ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Official Publication of the Scandinavian Association of Obstetricians and Gynecologists Supplement 126

DRUG USE DURING PREGNANCY AND BREAST-FEEDINGA classification sytem for drug informationB Y Fredrik Berglund, Hans Flodh, Per Lundborg, Britta Prame and Rune Sannerstedt

From the Medical Research Department and the Toxicological Research Department, KabiVitrum AB, Stockholm, the Department of Clinical Pharmacology, AB Hdlssle, Mdlndal Drug Information Ltd, Stockholm, and the Carlanderska Hospital, Gothenburg, Sweden

UmeA 1984

Copyright 0 1984 LBkemedelsinformation AB

Distributed by Acta Obstetricia et Gynecologica Scandinavica Box 443,S-901 09 UmeA, Sweden

ISBN 91-7626-049-6

Address for correspondence Lakemedelsinformation AB Box 1319 S - 1 1 1 83 Stockholm Sweden

Printing and binding by Nyheternas Tryckeri AB, UmeA, Sweden, 1984

CONTENTS

ABSTRACT ......... ......... ........ 1. HISTORICAL BACKGROUND ....................................................................................................... 2 . TRANSPLACENTAL TRANSPORT AND MILK SECRETION .................2.1. Transplacental transport .................................................................................................................................. 2.1.1. Mechanisms of transplacental drug transport ......................................................................................... 2.1.2. Fetal metabolism ........................................................................................................................................ 2.1.3. The fetus as a patient ....... 2.2. Excretion of drugs in breast ............................................................................................. 2.2.1. Formation and composi 2.2.2. Mechanisms of transfer into milk ............................................................................................................. 2.2.3. Lipid soluble contaminants in breast milk ............................................................................................... 2.2.4. Administration of vitamins and drugs via breast milk .

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9 9 9 10 10 11 11 11 12 12 13 13 13 14 14 15 15 15 16 16 16 18 18 18 19 19 19 20

3 . EXPERIMENTAL STUDIES FOR SAFETY EVALUATION OF DRUGS DURING PREGNANCY AND BREAST-FEEDING ..............................................3.1. Studies on fertility and general reproductive performance ........... 3.2. Teratogenicity studies ....................................................................................................................................... 3.3. Peri- and postnatal investigations .................................................................................................................... 3.4. Animal experiments as a tool for safety evaluation

4. CLINICAL EVALUATION OF DRUGS FOR USE DURING PREGNANCY .......4.1. Retrospective studi 4.2. 4.3. 4.4. 4.5. Prospective studies Especially designed Central registration of birth defects ................................................................................................................ Case reports ................................................. ................................................

5 PRESENTATION OF THE CLASSIFICATION SYSTEM ..............................................5.1. Pregnancy categories 5.1.1. Comments on Cat 5.1.2. Comments on Ca 5.2. Breast-feeding groups ....................................................................................................................................... 5.3. Drugs exempted from pregnancy and breast-feeding classification . ............................... 5.4. Present classification and standard texts ............................................ ...

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6. ALLOCATION OF DRUGS TO PREGNANCY CATEGORIES

....,..........

21 21 22 22 23 25 29 29 29 29 30 31 31 32 32 35 35 36 36 37 38

6.1. Animal data versus clinical data in the safety evaluation .............................................................................. ............................................................... .... 6.2. Category A ................................................................ .................................... 6.3. Category B ............................................................... 6.4. Category C ................................................................................................... 6.5. Category D ....................................................................................................................................................

7. ALLOCATION OF DRUGS TO BREAST-FEEDING GROUPS ...................................7.1. Iodine, inorganic iodides and bromides ............................................................................................... ................................................. ................................................. ...... 7.2. Gastrointestinal drugs ...._._ ............................................. ....... 7.3. Cardiovascular drugs ........................................................ 7.4. Diuretics ............................................................................................................................. 7.5. Hormones ................................................................................................... .

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7.6. Cytostatic drugs ............................................................................................................................................... ..................................... ..... .......... 7.7. Systemic chemotherapeutics and antibiotics ........ .................... 7.8. Central nervous system drugs ..........................................................................

8. CONCLUDING REMARKS .....................

..........,,.,..,.......,.......................................

....... 8.1. Allocation to pregnancy categories ................................................................................. ........,..,.,...................................,..,.,........,.................................. 8.2. Allocation to breast-feeding groups 8.3. Number of warnings before and after introducing the system ......................................................................

ACKNOWLEDGEMENTS, , , , , ,

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REFERENCES ............................ .. .. .. .. .... ...............................................

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APPENDIX 1. Pregnancy categories (A, B 1- 3, C, D) and breast-feeding groups ..................................... ................. 44 (I, 11, 111, IV) of active ingredients ...................... APPENDIX 2. Proposed standard texts__.

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ABSTRACT

Since 1978 the Swedish catalogue of registered pharmaceutical specialities (FASS) has carried a special section entitled Pregnancy and breast-feeding in each product presentation, intended to form an aid for the prescription of drugs to women during childbearing and lactation. After a brief review of transplacental transport and milk secretion, reproduction-toxicology studies in animals, and methods for clinical evaluation of drugs for use during pregnancy, the classification system is presented. On the basis of available data with regard to effects on early and late stages of pregnancy and labour, all the pharmaceutical specialities concerned are assigned to one of the following pregnancy categories: A, B 1, B 2, B 3, C or D. The letters refer to information based on findings in man, and the figures to information based on animal data. For drugs in categories B 3, C or D any harmful effects observed or likely to occur in man or animals are to be specified. The pregnancy categories are defined as follows: Category A. Drugs which may be assumed to have been used by a large number of pregnant women and women of child-bearing age, without any form of definite disturbance in the reproductive process having been noted so far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category B. Drugs which may be assumed to have been used by only a limited number of pregnant women and women of child-bearing age, without any form of definite disturbance in the reproduction process having been noted so far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category C. Drugs which by their pharmacological effects have caused, or must be suspected of causing disturbances in the reproduction process that may involve risk to the fetus without being directly teratogenic.

Category D . Drugs which have caused an increased incidence of fetal malformations or other permanent damage in man or which on the basis of e.g. reproduction-toxicology studies must be suspected of doing so. This category comprises drugs with primary teratogenic effects. If the drug also has pharmacological effects that may directly or indirectly have a harmful effect on the fetus, this must also be stated. As experience of effects of drugs in Category B is limited, results of reproduction-toxicology studies in animals are indicated by allocation to one of three subgroups according to the following definitions: Category B 1. Reproduction-toxicology studies have not given evidence of an increased incidence of fetal damage or other deleterious effects on the reproduction process. Category B 2. Reproduction-toxicology studies are inadequate or may be lacking, but available data reveal no evidence of an increased incidence of fetal damage or other deleterious effects on the reproduction process. Category B 3. Reproduction-toxicology studies have revealed an increased incidence of fetal damage or other deleterious effects on the reproduction process, the significance of which is considered uncertain in man. It should be noted that even drugs in Categories C and D may have important uses during pregnancy, e.g. 0-adrenoceptor blockers in the treatment of hypertension, chloroquine and hydroxychloroquine in the prophylaxis of malaria, prednisone and aspirine in the treatment of SLE, and anticonvulsants in the treatment of epilepsy. Other drugs in Categories C and D, e.g. dicoumarol and warfarin, should not be used during pregnancy. Effects on fertility in patients are not included in the pregnancy classification. Information on these effects is usually given under the heading Adverse Reactions. With respect to their use during breast-feeding,Acta Obstet Gynecol Scand SuppI1.76

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F. Berglund et al.The classification system has now been used in seven successive editions of the FASS catalogue.During the seven years, the number of active ingredients in Category C has increased from 65 to 118, mainly by including ingredients that initially were totally exempted (26 substances), e.g. glucocorticoids for topical use (16 substances). Also, about 20 substances were transferred from Category A, notably benzodiazepines and inhibitors of prostaglandin synthesis. For drug use during breast-feeding, Group IV unfortunately still comprises more than 50 Vo of the drugs in the system.

each pharmaceutical specialty has been allocated to one of four groups. The breast-feeding groups are defined as follows: Group I. Does not enter breast milk. Group ZZ. Enters breast milk but is not likely to affect the infant when therapeutic doses are used. Group ZZZ. Enters breast milk in such quantities that there is a risk of affecting the infant when therapeutic doses are used. Group ZV. Not known whether it enters breast milk or not. A number of drugs are exempted from the classification system. Such drugs are mainly those that due to type of use and administration should not represent a hazard to the fetus or the breast-fed infant.

