Epilepsin, 16:159-169,1975.
Raven Press, New York
The Teratogenic Risk of Antiepileptic Drugs Dieter Janz Freie Universitat Berlin, Abteilung fur Neurologie, Klinikum Charlottenburg, Berlin, Germany
INTRODUCTION Nearly all studies on the topic of teratogenic risks of antiepileptic drugs have concluded that congenital anomalies occur more frequently among children from mothers with epilepsy who took antiepileptic drugs during pregnancy than among children from motkrs- free of epilepsy or children from epileptic mothers who did not take any antiepileptic drugs during pregnancy. Among the malformations, cleft lip (with or without cleft palate) and congenital heart lesions are particularly noted. It has been suggested that these malformations are induced by antiepileptic drugs, since teratogenic effects have been induced in experiments on animalsunder rather artificial conditions, however, as the antiepileptic drugs pass through the placenta. Diphenylhydantoin (DPH) has been suspected to be especially teratogenic, since cleft lip and cleft palate have been induced-in certain strains of mice and under extreme conditions, however-by DPH ingestion. This suspicion is a grave one. A lot is at stake. Should these drugs, which have helped uncounted numbers of people, be held responsible for these damaging effects? The problem concerns approximately 0.3 to 0.5% of all pregnancies. Of all pregnancies studied in Saint Thomas Hospital, London, 0.28% were those of epileptic mothers (South, 1972). In Norway, the number was 0.28% (Bjerkedal and Bahna, 1973); in Cardiff, 0.42% were recorded (Speidel and Meadow, 1972); and 0.54% were affected in Groningen (Elshove and Van Eck, 1971). It is, therefore, urgent to know if there is an increased risk for malformations, what its measure is, and what Key words: Teratogenicity drugs
- Antiepileptic
other explanation can be sought. It is entirely possible that other risk factors, directly or indirectly associated with the epilepsy of the pregnant woman, such as seizure-related anoxemic or traumatic lesions of the fetus in utero, or genetic or environmental factors, could be responsible for the increased risk of malformations. FREQUENCY OF MALFORMATIONS IN CHILDREN FROM EPILEPTIC MOTHERS What are the statistical data that lead to the assumption that antiepileptic drugs are teratogenic? Table 1 shows all studies, which until recently have been only of the retrospective type, that included different control groups for comparison. In a number of studies, epileptic mothers who did not take any drugs during pregnancy served as a control group (Janz and Fuchs, 1964a,b; Maroni and Markoff, 1969; Speidel and Meadow, 1972; South, 1972; Lowe, 1973; Meyer, 1973; Starreveld-Zimmerman et al., 1973). In a second group of studies, the frequency of malformations in children of nonepileptic mothers served as, obviously, much larger control groups. This was done either by selecting the mother whose case sheet number was nearest to that of the epileptic mother (Watson and Spellacy, 1971; Speidel and Meadow, 1972) or by collecting all hospital births during a certain time (Elshove and Van Eck, 1971; South, 1972; Monson et al., 1973). In still other studies, all births reported by general practitioners (Kuenssberg and Knox, 1973) or all births in a geographically defined population (Lowe, 1973) served as control groups. Even though the term “malformation” has
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TABLE 1. Frequency o f malformations in children from mothers with epilepsy treated during pregnancy uersus untreated and versus malformations in children from mothers without epilepsy Live births of treated mothers with epilepsy Malf ormaReference Total tions Janz and Fuchs (1964a,b) 225 4 Maroni and Markoff (1969) 21 1 Elshove and Van Eck (1971) 65 10 3 Watson and Spellacy (1971) 51 Speidel and Meadow (1972) 324 16 South (1972) 22 2 Lowe (1973) 134 8 Kuenssberg and &ox (1973) 48 3 Monson et al. (1973) 93 4 Starreveld-Zimmerman et al. (1973) 279 20 Meyer (1973) 199 - 17 Total
1,461
88 = 6.0%
not been defined exactly and the studies varied as to methodological aspects and geographically came from different regions, their results show a common trend: mothers with epilepsy who took antiepileptic drugs during pregnancy have more frequent malformations in their offspring than epileptic mothers who were not treated. It is noteworthy that the latters’ risk of having a child with malformation is still higher than in the general population. The results, taken from the literature, confirm each other, as can be shown by comparison to two comprehensive studies (see Table 2). Bjerkedal and Bahna (1973) have recently shown in their study of all births in Norway during 1967 and 1968 that malformations are significantly more frequent in children of epileptic mothers compared to the nonepileptic population. The percentage in epilep-
Live births of untreated mothers with epilepsy MalformaTotal tions 120 0 14 0
Live births of mothers without epilepsy MalformaTotal tions
-
-
-
-
59 9 111
0 0 3
11,986 50 442 7,865 31,622
-
-
14,620 417 50,591 1,240
-
18 124
2 14
455
19 = 4.2%
117,176
221 0 7 190 865
2,940 = 2.5%
tic mothers was 4.576, or twice that of the control group, with 2.2%. These data resemble those taken from the literature, with 5.6% in epileptic mothers (treated and untreated) as compared with 2.5% in nonepileptic mothers. Unfortunately, the Norwegian study does not distinguish between epileptic mothers with treatment from those without treatment during pregnancy. This point has been considered by an American cohort-study of 50,897 pregnancies, collected from 12 hospitals with the objective of determining whether the frequency of selected malformations is higher in infants exposed to DPH in ufero and, in addition, which other variables are associated with these malformations (Monson et al., 1973). The Norwegian and American studies produced nearly the same percentage and the same tendency: malformations are twice as frequent
TABLE 2. Frequency o f malformations in children o f mothers with epilepsy versus those without epilepsy
Reference
Live births of mothers with epilepsy Malformations Total No. Percent
Literature review Bjerkedal and Bahna (1974)
1,916 378
107 ?
5.6 4.5
Live births of mothers without epilepsy Malformations No. Percent Total 117,176 113,511
2,940 ?
2.5 2.2
TERATOGEMC RISK OF ANTIEPILEPTIC DRUGS in infants of epileptic mothers as compared with the control groups. In addition, the American study shows that the rate in infants exposed to daily DPH in the first 4 months of pregnancy is, with 61 per 1,000, significantly higher than the corresponding rate of 25 per 1,000 in infants born to women who had no convulsive disorders @ < 0.05). Although the rates are also higher in all other categories of treatment, none differed significantly from the 25 per 1,000. This proves that malformations of children born to women with convulsive disorders are more frequent than in children born to nonepileptic mothers. Several studies (except that by Koppe et al., 1973) did show, however, that the rate of malformations in children born to treated and untreated mothers with convulsive disorders is not significantly different. This means that the conclusion of there being a causal relationship between antiepileptic treatment and the malformation rate has no statistical support. On the other hand, the published data do not allow one to exclude the existence of such a relationship. Meyer (1973) has calculated that for positive exclusion of the existence of such a relationship-provided there is a relatively similar incidence--1,800 pregnancies are needed instead of the published 600. TYPE AND/OR COMBINATION OF MALFORMATIONS An increased rate of malformations may be caused by various factors, such as the mother’s older age at pregnancy, unfavorable genetic background, or environmental factors. From a teratological standpoint, however, it is especially interesting as to whether particular malformations or a characteristic combination of malformations are seen with antiepileptic medication in general or even with certain antiepileptic drugs. Table 3 shows the different types of malformations according to their frequency. As can be seen, oro-facial clefts and congenital heart lesions predominate. Skeletal anomalies, such as club-foot, congenital hip, and distal pharyngeal hypoplasias, are less frequent. Finally, microcephaly, hypospadias, intestinal and anal abnormalities, anencephaly, and neural tube anomalies, such as meningomyelocele and
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spina bifida and, rarely, a case of primary hydrocephalus, do occur. A review of the literature shows that the specific rates for oro-facial clefts and for congenital heart lesions are increased in infants born to women with convulsive disorders. The average frequency of 1.8% for oro-facial clefts is about 6 to 1 2 times higher than the results published for nonepileptic controls, with 0.14% in Birmingham (Speidel and Meadow, 1972), 0.16% in Cardiff (Lowe, 1973), 0.2% in London (South, 1972), and 0.27% in Groningen (Elshove and Van Eck, 1971). Congenital heart lesions seem to be more frequent in infants born to women who took antiepileptic drugs, with a rate of 1.5% as compared to, however, quite heterogeneous controls from Birmingham with a rate of 0.42% (Speidel and Meadow, 1972). Cleft Lip and Cleft Palate According to the data published by Stevenson et al. (1966) in a WHO report, cleft lip-with or without cleft palate-ccurs in 7.7% of all cases with congenital anomalies. The ratio in the reviewed literature (31 of 98 cases = 32%) again confirms that there is a definite preponderance of this type of malformation over the other congenital anomalies in the offspring of mothers treated with antiepileptic drugs. In the study of Elshove and Van Eck (1971), “hare lip” (with and without cleft palate) comprised 13.9% of the abnormalities in a series of 12,014 general deliveries, but 50% of the total abnormalities in the epileptic series of 65 deliveries. The concept of a teratogenic drug effect is supported by experiments, which suggest a specific teratogenic effect of DPH. In the offspring of female mice given DPH, oro-facial cleft was more frequent compared with the spontaneous rate. This was shown, however, under extreme experimental conditions in particularly sensitive strains (Massey, 1966; Gibson and Becker, 1968; Harbison and Becker, 1969, 1970; Elshove, 1969; Kemis et al., 1973; Marsh and Fraser, 1973; ROSS,1973). There are some facts, however, that would not favor the concept that oro-facial clefts are induced by antiepileptic drugs, especially by DPH intake. First, oro-facial clefts do occur in families quite often and are said to be
5 0.3
5 0.3
2 0.1
5 0.3
5 0.5
18 1.0
5 0.3
1
1
2
10 0.6
2
3
2
1
1
of malformations occur'.the total numbers of cases can be lower than the sum of the different malformations stated.
