TERATOGENICITY OF ANTIEPILEPTIC DRUGS by A. A. E. Starreveld-Zimmerman, I¥. J. van der Kolk, J. Elshove and H. Meinardi*
SUMMARY A Dutch survey of teratology in 372 pregnancies in 153 outpatients of special epilepsy centres is presented. 7,4~ live-born babies suffered from congenital anomalies, abortion rate was 17,7%; the rate of stillbirth 2,4%. The influence of seizures and of five groups of antiepileptic drugs is discussed. The relevant literature is reviewed.
INTRODUCTION During the past ten years anticonvulsant drugs have been receiving increasing attention as potentially teratogenic agents. With few exceptions surveys of the offspring of mothers with epilepsy taking anticonvulsants during pregnancy have demonstrated that congenital malformations occur in a frequency surpassing that of the general population. Particularly cleft lip with or without cleft palate and congenital heart lesions are noted. Many issues are, however, still unclear: the size of the risk to the individual mother with epilepsy, the role of seizures with anoxia during early pregnancy, mutual genetic aspects of epilepsy and certain malformations and to extent the various drugs should be incriminated. To contribute to the general discussion and maybe shed some light on some aspects of the problem we made a survey of the incidence of congenital malformations occurring in children of mothers with epilepsy, treated at the outpatient departments of the Instituut voor Epilepsiebestrijding. These centres are located throughout the Netherlands (Apeldoorn, Arnhem, The Hague, Heemstede, Rotterdam and Utrecht). Thanks to the cooperation of the Dr. Hans Berger Epilepsy Centre we could include data of mothers with epilepsy in the vicinity of Breda. Special attention was given to the type of seizures during the first trimester of pregnancy, the drugs and various combinations used, the type of anomaly and familial occurrence of malformations and of epilepsy.
* Instituut voor Epilepsiebestrijding, Achterweg 5 - Heemstede - The Netherlands. Clin. Neurol. Neurosurg. 1974 - 2
82 TABLE 1
Outcome of 372 pregnancies in 153 women after the onset of epilepsy .-66 spontaneous
-71 abortions (19,1%)
(1,4%) 372 pregnancies
-9 stillbirths (2,4%) 275 normal babies (92,6% of all live births)
•297 live births (including 5 twins) (78,5 %)
I
-9 hare lip 5: cleft palate (3,0% of all live births)
22 babies with congenital lesions (7,4 ~ of all live births
-7 congenital heart lesions (2,4 % of all live births) 6 others (2,0% of all live births)
TABLE 11
Outcome of pregnancies after the onset of epilepsy in 153 women, with and without medication
pregnancies spontaneous abortions therapeutic abortions twin pregnancies live births (including twins) stillbirths (including twins) normal babies malformed babies neonatal deaths (within 1 month) infant deaths (1 month-I year) death after age 1 year
anticonvulsant medication during pregnancy
no anticonvulsant medication during pregnancy
total
352 63 5 4 279 9 259 20 x 4 2 1
20 3 0 1 18 0 16 22 0 0 0
372 66 5 5 297 9 275 22 4 2 1
t In one case imipramine hydrochloride was taken in addition to primidone. In one of these two cases levopromazine and amitryptiline HCI were taken.
83 PATIENTS AND METHODS
During the year elapsing between the 1st of September 1971 and the 1st of September 1972 data were collected by interviewing mothers older than 18 years and younger than 50 years, visiting the outpatient departments. Details concerning antiepileptic medication were completed from the medical charts and where necessary, general practitioners and specialists were asked for additional information. Malformations where doubt existed as to congenital nature, such as ocular ptosis, torticollis, umbilical and inguinal herniation of later date and retardation of unknown cause have not been taken into account, since detailed examination of the children could not be carried out.
RESULTS
Information was collected about 372 pregnancies in 153 women after the onset of epilepsy. The outcome of these pregnancies is given in Table I. Because of the usually deficient data in the cases of stillbirth, these were kept separate and the incidence of congenital anomalies is given in 297 live births (Table I). As regards live births the mean duration of epilepsy of the mother was 14 years when malformed children were born and 13 years for normal children. During only 20 out of these 372 pregnancies no antiepileptic medication had been taken. Table II gives the results of pregnancies with and without medication. Of the 22 children with congenital anomalies 2 were born after pregnancies, during which the mother took no antiepileptic medication; one of these, however, used tranquilizers. Two mothers who had diabetes did not get children with congenital anomalies, and experienced no stillbirth. There were no cases of German measles during the early months of pregnancy (see also Tables III and X). Congenital heart lesions in this survey take the second place to cases with cleft lip with and without cleft palate. Details of the cases of congenital malformations as regards birth order, sex of the child, duration of epilepsy and age of the mother are given in Table IlI. Added were data concerning the familial occurrence of malformations and epilepsy, as supplied by the patients during the interview. The 22 babies with congenital anomalies were born to 18 mothers: one mother had three, two mothers had two children with congenital anomalies. There were 9 cases of stillbirth (24%0) see Table IV. (KENNEDY(t967) remarks a higher incidence of defects in cases of stillbirth, however, as not always a systematic investigation of the foetus is available they are usually omitted from the statistics; the incidence of stillbirths in the general population in the Netherlands is approximately 11%0). The mean age of the mother at childbirth was 26,7 years, at the birth of a normal child 26,5 years, at the birth of a child with a congenital malformation 28,1 years and in 8 cases of stillbirth 30,5 years (in one case the age of the mother was not reported). Of the 153 mothers there were 92 with 169 children who had no complications at all: no abortions no stillbirths and no children with congenital anomalies. 35 Mothers had 57 abortions
84
TABLE
111
Congenitally malformed babies (22) born to mothers (18) after the onset of epilepsy (children of the same mother are identified by resp. ×, o and - - )
.= -~ ,
.=_ ~
~ .= x~
~
~
~6 =
oo
= = "=o
>~,..