Key words: Drugs, pregnancy, breast-feeding, classification

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1 . HISTORICAL BACKGROUND

The use of drugs during pregnancy and breastfeeding occupies a prominent place in the international drug debate of to-day. This is justified in view of the serious consequences to the fetus and infant that may be involved. Since the thalidomide disaster in the early sixties worldwide measures have been taken in order to prevent a recurrence. Guidelines for reproduction-toxicology studies have been issued by authorities in different countries. Reporting on observed or suspected damage on the human fetus is comprehensive in many countries with the aim of detecting as early as possible any increase in known malformations or new types of congenital abnormalities. The difficulties, however, of concluding unequivocally from available data are considerable. In this context one must bear in mind that drug use is only one of several factors that may affect the reproduction process. Other goods of consumption, especially alcohol and tobacco, and environmental factors can also markedly affect the development of the fetus. Besides, the risk of harming the fetus by means of drugs is seldom or never one-hundred-per-cent. It is a matter of increasing a risk that is already present, considering that the frequency of spontaneous fetal malformations is as high as about 2 per cent of all

)FASS is the abbreviation of Farmacevtiska specialiteter i Sverige(Pharmaceutica1Specialities in Sweden). The FASS catalogue is edited and published annually by Lakemedelsinformation AB (Drug Information Ltd) and is distributed without cost to all those allowed to prescribe drugs and to all pharmacies. The catalogue documents all pharmaceutical specialities that are registered in Sweden for human use. Each product monograph is written by the manufacturer and has to be approved by the regulatory authority. Drug Information Ltd is owned jointly by LIF (the Association of the Swedish Pharmaceutical Industry) and RUFI (the Association of Representativesof Foreign Pharmaceutical Industries).

births. These circumstances complicate the evaluation of isolated case reports. At present, there is unequivocal evidence of harmful effects on the course of pregnancy and on the breast-fed infant only for a relatively small number of all drugs available. On the other hand, only a few drugs have been convincingly shown to be harmless when used in these conditions. Consequently, our knowledge of possible harmful effects during pregnancy and breast-feeding is limited for most drugs. Awareness that harmful effects cannot be altogether excluded for many drugs has often led drug manufacturers to advise routinely, pending further experience, against the use of their preparations during pregnancy, especially during the first trimester. Warnings of this kind, based on dubious evidence, are unwarranted. The need of information about potential risks connected with drug consumption during pregnancy has been discussed in many countries. In Sweden the problem was taken up by the authorities in 1975. The National Board of Health and Welfare proposed to the manufacturers trade organizations (LIF and RUFI) that in their catalogue for registered pharmaceutical specialities, FASS), warnings against the use of a drug during pregnancy should be supplemented with information about the reason. A project group was set up by LIF and RUFI to study the problem. The project group considered it inadequate merely to scrutinize the background of existing warnings. Instead, it seemed desirable to aim at a uniform system for grouping all pharmaceutical specialities registered in Sweden with regard to their use during pregnancy and breast-feeding. This system should take into consideration the experience of use in humans and results in animal experiments, with regard not only to teratogenicity but also fertility as well as peri- and postnatal development. After consultations with the National Board of Health and Welfare and its Reference Group for MalActa Obstet Gynecol Scand Suppl 1.26

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F. Berglund et al.However, nowhere are there any official regulations on information texts that are adjusted to individual drugs (active ingredients) or to groups of drugs. Before presenting the Swedish Classification System we would like to briefly review placental transport and milk secretion (section 2) and also to discuss animal experiments as a tool for safety predictions (section 3). Comments on the methods and techniques used for clinical evaluation are described in section 4. The classification system is presented in section 5 , and the allocation of drugs to pregnancy categories and breast-feeding groups in sections 6 and 7, respectively.

formations and Development Disturbances, the project group presented a classification system. The system was used for the first time in the 1978 FASS catalogue. In USA the Food and Drug Administration (60) published a new regulation entitled Labelling of Prescription Drugs used in Man. According to this regulation the labelling of prescription drugs must include all available information about teratogenic and non-teratogenic effects. FDA has established five categories to indicate a drugs potential for causing birth defects. The system has, however, not been introduced in the Physicians Desk Reference except for some recently licensed drugs.

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2. TRANSPLACENTAL TRANSPORT AND MILK SECRETION

Drug administration during pregnancy and breastfeeding has, in general, been directed towards diseases in the mother. The clinical pharmacology of pregnancy is, however, unique in the respect that also the developing fetus and the suckling infant can be reached and affected by a number of drugs. This is not always a disadvantage. On the contrary, clinical situations exist where the offspring may be available for drug therapy already in ufero or via breast-feeding.

2.1.1. Mechanisms of transplacental drug transport The basic mechanisms by which substances cross the placenta are the same as those of other biological membranes (cf 133). They may be considered under four main headings - simple diffusion, facilitated diffusion, active transport, and special processes. Simple diffusion. In this instance, substances cross the placenta from regions of higher to regions of lower concentration, so as to equalize concentrations on both sides of the barrier. The rate at which placental transfer occurs by this means is thought to be governed by standard physico-chemical laws. Properties of the drug which are of importance to the rate of diffusion are, infer a h , molecular size, stereochemistry, degree of dissociation and lipid solubility (155). Substances with a small molecular weight generally penetrate the placenta easily, irrespective of whether they are water soluble or lipid soluble. Large molecules with a molecular weight above 1 OOO pass the placenta with difficulty or not at all. The degree of dissociation and lipid solubility are the main determinants for the rate of diffusion of smaller molecules. Facilitated diffusion. This transport also occurs along a concentration gradient. The rate of transfer is, however, higher than would be expected by physicochemical factors alone. It has been speculated that specific transfer mechanisms facilitate the transport. Active transport across a membrane. This implies molecular transfer against an electrochemical gradient and must entail the expenditure of metabolic energy. This mechanism is responsible for the transfer of a number of essential compounds like vitamins, amino acids, sodium, potassium, calcium, and iodide (192). Amino acid analogues like alpha-methyldopa and L-dopa can similarly be expected to utilize thisAcra Obstet Gynecol Scand Suppl1.26

2.1. TRANSPLACENTAL TRANSPORT

The placenta, during the major part of the pregnancy, constitutes the only connection between the fetus and its surrounding world. Its function is therefore of utmost importance for the existence of the fetus. The placenta is, however, not only a transporting organ, but also contains several active enzyme systems with the capacity to synthetize and catabolize exogenous and endogenous chemical compounds. For example, gonadotropins, estrogens, and progesterone are synthetized in the placenta through the entire pregnancy. From a metabolic point of view, the placenta and fetus in many ways function as one unit. The concept fetoplacental unit has therefore been created. The expression originates from studies on steroid metabolism, in which co-operation between metabolic systems in the fetal liver and the placenta have been observed (41). The so called placental barrier is no longer considered an anatomical barrier, which protects the fetus against infection and noxious substances. It constitutes a complex functional membrane, where a number of substances essential to the development and existence of the fetus are transported against a concentration gradient, whereas other exogenous substances depend on physico-chemical factors for their transport.

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F. Berglund et al.through the placenta, e.g. by vasoactive drugs (94) might interfere with the rate of transfer, especially on administration of highly lipid soluble unionized compounds, for which the rate of transfer is only limited by the blood flow through the placenta. In the fetus, the umbilical vein communicates with the portal vein. Hence, the predominant part of the blood in the umbilical vein is drained through the liver parenchyma and reaches the inferior portal vein via the hepatic vein. The prerequisites exist for accumulation in the liver, especially for compounds with high lipid solubility and high affinity, e.g. to cytochrome 450. Thereby the fraction exposing the central nervous system and other vital organs might be reduced. Accumulation of drugs in the fetal liver has been demonstrated, e.g. for short-acting barbiturates and lidocaine (56). 2.1.2. Fetal metabolism In contrast to other species, some functioning drug metabolizing enzyme systems are present in the human fetal liver early in pregnancy (206). Practical consequences from these findings might be:1.

mechanism and also to compete with other amino acids for transfer sites. Transport systems for vitamins can similarly be utilized by drugs being vitamin analogues. One such example is the folk acid antagonist methylaminopterin.Special processes. Pinocytosis is included under this heading. In this process minute plasma droplets can be engulfed by small invaginations in the villi and thereafter transferred to the fetal circulation. Presumably this is the way antibodies and viruses are transported. Other biologically active molecules might be transported in a similar way (see 39). Beside the mechanisms discussed above, additional factors may theoretically affect the transport of drugs across the placenta. 1. Binding of drugs to macromolecules in the placenta. Such a mechanism could delay considerably the transport of drugs across the placenta. 2. Active transport of drugs from the fetal to the maternal circulation. 3. Different affinity of fetal and adult blood proteins to various drugs. 4. Biotransformation of drugs during the transport across the placenta. 5. Biotransformation of drugs in fetal tissues. 6. Influence of vasoactive drugs on the placental circulation.

