]F, Carmichael L, Clarke DW, Patrick J. Effect of acute, multiple-dose ethanol on maternal and fetal blood gases and acid-base balance in the near­term pregnant ewe. Can] Physiol Pharmacal 1989;67: 686-8.

4. Brien ]F, Clarke DW, Richardson B, Patrick]. Disposition of ethanol in maternal blood, fetal blood, and amniotic fluid of third-trimester pregnant ewes. AM] OBSTET GYNECOL

1984;152:583-90. 5. Brien]F, Clarke DW, Smith GN, Richardson B, PatrickJ.

Disposition of acute, multiple-dose ethanol in the near­term pregnant ewe. AM] OBSTET GYNECOL 1987;157:204-11.

Reply To the Editors:

We appreciate the interest of Drs. Smith, Patrick, and Brien in our case report, especially because their work on the effects of alcohol on the fetus is well known. With regard to the postnatal behavior, there was noth­ing noted in the baby's chart at birth to suggest with­drawal symptoms. The vital signs were stable and the overall behavior during the first 48 hours after birth was unremarkable.

With respect to the possible mechanisms responsible for the observed responses, it is interesting that al­though the authors of the letter find our theory sci­entifically invalid, reference 4 of their letter states that acute high-dose intake of alcohol can cause a transient collapse in the umbilical vasculature, resulting in fetal hypoxia and acidosis. Also, low levels of acetaldehyde in the fetal sheep circulation is not conclusive proof that acetaldehyde or its metabolites may not have a role in the pathogenesis of abnormal responses in the hu­man fetus. Whereas tolerance to alcohol is a good ex­planation, the presence of fetal tachypnea and com­plete absence of fetal heart rate variability point toward an overall abnormal fetal response and not to an adaptive mechanism.

We look forward to the continuing work from this group of investigators in this area in which very little is known.

Ramon A. Castillo, MD Lawrence D. Devoe, MD

Department of Obstetrics and Gynecology Section of Maternal Fetal Medicine Medical College of Georgia Augusta, GA 30912

Blood sampling and transfusion in utero suggested in the pumping twin

To the Editors: We read with great interest the article by Stiller et al.

(Stiller Rl, Romero R, Pace S, Hobbins lC. Prenatal identification of twin rev.ersed arterial perfusion syn-

Volume 162 Number 6

drome in the first trimester. AM J OBSTET GYNECOL 1989; 160: 1194-6). Repeated ultrasonographic evalua­tion failed to reveal any sign of fetal congestive heart failure. Thus, the cord hemoglobin was 8.5 mg/dl at delivery and the infant died 3 days after birth. Unfor­tunately, the cause of death was not given. In accor­dance with the range of fetal hemoglobin concentra­tion, I this fetus suffered from moderate anemia.

Van Allan et al.! who reported the largest series of reversed arterial perfusion syndrome, noted that the main cause of morbidity and mortality of the pumping twin was congestive heart failure. Failure of ultra so­nographic parameters to predict the severity of the ane­mia in rhesus isoimmunization was recently reported and fetal blood sampling was suggested in these cases.'

In light of this information we suggest that blood sampling of the pumping fetus should be taken and blood transfusion should be performed in utero if in­dicated to prevent fetal anemia and congestive heart failure.

P.Jakobi, MD E. Z. Zimmer, MD

Department of Obstetrics and Gynecology "B" Rambam Medical Center Bat-Galim POB 9602 Haifa, Israel 31086

REFERENCES l. Nicolaides KH, Clewell WH, Mibashan RS, Sooth ill PW,

Rodeck CH, Cambell S. Fetal haemoglobin measurements in the assessment of red cell isoimmunization. Lancet 1988; 1: 1073-5.

2. Van Allen MI, Smith DW, Shepard TH. Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 1983;7:285-93.

3. Nicolaides KH, Fontanarosa M, Gabbe SG, Rodeck CH. Failure of ultrasonographic parameters to predict the se­verity of fetal anemia in rhesus isoimmunization. AM JOB­STET GYNECOL 1988;158:920-6.

Reply

To the Editors: We appreciate the comments related to our article.

It was suggested that fetal blood sampling be per­formed in the pump twin to assess for fetal anemia, with intrauterine transfusions to be performed if needed.

Unfortunately, little information exists in the litera­ture as to the incidence of fetal anemia in twin reversed arterial perfusion pump babies. In the Van Allen et al. series of 14 pregnancies complicated by twin reversed arterial perfusion, no hemoglobin information is avail­able. I A central question is whether the congestive heart failure that often occurs in pump fetuses is a result of the cardiovascular demands of supporting two circu­lations or whether it is a result of anemia.

Given the limited information concerning the fetal cardiovascular hemodynamics of the twin reversed ar­terial perfusion syndrome, the suggestion to perform

Correspondence 1633

fetal blood sampling is not unreasonable. It is hoped that further studies will document the value or lack there of in the management of this problem.

Robert J. Stiller, MD Roberto Romero, MD

Department of Obstetrics and Gynecology Yale University School of Medicine 333 Cedar St. New Haven, CT 06510

REFERENCE 1. Van Allen MI, Smith DW, Shepard TH. Twin reversed

arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 1983;7: 285.

Lichen sclerosus, invasive squamous cell carcinoma, and human papillomavirus

To the Editors: Invasive squamous cell carcinoma of the vulva ap­

pears to arise in association with a coexistent intraep­ithelial abnormality. I This abnormality usually falls into two main categories, either hyperplastic dystrophy, as­sociated with lichen sclerosus in most cases, or severe atypia grade 3 (vulvar intraepithelial neoplasia). Con­troversy exists over the malignant potential of lichen sclerosus, with studies demonstrating the coexistence of lichen sclerosus in excision specimens of squamous cell carcinoma ranging from little or no association2 to 63%.' In our own series of 78 cases of squamous cell carcinoma the histologic coexistence with lichen scle­rosus was 60%. Conversely, however, in clinical practice this relationship is small as we examine and treat a large number of patients with lichen sclerosus, few of whom subsequently develop a squamous cell carcinoma. 3

, 4

This discrepancy may reflect the beneficial effects of treatment as the majority of cases of lichen sclerosus recognized histologically in the squamous cell carci­noma specimens had not been diagnosed or treated previously. Alternatively, the difference may indicate the prerequisite of a cofactor such as concurrent in­fection with human papillomavirus (HPV). To test this hypothesis we analyze 10 cases of squamous cell car­cinoma with coexistent lichen sclerosus to determine the presence of HPV. The technique used for detection of the virus was Southern blot hybridization under stringent conditions. Table I indicates the probes used and the results.

The negative findings suggest either that the viral deoxyribonucleic acid tested was not present or that insufficient total deoxyribonucleic acid was available for detection in the tissues sampled. The latter explanation seems unlikely as we had conducted simultaneously an analysis with the same technique on 10 cases of squa­mous cell carcinoma with evidence of grade 3 vulvar intraepithelial neoplasia; we obtained positive results in seven of the II lesions (Lessana-Leibowitch M. Un­published data), and in six of seven HPV # 16 was de­tected.