._
~
.o
=
~
E~
>,
t-"
~o
~.~
=
.-,-'6
=
e
"~
-&
~
>,
~e
"
~o~
.~-
t~
._~ "O
.r~
1 2 1
5 19 11
20 36 29
1 1 2 5 2 3 1
t6 19 24 4 15 17 24
33 26 30 30 29 28 28
3
21
31
--
1
14
24
--
2 1 3
10 9 18
22 25 32
1
12
26
2
23
34
7 1 2 1 2
0 12 15 5 14
33 23 26 27 26
x
x
o
0 o
Harelip Harelip Harelip
m m m
+ + +
Harelip with cleft palate Harelip with cleft palate Harelip Harelip Harelip Harelip Congenital heart (tetralogy of Fallot) + hypoplasia of nails Congenital heart (atrial septal defect) Congenital heart (ventricular septal defect) Congenital heart Congenital heart Congenital heart (ventricular septal defect) Congenital heart (tetralogy of Fallot) Anal atresia, hypertelorism Down's syndrome Ectopic bladder meningomyelocele Polydactyly Anencephaly
f m m m f f m
+ -----+
m
Harelip Harelip Clubfoot, finger aptasia, consanguinity Harelip
E
+
÷ +
Congenital heart
-F
+ + + + + + +
+
Congenital deafness
+
+
f
+
Congenital deafness
+
+
m m f
----
+
+
--
+
+
+
f
--
--
-]-
m
+
--
+
m m m m f
------
--
+
+ +
Down's syndrome
--
+
+
--
a n d 73 n o r m a l c h i l d r e n . 26 M o t h e r s h a d t h e 9 c a s e s o f s t i l l b i r t h a n d 22 m a l f o r m e d c h i l d r e n , 14 a b o r t i o n s a n d 33 n o r m a l c h i l d r e n . T a b l e V gives t h e o c c u r r e n c e o f t o n i c - c l o n i c s e i z u r e s d u r i n g t h e first t r i m e s t e r o f p r e g n a n c y in all live b i r t h s , c a s e s o f n o r m a l a n d c a s e s o f m a l f o r m e d c h i l d r e n . T o n i c c l o n i c s e i z u r e s s e e m t o o c c u r a p p r e c i a b l y m o r e o f t e n in t h e c a s e o f m a l f o r m e d b a b i e s t h a n w h e n a n o r m a l b a b y is b o r n . T h e r e l a t i v e o c c u r r e n c e o f p s y c h o m o t o r a n d o t h e r s e i z u r e s w i t h o u t a n o x i a s h o w s less d i f f e r e n c e . A n t i e p i l e p t i c m e d i c a t i o n a n d o c c u r r e n c e o f c o n g e n i t a l l e s i o n s a r e s h o w n in T a b l e V I .
85 TABLE IV
Cases of stillbirth birth order
1 1
3 3
duration of epilepsy in years at stillbirth
age of mother in years at stillbirth
details if known
19
22
17 15 6
29 32 22 25 30 44 37 25
early separation of placenta strangulation by umbilical cord two months early, placental degeneration immature birth between 16th and 20th gestational week unknown unknown unknown immature birth at 20th week of gestation following CO-intoxication of mother
1
8
3 12 3 2
14 12 20 I1
TABLE V
Types of seizures during the first three months of pregnancy number
'grand mal'
psychomotor and other
no seizures
297 275 22
57 (19,2~o) 48 (17,5~) 9 (40,9 ~o)
65 (21,9~o) 55 (20,0~o) 7 (31,8 ~ )
175 (58,9~) 172 (62,5~) 6 (27,3 ~ )
medication
number of pregnancies (abortions excluded)
malformed babies
all phenytoin and barbiturate combinations (with or without other medication) phenytoin with barbiturates only phenytoin only barbiturates only (once with imipramine) all ethosuximide combinations ethosuximide only all trimetbadione combinations all carbamazepine combinations carbamazepine only all benzodiazepine combinations
124
14
all live births normal babies malformed babies
T A B L E VI
Antiepileptic medications and occurrence of congenital lesions
70 3 61 55 2 7 50 1
27
86 The only drug which has been given but is not listed is caffeine. Children with congenital lesions seem to be born after at least 10 70 of pregnancies, when phenytoin and barbiturates are given together or with other anticonvulsant drugs. It should be noted that phenobarbital, methylphenobarbital and primidone have been taken together as barbiturates. The benzodiazepines used are diazepam, chlordiazepoxide and nitrazepam. Carbamazepine was given during the first three months of 50 pregnancies in dosages varying from 150 to I000 m g a day (mean dosage/24 hours 550 mg). In none of these 50 children congenital malformations occurred. There was one stillbirth due to CO-intoxication of the mother. As shown in Table VII carbamazepine was given only once as the sole medication and in most cases with various other anticonvulsants. In 20 cases it was given with phenytoin and barbiturates, in 11 of these cases combined with still other types of antiepileptic and other drugs. In 11 of these 50 carbamazepine-treated pregnancies tonic-clonic seizures occurred during the first trimester of pregnancy. The mean duration of epilepsy at childbirth after these pregnancies was 15 years and the mean maternal age at delivery was 26,5 years. The statistical two-tail analysis of the finding that in 50 carbamazepine-treated pregnancies out of a total of 372 no congenital malformations occurred, yields P = 0,057 (chi 2 with the correction of Yates) so there is no strong significance. Since benzodiazepines have been given in 27 pregnancies also without the occurrence of congenital anomalies, Table VIII lists the various combinations in which benzodiazepines appeared. Because of the recent interest in the potential teratogenicity of amphetamines they have been listed separately (Table IX) in the various combinations they had been included in. Table X presents the antiepileptic and other medication during pregnancies which resulted in the birth of a malformed child. Cohort studies reveal that approximately 1,1 ~ of the mothers of babies with congenital anomalies had been using anticonvulsant drugs (VAN DUYNE, 1965: MONSON et al., 1973). TABLE VII
Carbamazepine and carbamazepine-combinations given during 50 pregnancies; in none of these cases anomalies occurred medication
number
carbamazepine only with barbiturates with phenytoin with barbiturates and phenytoin with barbiturates and pnenytoin and others (pheneturide, benzodiazepines, amphetamine, ethosuximide) with barbiturates and ethosuximide with phenytoin and amphetamine with phenytoin and benzodiazepines and acetazolamide
I 10 2 9 11 15 1 1
87 T A B L E VIII
Benzodiazepines and benzodiazepine-combinations given during 27 pregnancies; in none of these cases anomalies occurred medication
number