Irrespective of the transport mechanism utilized, most pharmacologically active compounds given to the mother pass from the mothers blood to the fetal blood. On single administration, e.g. in obstetric praxis, the rate of transfer determines the maximal drug concentration reached in the fetal blood. On drug administration over an extended period, as in the treatment of infections or of cardiovascular diseases, and when a steady-state concentration has been present for some time, even drugs passing at a very slow rate can be expected to reach maternal concentrations in the fetal blood. Under these circumstances, the placental barrier becomes very relative. A real barrier exists when the drug is metabolized in the enzyme-rich placenta. Hence, it has been demonstrated experimentally that monoamine oxidase and catechol o-methyl transferase metabolize isoprenaline and noradrenaline in the placenta (131). When the mother suffers from systemic diseases, like diabetes mellitus, preeclampsia, or erythroblastosis, the permeability of the placenta might change. Similarly, changes in the maternal or fetal blood flowActa Obstet Gynecol Scand Suppl1.26

2.

The human fetus can synthetize polar metabolites. The placental barrier impedes the return of these polar metabolites, which might accumulate in the fetus, and if toxic, thereby increase the risk for the fetus. There is a potential risk for the formation of epoxides and subsequent fetal damage. It has been speculated that drug induced tissue damage might be correlated to the formation of highly reactive epoxides, that are metabolic intermediates formed during the process of hydroxylation (20).

Drug metabolism generally constitutes a process of detoxification, which might be of importance to the fetus, pharmacodynamically as well as toxicologically. Further knowledge on drug metabolism may in the future help us to understand species differencies in drug teratology .2.1.3. The fetus as a patient From a pharmacokinetic point of view, the mother and fetus can be considered a two-compartment model, with the fetus being dependent on the mother for absorption, elimination, and to a large extent, metabolism. The technically simplest way to achieve pharmacologically active drug concentrations in the fetus is by

Drug use during pregnancy and breast-feedingmeans of drug administration to the mother from which a certain amount of drug can pass across the placenta and equilibrate with the fetal tissues. This route of administration has been successfully utilized for treatment of fetal tachycardia with digoxin (1 13), propranolol (loo), and procainamide (42). Another possible route of administration is by injection through the maternal abdominal and uterus wall, directly into the fetal abdominal cavity or musculature. Intraperitoneal administration has been utilized for blood transfusions in cases with severe Rhimmunization (19). 2.2. EXCRETION OF DRUGS IN BREAST MILK An extensive review on this subject (202, 203) covers physiological principles, pharmacokinetics and available information on a number of drugs. The advantages of breast-feeding have been more clearly realized only during the last 15 years. In addition to nutritional advantages, human breast milk provides considerable protection against infectious diseases due to its content of lactoferrin, lysozyme and IgA antibodies. The IgA antibodies are directed against organisms that occur in the mothers gastrointestinal tract. Hansson et al. (70) have proposed that sensitized lymphocytes pass from the gastrointestinal tract to the mammary gland, and there synthesize secretory IgA antibodies. There are several reports of lower incidence of diarrhoeal gastrointestinal infections in breast-fed infants in comparison to formulafed infants. Exclusive breast-feeding also acts to maintain raised plasma levels of prolactin and depressed leLels of estrogen, there-by delaying the return of ovulation (17,38,88). Even though the resulting anticonception effect is not completely dependable in individuals, its societal effect is an important factor in limiting population growth. 2.2.1. Formation and composition of breast milk The mammary glands are morphogenetically similar to sweat glands. Functional units consist of secretory cells surrounding a lumen (alveolus), ducts and blood supply. Alveoli are connected by larger ducts which empty into collecting or lactiferous ducts. These have a dilation (sinus lactiferous) prior to their termination in the nipple. The secretory cell of the alveoulus is rich in storage granules (lactose and protein), fat globules, and in endoplasmic reticulum near the basal portion of the

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cell. Milk is an emulsion of fat in water, with lactose and protein in the aqueous phase. Lactose (70 g/l) is the main solute in human milk, accounting for 205 mosm/kg HzO. Since milk is isotonic with blood (295 mosm/kg HzO), content of electrolytes is relativeits ly low. Protein exceeds 20 g/l in colostrum and averages around 10 g/l in mature milk. Fat content averages around 32 - 35 gA, somewhat less in colostrum. Lipid composition is influenced by the diet; linoleic acid contents of 1 - 45 70have been found in the triglyceride fraction (91). Even when breast-fed by apparently healthy women consuming conventional diets, infants may develop deficiencies of vitamin K, vitamin D and iron (59). Neonatal bleeding associated with hypoprothrombinaemia is much more common in breast-fed infants than in formula-fed in countries where vitamin K is not given routinely to all neonites (73, 125, 177). A maternal intake of 20 mg K, orally raises the vitamin K level in the breast milk to levels above 0.1 mg/l. The occurrence of rickets in breast-fed infants has been recognized for years, probably reflecting a combination of low vitamin intake and minimal exposure to sunlight. Supplementation with vitamin D (200-400 IU per day) is desirable unless regular exposure to sunlight can be assured. Women with nutrient deficiences may produce milk with an unusually low content of a particular nutrient.Infants breastfed by strictly vegetarian mothers may develop symptoms of B12deficiency within 6 months (83). Infantile beriberi occurs most frequently in infants 1-3 months of age breast-fed by mothers with incipient or acute beriberi. 2.2.2. Mechanisms of transfer into milk Transfer of drugs and micromolecular nutrients from blood to milk occurs through the same mechanisms as across other biological membranes: diffusion through waterfilled pores (ethanol, urea), diffusion of lipid soluble compounds through lipid membranes, and carrier-mediated (active) transport. The distribution of a substance between milk and plasma may therefore be influenced by the pKa of the substance and the pH of the milk. The pH of human milk ranges from 6.35 to 7.65 (average 7.1). Therefore weak bases may reach higher levels in the milk than in plasma, whereas the reverse is true for weak acids. The concentration of a substance may also be influenced by binding to milk proteins or dissolving in the lipid phase of milk.Acta Obstet Gynecol &and Suppl126

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F. Berglund et al.the uterus. Levels in body fat at birth are in equilibrium with those in the mother. Similarly, levels of lipid-soluble substance in breast milk reflect the levels in the body fat of the mother. Bagnell and Ellenberger (9) reported on a 6-weekold breast-fed infant with obstructive jaundice and hepatomegaly . Tetrachloroethylene, a dry-cleaning solvent, was detected in the mothers milk and blood. The fathers blood contained 0.18 mmol/l, the mothers blood contained 0.018 mmolA two hours after her lunch-hour visit to the drycleaning plant, and her breast milk contained 0.06 mmol/l one hour after the visit.2.2.4. Administration of vitamins and drugs via breast m l ik The concentration of vitamin K in breast milk depends on the maternal intake. An oral dose of 20 mg K, raised the vitamin K concentration in breast milk from 2 to 140 kg/l (73). Likewise the content of vitamin D in breast milk is increased by maternal intake or by exposure to ultraviolet light (187). Iodide is transferred to breast milk, and this route should be useful when the infant is to be protected against radioiodine exposure (cf section 7). Pyrimethamine administration to breast-feeding mothers protects the infant against malaria (cf section 7. )

The total amount of any substance ingested by the suckling infant will also depend on the total amount of milk consumed (usually 0.4- 0.9 l/day) and on the concentration in the mothers plasma. Blood levels in the infant will depend on degree of absorption in the gastrointestinal tract, and on distribution, metabolism and excretion in the infant. Also to be remembered is the amount of substance present in the newborn infant - usually there is equilibrium between infants and mothers blood at birth. Therefore, even if the concentration ratio between milk and blood in the mother may be predicted or known, this information will not suffice for a prediction of harmlessness or hazard of a drug to the suckling infant. A knowledge of physico-chemical principles does, however, help us to rationalize treatment.2.2.3. Lipid soluble contaminants in breast milk Levels of DDT + DDE + DDD, i.e.total DDT, of less than 0.2 mg/kg have been reported from Belgium, Canada, England, the Netherlands, Sweden, USA and West Germany. Levels around 0.2 mg/kg have been reported from the Soviet Union, 0.3 mg/kg from Poland, and 3 mg/kg from Guatemala. The DDT is stored in the body fat. Exposure of the infant to DDT and other organochlorine compounds in the environment (lindane, dieldrin, polychlorinated biphenyls) occurs already in

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3. EXPERIMENTAL STUDIES FOR SAFETY EVALUATION OF DRUGS DURING PREGNANCY AND BREAST FEEDING

Experience has shown that it is extremely difficult to predict teratogenic or fetotoxic effects in man on the basis of animal studies. Nevertheless, since the mid 60s it is generally accepted that new drugs should be tested in pregnant animals of several (at least two) species before given to women of child-bearing potential. The design and outline of reproduction toxicology studies used today is basicly the same as originally proposed in 1966 by the Food and Drug Administration in USA. Today the drug authorities in USA, UK, Sweden, and in fact in most of the developed countries of the world, require that new drugs shall be investigated in the animal species and according to the procedures described below. Marginal differences may exist between the requirements of different drug regulatory bodies. In essence, however, the required tests consist of the following three well-known types of investigations.