26 1.5
1 7
1
5
1
1
1
1
O A s combinations
31 1.8
1 1
1
1
2
1
3
1
1,726
7 5
1
5.
8
279 199
1
1
1
93
1 1
1
1
1
1
1 1
1
1
48 17 20
1
2
1
1
Anen- Microcephaly cephaly
1
5
2
3
Heart lesions
324 22 134
51
16
65
21
32
180
225
Orofacial clefts
Total Percentage
Janz and Fuchs ( 19640,b) German League (published by Janz and Fuchs) Melchior et al. (1967) Maroni and Markoff (1969) Elshove and Van Eck (1971) Mountain et al. (1970) Watson and Spellacy (1 971 ) Speidel and Meadow (1972) South (1972) Lowe (1973) Kuenssberg and Knox (1973) Michaelis (1973) Hill et al. (1973) Monson et al. (1973) StarreveldZimmerman et al. (1973) Meyer (1973)
Reference
No.of Pregnancies
Intestinal atresia Neural (includHydro- tube Hypo- Skeletal ing fisMiscephaly anomaly spadia anomalies tula) cellanea
Malformations
101 5.8
20 17
4
3 2 5
16 2 8
3
0
10
1
2
3
5
No. of cases with malformationsa
TABLE 3. Frequency of different malformations in children of mothers with antiepileptic treatment during pregnancy
TERATOGENIC RISK OF ANTIEPILEPTIC DRUGS associated with epilepsy, which would explain their high incidence in infants born to epileptih mothers. Dronamraju (1970) reports that 295 of his patients with oro-facial clefts have 42 first- or second-degree relatives with epilepsy. One has to consider, however, that infants born to untreated epileptic mothers do not have an increased rate of oro-facial clefts and congenital heart lesions. As for the familial occurrence, Meadow (1970) reports that 7 of the 32 children of his collection with cleft lip and/or cleft palate who have been born to treated mothers had “similarly affected siblings.” According to Fogh-Anderson (1968), there is a positive family history in just more than one-third of all cases. Starreveld-Zimmermanet al. (1975) showed that in 3 of his 9 families who had hare-lip infants after the mothers’ antiepileptic treatment, cases of hare lip again occurred. In order to draw conclusions from the animal experiments for human conditions, the congenital abnormalities should be related to a certain drug and be dose-dependent. Among 35 cases with oro-facial clefts, whose drug treatment during pregnancy is known, five cases had taken only barbiturates. Phenobarbital, however, does not produce oro-facial clefts, nor does it produce any other congenital abnormalities in animal experiments (Staples, 1972). In 6 other cases, barbiturates and other antiepileptic drugs-but again no DPH-were given. Taken together, DPH played no role in 11 of a total of 35 cases; this does not support the concept of a DPH-specificteratogenic effect in producing oro-facial clefts, which, by the way, had been based on questionable experimental evidence. As to the relation of the dose of drug intake during pregnancy to the occurrence of congenital abnormalities, Monson et al. (1973) wrote: “There was no evidence to suggest that malformations were more common in those taking higher doses.” Only Loughnan et al. (1973) pointed out that in 1case of congenital abnormalities, of not closer specified character, the mother had “at the fourteenth week’s gestation” an increased plasma level of DPH. Congenital Heart Lesions There is no experimental evidence for the increased rate of congenital heart lesions in
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infants born to epileptic mothers. The type of heart lesions is not known in 4 cases. As for the rest of 1 5 cases, 9 had septal defects (6 cases of ventricular-septal, 2 atrio-septal, and 1ventricular-atrio-septal); there were also 4 cases of Fallot’s tetratology, 1 aortic stenose, and 1 pulmonary atresia. The last-mentioned case and 1 case of ventricularatrio-septal defect in addition had a patent ductus arteriosus. A coarctation of the aorta appeared in combination with a ventricular and atrio-septal defect. Meadow (1970) considered a higher than randomly expected frequent combination of oro-facial clefts and congenital heart lesions after answers to his letter in Lancet revealed that among 32 cases of oro-facial clefts, 8 had combinations with congenital heart lesions. A review of the literature, however, shows that among 28 cases of oro-facial cleft only 1 case had a ventricular-septal defect (Speidel and Meadow, 1972). This does not exceed the statistically expected frequency of 3 to 5% for that combination (Drillien et al., 1966). Although it has never been claimed, it seems noteworthy that no certain drug is related to the occurrence of congenital heart lesions. Malformation Syndromes Meadow (1970) considered the possible association between anticonvulsive treatment during pregnancy and a syndrome of abnormalities involving lips and palate and the cardio-vascular and skeletal systems. Later, Speidel and Meadow (1972) described this syndrome that “in its full expression takes the form of congenital heart disease, cleft lip and palate, trigonocephaly or microcephaly and various minor anomalies which include hypertelorism, low-set abnormal ears, short neck with low posterior hair line, bilateral single transverse palmar creases, and minor skeletal abnormalities.” F’raser and MacGillivray (1969) suggested that this pattern was identical with the Wddervanck syndrome, which they postulate to be produced by chromosomal damage. Loughnan et al. (1973) described a different syndrome of skeletal anomalies in 7 children of mothers who took DPH and phenobarbital during pregnancy: “The basic abnormality was a variable degree of hypopIasia and irregular ossification of the distal phalanges, producing
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short narrow and misshaped ends to both the fingers and toes.” Hill et al. (1973) observed “a characteristic clustering of malformations,” which was similar to the pattern described by Speidel and Meadow (1972) as well as to that described by Loughnan et al. (1973). The 3 infants reported by Hill et al. (1973) had been born to one mother who received phenobarbital, DPH, and primidone during the pregnancies. They showed “a low hairline, separation of the metopic suture, broad nasal ridge, wide set eyes, as well as hypoplasia of the distal phalanx of the hands and feet and temporarily hypoplastic nails.” The relevance of these observations is quite unclear and will probably not be resolved before a prospective study is performed which systematically records causes for the increased risk of malformations. According to all studies which give a measure for the risk of malformation, the probability is 2 to 3 times higher for women with antiepileptic treatment during pregnancy compared with women with no history of epilepsy at all (Speidel and Meadow, 1972; Lowe, 1973; Monson et al., 1973). A review of the literature seems to show that the increased risk is due mainly to the increased rate of clefts and heart lesions (see Table 3).