benzodiazepine only with barbiturates with phenytoin with barbiturates and phenytoin with barbiturates and phenytoin and others (carbamazepine and amphetamine) with ethosuximide with barbiturates and ethosuximide with barbiturates and ethosuximide and others (acetazolamide, trimethadione, amphetamine) with phenytoin and carbamazepine and others (acetazolamide, amphetamine)
0 2 2 6 7 1 3 3 3
DISCUSSION
To be able to compare the percentages of babies with congenital anomalies born to mothers with epilepsy and anticonvulsant medication during pregnancy, as stated in the literature, we prepared Table XI. Where possible, percentages were modified to those in live births. The percentage of live births with congenital defects in our patients is 7,4 %. The lowest percentage in the literature is found in the patients of JANZ and FUCHS(1964), who made a survey of 426 pregnancies in 246 mothers with epilepsy and observed that 2,2 % of the babies in the treated group (130 pregnancies) had congenital anomalies. After the 262 pregnancies during which no antiepileptic drugs had been used there were no congenital anomalies. The highest percentage T A B L E IX
Amphetamine and amphetamine-combinations given during 25 pregnancies and occurrence of congenital lesions and stillbirth medication
number of pregnancies
amphetamine only with barbiturates with barbiturates and phenytoin with barbiturates and phenytoin and carbamazepine and benzodiazepine with barbiturates and ethosuximide with barbiturates and ethosuximide and trimethadione with barbiturates and ethosuximide and trimethadione and benzodiazepine with barbiturates and ethosuximide and benzodiazepines with phenytoin and carbamazepine with barbiturates and bromide valerianate
0 8 7 3 2 I 1 1 1 1
congenital lesions
stillbirth
1
2
88 TABLE X
Ant±epileptic (and other) medication during pregnancies in cases of malformed babies medication
N(22)
malformations
none barbiturates only
1 2
hare lip i cleft palate
phenytoin only barbiturates and phenytoin
0 9
Down's syndrome congenital heart lesion ectopic bladder meningomyelocele
hare lip 4- cleft palate ( x 5) barbiturates and phenytoin and others (ethos0"ximide, meprobamate, amphetamine, ephedrine) barbiturates and trimethadione and ethosuximide and amphetamine barbiturates and trimethadione barbiturates and ethosuximide barbiturates and imipramine hydrochloride levopromazine and amitryptiline HCI
5
congenital heart lesion ( × 2) congenital heart lesion ( × 3)
hare lip i cleft palate anal atresia I
hare lip ± cleft palate
I 1 I 1
congenital heart lesion anencephaly
hare lip ± cleft palate polydactyly
T A B L E XI
Percentages from literature. Percentages between brackets indicate that the number of babies born alive is not specifically staged. If known, the percentage of treated pregnancies versus all pregnancies during epilepsy is given author and year of publication
Janz and Fuchs German et al. Watson and Spellacy Elshove Elshove and Van Eck Ritter and Weidekam Speidel and Meadow South Lowe Koppe et al. Millar and Nevin Total
precentage treated versus all pergnancies during epilepsy
number of live births after treated pregnancies
number of babies with congenital defects after treated pregnancies
percentage of babies with congenital defects in live births after treated pregnancies
1964 1970
64 ~o
225 243
5 14
2,2 (5,8 70)
197 I 1970
100~ 95,470
51 62
3 8
5,9~ 12,970
43
3
7,0~o
324 22 134 197 110
17 2 9 13 7
5,3 70 9,1 70 (6,7 70) (6,670) (6,4 ~ )
1411
81
5,7~
1971 1972 1972 1972 1973 1973 1973
85,5 ~ 71 ~ 54,7 70 65,1 ~
89 is mentioned by ELSHOVE (1970, 1971) who found 15,47o babies with congenital anomalies after 65 pregnancies, during which the mother had taken antiepileptic medication. The percentage of children with congenital anomalies in live births is calculated as 12,9 7oo- There is a tendency of a preponderance of male infants amongst those with congenital anomalies (ELSHOVE, 1970), which is also reflected in Table III; this difference is not significant (ct0,05). Patients referred to special centres for epilepsy tend to have more severe forms of epilepsy. This seems to be reflected in this investigation by the high percentage of treated pregnancies (352 out of 372: 94,6 70) and by the mean duration of epilepsy at childbirth of 13 years. The fact that we found a rather high percentage (7,470) of babies with congenital anomalies compared to the mean percentage of 5,7700 calculated from the literature may signify that there is a relationship between the severity of the epilepsy of the mother and the occurrence of congenital lesions in her offspring. From Table V a higher incidence of tonic-clonic seizures during the first three months of pregnancy in mothers of malformed babies can be seen. The severity of epilepsy again manifests itself in several aspects like the number of anoxic seizures, but also in the intensity of treatment (duration and amount of medication). The percentage of congenital anomalies in 421.781 births in 16 countries as given by the World Health Organization (STEVENSONet al., 1966) varied from 0,370 to 2,370, with a mean of 1,3 ~ . KENNEDY (1967) reviewed 238 reports to a total of 20.003.307 births from the world literature and concluded to a mean percentage of 1,1 70 for live births (varying with criteria used from 1-5 7o).
Risk of the individual mother with epilepsy Table XII gives the relative numbers of mothers giving birth to children with congenital anomalies, as calculated by us from data of the different authors. The risk, approximated from the literature, seems to be about 1 : 11. TABLE XII
Number of mothers with live -born children with congenital anomalies compared to all mothers with epilepsy receiving anticonvulsant medication during pregnancy author and year of publication
number of mothers with epilepsy, taking anticonvulsants during pregnancy
number of mothers with live-born children with congenital anomalies
Watson and Spellacy 1971 Elshove and Van Eck 1970, 1971 Speidel and Meadow 1972 South 1972 Lowe 1973 Koppe et al. 1973 Millar and Nevin 1973
42 62 168 22 134 125 57
3 7 16 2 (9)* (I 1)* (7)*
total
610
55 (9,070)
* Brackets indicate that the number of live-born infants is not specifically stated.