birth to their pups which are followed and observed during the period of lactation. The litters are analysed for number of alive, dead and malformed pups. The pups are weighed, and the weight gain and growth during lactation are closely followed up to three weeks post partum. This general design may, and many times is, modified in different ways. Instead of treating both males and females only one sex may be treated during the premating period. The sacrifice of half of the animals may be postponed to the end of the gestation period in order to make possible an analysis of the fetal development of skeleton and viscera. Post-parturn treatment of the weaned offspring may sometimes be continued over a new generation. 3.2. TERATOGENICITY STUDIES The purpose of the teratological investigations is to study the embryotoxic effects or effects on the development during the period of organogenesis. In general, rats and rabbits are used. The pregnant animals are treated during the period of organogenesis which in rats occurs between days 6 and 15 of pregnancy and in rabbits between days 6 and 18. At the end of the gestation period or the day before the day of expected parturition the fetuses are removed by cesarean section. For each pregnant female the number of alive and dead fetuses, fetal resorptions and uterine implantations is determined. All fetuses are examined for macroscopically observable external malformations. Fetuses being alive are weighed. The fetuses are then examined for internal, visceral and skeletal malformations. The results from the dose groups are compared statistically with the results from the control group and also with results obtained earlier in the same animal species and strain (laboratory standard). This makes it possible to determine whether or not the agent tested is a teratogen in the animal species used.Acta Obstet Gynecol Scand Suppl 126

3.1. STUDIES ON FERTILITY AND GENERAL REPRODUCTIVE PERFORMANCE

The purpose of this investigation is to study the effects of drugs on gonadal function and on the fertilized eggs during the period of pre-implantation and early gestational stages. In general rats are used as experimental animals. Both male and female animals are treated before mating. Females are treated continuously for two weeks in order to cover the oogenesis during 3 - 4 estrous cycles. Males are treated during a period of eight weeks in order to cover two whole periods of spermatogenesis. After mating and conception the pregnant animals are treated during the whole period of gestation and through parturition and lactation. Half of the animals are sacrificed at mid-pregnancy and analysed for the number of uterine implantations, dead and alive fetuses and fetal resorptions. Remaining animals are allowed to give

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F. Berglund et al.quate comparisons. In epidemiological studies the clinical material is often very heterogenous. The subjects involved may have been treated with different, in general fairly low doses during various periods of gestation. Age, life style and disease are other factors which may vary and adversely influence the results of an investigation. Animal studies, on the other hand, in general deal with a very homogeneous material, the dose levels are fairly high, and the test compounds are normally given during the whole period of organogenesis. In this perspective it is obvious that a higher frequency of malformations is to be expected in the animal studies than in clinical trials or epidemiological studies. In spite of the obvious limitations of animal experiments as tools for safety predictions we have today no better alternative as a base for safety evaluation of new drugs. A variety of test methods including in vitro studies using cell embryo and organ culture techniques and specially designed in vivo studies have been suggested during the last decade in order to improve on the established methods. In recent years great attention has been paid to developmental disturbances induced during the peri- and postnatal periods and many techniques have been developed for more detailed studies on physical development, auditory and visual function, and behaviour. The search for new tests and screening methods may well be justified. Just as important, however, are the efforts to systematically evaluate and compare methods in order to increase our knowledge about the limitations but also the possibilities of existing techniques. Hopefully, increased knowledge in biochemistry and physiology and about the influence of different genetic factors for the development of malformations may lead to a better understanding of teratogenic mechanisms and accordingly better possibilities to evaluate teratogenic effects in animals.

3.3. PERI- AND POSTNATAL INVESTIGATIONThe aim of the peri- and postnatal investigations is to study the effects on late gestational stages, parturition and early postnatal development. In general rats are used. The pregnant animals are treated during the last third of the gestational period and treatment continues during the whole period of lactation. The length of the gestational period and delivery times as well as litter size and the number of alive, dead and malformed pups are recorded. The fetal weights are registered, and weight gain and growth are observed up to three weeks post partum.

3.4. ANIMAL EXPERIMENTS AS A TOOL FOR SAFETY EVALUATIONEver since the beginning of the 1960s almost every new drug, as well as many old ones, have been examined in reproduction toxicology studies. Thalidomide, corticosteroids and salicylates are examples of drugs which illustrate how difficult it is to predict the risk for man on basis of results from animal experiments. The absence of adverse reactions in animal experiments, which in the beginning was the case with thalidomide, does not guarantee that adverse reactions will not occur in man. On the other hand, if adverse effects occur in animals, such as the well-known malformations seen after treatment with corticosteroids and salicylates, this does not necessarily mean that similar effects have to occur in man. A substantial number of drugs have been shown to be teratogenic in animals, while only a few have been identified as teratogens in man. This fact has contributed to the strong criticism of the animal experiments as tools for safety evaluations of drugs for human use during pregnancy. The sometimes surprising lack of correlation between animal and human data may also depend on the difficulties to make ade-

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4. CLINICAL EVALUATION OF DRUGS FOR USE DURING PREGNANCY

The information available on adverse drug effects on human reproduction in general, and above all during pregnancy and delivery, varies considerably from one compound to another. For many traditional drugs any firm knowledge may be based simply on experience from extensive clinical use in fertile women, that over the years is considered to have proven the full feasibility of drug. As one example of this, digitalis may be mentioned (145). However, extended clinical use of a drug may lull the clinician into a state of fallacious security, that should be actively counteracted through a continuous watch over the safety of drugs used during pregnancy. On the other hand, repeated case reports together with data obtained in animal experiments may at an early stage have indicated the presence of teratogenic properties that preclude the use of the drug during pregnancy. Quinine belongs to this category (61). Similarly, a fairly firm knowledge on negative effects on the reproduction process may be available for more recently introduced agents that have been subjected to thorough trials especially designed to detect any unfavourable effects in fertile and pregnant women. An example of this is the group of P-adrenoceptor blocking agents (64, 153). Regrettably the vast majority of drugs fall in between these two categories, i.e. there is neither any clinical experience available from wide use in fertile and pregnant women, nor any reliable data from especially designed trials. A major reason for this is the obvious difficulty to carry through clinical studies in fertile and pregnant women that yield reasonably convincing data on the risk, or the absence of risk, of using a drug in this group of patients. The methods and techniques used in this context include the following types of studies: 1. retrospective studies; 2. prospective studies; 3. especially designed clinical trials; 4. central registration of all malformations and

5.

other reproductive disturbances as related to drug use in pregnant women; case reports as a result of clinical alertness.4.1. RETROSPECTIVE STUDIES

These analyse the frequency of birth defects in children of big cohorts of mothers, relating the distribution of defect vs. normal children to any drug consumption by their mothers during pregnancy. The disadvantages of this type of studies are obvious: original information about any drug consumption during pregnancy may be incomplete or missing, and, if asked for in retrospect, misleading statements may be made; confounding factors like diseases and the use of tobacco and alcohol are frequent; huge numbers of women must be included in order to get statistically reliable results, especially when dealing with rarely seen birth defects, or with drugs seldom used in pregnant women; inevitably, there is a long time-lag between the clinical introduction of the drug and the point of firm conclusions about any negative effects on the reproductive system. There are, however, also advantages: a great number of drugs may be screened at the same time, or a single compound may be picked up for scrutiny. Examples of this type of studies are those on the use of diphenylhydantoin (85, 130).4.2. PROSPECTIVE STUDIES

These allow a detailed and reliable history of any drugs consumed by the mother during pregnancy. The distribution of normal vs. defect children may then be directly related to the presence or absence of any drug consumption among the mothers.Acto Obstet Gynecol Scand Supp1126

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F. Berglund et al.Good examples of this kind of studies are those dealing with P-adrenoceptor blocking agents (5 1, 153), and an intramuscular iron preparation (179).

Also this type of studies suffers from weaknesses: huge numbers of pregnancies have to be followed, before statistically significant data on various drugs are obtained; this results in an extended time-lag, before any conclusive information is available; confounding factors, like diseases and the use of tobacco and alcohol, are frequent. The advantages are self-evident: a detailed information on drug consumption may be obtained; confounding factors may be followed and corrected for. Examples of this kind of studies are the Collaborative Perinatal Project in the USA (162, 165), and the studies by Kullander and K d l h (107).