Seizures One could ask whether a single seizure or several seizures might possibly impose considerable hazards to the health of the unborn child as well as to that of the mother. Janz and Fuchs (1964a,b) did not find any evidence for the possibility that seizures produce either anoxemic or traumatically induced complications of pregnancy or damage to the fetus. According to the literature, they pointed out that healthy infants were born even to mothers who suffered from a malignant course of epilepsy and status epilepticus. Similar reports came from Maroni and Markoff (1969). Meadow (1970), however, mentions that about a quarter of the mothers of 32 children with lip and/or palate cleft had had a fit during the first 3 months of their pregnancies. According to Starreveld-Zimmerman et al. (1975), tonicclonic seizures of the mother seemed to occur appreciably more often in the cases of malformed babies compared with normal ones. Genetics
A genetical association between epilepsy and malformation has been mentioned in the section dealing with clefts. Elshove (1969) found a familial occurrence of congenital RISK FACTORS anomalies in 4 cases among 10 women with As long as a statistically significant differ- epilepsy who gave birth to children with ence in the risk of malformation for epileptic congenital abnormalities. Starreveld-Zimmerwomen compared to those without antiepilep- man et al. (1975) reported that 6 of 18 mothers tic treatment during pregnancy has not been had relatives with congenital abnormalities. proved, the described difference cannot be attributed unequivocally and solely to the Environment teratogenic effects of antiepileptic drugs. It is, therefore, necessary to define as exactly as Among the socioeconomic factors, such as possible the conditions not related to drug their relatively low social status as shown by intake as part of the risk of malformation. Monson et al. (1973), the generally limited According to Monson et al. (1973), women choice of partners for patients with epilepsy with epilepsy “tended to have characteristics should be mentioned. This is, according to associated with an increased risk of malforma- Speidel and Meadow (1972), one of the reasons tions-for example, they tended to be older, why children born to epileptic parents have a were of a lower social class, gave birth more relatively bad genetic background. Among the frequently to stillborn children, and more often social factors, old age at pregnancy also plays had hydramnios.” Thus it is possible that these an important role. Thus, there are quite a few and not factors can partly or wholly explain the association between DPH and congenital unimportant factors which could explain the increased risk for malformation in the offspring malformations.
TERATOGENIC RISK OF AIWIEPILEPTIC DRUGS TABLE 4. Drug regimen in pregnancy followed by birth o f children with selected malformations
Drug regimen
Cleft lip and/or palate
Heart lesion
29,alone in 5 21,alone in 6 Barbiturates H y dantoins 22,alone i.n 4 14,alone in 1 Diones 7, alone in 2 6,alone in 2 Carbamazepine 1,alone in 1 Ethosuximide 2, alone Benzodia1,alone 1,alone zepines
of epileptic women, apart from the antiepileptic drug treatment. Antiepileptic Drugs According to the literature, there seems to exist no antiepileptic drug of which the intake during pregnancy has not been followed by the birth of a child with congenital abnormalities. This is true not only for barbiturates and hydantoins but also for oxazolidines (German et al., 197Oa,b; Speidel and Meadow, 1972), succinimides (Lowe, 1973; Starreveld-Zimmerman et al., 1973; Meyer, 1973), benzodiazepines (Speidel and Meadow, 1972), acetylurea (Speidel and Meadow, 1972), and carbamazepine (Michaelis,personal communication; Meyer, 1973). In most cases, however, a combination of drugs was prescribed, so that a causal relationship to a certain drug is hard to establish. To trace a certain type of malformation to a certain drug is even harder, because the numbers are too small. Drug regimen in pregnancy which has been followed by births of children with cleft lesions and congenital heart lesions probably only reflects the general use of antiepileptic drugs (Table 4). This survey, however, allows us to recognize that a special relationship between the type of drug and the type of malformation most likely does not exist. Based on animal experiments, DPH is said to have a teratogenic effect. From a practical point of view, rarely does a treatment consist of DPH alone. Of 36 pregnant women treated with hydantoin alone, just 5 took DPH only (see Table 4). Even less recognizable is the
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evidence of a relationship between drug intake and type and frequency of malformations as should be expected, based on experiments on animals. As far as the amount of dosage has been given, the reported malformations did occur at a large drug intake, too, which has been pointed out by Speidel and Meadow (1972) especially. As there is no constant ratio between doses of intake and serum concentration, it is absolutely necessary to determine serum concentrations during pregnancy in order to investigate the question of a causal relationship. Studies using serum concentration of DPH during pregnancy and at the time of birth with data on child and mother are few (Baughman and Randinitis, 1970; Mirkin, 1971a,b; Loughnan et al., 1973). According to Mirkin (1971a,b), mother and child have identical serum concentrations at birth. Westmoreland and Bass (1971) reported that gravid rats are more susceptible to DPH toxicity than nongravid ones. A correlation between human maternal plasma levels of anticonvulsant drugs and outcome of their pregnancies may clarify the sporadic occurrence of anomalies in the infants. Phenobarbital was suspected to be a teratogenic drug as early as 1963 by Wheatly (1963), after 4 of 61 children, whose mothers were treated with phenobarbital because of threatened abortions, showed congenital anomalies. Nelson and Forfar (1971) found a significant association between barbiturate intake and congenital anomalies, comparing drug intake during pregnancy with the rate of malformation. According to the survey given in Table 4, there seems to be no difference between barbiturates and hydantoins-given in combination or alone-d the occurrence of selected malformations. Whether oxazolidines do have teratogenic effects is an open issue after the impressive examples of German et al. (1970u,b). Of.the 13 cases recorded in the literature, 4 remarkably did have only oxazolidine intake alone. Succinimide (Starreveld-Zimmerman et al., 1973; Lowe, 1973; Meyer, 1973), benzodiazepine (Speidel and Meadow, 1972), acetylurea (Speidel and Meadow, 1972) and carbamazepine (Meyer, 1973; Michaelis, personal communication) are represented in cases taken from the literature and our own cases.
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MECHANISM OF TERATOGENIC EFFECTS evidence for mutagenic effects. The result of this study, however, does support his opinion Malformation could be produced by muta- that investigators of possible teratogenic effects genic and teratogenic effects. of antiepileptic drugs should always be aware of mutagenic effects, as those drugs have been taken in most cases long before pregnancy Mutagenic Effects occurred. Quite contradictory reports about the effect of antiepileptic drugs on human chromosomes have been published. Muniz et al. (1969)and BrGgger (1970) found no significant chromosomal breaks in uitro in the therapeutic range of DPH (Muniz et al., 1969) and ethotoin (BrGgger, 1970). In the toxic range, however, significantly frequent chromosomal breaks occurred (Muniz et al., 1969). As far as in uitro studies are concerned, no structural anomalies were reported in the chromosomes of white blood cells of 7 patients treated with DPH at a therapeutic level. BrGgger (1970), however, reported that one boy being treated with ethotoin showed too many chromosomes and chromatid breaks and gaps. Ayraud et al. (1968) showed chromosomal breaks in a girl and her mother who was treated with antiepileptic drugs during pregnancy. Other studies (Caratzali and Roman, 1969, 1971) showed an inhibiting effect of several antiepileptic drugs on the mitosis in uitro. The most comprehensive study was done by Grosse et al. (1972). Their results showed that the rate of structural chromosomal abnormalities of 32 mothers with epilepsy and their children with an age from birth to 3 years, who were exposed to antiepileptic drugs in utero, was significantly more frequent @ < 0.001) than in untreated healthy controls. There was a significant correlation between the values of the mothers and their children. The rate of abortions, stillbirths, and malformations was not given, however. In order to distinguish between mutagenic and primary genetic anomalies, Meyer (1973) has compared the children of treated epileptic fathers with those of untreated epileptic fathers. Among 157 children of treated fathers, he found 27 anomalies. In the 107 children of untreated fathers, only 3 anomalies occurred. He could not exclude a nonrandom distribution of other variables within the two groups; thus he does not consider the significantly more frequent Occurrence of anomalies stringent
Teratogenic Effects by Mechanical Destruction
It should not be omitted that an increased risk of malformation for children born to epileptic mothers is already inherent in seizure-related falls, which can be traumatically destructive to the fetus. It is conceivable that direct and indirect (by way of bleeding) trauma does occur. If the reports about neonatal coagulation defects are confirmed, fetal bleeding due to coagulation defects also has to be considered (Mountain et al., 1970). Teratogenic Effects by Metabolic Damage That fits during early pregnancy could damage the fetus by oxygen shortage is a considered possibility which has not been proved. Two means of drug-induced metabolic damage must be considered: a direct dose-related toxicity and a drug-induced effect on essential enzymes. The assumption of dose-related fetal damage is based on experimental production of malformations by DPH either in particularly sensitive strains of mice (Massey, 1966) or less sensitive mice by intraperitoneal application with high dosage (Gibson and Becker, 1968; Elshove, 1969; Harbison and Becker, 1969, 1970). Earlier experiments with nontoxic levels and subcutaneous application of DPH did not produce malformations (Sinclair and Abreu, 1965). Staples (1972), in his review, has subjected the experimental teratology of antiepileptic drugs to a sharp critique. He concluded that experiments which closely approximate human conditions as far as the level of drug and type of application are concerned have not yet been made. In addition, other species should be studied, as it is known that 23 substances do induce cleft palate in mice. The suspicion that malformations are produced by intoxication has been supported by reports that gravid rats had higher serum
TERATOGENIC RISK OF ANTIEPILEPTIC DRUGS concentrations and toxic syndromes than nongravid rats with identical drug intake (Gabler, 1968;Westmoreland and Bass, 1971). For human beings this could not be shown. There is a lack, however, of systematic investigations of serum concentration in pregnant women. Meadow (1968, 1970) has pointed out that the known teratogenic drugs aminopterin and methotrexate are folic acid antagonists, just as are hydantoins and barbiturates. He suggested that malformations could be related to drug-induced lack of folic acid. Thii assumption was supported by the finding that animals not susceptible to DPH-iinduced anomalies, such as the rat, do not have a reduced folic acid level either (Kemis et al., 1973). The simultaneous application of folic acid and DPH did not reduce the frequency of cleft palate in mice. Thii could be done, however, by leucovorin (Marsh and Frazer, 1973). The authors suggest that DPH does not reduce the level of folic acid, but that it disturbs the conversion of folic acid to metabolically more active derivatives. According to these studies, it is not the lack of folic acid but rather the disturbed folic acid metabolism that has to be considered with human embryopathies (Hibbard and Smithells, 1965; Davis, 1973). As cleft palates are also produced by cortisone and the combination with cyanocobalamin does reduce its frequency, recent experiments have investigated the question of whether it is sensible to give vitamin B12 prophylactically during pregnancy if DPH has been taken (Mann and Gautieri, 1973).