90 TABLE Xlll
Relative occurrence of cleft lip with or without cleft pamte and congenital heart lesions in children with congenital lesions, born to mothers with epilepsy, in literature author and year of publication
total number of cases with congenital anomalies
Janz and Fuchs German et al. Watson and Spellacy Van Duyne (publ. bij Elshove) 1970, Elshove (et al.) 1970, Ritter and Weidekamm Speidel and Meadow South Lowe Koppe et al. Millar and Nevin This study
1964 1970 1971
5 14 3
3 I
1971 1971 1972 1972 1972 1973 1973 1973
18 10 3 17 2 9 13 7 22
10 5 I 3 2 I I 2 9
123
38
Total
CL + CP
congenital heart defects
other defects
1
I
2
I1
1
2
4 2
4 3
1
I
6
8
1
7
4
8
-
5
7
6
29
56
Relative frequency of types of anomalies In Table XIII the relative occurrence of malformations as found in the literature is reviewed. MEADOW (1968) raised the possibility of an association between anticonvulsant medication during pregnancy and syndrome of the first arch anomalies. FRASER and MACGILLIVRAY(1969) suggested this syndrome being identical with the Wildervanck syndrome (WILDERVANCK, 1960), which they postulate is being caused by chromosomal damage. The w h o Report (STEVENSON et al., 1966) found cleft lip with or without cleft palate to occur in 7,7 9/0 of all cases of congenital anomalies. In our patients a ratio of 9 in 22 cases is found (.approximated percentage 40), the ratio in the reviewed literature we found to be 29 in 101 cases (percentage approximately 29). Cases of cleft lip with or without cleft palate seem to have a definite preponderance over the other congenital anomalies in the offspring of mothers with epilepsy, requiring treatment during pregnancy. Congenital malformations of the heart seem to take the second place. KUENSSBERG and KNOX (1973) found no cases of cleft lip with or without cleft palate in the offspring of 48 mothers with epilepsy, taking anticonvulsant drugs during pregnancy. They reported a prospective study in Scotland between 1965 and 1967, when 272 general practitioners reported on over 15.000 pregnancies. They did find 5 cases of other anomalies (1 hydrocephalus, 1 hypospadias, 1 supra-anal sinus, 1 meconiumileus and one systolic heart murmur). They believe that the evidence for an association between anticonvulsant therapy and congenital abnormality is insufficient. BiRD (1969) denied observing any congenital anomalies during 20 years
91 of treating patients with epilepsy (about 3200 pregnancies included). KOPPE et al. (1973) found within the category of children with congenital anomalies born to mothers with epilepsy no preponderance of cleft lip with or without cleft palate. They did find an unusually high incidence of cheiloschisis and (or) palatoschisis among 4540 deliveries (none of epileptic women) in the Temporary Hospital Zeeburg of Amsterdam over the period 1963 to 1967 inclusive. This incidence was 0,427o and four times as high as the world average. The authors warn that unexplained clusters like these may influence the outcome in studies of a causal relationship between for instance epilepsy of the mother and cleft lip anomaly in the offspring.
The antiepileptic drugs From Tables VI and X it becomes apparent that no single drug can very well be accused of eratogenicity. Combinations of anticonvulsants that include phenytoin and barbiturates are found to lead to the occurrence of congenital anomalies in 14 of the 124 cases (I 1,3 7O) in which they are prescribed. If phenytoin and barbiturates are given together without any other drug congenital lesions occur in 12,9 % of cases. Barbiturates given exclusively in 61 cases led to 2 cases with congenital anomalies, phenytoin given singly in 3 cases did not lead to congenital anomalies. Of course, these numbers are too small to reach definite conclusions and of course the combination of barbiturates with phenytoin is the one most often given, with or without other drugs. In the literature usually phenytoin is incriminated, but it is in fact difficult to find many cases where phenytoin was given as the single anticonvulsant in the case of a congenital anomaly. WATSON and SPELLAC¥ (1971) included in their drug group women who were receiving phenytoin in doses of 300 mg/day or more during pregnancy. In 46 of of these 51 cases, however, barbiturates had also been used, in 5 cases phenytoin alone. The 3 cases with anomalies were hydrocephalus (phenytoin with phenobarbital), congenital heart lesion (phenytoin and phenobarbital) and a cystic hygroma, measuring 1,5 cm in diameter (phenytoin alone). MILLAR and NEVIN (1973) reported phenytoin alone given in 5 cases in which two children proved not normal: one had a strabismus and one child was mentally retarded. LOWE (1973) mentions phenytoin as the only medication in 9 cases, leading to a minor malformation of the ear in one and in another case bilateral talipes equinovarus. Phenytoin has proven teratogenic in mice (MASSEV 1966, HARmSON and BECKER 1969 and 1970, GmSON and BECKER 1968, ELSHOVE 1969 and 1970). The teratogenic effect proved to be dose-dependent and influenced by factors enhancing or inhibiting phenytoin metabolism (HARmSOWand BECKER 1969, 1970). Phenobarbital was found by WHEA'rLEV (1963) to cause congenital anomalies in 4 children of 61 women who had used it because of threatening abortion. NELSON and FORFAR (1971) in a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without found the most significant association between any drug or group of drugs and the
92 occurrence of congenital abnormalities with barbiturates. Dosage tended to be higher in mothers giving birth to abnormal infants. The anomalies seen included anencephaly, congenital heart disease, severe limb deformities, cleft lip and palate and intersex. GERMAN et al. (1970) presented evidence strongly suggesting a teratogenic action in man of trimethadione. Carbamazepine is relatively new as an antiepileptic. After the 50 pregnancies in our patients during which it had been taken in various combinations with other antiepileptic drugs, not one congenital anomaly was observed. HAGEN (1969) reported three normal children after pregnancies in mothers with epilepsy, treated with carbamazepine throughout pregnancy. Recently (SONNEN, personal comm.) a case of atresia ani in a child of an epileptic mother, using carbamazepine, came to our attention.
Causal aspects In some forms of epilepsy as in some types of congenital abnormalities a genetic predisposition is present. ELSHOVE(1970, 1971) found in the ten women with epilepsy who gave birth to children with congenital abnormalities a familial occurrence of congenital anomalies in 4 cases. In our study 6 out of the 18 mothers of malformed children had relatives with congenital malformations (Table III); about the remaining 135 mothers congenital malformations in relatives were reported in 7 cases. This may indicate that a predisposition for epilepsy and congenital anomalies may occur combined. In fact Marchand, cited in LENNOX (1960), in his discussion of hereditary organic epilepsy observes that patients and their non-epileptic relatives frequently exhibit signs of a dysplasia of the neuroectodermal layer, and specifically includes 'bone defects such as harelip and spina bifida'. It is interesting to note in this context that DRONAMRAJU (1970) found epilepsy in a first or second degree relative in 34 out of 204 patients with cleft lip with and without cleft palate (16,77o). He suggests further investigation of the possibility of a genetic relationship between epilepsy and oral clefts, particularly not only from the clinical evidence of overt seizures but also by studying the occurrence of abnormal electroencephalogram patterns in relatives. In our study familial occurrence of epilepsy was reported in 52 out of 154 cases. These were distributed in fair proportions with respect to the groups of mothers with, respectively without malformed children (7 out of 18 respectively 45 out of 136 cases). The seven mothers having a child with cleft lip reported in 3 out of 7 cases a familial history of epilepsy.