4.3.ESPECIALLY DESIGNED CLINICAL TRIALSThese have so far, been conducted only occasionally. They are limited to drugs that already are, or may become, commonly used during pregnancy and delivery. Such studies are characterized by having a predetermined trial plan detailing inclusion criteria, dosages, frequency of administration, duration of treatment, concomitant medication, recording of positive and negative effects etc. The superiority of such studies are evident: sources of error may be avoided and confounding factors can be controlled; sufficient data to allow firm conclusions may be collected during a short time period; even relatively small numbers of women studied will yield statistically reliable results. Draw-backs are, however, also present: only drugs having well supported indications for regular use during pregnancy and delivery can come into question; the rigid study conditions necessary may differ considerably from the usual clinical routine, and this may invalidate the practical value of the results.")The International Clearinghouse for Birth Defects Monitoring Systems is an association of programs engaged in surveillance or monitoring of congenital malformations and other birth defects. It was established in 1974 as a communication network to share information about changes in the incidence of specific birth defects, the appearance of suspected teratogens, and other intelligence relevant to the detection and investigation of possible outbreaks of congenital malformations. In 1982 monitoring systems from 22 countries were members of the association.Acra Obstet Gynecol Scand Suppl126

4.4.CENTRAL REGISTRATION OF BIRTH DEFECTS Central registration is nowadays routine in e.g. Sweden, requiring obstetricians and pediatricians to report to the authorities. The advantages of such a system are numerous: it allows a complete and continuous survey over all types of reproductive disturbances in a geographically well defined area; also rare birth defects may be picked up in numbers large enough to allow an analysis in relation to drug consumption by the mother; changes in the general spectrum of birth defects may be notified at an early stage; the appearance of new types of defects may be rapidly detected. Nevertheless, also here disadvantages may be found: the bureaucracy may supersede, concealing the biological and clinical importance of the finding; protracted time-lag between incoming reports and central evaluation of data may easily arise. Examples of valuable information stemming from central registration are those on antiepileptics coming from Finland and more recently from the International Clearing House for Birth Defects Monitoring Systems") (15).

. .

4.5. CASE REPORTSCase reports may occasionally pin-point the causal relationship between reproductive disturbances and drug consumption during pregnancy. Although there are advantages present with this method, the disadvantages are probably even more evident: the reports are often anecdotal lacking the possibility of proving anything; the author may be misled to overemphasize his own findings and to make too far-reaching conclusions; this may in turn lead to undue concern among colleagues and patients. The classical example of a case report suddenly opening the eyes of the medical world is the observation made by McBride on thalidomide. Ironically enough, some 15 years later the same author used isolated case reports in a similar way to implicate an an-

Drug use during pregnancy and breast-feedingtihistamine as being teratogenic (122); subsequent studies did not support that hypothesis. In the future especially designed prospective clinical studies may be more frequently used than hitherto seen. Similarly, central registration of reproductive disturbances will probably gain in importance, while extensive retrospective studies will be used to a lesser extent.

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Clinical alertness will also in the future be the mainstay in our efforts to detect drug-induced reproductive disturbances at the earliest stage ever possible. Here the well prepared, stringent case report will still form a platform, from which further studies may be launched.

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5 . PRESENTATION OF THE CLASSIFICATION SYSTEM

As already mentioned the intention has been to create a uniform system for classifying all pharmaceutical specialities registered in Sweden, taking into consideration the experience of use in humans as well as results in animal experiments. The increased incidence of abortions in anaesthetists and of congenital malformation in their offspring (170) is not included in the classification. Heavy narcotic addiction, which may cause withdrawal symptoms in the neonate, also falls outside the realm of the system. The classification system therefore only comprises drugs that are used for medical purposes during pregnancy and breastfeeding. Effects on fertility in patients, such as diminished libido, impotence and disturbances in spermatogenesis in men, and amenorrhea in women, have also been handled separately. Such effects have been reported to occur during treatment with salicylazosulfapyridine (oligospermia), spironolactone, cyclophosphamide and a number of anabolic or sex steroids, and are usually reversible. Information on these effects is usually given in FASS under the heading Adverse reactions.

been used by only a limited number of pregnant women and women of childbearing age, without any form of definite disturbance in the reproduction process, having been noted so-far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category C. Drugs which by their pharmacological effects have caused, or must be suspected of causing disturbances in the reproduction process that may involve risk to the fetus without being directly teratogenic. Category D. Drugs which have caused an increased incidence of fetal malformations or other permanent damage in man, or which on the basis of e.g. reproduction-toxicology studies must be suspecting of doing so. This category comprises drugs with primary teratogenic effects. If the drug also has pharmacological effects that may directly or indirectly have a harmful effect on the fetus, this must also be stated. 5.1.1. Comments on category A Generally Category A comprises: drugs that have been available for many years, e.g.theophylline, cardiac glycosides, caffeine; drugs whose indications are such that they most probably have been used by many pregnant women and women of childbearing age, e.g. antiemetics, systemic antihistamines, antacids; drugs that have been available only for a short time but for which satisfactory retrospective and prospective studies in pregnant women are considered to have been carried out, e.g. hydralazines, local anesthetics, parenteral iron preparations. Since the results of reproduction-toxicology studies in animals are of minor value compared to extensive experience of the effects in man, no regard is paid to animal studies for products in this category even if they have shown fetal damage or other harmful effects on the reproduction process.

5.1. PREGNANCY CATEGORIES

On the basis of available data with regard to effects on early and late stages of pregnancy and labour, all the pharmaceutical specialities concerned are assigned to one of the Categories A, B, C or D. The pregnancy categories are defined as follows: Category A. Drugs assumed to have been used by a large number of pregnant women and women of child-bearing age, without any form of definite disturbance in the reproductive process having been noted so-far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category B. Drugs which may be assumed to haveActa Obstet Gynecol Scand Suppi126

Drug use during pregnancy and breast-feeding5.1.2. Comments on category B

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Correspondingly category B comprises: drugs that have been available only for a short time; drugs whose indications are such that they may be assumed to have been used only by a limited number of pregnant women and women of child-bearing age; drugs for which satisfactory retrospective or prospective studies are lacking or sparse. As experience of effects of drugs in this category in man is limited, results of reproduction-toxicology studies in animals are indicated by allocation to one of three subgroups B 1, B 2 and B 3, according to the following definitions: Category B I. Reproduction-toxicology studies have not given evidence of an increased incidence of fetal damage or other deleterious effects on the reproduction process. E.g. amiloride, cimetidine, tranexamic acid. Category B 2. Reproduction-toxicology studies are inadequate or may be lacking, but available data do not indicate an increased incidence of fetal damage or other deleterious effects on the reproduction process. E.g. procainamide, clonidine. Category B 3. Reproduction-toxicology studies have revealed an increased incidence of fetal damage or other deleterious effects on the reproduction process, the significance of which is considered uncertain in man. E.g. prenalterol, trimethoprim, meprobamate. Results from animal experiments may vary greatly owing to species and strain differences, different dose levels, differences in the mode and frequency of administration etc. Also the effects which may lead to a drug being placed in Category B 3 are of several kinds (fertility disturbance, teratogenic effects, etc.) The results of the animal experiments that have led to the product being assigned to category B 3 should be briefly summarized in the text. It must be emphasized that a drug is to be assigned to category B 3 only if it is considered unlikely that fetal damage observed in animals is of relevance to man. If the animal experiments are considered to indicate a significant risk in the human being, the product is to be assigned to Category C or D.5.2. BREAST-FEEDING GROUPS

the infant when therapeutic doses are used. Group HI. Enters breast milk in such quantities that there is a risk of affecting the infant when therapeutic doses are used. Group IV. Not known whether it enters breast milk or not. The evaluation of passage into breast milk naturally concerns single ingredients of drugs as well as metabolites.

5.3. DRUGS EXEMPTED FROM PREGNANCY AND BREAST-FEEDING CLASSIFICATIONA number of drugs have not been given a pregnancy and breast-feeding text (Table I). Such drugs are

Table I. Drugs exempted from pregnancy and breastfeeding classifcation. Nomenclature principally according to Nordic Council on Medicines (139).Stomatologicals, mouth preparations Antiflatulents (silicones) Bile acid preparations Certain laxatives: lactulose, bulk producers and enemas Charcoal preparations Digestives, including enzymes Vitamins, mineral supplements and general nutrients Antihaemorrhagics: antifibrinolytics, fibrinogen, blood coagulation factors Iron, oral preparations Plasma substitutes and perfusion solutions, including solutions for intravenous feeding Enzymes (haematological), including fibrinolytics and hyaluronidase Topical antihaemorrhoidals,except those containing corticosteroids Topical organoheparinuids Zinc bandages Topical dermatologicals, except those containing corticosteroids or neomycin Insulins and glucagon Hormones that are only indicated for interruption of pregnancy, postmenopausal substitution therapy, male hypogonadism, amenorrhea, metropathia haemorrhagica cystica, or prostate cancer Urinary sediment solvents Sera and gammaglobulins Topical antirheumatics Scabicides, except when containing DDT, lindane or malathion Topical nasal decongestants, sympathomimetics and combinations, excluding steroids Ophthalmologicals, except idoxuridin, ecothiopate and carbonic anhydrase inhibitors Otologics for topical use Certain anti-poisoning agents: potassium iodide, obidoxime Diagnostic agents, except metyraponeAeta Obstet Gyneeol Seand Suppl I26