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teratogenic way, the effect is weak. The frequency and the type of risk do not justify discouraging a woman who needs antiepileptic medication from having a chdd. It is reason enough, however, for extensive counseling with the aim of reducing all possible risk factors for malformations. What steps can be taken before pregnancy begins? A family history of malformations should be regarded as a contraindication. A pregnancy should not be encouraged if one or more of the following factors do exist: age over 35 years, diabetes mellitus of the mother, former miscarriage, or stillborn children. To keep the risk at the lowest, all combinations of antiepileptic drugs should be avoided insofar as possible, trying to limit therapy to as few substances as possible. Even the frequently prescribed combination of hydantoins and barbiturates, instead of just one of these drugs, could mean an addition or even multiplication of teratogenic influences. What can be done if a woman has become pregnant? Regular serum concentration controls with adjustment of dosage downward are recommended. In the critical twentieth to fortieth days of pregnancy, a reduction of any teratogenic factors is valuable. An additional prescription of vitamin B I 2 or folic acid has not been justified up to now, neither by clinical experience nor by experiments. Just the chance that folic acid could increase the frequency of seizures, or has been given while the woman is not yet pregnant and could increase fertility (Davis, 1973), does not sound very attractive. ACKNOWLEDGMENT
RECOMMENDATIONS What are the consequences that follow these diverse studies and findings which have been presented here? The risk of having a child with congenital abnormalities is 2 to 3 times higher for a mother who took antiepileptic drugs during pregnancy compared with a nonepileptic mother. The increased risk seems to be related in part to the epilepsy itself. Among the malformations, cleft lesions and congenital heart lesions seem to be predominant. If there is a causal relationship between antiepileptic drugs and congenital abnormalities, it is stiil an open issue. If antiepileptic drugs do act in a
This work was supported by the Stiftung Volkswagenwerk. REFERENCES Ayraud N, Kermarec J, and Martinon J. Effects cytogenetiques des.medicaments anticonvulsivants. Ann Genet 11:253-257,1968. Baughman FA and Randinitis EJ. Passage of diphenylhydantoin across the placenta. JAMA 213:466,1970. Bjerkedal T and Bahna L. The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 52~245-248.1973.
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BrGgger A. Anticonvulsant drugs and chromosomes. Lancet 2:1296,1970. Caratzali A and Roman IC. Action stathmocinetique de quelques derives barbituriques sur le lymphocyte humain en culture. CR Acad Sci (Paris) 268:191-192, 1969. Caratzali A and Roman IC. Action de la dipenyl-hydantoine sur .les chromosomes. CR Acad Sci (Paris) 272:663-664,1971. Davis RE. Congenital malformations and anticonvulsant drugs. Lancet 1:492-493, 1973. Drillien CM,Ingram TTS, and Wilkinson EM. The Causes and Natural History of Cleft Lip and Palate. Livingstone, Edinburgh and London, 1966. Dronamraju KR. Epilepsy and cleft lip and palate. Lancet 2:876-877,1970. Elshove J. Cleft palate in the offspring of female mice treated with -~ phenytoin. Lancet 2:1074,1969. Elshove J and Van Eck JHM. Aangeboren misvormingen, met name gespleten iip-met of zonder gespleten verhemelte, bij kinderen van moeders met epilepsie. Ned Tijdschr Geneesk 115 :1371-1375,1971. Fogh-Anderson C. In: JJ Longacre (Ed.), Craniofaciul Anomalies; Pathogenesis and Repair. Lippincott, Philadelphia, 1968. Fraser WI and MacGillivray RC. Anticonvulsant drugs and congenital abnormalities. Lancet 156,1969. Gabler WL. The effect of 5.5 diphenylhydantoin on the rat uterus and its fetuses. Arch Int Pharrnacodyn 175:141-152,1968. German I, Ehlers KH, Kowal A, De George FV, Engle MA, and Passarge E. Possible teratogenicity of Trimethadione and Paramethadione. Lancet 2:261-262,1970~. German I, Kowal A, and Ehlers KH. Trimethadione and human teratogenesis. Teratology 3:349-361,1970b. Gibson IE and Becker BA. Teratogenic effects of diphenylhydantoin in Swiss Webster and A/I mice. Proc Soc Exp Biol 128:905-909, 1968. Grosse K-P, Schwanitz G, Rott H-D, and Wissmueller HF. Chromosomenuntersuchungen bei Behandlung mit Anticonvulsiva. Humangenetik 16:209-216,1972. Harbison RD and Becker BA. Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice. Temtology 2:305-312,1969. Harbison RD and Becker BA. Effect of phenobarbital and SKF525A pretreatment on diphenylhydantoin teratogenicity in mice. J Pharmacol Exp Ther 175:283-288, 1970. Hibbard ED and Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1:1254,1965. Hill RM, Horning MG, and Horning EC. Antiepileptic drugs and fetal well-being.
Presented a t International Symposium o n Fetal Pharmacology, Stockholm, Sweden, December 1971. In: LO Boreus (Ed.), International Symposium on Fetal Pharmacology. Raven Press, New York, 1973, pp. 375-380. Janz D and Fuchs U. Sind antiepileptische Medikamente wahrend der Schwangerschaft schadlich? Dtsch M Wochenschr 89:241-243,1964~. Janz D and Fuchs U. Are antiepileptic drugs harmful when given during pregnancy? Ger Med Mon 9:20-23,1964b. Kernis MM, Pashayan HM, and Pruzansky S. Dilantin-induced teratogenicity and folic acid deficiency. Teratol SOCAnn Meet 1973. Teratology 7,1973. Koppe IG, Bosman W, Oppers VM, Spaans F, and Klosterman GI. Epilepsie en aangeboren Ned Tijdschr Geneesk afwijkingen. 117:220-224,1973. Kuenssberg EV and Knox JDE. Teratogenic effect of anticonvulsants. Lancet 1:198, 1973. Loughnan PM, Gold H, and Vance JC. Phenytoin teratogenicity in man. Lancet 1:70-72,1973. Lowe CR. Congenital malformations among infants born to epileptic women. Lancet 1:9-10,1973. Mann DE and Gautieri RF. Cyanocobalamin and anticonvulsant-associated congenital defects. Lancet 1:1451-1452,1973. Maroni E and Markoff R. Epilepsie und Sc h w a n g e r s c h a f t . G y naecologia 168:418-421,1969. Marsh L and Fraser FC. Studies on Dilantininduced cleft palate in mice. Teratol SOC Ann Meet 1973.Teratology 7,1973. Massey KM. Teratogenic effects of diphenylhydantoin sodium. J Oral Ther Pharmacol 2:380-385,1966. Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet 2:1296,1968. Meadow SR. Congenital abnormalities and anticonvulsant drugs. Proc R Soc Med 63:48-49,1970. Melchior IC, Svensmark 0, and'Trolle D. Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet 2:860-861,1967. Meyer J. The teratological effects of anticonvulsank and the effects on pregnancy and birth. Eur Neurol10:179-190,1973. Mirkin BL. Diphenylhydantoin : placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects. J Pediatr 78:329-337,1971a. Mirkin BL. Placental transfer and neonatal elimination of diphenylhydantoin. A m J Obstet GynecollO9:930-933,1971b. Monson RR, Rosenberg L, Hartz SC, Shapiro S, Heinonen OP, and Slone D. Diphenylhydantoin and selected congenital malformations.