Drug metabolism during pregnancy Both phenobarbital (MELCHIOR 1967) and phenytoin (MIRKIN 1971) seem to pass the human placenta readily. Neonatal elimination of both drugs seems slower than
93 in the adult. WESTMORELANDand BASS (1971) showed that blood and tissue levels of phenytoin in the pregnant rat were two to three times greater than those of nonpregnant controls. Westmoreland offers the hypothesis that inhibition of hydroxylation in maternal liver by high concentrations of female sex hormones as a probable mechanism for the accumulation of toxic concentrations of the drug in the tissues of the pregnant rat and fetus. LOUGHNANet al. (1973) found toxic bloodlevels of phenytoin (32.4 and 21.5 micrograms/ml) in two out of seven mothers with epilepsy, on phenytoin treatment in combination with phenobarbital), who gave birth to children with skeletal anomalies. In the review article by CONNEY (1967) covering 379 publications on the pharmacological implications of microsomal induction the fact is mentioned that inducers of liver microsomal enzymes like phenobarbital stimulate the catabolism or synthesis of several normal body substrates such as steroid hormones, pyridine, nucleotides, cytochrome and bilirubin. This is paralleled in vivo by a decreased action of steroids such as estradiol, estrone and progesterone. Enzyme induction may raise the need for vitamins especially pyridoxine and folate. This may very well explain the higher than normal abortion-rate in our patients with epilepsy. The high abortion rate merits more attention than it has received so far. DAVIS and WOODLIFF (1971) found that 87 out of 149 patients treated with anticonvuisants had serum folate concentrations below the lower limit of the normal range. The incidence of low folate concentrations was highest in females between the ages of l0 and 49 years. Patients receiving carbamazepine only did appear to have normal folate levels (KEUTER, pers.comm.). The suggested relation between folate metabolism and the teratogenic action of certain antiepileptic drugs seems to warrant further investigation in animal experiments and patient studies during early pregnancy. As STAPLES(1972) points out, consideration should be given to testing combinations of certain drugs to ascertain their interactions in the fields of teratology, since this is the usual nature of drug therapy used in the human epileptic. For the time being close surveillance of the pregnant woman who is being treated with anticonvulsant drugs is indicated with respect to folate levels, antiepileptic blood levels and hormonal levels. As pointed out by DAVlS (1973) there is little point in giving folate for the purpose of preventing embryopathy once conception has occurred, since the damage may already have been done. The regular administration of folic acid in a dosage of 1 mg/day to epileptic women of childbearing age seems to be indicated. However, REYNOLDS(1968) has pointed out that in certain cases an increase in seizure rate is observed (a daily dose of 15 mg folic acid was given). Neither SPAANS (1970) nor HOUBEN et al. (1971) have been able to confirm these data in hospitalized epileptics and recently the results of a controlled study over a six-month period by MATTSON et al. (1973) agreed to their view. Certain experimental data support the concept of an epileptogenic action of folate especially if the bloodbrain barrier is damaged (HOMMES and OBBENS, 1972). If the human female is less able to metabolize phenobarbital and phenytoin during pregnancy even closer observation of drug levels is indicated. Furthermore there is
94 suggestive evidence that - where possible - particularly in the women with epilepsy in the childbearing years, a shift in the antiepileptic medication towards carbamazepine may be considered.
REFERENCES BIRD, A. V. (1969)Anticonvulsant drugs and congenital abnormalities, Lancet, 1." 311. CONNEY, A. H. (1967) Pharmacological implications of microsomal enzyme induction, Pharmacol. Rev. 19: 317. DAVIS, R. E. and WOODLI~E, H. J. (1971) Folic acid deficiency in patients receiving anticonvulsant drugs, Med. J. Aust., 2: 1070. DAVIS, R. E. (1973) Congenital malformations and anticonvulsant drugs, Lancet 1: 492. DRONAMRAJU,K. R. (1970) Epilepsy and cleft lip and palate, Lancet, 2: 876. DUYNE, W. M. J. VAN (1963) Enqu6te aangeboren afwijkingen, Bull. Geneesk. Hoofdinsp., juni 1965. ELSHOVE,J. (1969) Cleft palate in the offspring of female mice treated with phenytoin, Lancet 2: 1074. ELSHOVE, J. (1970) Teratogene werking van fenytoine, Groningen, dissertatie, 142. ELSHOVE, J. and VAN ECK, J. H. M. (1971) Aangeboren misvormingen, met name gespleten lip met of zonder gespleten verhemelte, bij kinderen van moeders met epilepsie, Ned. T. Geneesk. 115: 1371. FRASER, W. I. and MACGILLIVRAY,R. C. (1969) Anticonvulsant drugs and congenital abnormalities, Lancet 1: 56. GERMAN,J., KOWAL, A. and EHLERS, K. H. (1970) Trimethadione and human teratogenesis, TeratoIogy 3: 349. GlaSON, J. E. and BECKER, B. A. (1968) Teratogenic effects of diphenylhydantoin in Swiss-Webster and A/J mice, Proc. Soc. exp. Biol. Med., 128: 905. HAGEN, K. (1969) Zur Frage der Verordnung yon Tegretal bei graviden Anfallskranken, Nervenarzt, 40: 590. HARBISON,R. D. and BECKER,B. A. (1969) Phenobarbital and SKF 525-A effect on placental transfer, distribution andexcretion of diphenylhydantoin in pregnant mice, Pharmacologist, Fall, 11: 248. HARBISON, R. D. and BECKER,B. A. (1970) Effect of phenobarbital and SKF 525-A pretreatment on diphenylhydantoin teratogenicity in mice, J. Pharmacol. exp. Ther., 175: 283. HOMMES, O. R. and OSBENS, E. A. M. T. (1972) The epileptogenic action of Na-folate in the rat, J. Neurol. Sci., 16: 271. HOUBEN, P. F. M., HOMMES,O. R. and KNAVEN,P. J. H. (1971) Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients, Epilepsia, 12: 235. JANZ, D. und FUCHS, U. (1964) Sind antiepileptische Medikamente w~ihrend der Schwangerschaft schadlich?, Dtsch. reed. Wschr., 89: 241. KENNEDY, W. P. (1967) Epidemiologic aspects of the problem of congenital malformations, Birth defects original article series, 3: I . KOPPE, J. G., BOSMAN,W., OPPERS,Y. M., SPAANS,F. and KLOOSTERMAN,G. J. (1973) Epilepsie en aangeboren afwijkingen, Ned. T. Geneesk., 117: 220. KUENSSBERG,E. V. and KNox, J. D. E. (1973) Teratogenic effect of anticonvulsants, Lancet, 1: 198. LENNOX, W. G. (1960) Epilepsy and related disorders, vol. 2, Little, Brown & Co., Boston, Mass., 579. LOOGHNAN, P. M., GOLD, H. and VANCE,J. C. (1973) Phenytoin teratogenicity in man, Lancet, 1: 70. LOWE, C. R. (1973) Congenital malformations among infants born to epileptic women, Lancet, 1: 9. MASSEY, K. M. (1966) Teratogenic effects of diphenylhydantoin sodium, J. Oral. Ther., 2: 380. MATTSON, R. H., GALLAGHER,B. B., REYNOLDS, E. H. and GLASS, D. (1973) Folate therapy in epilepsy, a controlled study, Arch. NeuroL, 29: 78. MEADOW, S. R. (1968) Anticonvulsant drugs and congenital abnormalities, Lancet, 2: 1296. MELCHIOR, J. C., SVENSMARK,O., and TROLLE, D. (1967) Placental transfer of phenobarbitone in epileptic women, and elimination in newborns, Lancet, 2: 860. MILLAR, J. H. D. and NEVIN, N. C. (1973) Congenital malformations and anticonvulsant drugs, Lancet, 1: 328.