With respect to breast-feeding each pharmaceutical speciality, with a few exceptions, is allocated to one of the following groups: Group Z. Does not enter breast milk. Group ZI. Enters breast milk but is not likely to affect

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F. Berglund et al.considered necessary. When the same drug is also registered for systemic use it has been given a pregnancy and breast-feeding text.

mainly those that due to type of use and administration are not considered to represent a hazard to the fetus or the breast-fed infant. Thus, allotment to specific categories was either superfluous (e.g. for infusion solutions and preparations for topical use), or not warranted (e.g. for technical and diagnostic aids), or not possible (e.g. for certain hormone preparations and agents intended for discontinuation of pregnancy or only intended for use in male patients). Vitamins have been exempted since the treatment aims to correct a vitamin deficiency. It is well known, however, that both lack and excess of certain vitamins can have a deleterious effect on fetal development. Over-dosage should especially be avoided with the fat-soluble A and D vitamins. Iron deficiency in pregnant women can be reduced by adequate iron therapy. As the absorption of iron from the gastrointestinal tract is largely governed by the bodys iron balance, the risk of over-dosage during adequate oral iron therapy is not great enough to warrant a pregnancy declaration. Parenteral iron products, on the other hand, are given a declaration. There are drugs intended for topical treatment at such low doses that a pregnancy declaration is not

5.4. PRESENT CLASSIFICATION AND

STANDARD TEXTS The classification of active ingredients in FASS 1984, in pregnancy categories and breast-feeding groups, is listed in APPENDIX 1 . In order to avoid repetition, we have grouped such compounds that have similar pharmacological actions on more than one organ system under functional headings: Antihistamines, Antiinfectives, Autonomics (adrenergics, anticholinergic), Cytostatic drugs, Hormones, Vaccines. In collaboration with the National Swedish Board of Health and Welfare and with representatives for relevant medical specialties, we have presented standard texts for about 25 groups of substances in Categories B 3, C and D. A few standard texts for breastfeeding have also been worked out. The standard texts are presented in APPENDIX 2 . The standard texts have served to facilitate the work of the drug companies and to avoid discrepancies between products belonging to the same group of drugs.

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6. ALLOCATION OF DRUGS TO PREGNANCY CATEGORIES

6.1. ANIMAL DATA VERSUS CLINICAL DATA IN SAFETY EVALUATION When allocating drugs to the different categories (see section 5) we considered a variety of data generated through animal studies, investigations aimed to reveal the mechanism of action, clinical trials and continued clinical use. The final allocation of a drug to one of the categories thus expresses the result of a safety evaluation which has taken into account not only qualitative but also quantitative data obtained under clinical conditions using therapeutic dose levels. It must be emphasized that human data constitute the most important base for allocation of a drug to a certain category. Long experience from well-controlled human use of or exposure to drugs has generated the most conclusive results and so far seems to be the most adequate base for safety predictions. Several reviews have shown that a substantial number of drugs and chemicals have been identified as teratogens in laboratory animals. Only a few, however, are known to be teratogenic in man (172). As elaborated on in section 3, this emphasizes the importance of a careful analysis of animal data generated from reproduction toxicology studies before using such data in the risk assessment for man. It was therefore agreed that animal data should be considered and presented when only limited experience from human use existed but so far no signs of disturbances of the human reproductive process had been experienced. Thus, only drugs allocated to Category B 3 carry information from results obtained in animal studies. The drugs in Category D are known to be teratogenic in man or to irreversibly damage the human fetus. In general these drugs are also teratogenic in animals. Most of the drugs allocated to this category have been so because of effects observed in man. A few compounds, such as some anticancer drugs, however, have been allocated to Category D on the

basis of their mechanism of action even if no experimental or clinical evidence for teratogenicity exists. In several cases fetal adverse effects have been observed in animals long before teratogenic effects were shown or even suspected in man. The question whether early knowledge about teratogenic effects in animals have been ignored or whether animal tests currently in use have been too insensitive to detect fetal adverse effects can not be fully answered. The question is interestingly highlighted by a retrospective comparison between animal and human data for some of the drugs allocated to Category D. The teratogenic effects of folk acid antagonists such as aminopterin and the virilizing effect of androgens were known from animal studies long before the drugs were used in man (185). Aminopterin carried a warning based on animal studies already when it was introduced on the market in 1951 (101). Streptomycin and related aminoglycosides may damage the auditory nerves of the human fetus, leading to deafness (148). Several investigators have failed to detect deafness in the offspring of mice and rats (178). The situation is similar for the antimalarial compound chloroquine, which in high doses may cause neurological disturbances in the human fetus interfering with hearing, vision and balance (166). The ototoxic effects of aminoglycoside antibiotics and chloroquine are not easily detected in general toxicological routine tests if not specially looked for by using special function tests and histological methods (37). Teratogenic effects of the anticonvulsant diphenylhydantoin were detected in animals in the middle of the 60s (120). The causality in man now seems quite clear with about two to three times higher risk for malformations such as cleft lip, cleft palate and congenital heart disease in the offspring of epileptic mothers treated with diphenylhydantoin (85, 130). The compound had been used for more than 35 years without any suspicion of human teratogenesis. EviAeta Obstet Gynecol Seand Suppl 126

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F. Berglund et al.for man of these effects observed in animals is extremely difficult to evaluate, especially since the dose levels used under clinical conditions are fairly low. Similar effects have, however, so far not been observed in man in spite of rather extensive use.Phenobarbital. Phenobarbital has been placed in Category A except when used as an anticonvulsant, or in the drug combination BellergalR (cf section 6.5.)

dence from epidemiological studies became convincing only in the mid 70s. The transplacental carcinogen diethylstilbestrol was frequently prescribed for pregnant women in the USA between 1940 and the late 50s for threatened abortions, diabetes and toxemia. The long latency period for the vaginal cancers to appear in the offspring prohibited early detection which was reported only in 1971 (81). Diethylstilbestrol is an epigenetic carcinogen and exhibits tumourogenic properties in several animal species (124). Vaginal cancer in mice after treatment with diethylstilbestrol was reported already in 1963 (44). Striking discrepancies between animals and man regarding teratogenic drug effects are illustrated by the corticosteroids and salicylates. These drugs are allocated to Category C, which includes drugs with pharmacologic effects which can adversely influence the human offspring without being directly teratogenic. Although the corticosteroids and salicylates are wellknown animal teratogens this does not justify an allocation to Category D (12). The teratogenic effects in animals caused by the compounds have not been observed in man, in spite of extensive prospective epidemiological studies (160, 165). The experimental and clinical background for allocation of drugs to specified categories will in the following be described and examplified.6.2. CATEGORY A

6.3. CATEGORY B

Drugs allocated to Categories B 1 or B 2 are of limited interest from a safety evaluation aspect since no fetal adverse effects have been observed either in animals or in man following treatment with these drugs. 49 substances have been allocated to Category B 1 and 98 to Category B 2. It is somewhat worrying that Category B 2 mainly consists of older drugs which have not been subjected to adequate experimental studies. All new Category B drugs will be allocated to either subgroup 1 or 3. Of greater interest are the drugs allocated to Category B 3, at present 36 compounds. By definition this category contains drugs which are known to cause fetal adverse effects in animals, the significance of which is considered uncertain in man. Products containing meprobamate, oral contraceptives, and trimethoprim belong to this category.Meprobamate. In a prospective study of pregnancy and child health Milkovich and van den Berg (126) found an increased frequency of congenital heart lesions in children whose mothers had been treated with meprobamate during early pregnancy (the first 42 days). These results could not be confirmed in a follow-up study of over SOOOO pregnancies where a total of 1870 children exposed in utero to meprobamate or chlordiazepoxide were compared with 48412 children who were not. In this study no significant differencies were found either over all or in specific defects. Rates were also similar when exposure occurred during the first trimester or at other times during pregnancy (75). Neither did similar studies reported by Crombie et al. (35) confirm the results reported by Milkovich and van den Berg (126). Studies in rats have shown that meprobamate given during pregnancy and lactation may adversely affect the learning ability of the newborn (25, 11). There is no evidence of interference with mental processes in

Of the 675 active substances identified in the different drugs presented in EASS 1984, 205 have been allocated to Category A. For the majority of these substances neither animal experiments nor epidemiological studies have revealed any fetal adverse effects or other disturbances of the reproductive process. Some compounds, however, are known to cause adverse effects in animals, but similar adverse effects have not occurred in man in spite of extensive human use.Haloperidol. Delayed learning ability and disturbances in motor development can be induced in suckling rabbit pups by treating the mothers with haloperidol (Lundborg, 1972). The results are interpreted as a consequence of a continuous blockade of central dopamine receptors in the brain during a period when central dopamine mechanisms are undergoing maturation. It is also well-known from studies in rats that early receptor blockade of this type may result in persistent behavioural impairment (2). The significanceActa Obsret Gynecol Scand Suppl126

