Table Of ContentDRUGS AND FETAL
DEVELOPMENT
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
Nathan Back Chairman, Department of Biochemical Pharmacology, School of Pharmacy,
State University of New York, Buffalo, New York
N. R. Di Luzio Chairman, Department of Physiology,
Tulane University School of Medicine, New Orleans, Louisiana
Alfred Gellhorn University of Pennsylvania Medical School, Philadelphia, Pennsylvania
Bernard Halpern College de France,
Director of the Institute of Immuno.Biology, Paris, France
Ephraim Katchalski Department of Biophysics, The Weizmann Institute of Science,
Rehovoth, Israel
David Kritchevsky Wistar Institute, Philadelphia, Pennsylvania
Abel Lajtha New York State Research Institute for Neurochemistry and Drug Addiction,
Ward's Island, New York
Rodolfo Paoletti Institute of Pharmacology, University of Milan, Milan, Italy
Volume 1
THE RETICULOENDOTHELIAL SYSTEM AND ATHEROSCLEROSIS
Edited by N. R. Di Luzio and R. Paoletti· 1967
Volume 2
PHARMACOLOGY OF HORMONAL POLYPEPTIDES AND PROTEINS
Edited by N. Back, L. Martini, and R. Paoletti' 1968
Volume 3
GERM·FREE BIOLOGY: Experimental and Clinical Aspects
Edited by E. A. Mirand and N. Back' 1969
Volume 4
DRUGS AFFECTING LIPID METABOLISM
Edited by W. L. Holmes, L. A. Carlson, and R. Paoletti' 1969
Volume 5
LYMPHATIC TISSUE AND GERMINAL CENTERS IN IMMUNE RESPONSE
Edited by L. Fiore·Donati and M. G. Hanna, Jr.' 1969
Volume 6
RED CELL METABOLISM AND FUNCTION
Edited by George J. Brewer' 1970
Volume 7
SURFACE CHEMISTRY OF BIOLOGICAL SYSTEMS
Edited by Martin Blank' 1970
Volume 8
BRADYKININ AND RELATED KININS: Cardiovascular, Biochemical, and
Neural Actions
Edited by F. Sicuteri, M. Rocha e Silva, and N. Back' 1970
Volume 9
SHOCK: Biochemical, Pharmacological, and Clinical Aspects
Edited by A. Bertelli and N. Back' 1970
Volume 10
THE HUMAN TESTIS
Edited by E. Rosemberg and C. A. Paulsen' 1970
Volume 11
MUSCLE METABOLISM DURING EXERCISE
Edited by B. Pernow and B. Saltin • 1971
Volume 12
MORPHOLOGICAL AND FUNCTIONAL ASPECTS OF IMMUNITY
Edited by K. Lindahl.Kiessling, G. Aim, and M. G. Hanna, Jr. • 1971
Yolume 13
CHEMISTRY AND BRAIN DEYELOPMENT
Edited by R. Paoletti and A. N. Davison· 1971
Yolume 14
MEMBRANE·BOUND ENZYMES
Edited by G. Porcellati and F. di Jeso • 1971
Yolume 15
THE RETICULOENDOTHELIAL SYSTEM AND IMMUNE PHENOMENA
Edited by N. R. Di Luzio and K. Flemming· 1971
Yolume 16A
THE ARTERY AND THE PROCESS OF ARTERIOSCLEROSIS: Pathogenesis
Edited by Stewart Wolf· 1971
Yolume 16B
THE ARTERY AND THE PROCESS OF ARTERIOSCLEROSIS: Measurement and
Modifiration
Edited by Stewart Wolf· 1972
Yolume 17
CONTROL OF RENIN SECRETION
Edited by Tatiana A. Assaykeen ·1972
Yolume 18
THE DYNAMICS OF MERISTEM CELL POPULATIONS
Edited hy Morton W. Milll'r and Charles r.. Kuehnert. 1972
Yolume 19
SPHINGOLIPIDS, SPIIINGOLIPIDOSES AND ALLIED DISORDERS
Edited by Bruno W. Yolk and Stanley M. Aronson • 1972
Volume 20
DRUG ABUSE: Nonmedical Use of Dependence.Producing DruJ!;s
Edited by Simon Btesh • 1972
Yolume 21
V ASOI'EI'TI)) ES: C1l1'llIi,try. I'harma('()I()~y. and I'athophy,iolop:y
Edited hy N. B(\(·k and F. Si(,lIt<"ri • 1'172
Volume 22
COMPARATIVE PATHOPHYSIOLOGY OF CIRCULATORY DISTURBANCES
Edited by Colin M. Bloor. 1972
Volume 23
THE FUNDAMENTAL MECHANISMS OF SHOCK
Edited by Lerner B. Hinshaw and Barbara G. Cox. 1972
Volume 24
THE VISUAL SYSTEM: Ncurophysiolo!(y, Biophysirs, and Their Cliniral Appli"ations