95 MIRKIN, B. L. (1971) Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects, J. Pediat., 78: 329. MONSON, R. R., ROSENBERG,L., HARTZ, S. C., SrtAPmO, S., HEINONEN,O. P. and SLONE, D. (1973) Diphenylhydantoin and selected congenital malformations, New Engl. J. Med., 289: 1049. NELSON, M. M. and FORFAR,J. O. (1971) Associations between drugs administered during pregnancy and congenital abnormalities of the fetus, Brit. reed. J., 1: 523. REYNOLDS,E. H. (1968) Mental effects of anticonvulsants, and folic acid metabolism, Brahl, 91: 197. RITTER, G. and WEIDEKAMM,B. (1972) Epilepsie und Graviditiit, Dtsch. Aerztebl. no. 20: 1275. SOUTH, J. (1972) Teratogenic effect of anticonvulsants, Lancet, 2:1154. SPAANS, F. (1970) Epilepsie en foliumzuur, Amsterdam, dissertatie, 128. SPEIDEL, B. D. and MEADOW, S. R. (1972) Maternal epilepsy and abnormalities of the fetus and newborn, Lancet, 2: 839. STAPLES, R. E., TERATOLOGY,(1972) In: D. M. Woodbury, J. Kiffin Penry and R. P. Schmidt (Eds.), Antiepileptic drugs, Raven Press Publ., New York, 55. STEVENSON, A. C., JOHNSTON, H. A., STEWART, M. I. P. and GOLDING, D. R. (1966) Congenital malformations, A report of a study of series of consecutive births in 24 centres, Bull. WId. Hlth. Org., 34: suppl. 9, 127. WATSON, J. D. and SPELLACY,W. N. (1971) Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin, Obstet. and Gynec., 37: 881. WESTMORELAND, B. and BASS, N. H. (1971) Diphenylhydantoin intoxication during pregnancy, Arch. Neurol., 24: 158. WHEATLV, D. (1963) Drugs in pregnancy survey, Practitioner, 191: 775. WlLOERVANCK L. S. (1960) Een cervico-oculo-acusticussyndroom, Ned. T. Geneesk., 104: 2600.
SUMMARY A Dutch survey of teratology in 372 pregnancies in 153 outpatients of special epilepsy centres is presented. 7,4~ live-born babies suffered from congenital anomalies, abortion rate was 17,7%; the rate of stillbirth 2,4%. The influence of seizures and of five groups of antiepileptic drugs is discussed. The relevant literature is reviewed.
INTRODUCTION During the past ten years anticonvulsant drugs have been receiving increasing attention as potentially teratogenic agents. With few exceptions surveys of the offspring of mothers with epilepsy taking anticonvulsants during pregnancy have demonstrated that congenital malformations occur in a frequency surpassing that of the general population. Particularly cleft lip with or without cleft palate and congenital heart lesions are noted. Many issues are, however, still unclear: the size of the risk to the individual mother with epilepsy, the role of seizures with anoxia during early pregnancy, mutual genetic aspects of epilepsy and certain malformations and to extent the various drugs should be incriminated. To contribute to the general discussion and maybe shed some light on some aspects of the problem we made a survey of the incidence of congenital malformations occurring in children of mothers with epilepsy, treated at the outpatient departments of the Instituut voor Epilepsiebestrijding. These centres are located throughout the Netherlands (Apeldoorn, Arnhem, The Hague, Heemstede, Rotterdam and Utrecht). Thanks to the cooperation of the Dr. Hans Berger Epilepsy Centre we could include data of mothers with epilepsy in the vicinity of Breda. Special attention was given to the type of seizures during the first trimester of pregnancy, the drugs and various combinations used, the type of anomaly and familial occurrence of malformations and of epilepsy.
* Instituut voor Epilepsiebestrijding, Achterweg 5 - Heemstede - The Netherlands. Clin. Neurol. Neurosurg. 1974 - 2
82 TABLE 1
Outcome of 372 pregnancies in 153 women after the onset of epilepsy .-66 spontaneous
-71 abortions (19,1%)
(1,4%) 372 pregnancies
-9 stillbirths (2,4%) 275 normal babies (92,6% of all live births)
•297 live births (including 5 twins) (78,5 %)
I
-9 hare lip 5: cleft palate (3,0% of all live births)
22 babies with congenital lesions (7,4 ~ of all live births
-7 congenital heart lesions (2,4 % of all live births) 6 others (2,0% of all live births)
TABLE 11
Outcome of pregnancies after the onset of epilepsy in 153 women, with and without medication
pregnancies spontaneous abortions therapeutic abortions twin pregnancies live births (including twins) stillbirths (including twins) normal babies malformed babies neonatal deaths (within 1 month) infant deaths (1 month-I year) death after age 1 year
anticonvulsant medication during pregnancy
no anticonvulsant medication during pregnancy
total
352 63 5 4 279 9 259 20 x 4 2 1
20 3 0 1 18 0 16 22 0 0 0
372 66 5 5 297 9 275 22 4 2 1
t In one case imipramine hydrochloride was taken in addition to primidone. In one of these two cases levopromazine and amitryptiline HCI were taken.
83 PATIENTS AND METHODS
During the year elapsing between the 1st of September 1971 and the 1st of September 1972 data were collected by interviewing mothers older than 18 years and younger than 50 years, visiting the outpatient departments. Details concerning antiepileptic medication were completed from the medical charts and where necessary, general practitioners and specialists were asked for additional information. Malformations where doubt existed as to congenital nature, such as ocular ptosis, torticollis, umbilical and inguinal herniation of later date and retardation of unknown cause have not been taken into account, since detailed examination of the children could not be carried out.