TERATOGENIC RISK OF ANTIEPILEPTIC DRUGS N Engl JMed 1049-1052,.1973. Mountain KR, Hirsch I, and Gallus AS. Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1:265-268,1970. Muniz EH. Schneider R. and Nusyowitz M. Clwom&omal effects of diphenylhydantoin. Clin Res 17:28,1969. Nelson MM and Forfar 10. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Brit Med J1:523-527,1971. Ross LM. Diphenylhydantoin (DPH) induced cleft palate. Teratol SOC Meet 1973. Teratology 7,1973. Sinclair JG and Abreu BE. Transplacental effect of drugs in mice. Tex Rep Biol Med 23~849-853,1965. Speidel BD and Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2:839-843,1972. South J. Teratogenic effect of anticonvulsants. Lancet 2:1154,1972. Staples RE. Teratology. In: DM Woodbury, JK Penry, and RP Schmidt (Eds.), Antiepileptic Drugs. Raven Press, New York, 1972, pp. 55-62. Starreveld-Zimmerman AAE, van der Kolk WJ, Elshove J, and Meinardi H. Teratogenicity of ~~
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antiepileptic drugs. Clin Neurol Neurosurg (Netherlands) 1975 (in press). Starreveld-Zimmerman AAE, van der Kolk WJ, and Meinardi H. Are anticonvulsants teratogenic? Lancet 2:48,1973. Stevenson AC, Johnston HA, Stewart ME', and Golding DR. Congenital malformations. A report of a study of series of consecutive births in 24 centres. Bull WHO 34, suppl. 9, 1966,127 pp. Watson ID and Spellacy WN. Neonatal effects of maternal treatment with anticonvulsant drug diphenylhydantoin. Obstet Gynecol 71:881-885,1971. Westmoreland B and Bass NH. Diphenylhydantoin intoxication during pregnancy. Arch Neurol 24:158-164,1971. Wheatly D. Drugs in pregnancy survey. Practitioner 191:775-780,1963. N.B.: This paper was presented at the Symposium on Antiepileptic Drugs, session on Iatrogenic Aspects of Antiepileptic Drugs: Toxicity, held at the XII International Congress of Epilepsy, organized by the International League Against Epilepsy, X International. Congress of Neurology, Barcelona, September 8 and 9,1973.
Raven Press, New York
The Teratogenic Risk of Antiepileptic Drugs Dieter Janz Freie Universitat Berlin, Abteilung fur Neurologie, Klinikum Charlottenburg, Berlin, Germany
INTRODUCTION Nearly all studies on the topic of teratogenic risks of antiepileptic drugs have concluded that congenital anomalies occur more frequently among children from mothers with epilepsy who took antiepileptic drugs during pregnancy than among children from motkrs- free of epilepsy or children from epileptic mothers who did not take any antiepileptic drugs during pregnancy. Among the malformations, cleft lip (with or without cleft palate) and congenital heart lesions are particularly noted. It has been suggested that these malformations are induced by antiepileptic drugs, since teratogenic effects have been induced in experiments on animalsunder rather artificial conditions, however, as the antiepileptic drugs pass through the placenta. Diphenylhydantoin (DPH) has been suspected to be especially teratogenic, since cleft lip and cleft palate have been induced-in certain strains of mice and under extreme conditions, however-by DPH ingestion. This suspicion is a grave one. A lot is at stake. Should these drugs, which have helped uncounted numbers of people, be held responsible for these damaging effects? The problem concerns approximately 0.3 to 0.5% of all pregnancies. Of all pregnancies studied in Saint Thomas Hospital, London, 0.28% were those of epileptic mothers (South, 1972). In Norway, the number was 0.28% (Bjerkedal and Bahna, 1973); in Cardiff, 0.42% were recorded (Speidel and Meadow, 1972); and 0.54% were affected in Groningen (Elshove and Van Eck, 1971). It is, therefore, urgent to know if there is an increased risk for malformations, what its measure is, and what Key words: Teratogenicity drugs
- Antiepileptic
other explanation can be sought. It is entirely possible that other risk factors, directly or indirectly associated with the epilepsy of the pregnant woman, such as seizure-related anoxemic or traumatic lesions of the fetus in utero, or genetic or environmental factors, could be responsible for the increased risk of malformations. FREQUENCY OF MALFORMATIONS IN CHILDREN FROM EPILEPTIC MOTHERS What are the statistical data that lead to the assumption that antiepileptic drugs are teratogenic? Table 1 shows all studies, which until recently have been only of the retrospective type, that included different control groups for comparison. In a number of studies, epileptic mothers who did not take any drugs during pregnancy served as a control group (Janz and Fuchs, 1964a,b; Maroni and Markoff, 1969; Speidel and Meadow, 1972; South, 1972; Lowe, 1973; Meyer, 1973; Starreveld-Zimmerman et al., 1973). In a second group of studies, the frequency of malformations in children of nonepileptic mothers served as, obviously, much larger control groups. This was done either by selecting the mother whose case sheet number was nearest to that of the epileptic mother (Watson and Spellacy, 1971; Speidel and Meadow, 1972) or by collecting all hospital births during a certain time (Elshove and Van Eck, 1971; South, 1972; Monson et al., 1973). In still other studies, all births reported by general practitioners (Kuenssberg and Knox, 1973) or all births in a geographically defined population (Lowe, 1973) served as control groups. Even though the term “malformation” has
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160
TABLE 1. Frequency o f malformations in children from mothers with epilepsy treated during pregnancy uersus untreated and versus malformations in children from mothers without epilepsy Live births of treated mothers with epilepsy Malf ormaReference Total tions Janz and Fuchs (1964a,b) 225 4 Maroni and Markoff (1969) 21 1 Elshove and Van Eck (1971) 65 10 3 Watson and Spellacy (1971) 51 Speidel and Meadow (1972) 324 16 South (1972) 22 2 Lowe (1973) 134 8 Kuenssberg and &ox (1973) 48 3 Monson et al. (1973) 93 4 Starreveld-Zimmerman et al. (1973) 279 20 Meyer (1973) 199 - 17 Total
1,461
88 = 6.0%
not been defined exactly and the studies varied as to methodological aspects and geographically came from different regions, their results show a common trend: mothers with epilepsy who took antiepileptic drugs during pregnancy have more frequent malformations in their offspring than epileptic mothers who were not treated. It is noteworthy that the latters’ risk of having a child with malformation is still higher than in the general population. The results, taken from the literature, confirm each other, as can be shown by comparison to two comprehensive studies (see Table 2). Bjerkedal and Bahna (1973) have recently shown in their study of all births in Norway during 1967 and 1968 that malformations are significantly more frequent in children of epileptic mothers compared to the nonepileptic population. The percentage in epilep-
Live births of untreated mothers with epilepsy MalformaTotal tions 120 0 14 0
Live births of mothers without epilepsy MalformaTotal tions
-
-
-
-
59 9 111
0 0 3
11,986 50 442 7,865 31,622
-
-
14,620 417 50,591 1,240
-
18 124
2 14
455
19 = 4.2%
117,176
221 0 7 190 865
2,940 = 2.5%
tic mothers was 4.576, or twice that of the control group, with 2.2%. These data resemble those taken from the literature, with 5.6% in epileptic mothers (treated and untreated) as compared with 2.5% in nonepileptic mothers. Unfortunately, the Norwegian study does not distinguish between epileptic mothers with treatment from those without treatment during pregnancy. This point has been considered by an American cohort-study of 50,897 pregnancies, collected from 12 hospitals with the objective of determining whether the frequency of selected malformations is higher in infants exposed to DPH in ufero and, in addition, which other variables are associated with these malformations (Monson et al., 1973). The Norwegian and American studies produced nearly the same percentage and the same tendency: malformations are twice as frequent
TABLE 2. Frequency o f malformations in children o f mothers with epilepsy versus those without epilepsy
Reference
Live births of mothers with epilepsy Malformations Total No. Percent
Literature review Bjerkedal and Bahna (1974)
1,916 378
107 ?