Edited by G. B. Arden. 1972
Volume 25
GLYCOLIPIDS, GLYCOPROTEINS, AND MUCOPOLYSACCHARIDES
OF THE NERVOUS SYSTEM
Edited hy Vittorio Zambotti, Guido Tettamanti, and Maria!\razia Arrigoni • 1972
Volume 26
PHARMACOLOGICAL CONTROL OF LIPID METABOLISM
Edited by William L. Holmes, Rodolfo Paoletti,
and David Kritchevsky • 1972
Volume 27
DRUGS AND FETAL DEVELOPMENT
Edited by Marcus A. KlinJ(berJ(, Armand Abramovici, and Juan Chemke· 1972
Volume 28
HEMOGLOBIN AND RED CELL STRUCTURE AND FUNCTION
Edited hy George J. Brewer. 1972
DRUGS AND FETAL
DEVELOPMENT
Proceedin~s of an International Symposium on The Effect of
Prolonged Drug Usa~e on Fetal Development held at Beit-Berl.
I(far Saba, Israel. September 14-17, 1971
Edited by
Marcus A. Klingberg
Head, Department of Epidemiology and Deputy Scientific Director
Israel Institute for Biological Research and
Tel.Aviv University Medical School
Ness·Ziona, Israel
Armand Abramovici
Director, Laboratory of Developmental Pathology
J. Casper Department of Pathology, Beilinson Hospital and
Tel·Aviv University Medical School
Petah·Tikva, Israel
and
Juan Chemke
Director, Birth Defects Clinic
Departments of Pediatrics A and Pediatric Research
Kaplan Hospital (affiliated with the Hebrew University and
Hadassah :\Iedil'al School, Jerusalem)
Rehovot, Israel
The Symposium on The Effect of Prolonged Drug Usage on Fetal
Development was held under the auspices of
Israel Academy of Sciences and Humanities
Tel-Aviv University Medical School
Israel Institute for Biological Research
Israel Society for Congenital Malformations
Library of Congress Catalog Card Number 72-86141
ISBN-13: 978-1-4684-3221-3 e-ISBN-13: 978-1-4684-3219-0
DOl: 10.1007/978-1-4684-3219-0
© 1972 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1972
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
United Kingdom edition published by Plenum Press, London
A Division of Plenum Publishing Company, Ltd.
Davis House (4th Floor), 8 Scrubs Lane, Harlesden, London,
NW10 6SE, England
All rights reserved
No part of this publication may he reproduced in any form
without written permission from the publisher
ORGANIZATION OF THE SYMPOSIUM
Chairman of the Symposium: Prof. Marcus A. Klingberg
Organizing Committee: Dr. A. Abramovici
Prof. E.D. Bergmann
Dr. J. Chemke
Prof. S. Gitter
Prof. I.G. Halbrecht
Dr. M. Kesten - Treasurer
Prof. M.A. Klingberg - Chairman
Prof. S. Levin - Vice Chairman
Prof. E. Liban - Vice Chairman
Prof. H.N. Neufeld
Prof. W.Z. Polishuk
Prof. M. Streifler - Vice Chairman
Dr. M. Torten - Secretary General
vii
Acknowledgement is gratefully made to the following firms who
provided funds to help support the Symposium:
ABIC LTD., Chemical & Pharmaceutical Industries, Ramat-Gan,
Israel
AGENTEX LTD., Tel-Aviv, Israel
ASSIA CHEMICAL LABORATORIES LTD., Petah-Tikva, Israel
lKAPHARM LTD., Pharmaceutical & Chemical Laboratories,
Ramat-Gan, Israel
NISSEN PREMINGER LTD., Medical Supplies, Tel-Aviv, Israel
PHARMAPLANTEX LTD., Pharmaceutical Works, Nathanya, Israel
RAFA LABORATORIES LTD., Jerusalem, Israel
SANDOZ LTD., Basel, Switzerland
TEVA MIDDLE EAST PHARMACEUTICAL & CHEMICAL WORKS LTD.,
Jerusalem, Israel
VARON CHEMICALS LTD., Tel-Aviv, Israel
viii
FOREWORD
This volume contains most of the papers presented at the
First International Symposium on The Effect of Prolonged Drug
Usage on Fetal Development held at the Beit-Berl Convention Center,
Kfar Saba, Israel, on September 14 - 17, 1971.