RESULTS
Information was collected about 372 pregnancies in 153 women after the onset of epilepsy. The outcome of these pregnancies is given in Table I. Because of the usually deficient data in the cases of stillbirth, these were kept separate and the incidence of congenital anomalies is given in 297 live births (Table I). As regards live births the mean duration of epilepsy of the mother was 14 years when malformed children were born and 13 years for normal children. During only 20 out of these 372 pregnancies no antiepileptic medication had been taken. Table II gives the results of pregnancies with and without medication. Of the 22 children with congenital anomalies 2 were born after pregnancies, during which the mother took no antiepileptic medication; one of these, however, used tranquilizers. Two mothers who had diabetes did not get children with congenital anomalies, and experienced no stillbirth. There were no cases of German measles during the early months of pregnancy (see also Tables III and X). Congenital heart lesions in this survey take the second place to cases with cleft lip with and without cleft palate. Details of the cases of congenital malformations as regards birth order, sex of the child, duration of epilepsy and age of the mother are given in Table IlI. Added were data concerning the familial occurrence of malformations and epilepsy, as supplied by the patients during the interview. The 22 babies with congenital anomalies were born to 18 mothers: one mother had three, two mothers had two children with congenital anomalies. There were 9 cases of stillbirth (24%0) see Table IV. (KENNEDY(t967) remarks a higher incidence of defects in cases of stillbirth, however, as not always a systematic investigation of the foetus is available they are usually omitted from the statistics; the incidence of stillbirths in the general population in the Netherlands is approximately 11%0). The mean age of the mother at childbirth was 26,7 years, at the birth of a normal child 26,5 years, at the birth of a child with a congenital malformation 28,1 years and in 8 cases of stillbirth 30,5 years (in one case the age of the mother was not reported). Of the 153 mothers there were 92 with 169 children who had no complications at all: no abortions no stillbirths and no children with congenital anomalies. 35 Mothers had 57 abortions
84
TABLE
111
Congenitally malformed babies (22) born to mothers (18) after the onset of epilepsy (children of the same mother are identified by resp. ×, o and - - )
.= -~ ,
.=_ ~
~ .= x~
~
~
~6 =
oo
= = "=o
>~,..
._
~
.o
=
~
E~
>,
t-"
~o
~.~
=
.-,-'6
=
e
"~
-&
~
>,
~e
"
~o~
.~-
t~
._~ "O
.r~
1 2 1
5 19 11
20 36 29
1 1 2 5 2 3 1
t6 19 24 4 15 17 24
33 26 30 30 29 28 28
3
21
31
--
1
14
24
--
2 1 3
10 9 18
22 25 32
1
12
26
2
23
34
7 1 2 1 2
0 12 15 5 14
33 23 26 27 26
x
x
o
0 o
Harelip Harelip Harelip
m m m
+ + +
Harelip with cleft palate Harelip with cleft palate Harelip Harelip Harelip Harelip Congenital heart (tetralogy of Fallot) + hypoplasia of nails Congenital heart (atrial septal defect) Congenital heart (ventricular septal defect) Congenital heart Congenital heart Congenital heart (ventricular septal defect) Congenital heart (tetralogy of Fallot) Anal atresia, hypertelorism Down's syndrome Ectopic bladder meningomyelocele Polydactyly Anencephaly
f m m m f f m
+ -----+
m
Harelip Harelip Clubfoot, finger aptasia, consanguinity Harelip
E
+
÷ +
Congenital heart
-F
+ + + + + + +
+
Congenital deafness
+
+
f
+
Congenital deafness
+
+
m m f
----
+
+
--
+
+
+
f
--
--
-]-
m
+
--
+
m m m m f
------
--
+
+ +
Down's syndrome
--
+
+
--
a n d 73 n o r m a l c h i l d r e n . 26 M o t h e r s h a d t h e 9 c a s e s o f s t i l l b i r t h a n d 22 m a l f o r m e d c h i l d r e n , 14 a b o r t i o n s a n d 33 n o r m a l c h i l d r e n . T a b l e V gives t h e o c c u r r e n c e o f t o n i c - c l o n i c s e i z u r e s d u r i n g t h e first t r i m e s t e r o f p r e g n a n c y in all live b i r t h s , c a s e s o f n o r m a l a n d c a s e s o f m a l f o r m e d c h i l d r e n . T o n i c c l o n i c s e i z u r e s s e e m t o o c c u r a p p r e c i a b l y m o r e o f t e n in t h e c a s e o f m a l f o r m e d b a b i e s t h a n w h e n a n o r m a l b a b y is b o r n . T h e r e l a t i v e o c c u r r e n c e o f p s y c h o m o t o r a n d o t h e r s e i z u r e s w i t h o u t a n o x i a s h o w s less d i f f e r e n c e . A n t i e p i l e p t i c m e d i c a t i o n a n d o c c u r r e n c e o f c o n g e n i t a l l e s i o n s a r e s h o w n in T a b l e V I .
85 TABLE IV
Cases of stillbirth birth order
1 1
3 3
duration of epilepsy in years at stillbirth
age of mother in years at stillbirth
details if known
19
22
17 15 6
29 32 22 25 30 44 37 25
early separation of placenta strangulation by umbilical cord two months early, placental degeneration immature birth between 16th and 20th gestational week unknown unknown unknown immature birth at 20th week of gestation following CO-intoxication of mother
1
8
3 12 3 2
14 12 20 I1
TABLE V
Types of seizures during the first three months of pregnancy number
'grand mal'
psychomotor and other
no seizures
297 275 22
57 (19,2~o) 48 (17,5~) 9 (40,9 ~o)
65 (21,9~o) 55 (20,0~o) 7 (31,8 ~ )
175 (58,9~) 172 (62,5~) 6 (27,3 ~ )
medication
number of pregnancies (abortions excluded)
malformed babies
all phenytoin and barbiturate combinations (with or without other medication) phenytoin with barbiturates only phenytoin only barbiturates only (once with imipramine) all ethosuximide combinations ethosuximide only all trimetbadione combinations all carbamazepine combinations carbamazepine only all benzodiazepine combinations
124
14
all live births normal babies malformed babies
T A B L E VI
Antiepileptic medications and occurrence of congenital lesions
70 3 61 55 2 7 50 1
27
86 The only drug which has been given but is not listed is caffeine. Children with congenital lesions seem to be born after at least 10 70 of pregnancies, when phenytoin and barbiturates are given together or with other anticonvulsant drugs. It should be noted that phenobarbital, methylphenobarbital and primidone have been taken together as barbiturates. The benzodiazepines used are diazepam, chlordiazepoxide and nitrazepam. Carbamazepine was given during the first three months of 50 pregnancies in dosages varying from 150 to I000 m g a day (mean dosage/24 hours 550 mg). In none of these 50 children congenital malformations occurred. There was one stillbirth due to CO-intoxication of the mother. As shown in Table VII carbamazepine was given only once as the sole medication and in most cases with various other anticonvulsants. In 20 cases it was given with phenytoin and barbiturates, in 11 of these cases combined with still other types of antiepileptic and other drugs. In 11 of these 50 carbamazepine-treated pregnancies tonic-clonic seizures occurred during the first trimester of pregnancy. The mean duration of epilepsy at childbirth after these pregnancies was 15 years and the mean maternal age at delivery was 26,5 years. The statistical two-tail analysis of the finding that in 50 carbamazepine-treated pregnancies out of a total of 372 no congenital malformations occurred, yields P = 0,057 (chi 2 with the correction of Yates) so there is no strong significance. Since benzodiazepines have been given in 27 pregnancies also without the occurrence of congenital anomalies, Table VIII lists the various combinations in which benzodiazepines appeared. Because of the recent interest in the potential teratogenicity of amphetamines they have been listed separately (Table IX) in the various combinations they had been included in. Table X presents the antiepileptic and other medication during pregnancies which resulted in the birth of a malformed child. Cohort studies reveal that approximately 1,1 ~ of the mothers of babies with congenital anomalies had been using anticonvulsant drugs (VAN DUYNE, 1965: MONSON et al., 1973). TABLE VII