5.6 4.5
Live births of mothers without epilepsy Malformations No. Percent Total 117,176 113,511
2,940 ?
2.5 2.2
TERATOGEMC RISK OF ANTIEPILEPTIC DRUGS in infants of epileptic mothers as compared with the control groups. In addition, the American study shows that the rate in infants exposed to daily DPH in the first 4 months of pregnancy is, with 61 per 1,000, significantly higher than the corresponding rate of 25 per 1,000 in infants born to women who had no convulsive disorders @ < 0.05). Although the rates are also higher in all other categories of treatment, none differed significantly from the 25 per 1,000. This proves that malformations of children born to women with convulsive disorders are more frequent than in children born to nonepileptic mothers. Several studies (except that by Koppe et al., 1973) did show, however, that the rate of malformations in children born to treated and untreated mothers with convulsive disorders is not significantly different. This means that the conclusion of there being a causal relationship between antiepileptic treatment and the malformation rate has no statistical support. On the other hand, the published data do not allow one to exclude the existence of such a relationship. Meyer (1973) has calculated that for positive exclusion of the existence of such a relationship-provided there is a relatively similar incidence--1,800 pregnancies are needed instead of the published 600. TYPE AND/OR COMBINATION OF MALFORMATIONS An increased rate of malformations may be caused by various factors, such as the mother’s older age at pregnancy, unfavorable genetic background, or environmental factors. From a teratological standpoint, however, it is especially interesting as to whether particular malformations or a characteristic combination of malformations are seen with antiepileptic medication in general or even with certain antiepileptic drugs. Table 3 shows the different types of malformations according to their frequency. As can be seen, oro-facial clefts and congenital heart lesions predominate. Skeletal anomalies, such as club-foot, congenital hip, and distal pharyngeal hypoplasias, are less frequent. Finally, microcephaly, hypospadias, intestinal and anal abnormalities, anencephaly, and neural tube anomalies, such as meningomyelocele and
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spina bifida and, rarely, a case of primary hydrocephalus, do occur. A review of the literature shows that the specific rates for oro-facial clefts and for congenital heart lesions are increased in infants born to women with convulsive disorders. The average frequency of 1.8% for oro-facial clefts is about 6 to 1 2 times higher than the results published for nonepileptic controls, with 0.14% in Birmingham (Speidel and Meadow, 1972), 0.16% in Cardiff (Lowe, 1973), 0.2% in London (South, 1972), and 0.27% in Groningen (Elshove and Van Eck, 1971). Congenital heart lesions seem to be more frequent in infants born to women who took antiepileptic drugs, with a rate of 1.5% as compared to, however, quite heterogeneous controls from Birmingham with a rate of 0.42% (Speidel and Meadow, 1972). Cleft Lip and Cleft Palate According to the data published by Stevenson et al. (1966) in a WHO report, cleft lip-with or without cleft palate-ccurs in 7.7% of all cases with congenital anomalies. The ratio in the reviewed literature (31 of 98 cases = 32%) again confirms that there is a definite preponderance of this type of malformation over the other congenital anomalies in the offspring of mothers treated with antiepileptic drugs. In the study of Elshove and Van Eck (1971), “hare lip” (with and without cleft palate) comprised 13.9% of the abnormalities in a series of 12,014 general deliveries, but 50% of the total abnormalities in the epileptic series of 65 deliveries. The concept of a teratogenic drug effect is supported by experiments, which suggest a specific teratogenic effect of DPH. In the offspring of female mice given DPH, oro-facial cleft was more frequent compared with the spontaneous rate. This was shown, however, under extreme experimental conditions in particularly sensitive strains (Massey, 1966; Gibson and Becker, 1968; Harbison and Becker, 1969, 1970; Elshove, 1969; Kemis et al., 1973; Marsh and Fraser, 1973; ROSS,1973). There are some facts, however, that would not favor the concept that oro-facial clefts are induced by antiepileptic drugs, especially by DPH intake. First, oro-facial clefts do occur in families quite often and are said to be
5 0.3
5 0.3
2 0.1
5 0.3
5 0.5
18 1.0
5 0.3
1
1
2
10 0.6
2
3
2
1
1
of malformations occur'.the total numbers of cases can be lower than the sum of the different malformations stated.
26 1.5
1 7
1
5
1
1
1
1
O A s combinations
31 1.8
1 1
1
1
2
1
3
1
1,726
7 5
1
5.
8
279 199
1
1
1
93
1 1
1
1
1
1
1 1
1
1
48 17 20
1
2
1
1
Anen- Microcephaly cephaly
1
5
2
3
Heart lesions
324 22 134
51
16
65
21
32
180
225
Orofacial clefts
Total Percentage
Janz and Fuchs ( 19640,b) German League (published by Janz and Fuchs) Melchior et al. (1967) Maroni and Markoff (1969) Elshove and Van Eck (1971) Mountain et al. (1970) Watson and Spellacy (1 971 ) Speidel and Meadow (1972) South (1972) Lowe (1973) Kuenssberg and Knox (1973) Michaelis (1973) Hill et al. (1973) Monson et al. (1973) StarreveldZimmerman et al. (1973) Meyer (1973)
Reference
No.of Pregnancies
Intestinal atresia Neural (includHydro- tube Hypo- Skeletal ing fisMiscephaly anomaly spadia anomalies tula) cellanea
Malformations
101 5.8
20 17
4
3 2 5
16 2 8
3
0
10
1
2
3
5
No. of cases with malformationsa
TABLE 3. Frequency of different malformations in children of mothers with antiepileptic treatment during pregnancy
TERATOGENIC RISK OF ANTIEPILEPTIC DRUGS associated with epilepsy, which would explain their high incidence in infants born to epileptih mothers. Dronamraju (1970) reports that 295 of his patients with oro-facial clefts have 42 first- or second-degree relatives with epilepsy. One has to consider, however, that infants born to untreated epileptic mothers do not have an increased rate of oro-facial clefts and congenital heart lesions. As for the familial occurrence, Meadow (1970) reports that 7 of the 32 children of his collection with cleft lip and/or cleft palate who have been born to treated mothers had “similarly affected siblings.” According to Fogh-Anderson (1968), there is a positive family history in just more than one-third of all cases. Starreveld-Zimmermanet al. (1975) showed that in 3 of his 9 families who had hare-lip infants after the mothers’ antiepileptic treatment, cases of hare lip again occurred. In order to draw conclusions from the animal experiments for human conditions, the congenital abnormalities should be related to a certain drug and be dose-dependent. Among 35 cases with oro-facial clefts, whose drug treatment during pregnancy is known, five cases had taken only barbiturates. Phenobarbital, however, does not produce oro-facial clefts, nor does it produce any other congenital abnormalities in animal experiments (Staples, 1972). In 6 other cases, barbiturates and other antiepileptic drugs-but again no DPH-were given. Taken together, DPH played no role in 11 of a total of 35 cases; this does not support the concept of a DPH-specificteratogenic effect in producing oro-facial clefts, which, by the way, had been based on questionable experimental evidence. As to the relation of the dose of drug intake during pregnancy to the occurrence of congenital abnormalities, Monson et al. (1973) wrote: “There was no evidence to suggest that malformations were more common in those taking higher doses.” Only Loughnan et al. (1973) pointed out that in 1case of congenital abnormalities, of not closer specified character, the mother had “at the fourteenth week’s gestation” an increased plasma level of DPH. Congenital Heart Lesions There is no experimental evidence for the increased rate of congenital heart lesions in
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infants born to epileptic mothers. The type of heart lesions is not known in 4 cases. As for the rest of 1 5 cases, 9 had septal defects (6 cases of ventricular-septal, 2 atrio-septal, and 1ventricular-atrio-septal); there were also 4 cases of Fallot’s tetratology, 1 aortic stenose, and 1 pulmonary atresia. The last-mentioned case and 1 case of ventricularatrio-septal defect in addition had a patent ductus arteriosus. A coarctation of the aorta appeared in combination with a ventricular and atrio-septal defect. Meadow (1970) considered a higher than randomly expected frequent combination of oro-facial clefts and congenital heart lesions after answers to his letter in Lancet revealed that among 32 cases of oro-facial clefts, 8 had combinations with congenital heart lesions. A review of the literature, however, shows that among 28 cases of oro-facial cleft only 1 case had a ventricular-septal defect (Speidel and Meadow, 1972). This does not exceed the statistically expected frequency of 3 to 5% for that combination (Drillien et al., 1966). Although it has never been claimed, it seems noteworthy that no certain drug is related to the occurrence of congenital heart lesions. Malformation Syndromes Meadow (1970) considered the possible association between anticonvulsive treatment during pregnancy and a syndrome of abnormalities involving lips and palate and the cardio-vascular and skeletal systems. Later, Speidel and Meadow (1972) described this syndrome that “in its full expression takes the form of congenital heart disease, cleft lip and palate, trigonocephaly or microcephaly and various minor anomalies which include hypertelorism, low-set abnormal ears, short neck with low posterior hair line, bilateral single transverse palmar creases, and minor skeletal abnormalities.” F’raser and MacGillivray (1969) suggested that this pattern was identical with the Wddervanck syndrome, which they postulate to be produced by chromosomal damage. Loughnan et al. (1973) described a different syndrome of skeletal anomalies in 7 children of mothers who took DPH and phenobarbital during pregnancy: “The basic abnormality was a variable degree of hypopIasia and irregular ossification of the distal phalanges, producing