In order to obtain an overview of the effect of drugs on
fetal development, it appeared desirable to gather the opinions
of noted investigators regarding the goals already achieved and
the future potential of prevention of fetal disorders due to
drugs.
More than one hundred and sixty scientists from fifteen
countries participated, and over forty presented data which were
collected in extensive laboratory, clinical and field studies.
This small, comparatively informal, International Symposium
was held in a relaxed environment and provided a suitable forum
for scientists in many differing lines of research to evaluate
together the recent advances in the role of drugs as teratogenic
agents and methods for the rapid uncovering of the teratogenic
potential of drugs to mankind.
The success of the Symposium was due not only to the partici-
pants who presented their papers, joined in the discussions, and
so willingly cooperated in their contribution to this record of
the conference, but in no small part to the efficient conduct of
the Sessions by the Chairmen - Messrs. F. Bergmann, R.L. Brent,
A.M. Davies, K.H. Degenhardt, S. Gitter, E. Liban, H. Lutz,
U. Murakami, L. Nebel, H.N. Neufeld, W.Z. Polishuk, A. Robinson,
J.A. Robson, L. Saxen, D.M. Serr, H.C. Shirkey, M. Streifler and
J. Yerushalmy.
We believe that this Symposium provided an opportunity for
the cross fertilization and stimulation of ideas between scientists
in the various disciplines. The present volume of the Proceedings
shows how much has already been done and what prospects lie ahead.
ix
x FOREWORD
The meeting could not have been organized without the help of
of Dr. Michael Torten, Secretary of the Symposium, and Messrs.
Mordechai Nawon and Menachem Iris who helped with extracurricular
tasks. Likewise, we are happy to thank the secretaries, Mmes.
Yehudity Lahav, Rachel Straks and Ilana Turner, for their tire-
less efforts on our behalf.
The editors wish to convey their warm appreciation to Mmes.
Myra Kaye and LaVerne Binstock for their untiring help and effi-
cient assistance in the editing and technical preparation of this
book.
This meeting was held thanks to the generous support of the
Ministry of Health, Ministry of Tourism, Tel-Aviv University
Medical School, the Israel Institute for Biological Research and
the Israel Foundation Trustees, and of the ten pharmaceutical
organizations already mentioned.
Marcus A. Klingberg
Armand Abramovici
- Juan Chemke
CONTENTS
Chairman's Introductory Address ..... 3
Marcus A. Klingberg
Congenital Malformations through the Ages 7
Josef Warkany
Human Experiences Related to Adverse Drug Reactions
to the Fetus or Neonate from Some Maternally
Administered Drugs .. . . . . . 17
Harry C. Shirkey
Drug Testing for Teratogenicity:
Its Implications, Limitations and Application to Man. . .. 31
Robert L. Brent
Sporadic Malformations in Laboratory Animals and
Their Influence on Drug Testing . . . . . . 45
A. k. Palmer
Fetal Outcome from Prolonged Versus Acute
Drug Administration in the Pregnant Rat . . . . . 61'
C. T. G. King, E. Horigan and A. L. wilk
Multiphasic Screening, a Contribution to the
Methodology of Teratological Research . 77
S. Sandor
Study of Carbohydrate Metabolism in the Newborn Rat
as a Tool for Evaluating Effects of Drugs Administered
During Pregnancy . . . . . . . . . . . . . . . . . 8:)
R. De Meyer, G. Verellen and P. Gerard
Effects of Chemical Agents on Protein Biosynthesis
During Embryonic Development . . . . 97
OWen M. Rennert
Effect of Natural Teratogens in Poisonous Plants on
Fetal Development in Domestic Animals ..... 107
Richard F. Keeler
The Action of Different Pesticides on the Development
of Bi rd Emb ryos . . . . . . . . . . . . 127
Hubert Lutz and Yvonne Lutz-Ostertag
xi