Drug use during pregnancy and breast-feedingman, but meprobamate should not be used during pregnancy except when strictly indicated. The difficulty of deciding whether a drug should be allocated to Category B 3 or Category A is illustrated by comparing meprobamate with haloperidol mentioned above (see Category A).Oral contraceptives. It is well known from animal studies that high doses of gestagens can cause masculinization of the female fetus. Similar effects may occur in man. A few gestagens have therefore been allocated to Category D (see section 6 5 . ) There is, however, no evidence of fetal adverse effects with the low doses of gestagens used in oral contraceptives if used accidentily during pregnancy. These have therefore been placed in category B 3. Trimethoprim and pyrimethamine. Trimethoprim and pyrimethamine in high doses may block the enzymes dihydrofolate-reductase and lead to folic acid deficiency. In rats, trimethoprim given in high doses during the period of organogenesis causes malformations similar to those seen after treatment with other falate antagonists such as pyrimethamine or aminopterin (191). Although clinical findings confirming this have so far not been published, Category B 3 has been agreed upon. In pregnant women given trimethoprim or pyrimethamine, the folic acid levels should, however, be checked and leucovorin be given if necessary. Prenalterol. Prenalterol is a new selective PI agonist which has been available for clinical use only for a few years. Prenalterol caused cardiovascular defects in the rabbit fetus manifested as a distension of the aortic arch and the pulmonary artery. The defects are dose dependent. Morever, the sensitivity for development of the cardiovascular defects in rabbits is maximal during the later stages of pregnancy, while no changes are observed after treatment during early pregnancy. The effects are most probably related to the development of cardiovascular receptors which occurs around mid-term in rabbits. The effect can be inhibited by pretreatment with PI selective receptor blocking agents given approximately half an hour before giving prenalterol. Similar cardiovascular defects were not observed in rats given doses up to four times the highest dose used in rabbits. Fetal cardiovascular adverse effects are not expected to occur in man treated with normal therapeutic dose levels. Prenalterol thus examplifies a drug with pharmacological

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effects resulting in permanent irreversible fetal toxicity in rabbits, the relevance of which is uncertain in man. This justifies an allocation of prenalterol to category B 3 (58) .6.4. CATEGORY C

By definition this group includes drugs, which by their pharmacological effects, have caused, or must be suspected of causing, reproduction disturbances that may involve risks to the human fetus without being directly teratogenic. So-far, altogether 118 active ingredients in drugs used in Sweden have been allocated to Category C in our classification system. Nine groups of drugs were included from the start in 1978. Since then several drugs have been added. Ergotamine and dihydroergotamine were added in 1979, glucocorticoids for systemic use in 1980, glucocorticoids for topical use and bensodiazepines in 1981, and prostaglandin inhibitors in 1982.P-Adrenoceptor blocking agents. Animal data together with scattered clinical observations (5, 68) suggested that blockade of P-adrenoceptors reduced uterine relaxation and thus might affect labour. Clinical studies in recent years have, however, indicated that any influence by 0-adrenoceptor blockers on the human uterus during labour may be neglected (182). Cases of neonatal hypoglycemia and sinus bradycardia have been reported (34, 68), but the relevance of these effects for neonatal survival is uncertain. During the final part of pregnancy and partus these drugs should therefore only be given after weighing the needs of the mother against the hazard to the fetus. Benzothiadiazines and related diuretics, furosemide and bumetamide. Thiazides, related diuretics and loop diuretics enter the fetal circulation (13) and may cause electrolyte disturbances (7). Neonatal thrombocytopenia has been reported with thiazides and related diuretics (149). Loop diuretics like furosemide and bumetamide are probably also associated with this risk. During the final phases of pregnancy, products of this type should therefore only be given on strict indications, and then in the lowest effective dose. Neonatal electrolyte disturbances have not been reported to occur with potassium retaining diuretics including spironolactones. These have been grouped inActa Obster Gynecol Scand Suppl I26

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F. Berglund et al.cyanosis and hypothermia owing to the limited glucuronidation capacity of the newborn infants liver (63, 176). Chloramphenicol treatment should therefore be avoided during the last week before partus and during breast-feeding. Glucocorticoids for systemic use. In animal experiments corticosteroids have been found to cause malformations of various kinds (cleft palate, skeletal malformations). The findings in these animal experiments do, however, not seem to be relevant to man. Reduced placental and birth weight have been recorded in animals and man after long-term treatment (104). Furthermore, neonatal adrenal suppression due to treatment with glucocorticoids during pregnancy can not be ruled out (136).Therefore the needs of the mother must be carefully weighed against the possible hazards to the fetus when glucocorticoids are prescribed. Suppression of lupus anticoagulant activity and improved fetal survival by treatment with prednisone 40-60 mg/day and aspirin 75 mg/day throughout pregnancy in SLE patients has recently been reported (116). Thus, in patients with SLE, advantages outweigh possible hazards. Glucocorticoids for topical use. Substantial amounts of glucocorticoids may be absorbed through the skin and thereby exert systemic effects (cf 135). In accordance with glucocorticoids for systemic use, topically used glucocorticoids, except hydro-cortisone and prednisolone, were therefore placed in Category C in 1981. During pregnancy low-potency steroids should be used as far as possible for long-term treatment of large areas of the skin. Glucocorticoids for use by inhalation still remain in Category B 3. Antithyroid substances. Antithyroid agents cross the placenta and may induce a state of hypothyroidism in the fetus and congenital goiter by inhibiting thyroxine synthesis in the fetus. This has repeatedly been verified in the clinic (cf 23). During pregnancy antithyroid substances should therefore only be used after carefully weighing the mothers needs against the hazards to the fetus. Sulfonylurea antidiabetics. These agents readily cross the placenta, and there is substanital evidence that they may induce neonatal hypoglycemia (102). They should therefore not be used during pregnancy but should be replaced by insulin.

Categories A or B and may serve as alternatives to thiazides for use in pregnant women. Dicoumarol. Coumarin derivatives may enter the fetal circulation and have been reported to cause bleeding and fetal death (69, 86). These products should therefore be avoided during pregnancy and should only be used after carefully weighing the needs of the mother against the possible hazards to the fetus. Note that Warfarin, also a coumarin derivative, is placed in Category D. For pregnant women in need of anticoagulant treatment heparin may be used without any hazard to the fetus. The large heparin molecule does not pass the placenta barrier, and heparin will accordingly not appear in the fetal blood (57). However, for long term therapy with large doses of heparin during pregnancy the risk of inducing osteoporosis in the mother has to be considered (1, 79, 171, 204). Sulfonamides. Neonatal kernicterus secondary to sulfonamides given to the mother during the last month of pregnancy is a wellknown clinical entity, but available documentation is sparse, consisting mainly of scattered case reports from the 40s and 50s (80). Sulfonamides should therefore be avoided during the last month of pregnancy. Trimethoprim-sulfonamide and pyrimethaminesulfonamide combinations. The sulfonamide component of these drug combinations places them in Category C. Rifampicin. Rifampicin crosses the placenta and may counteract the synthesis of prothrombin in the liver by its latent quinone structure resembling vitamin K. Haemorrhages in newborn babies and their mothers, who had been treated with rifampicin, have been reported (27, 48). When given during organogenesis in animal experiments, rifampicin has given rise to skeletal malformation. Rifampicin should not be a first hand choice in combination therapy of tuberculosis during pregnancy. If rifampicin is given during the final weeks of pregnancy, vitamin K should be given to the mother and the neonate. Chloramphenicol. Chloramphenicol enters the fetal circulation, and, if given to the mother shortly before partus, may cause the grey baby syndrome withActa Obstet Gynecol &and Suppl126

Drug use during pregnancy and breast-feedingBiguanides reportedly do not cross the placenta. Thus, metformin has been labelled by the manufacturer as Category B 2, but with an added annotation that the diabetic pregnant woman should be treated with insulin.