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short narrow and misshaped ends to both the fingers and toes.” Hill et al. (1973) observed “a characteristic clustering of malformations,” which was similar to the pattern described by Speidel and Meadow (1972) as well as to that described by Loughnan et al. (1973). The 3 infants reported by Hill et al. (1973) had been born to one mother who received phenobarbital, DPH, and primidone during the pregnancies. They showed “a low hairline, separation of the metopic suture, broad nasal ridge, wide set eyes, as well as hypoplasia of the distal phalanx of the hands and feet and temporarily hypoplastic nails.” The relevance of these observations is quite unclear and will probably not be resolved before a prospective study is performed which systematically records causes for the increased risk of malformations. According to all studies which give a measure for the risk of malformation, the probability is 2 to 3 times higher for women with antiepileptic treatment during pregnancy compared with women with no history of epilepsy at all (Speidel and Meadow, 1972; Lowe, 1973; Monson et al., 1973). A review of the literature seems to show that the increased risk is due mainly to the increased rate of clefts and heart lesions (see Table 3).
Seizures One could ask whether a single seizure or several seizures might possibly impose considerable hazards to the health of the unborn child as well as to that of the mother. Janz and Fuchs (1964a,b) did not find any evidence for the possibility that seizures produce either anoxemic or traumatically induced complications of pregnancy or damage to the fetus. According to the literature, they pointed out that healthy infants were born even to mothers who suffered from a malignant course of epilepsy and status epilepticus. Similar reports came from Maroni and Markoff (1969). Meadow (1970), however, mentions that about a quarter of the mothers of 32 children with lip and/or palate cleft had had a fit during the first 3 months of their pregnancies. According to Starreveld-Zimmerman et al. (1975), tonicclonic seizures of the mother seemed to occur appreciably more often in the cases of malformed babies compared with normal ones. Genetics
A genetical association between epilepsy and malformation has been mentioned in the section dealing with clefts. Elshove (1969) found a familial occurrence of congenital RISK FACTORS anomalies in 4 cases among 10 women with As long as a statistically significant differ- epilepsy who gave birth to children with ence in the risk of malformation for epileptic congenital abnormalities. Starreveld-Zimmerwomen compared to those without antiepilep- man et al. (1975) reported that 6 of 18 mothers tic treatment during pregnancy has not been had relatives with congenital abnormalities. proved, the described difference cannot be attributed unequivocally and solely to the Environment teratogenic effects of antiepileptic drugs. It is, therefore, necessary to define as exactly as Among the socioeconomic factors, such as possible the conditions not related to drug their relatively low social status as shown by intake as part of the risk of malformation. Monson et al. (1973), the generally limited According to Monson et al. (1973), women choice of partners for patients with epilepsy with epilepsy “tended to have characteristics should be mentioned. This is, according to associated with an increased risk of malforma- Speidel and Meadow (1972), one of the reasons tions-for example, they tended to be older, why children born to epileptic parents have a were of a lower social class, gave birth more relatively bad genetic background. Among the frequently to stillborn children, and more often social factors, old age at pregnancy also plays had hydramnios.” Thus it is possible that these an important role. Thus, there are quite a few and not factors can partly or wholly explain the association between DPH and congenital unimportant factors which could explain the increased risk for malformation in the offspring malformations.
TERATOGENIC RISK OF AIWIEPILEPTIC DRUGS TABLE 4. Drug regimen in pregnancy followed by birth o f children with selected malformations
Drug regimen
Cleft lip and/or palate
Heart lesion
29,alone in 5 21,alone in 6 Barbiturates H y dantoins 22,alone i.n 4 14,alone in 1 Diones 7, alone in 2 6,alone in 2 Carbamazepine 1,alone in 1 Ethosuximide 2, alone Benzodia1,alone 1,alone zepines
of epileptic women, apart from the antiepileptic drug treatment. Antiepileptic Drugs According to the literature, there seems to exist no antiepileptic drug of which the intake during pregnancy has not been followed by the birth of a child with congenital abnormalities. This is true not only for barbiturates and hydantoins but also for oxazolidines (German et al., 197Oa,b; Speidel and Meadow, 1972), succinimides (Lowe, 1973; Starreveld-Zimmerman et al., 1973; Meyer, 1973), benzodiazepines (Speidel and Meadow, 1972), acetylurea (Speidel and Meadow, 1972), and carbamazepine (Michaelis,personal communication; Meyer, 1973). In most cases, however, a combination of drugs was prescribed, so that a causal relationship to a certain drug is hard to establish. To trace a certain type of malformation to a certain drug is even harder, because the numbers are too small. Drug regimen in pregnancy which has been followed by births of children with cleft lesions and congenital heart lesions probably only reflects the general use of antiepileptic drugs (Table 4). This survey, however, allows us to recognize that a special relationship between the type of drug and the type of malformation most likely does not exist. Based on animal experiments, DPH is said to have a teratogenic effect. From a practical point of view, rarely does a treatment consist of DPH alone. Of 36 pregnant women treated with hydantoin alone, just 5 took DPH only (see Table 4). Even less recognizable is the
165
evidence of a relationship between drug intake and type and frequency of malformations as should be expected, based on experiments on animals. As far as the amount of dosage has been given, the reported malformations did occur at a large drug intake, too, which has been pointed out by Speidel and Meadow (1972) especially. As there is no constant ratio between doses of intake and serum concentration, it is absolutely necessary to determine serum concentrations during pregnancy in order to investigate the question of a causal relationship. Studies using serum concentration of DPH during pregnancy and at the time of birth with data on child and mother are few (Baughman and Randinitis, 1970; Mirkin, 1971a,b; Loughnan et al., 1973). According to Mirkin (1971a,b), mother and child have identical serum concentrations at birth. Westmoreland and Bass (1971) reported that gravid rats are more susceptible to DPH toxicity than nongravid ones. A correlation between human maternal plasma levels of anticonvulsant drugs and outcome of their pregnancies may clarify the sporadic occurrence of anomalies in the infants. Phenobarbital was suspected to be a teratogenic drug as early as 1963 by Wheatly (1963), after 4 of 61 children, whose mothers were treated with phenobarbital because of threatened abortions, showed congenital anomalies. Nelson and Forfar (1971) found a significant association between barbiturate intake and congenital anomalies, comparing drug intake during pregnancy with the rate of malformation. According to the survey given in Table 4, there seems to be no difference between barbiturates and hydantoins-given in combination or alone-d the occurrence of selected malformations. Whether oxazolidines do have teratogenic effects is an open issue after the impressive examples of German et al. (1970u,b). Of.the 13 cases recorded in the literature, 4 remarkably did have only oxazolidine intake alone. Succinimide (Starreveld-Zimmerman et al., 1973; Lowe, 1973; Meyer, 1973), benzodiazepine (Speidel and Meadow, 1972), acetylurea (Speidel and Meadow, 1972) and carbamazepine (Meyer, 1973; Michaelis, personal communication) are represented in cases taken from the literature and our own cases.
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MECHANISM OF TERATOGENIC EFFECTS evidence for mutagenic effects. The result of this study, however, does support his opinion Malformation could be produced by muta- that investigators of possible teratogenic effects genic and teratogenic effects. of antiepileptic drugs should always be aware of mutagenic effects, as those drugs have been taken in most cases long before pregnancy Mutagenic Effects occurred. Quite contradictory reports about the effect of antiepileptic drugs on human chromosomes have been published. Muniz et al. (1969)and BrGgger (1970) found no significant chromosomal breaks in uitro in the therapeutic range of DPH (Muniz et al., 1969) and ethotoin (BrGgger, 1970). In the toxic range, however, significantly frequent chromosomal breaks occurred (Muniz et al., 1969). As far as in uitro studies are concerned, no structural anomalies were reported in the chromosomes of white blood cells of 7 patients treated with DPH at a therapeutic level. BrGgger (1970), however, reported that one boy being treated with ethotoin showed too many chromosomes and chromatid breaks and gaps. Ayraud et al. (1968) showed chromosomal breaks in a girl and her mother who was treated with antiepileptic drugs during pregnancy. Other studies (Caratzali and Roman, 1969, 1971) showed an inhibiting effect of several antiepileptic drugs on the mitosis in uitro. The most comprehensive study was done by Grosse et al. (1972). Their results showed that the rate of structural chromosomal abnormalities of 32 mothers with epilepsy and their children with an age from birth to 3 years, who were exposed to antiepileptic drugs in utero, was significantly more frequent @ < 0.001) than in untreated healthy controls. There was a significant correlation between the values of the mothers and their children. The rate of abortions, stillbirths, and malformations was not given, however. In order to distinguish between mutagenic and primary genetic anomalies, Meyer (1973) has compared the children of treated epileptic fathers with those of untreated epileptic fathers. Among 157 children of treated fathers, he found 27 anomalies. In the 107 children of untreated fathers, only 3 anomalies occurred. He could not exclude a nonrandom distribution of other variables within the two groups; thus he does not consider the significantly more frequent Occurrence of anomalies stringent
Teratogenic Effects by Mechanical Destruction
It should not be omitted that an increased risk of malformation for children born to epileptic mothers is already inherent in seizure-related falls, which can be traumatically destructive to the fetus. It is conceivable that direct and indirect (by way of bleeding) trauma does occur. If the reports about neonatal coagulation defects are confirmed, fetal bleeding due to coagulation defects also has to be considered (Mountain et al., 1970). Teratogenic Effects by Metabolic Damage That fits during early pregnancy could damage the fetus by oxygen shortage is a considered possibility which has not been proved. Two means of drug-induced metabolic damage must be considered: a direct dose-related toxicity and a drug-induced effect on essential enzymes. The assumption of dose-related fetal damage is based on experimental production of malformations by DPH either in particularly sensitive strains of mice (Massey, 1966) or less sensitive mice by intraperitoneal application with high dosage (Gibson and Becker, 1968; Elshove, 1969; Harbison and Becker, 1969, 1970). Earlier experiments with nontoxic levels and subcutaneous application of DPH did not produce malformations (Sinclair and Abreu, 1965). Staples (1972), in his review, has subjected the experimental teratology of antiepileptic drugs to a sharp critique. He concluded that experiments which closely approximate human conditions as far as the level of drug and type of application are concerned have not yet been made. In addition, other species should be studied, as it is known that 23 substances do induce cleft palate in mice. The suspicion that malformations are produced by intoxication has been supported by reports that gravid rats had higher serum
TERATOGENIC RISK OF ANTIEPILEPTIC DRUGS concentrations and toxic syndromes than nongravid rats with identical drug intake (Gabler, 1968;Westmoreland and Bass, 1971). For human beings this could not be shown. There is a lack, however, of systematic investigations of serum concentration in pregnant women. Meadow (1968, 1970) has pointed out that the known teratogenic drugs aminopterin and methotrexate are folic acid antagonists, just as are hydantoins and barbiturates. He suggested that malformations could be related to drug-induced lack of folic acid. Thii assumption was supported by the finding that animals not susceptible to DPH-iinduced anomalies, such as the rat, do not have a reduced folic acid level either (Kemis et al., 1973). The simultaneous application of folic acid and DPH did not reduce the frequency of cleft palate in mice. Thii could be done, however, by leucovorin (Marsh and Frazer, 1973). The authors suggest that DPH does not reduce the level of folic acid, but that it disturbs the conversion of folic acid to metabolically more active derivatives. According to these studies, it is not the lack of folic acid but rather the disturbed folic acid metabolism that has to be considered with human embryopathies (Hibbard and Smithells, 1965; Davis, 1973). As cleft palates are also produced by cortisone and the combination with cyanocobalamin does reduce its frequency, recent experiments have investigated the question of whether it is sensible to give vitamin B12 prophylactically during pregnancy if DPH has been taken (Mann and Gautieri, 1973).
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teratogenic way, the effect is weak. The frequency and the type of risk do not justify discouraging a woman who needs antiepileptic medication from having a chdd. It is reason enough, however, for extensive counseling with the aim of reducing all possible risk factors for malformations. What steps can be taken before pregnancy begins? A family history of malformations should be regarded as a contraindication. A pregnancy should not be encouraged if one or more of the following factors do exist: age over 35 years, diabetes mellitus of the mother, former miscarriage, or stillborn children. To keep the risk at the lowest, all combinations of antiepileptic drugs should be avoided insofar as possible, trying to limit therapy to as few substances as possible. Even the frequently prescribed combination of hydantoins and barbiturates, instead of just one of these drugs, could mean an addition or even multiplication of teratogenic influences. What can be done if a woman has become pregnant? Regular serum concentration controls with adjustment of dosage downward are recommended. In the critical twentieth to fortieth days of pregnancy, a reduction of any teratogenic factors is valuable. An additional prescription of vitamin B I 2 or folic acid has not been justified up to now, neither by clinical experience nor by experiments. Just the chance that folic acid could increase the frequency of seizures, or has been given while the woman is not yet pregnant and could increase fertility (Davis, 1973), does not sound very attractive. ACKNOWLEDGMENT
RECOMMENDATIONS What are the consequences that follow these diverse studies and findings which have been presented here? The risk of having a child with congenital abnormalities is 2 to 3 times higher for a mother who took antiepileptic drugs during pregnancy compared with a nonepileptic mother. The increased risk seems to be related in part to the epilepsy itself. Among the malformations, cleft lesions and congenital heart lesions seem to be predominant. If there is a causal relationship between antiepileptic drugs and congenital abnormalities, it is stiil an open issue. If antiepileptic drugs do act in a
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antiepileptic drugs. Clin Neurol Neurosurg (Netherlands) 1975 (in press). Starreveld-Zimmerman AAE, van der Kolk WJ, and Meinardi H. Are anticonvulsants teratogenic? Lancet 2:48,1973. Stevenson AC, Johnston HA, Stewart ME', and Golding DR. Congenital malformations. A report of a study of series of consecutive births in 24 centres. Bull WHO 34, suppl. 9, 1966,127 pp. Watson ID and Spellacy WN. Neonatal effects of maternal treatment with anticonvulsant drug diphenylhydantoin. Obstet Gynecol 71:881-885,1971. Westmoreland B and Bass NH. Diphenylhydantoin intoxication during pregnancy. Arch Neurol 24:158-164,1971. Wheatly D. Drugs in pregnancy survey. Practitioner 191:775-780,1963. N.B.: This paper was presented at the Symposium on Antiepileptic Drugs, session on Iatrogenic Aspects of Antiepileptic Drugs: Toxicity, held at the XII International Congress of Epilepsy, organized by the International League Against Epilepsy, X International. Congress of Neurology, Barcelona, September 8 and 9,1973.