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Benzodiazepines. During recent years a number of case histories have been published, that report on a floppy infant syndrome of hypotonia, hypothermia and respiratory distress in children to mothers exposed to repeated administration of benzodiazepines during pregnancy (cf 46). Accumulation of the drug in the fetus is probably a major contributing factor to development of the syndrome (98). Continuous treatment during pregnancy and administration of high doses in connection with delivery should therefore be avoided. Withdrawal symptoms in newborn infants have occasionally been reported. Other types of sedating agents, including antidepressants with sedative properties, have not been assigned to Category C, although it may reasonably be assumed that many of these compounds also may cause neonatal disturbances. Narcotic analgetics. While morphine itself and related drugs are apparently harmless to the fetus when given well before partus, they may induce neonatal respiratory depression and irreparable damages in the newborn child, if given close to delivery (43, 64). During the last 2 - 3 hours before expected partus, these products should therefore only be used after weighing the needs of the mother against the possible hazards to the fetus. Ergotamine and dihydroergotamine. Spontaneous abortion is common in ergot poisoning. Ergotamine induces uterine contractions and may therefore cause premature partus or hypertonic labour (cf 143). Products containing ergot alkaloids should therefore be avoided as far as possible during pregnancy.This also applies to dihydroergotamine in injectible form. Drug combinations of ergotamine (C) with meprobamate (B 3) are classified in Category C. Inhibitors of prostaglandin synthesis. Antiphlogistics that inhibit prostaglandin synthesis may be used therapeutically in the newborn to close a patent ductus arteriosus (62, 82). Closure of the ductus might also occur inadvertently in utero when pregnant women take such drugs (45, 99). After thorough consideration we concluded, that this risk must be appreciable

enough to include in Category C all agents with a documented inhibiting effect on prostaglandins. When given at term they prolong labour and delay partus. Continuous treatment with antiphlogistics during the last month of pregnancy should only be given on strict indications. During the last few days before expected partus agents with an inhibitory effect on prostaglandin synthesis should be avoided. The list of substances that inhibit prostaglandin synthesis includes derivatives of salicylic acid, and this will have consequences of both a practical and delicate nature. Firstly, salicylic acid derivatives are present in a great number of fixed combination preparations, that also contain sedatives, muscle relaxants, spasmolytics, or other analgetics in various proportions. These fixed combinations are used in a wide variety of ailments ranging from menstrual pain and migraine to sleep disturbances. Secondly, many of the salicylate preparations are OTC drugs. This is contrary to the general rule that OTC drugs must have a high level of safety and a wide range of tolerability. In addition, aspirin taken within a few days before delivery produces an increased bleeding tendency in the mother and the infant due to its effect on platelets (31, 175, 189). This information is included in FASS 1984. Concerning aspirin in the treatment of SLE, cf under Glucocorticoids.

Succinylcholine. Normally this drug presents no hazard to the fetus, but a case of respiratory depression in a newborn infant with deficiency of pseudocholinesterase has been reported (87).6.5. CATEGORY D

Approximately 70 active ingredients in FASS are categorized as potentially teratogenic in man. Among these are anticoagulant, cytostatic, antibiotic, hormonal, antipsoriasis and anticonvulsant drugs. Thus, they span over a wide therapeutic range. Most troublesome are probably the anticonvulsants, since harmless replacements seem to be lacking.

Ethanol. Although not a drug, ethanol cannot be ignored in a review of drugs in pregnancy. The fetal alcohol syndrome is now well recognized. The defects in this syndrome can be divided into four major groups: 1. central nervous system dysfunction; 2. growth deficiency; 3. characteristic facies; and 4. associated anomalies. References are given in the reviews by Hays (78) and Ashley et al. (8).Acta Obstet Gynecol Scand Suppl126

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F. Berglund et al.farin embryopathy, characterized by nasal hypoplasia and stippled epiphyses on X-ray - a number of other anomalies have also been reported (microcephaly, mental retardation, blindness). In a recent review Hall et al. (69) found 27 cases exposed between the 6th and %h weeks of gestation - 8 of these died in infancy. They also mention 13 individuals who were exposed to coumarin derivatives in the 2nd and 3rd trimesters who had various central nervous system abnormalities not directly attributable to late prenatal or perinatal haemorrhage. They conclude that use of warfarin in the first trimester is associated with the warfarin embryopathy in some infants, while use in the 2nd and 3rd trimesters is associated with an increased incidence of central nervous system defects, and administration late in pregnancy may result in perinatal haemorrhage. Hall et al. point out that all embryopathic manifestations have occurred when mothers took coumarin derivatives between six and nine weeks of gestation, when clotting factors that can be affected by vitamin K antagonists cannot yet be demonstrated in the embryo. They propose that coumarin derivatives act through inhibitory calcium-binding , vitamin K-dependent gamma-carboxyglutamate-containing proteins in bone. Inhibition of these osteocalcins during a critical embryologic period of ossification could explain many of the features of warfarin embryopathy, including nasal hypoplasia, stippled calcification, extremity shortening and vertebral abnormalities. Hall et al. also suggest that a similar mechanism may account for the fetal hydantoin syndrome. Concerning coumarin and heparin, see section 6.4.Cytostatic drugs. Anticancer drugs are generally placed in the category of human teratogens. An exception in FASS is tamoxifen, which acts as an antiestrogen. With cytostatic agents, notably aminopterin, methotrexate, 6-mercaptopurine, busulfan and cyclophosphamide, teratologic effects have been obtained when the drugs were given during the first trimester. In a review of eight cases of methotrexate-induced malformations, Milunsky et al. (127) noted a high incidence of cranial anomalies. Aminopterin produces skeletal defects, depression of haematopoiesis, and necrosis of the adrenal and intestinal epithelia. Besides the stage of gestation, dosage and combination of drugs determine the outcome. Blatt et al. (16) mention that busulfan and 6-mercaptopurine have been given alone without causing malformations but given together have been associated with multiple congenital

Quinine and quinidine. There is ample human evidence to show that quinine administered during pregnancy to induce labour, as an abortifacient or in the treatment of concurrent disease may cause deafness and amblyopia in the offspring (61, 123). Recommended doses in clinical therapy are relatively high, 0.2-0.3 g for nocturnal muscle cramps, 0.3-0.6 g 2 - 3 times daily for myotonia. The presence of quinine in tonic water and certain strong wines is of some concern. In Sweden 100 mg/l is allowed. Evans et al. (53) described an infant who was jittery for a week after birth, presumably due to quinine withdrawal. The mother had consumed more than 1 litre of tonic water daily from 24 weeks gestation until birth, and quinine was present in the infants urine. In view of the chemical similarity, and similar sideeffects, quinidine is also placed in category D. There are, however, reports on the use of quinidine use through pregnancy at a dosage of 1.8 or 2.4 g per day (84) without apparent damage to the infants, but audiometry was not reported. Chloroquine and hydroxycbloroquine. Hart and Naunton (74) reported 2 children with profound sensorineural hearing loss following administration of chloroquine to the mother during pregnancy. The maternal dosage was 0.25 g once daily in one pregnancy and 0.25 g b.i.d. in the other. One child, exposed to a maternal dose of 0.25 g b i d . during the first six weeks of gestation, had normal audiometry and vestibular function, but hemihypertrophy of the left side. Three children with no exposure to the drug were normal. For prophyluxis against malaria the recommended dosage varies from 0.5 g weekly to 0.16 g six days per week, depending on whether non-malignant or malignant malaria occurs in the area. Recommended dosages of hydroxychloroquine are almost identical. These doses are considered sufficiently safe even during pregnancy. Thus, these compounds are recommended in prophylactic doses during pregnancy even though they are categorized as human teratogens. It should be emphasized that the principle hazard to the fetus is the development of malaria in the pregnant mother rather than drug toxicity. Only a few antimalarial drugs are registered in Sweden. For more complete advice, cf Bruce-Chwatt (22). Warfarin. Warfarin and certain other coumarin derivatives give rise to a cluster of anomalies, the warActa Obstet Gynecol Scand SuppI1.26

Drug use during pregnancy and breast-feedinganomalies including microphtalmus, corneal opacities, cleft palate and hypoplasia of the thyroid and ovaries. Likewise, a significant increase in anomalies was found in offspring of women with Hodgkins disease who were treated with radiotherapy plus chemotherapy.Tetracyclines.All tetracyclines are classified as potential human teratogens. There are case reports of malformations associated with tetracycline, including digit defects, cataracts and limb anomalies. Tetracyclines get deposited in high concentrations in the skeleton, and in teeth during the period of mineralization (cf 78). The skeletal deposits are associated with reduced growth of limbs. The deposits in teeth cause light yellow discoloration of the enamel - this turns brown in older children, possibly due to decomposition of the tetracycline. Often the stained teeth have hypoplastic enamel and dentin. - Mineralization of bone and teeth starts only in the fourth month of gestation, and use of tetracyclines should therefore be avoided during the second half of pregnancy. Aminoglycosides. Streptomycin and dihydrostreptomycin have been associated with numerous reports of congenital deafness. Other aminoglycosides also possess ototoxic properties, although fetotoxic effects do not seem to have been reported. They should not be used in pregnant women. Androgens and other anabolic steroids. When administered to a pregnant woman, these can produce pseudohermafroditism in the female fetus. They should be avoided by pregnant women (66). Gestagens. Gestagens have not been uniformly evaluated by the manufacturers. Most of them have been placed in Category A, two in B 2 (gestonoron and megestrol) and one in D (lynestrenol). Because of the paucity of documentation we cannot judge whether the placing in different categories reflects a real difference between gestagens or only a difference in evaluation, perhaps due to different indications. Diethylstilbestrol. Herbst et al. (81) reported a link between maternal diethylstilbestrol therapy and