Carbamazepine and carbamazepine-combinations given during 50 pregnancies; in none of these cases anomalies occurred medication
number
carbamazepine only with barbiturates with phenytoin with barbiturates and phenytoin with barbiturates and pnenytoin and others (pheneturide, benzodiazepines, amphetamine, ethosuximide) with barbiturates and ethosuximide with phenytoin and amphetamine with phenytoin and benzodiazepines and acetazolamide
I 10 2 9 11 15 1 1
87 T A B L E VIII
Benzodiazepines and benzodiazepine-combinations given during 27 pregnancies; in none of these cases anomalies occurred medication
number
benzodiazepine only with barbiturates with phenytoin with barbiturates and phenytoin with barbiturates and phenytoin and others (carbamazepine and amphetamine) with ethosuximide with barbiturates and ethosuximide with barbiturates and ethosuximide and others (acetazolamide, trimethadione, amphetamine) with phenytoin and carbamazepine and others (acetazolamide, amphetamine)
0 2 2 6 7 1 3 3 3
DISCUSSION
To be able to compare the percentages of babies with congenital anomalies born to mothers with epilepsy and anticonvulsant medication during pregnancy, as stated in the literature, we prepared Table XI. Where possible, percentages were modified to those in live births. The percentage of live births with congenital defects in our patients is 7,4 %. The lowest percentage in the literature is found in the patients of JANZ and FUCHS(1964), who made a survey of 426 pregnancies in 246 mothers with epilepsy and observed that 2,2 % of the babies in the treated group (130 pregnancies) had congenital anomalies. After the 262 pregnancies during which no antiepileptic drugs had been used there were no congenital anomalies. The highest percentage T A B L E IX
Amphetamine and amphetamine-combinations given during 25 pregnancies and occurrence of congenital lesions and stillbirth medication
number of pregnancies
amphetamine only with barbiturates with barbiturates and phenytoin with barbiturates and phenytoin and carbamazepine and benzodiazepine with barbiturates and ethosuximide with barbiturates and ethosuximide and trimethadione with barbiturates and ethosuximide and trimethadione and benzodiazepine with barbiturates and ethosuximide and benzodiazepines with phenytoin and carbamazepine with barbiturates and bromide valerianate
0 8 7 3 2 I 1 1 1 1
congenital lesions
stillbirth
1
2
88 TABLE X
Ant±epileptic (and other) medication during pregnancies in cases of malformed babies medication
N(22)
malformations
none barbiturates only
1 2
hare lip i cleft palate
phenytoin only barbiturates and phenytoin
0 9
Down's syndrome congenital heart lesion ectopic bladder meningomyelocele
hare lip 4- cleft palate ( x 5) barbiturates and phenytoin and others (ethos0"ximide, meprobamate, amphetamine, ephedrine) barbiturates and trimethadione and ethosuximide and amphetamine barbiturates and trimethadione barbiturates and ethosuximide barbiturates and imipramine hydrochloride levopromazine and amitryptiline HCI
5
congenital heart lesion ( × 2) congenital heart lesion ( × 3)
hare lip i cleft palate anal atresia I
hare lip ± cleft palate
I 1 I 1
congenital heart lesion anencephaly
hare lip ± cleft palate polydactyly
T A B L E XI
Percentages from literature. Percentages between brackets indicate that the number of babies born alive is not specifically staged. If known, the percentage of treated pregnancies versus all pregnancies during epilepsy is given author and year of publication
Janz and Fuchs German et al. Watson and Spellacy Elshove Elshove and Van Eck Ritter and Weidekam Speidel and Meadow South Lowe Koppe et al. Millar and Nevin Total
precentage treated versus all pergnancies during epilepsy
number of live births after treated pregnancies
number of babies with congenital defects after treated pregnancies
percentage of babies with congenital defects in live births after treated pregnancies
1964 1970
64 ~o
225 243
5 14
2,2 (5,8 70)
197 I 1970
100~ 95,470
51 62
3 8
5,9~ 12,970
43
3
7,0~o
324 22 134 197 110
17 2 9 13 7
5,3 70 9,1 70 (6,7 70) (6,670) (6,4 ~ )
1411
81
5,7~
1971 1972 1972 1972 1973 1973 1973
85,5 ~ 71 ~ 54,7 70 65,1 ~
89 is mentioned by ELSHOVE (1970, 1971) who found 15,47o babies with congenital anomalies after 65 pregnancies, during which the mother had taken antiepileptic medication. The percentage of children with congenital anomalies in live births is calculated as 12,9 7oo- There is a tendency of a preponderance of male infants amongst those with congenital anomalies (ELSHOVE, 1970), which is also reflected in Table III; this difference is not significant (ct0,05). Patients referred to special centres for epilepsy tend to have more severe forms of epilepsy. This seems to be reflected in this investigation by the high percentage of treated pregnancies (352 out of 372: 94,6 70) and by the mean duration of epilepsy at childbirth of 13 years. The fact that we found a rather high percentage (7,470) of babies with congenital anomalies compared to the mean percentage of 5,7700 calculated from the literature may signify that there is a relationship between the severity of the epilepsy of the mother and the occurrence of congenital lesions in her offspring. From Table V a higher incidence of tonic-clonic seizures during the first three months of pregnancy in mothers of malformed babies can be seen. The severity of epilepsy again manifests itself in several aspects like the number of anoxic seizures, but also in the intensity of treatment (duration and amount of medication). The percentage of congenital anomalies in 421.781 births in 16 countries as given by the World Health Organization (STEVENSONet al., 1966) varied from 0,370 to 2,370, with a mean of 1,3 ~ . KENNEDY (1967) reviewed 238 reports to a total of 20.003.307 births from the world literature and concluded to a mean percentage of 1,1 70 for live births (varying with criteria used from 1-5 7o).
Risk of the individual mother with epilepsy Table XII gives the relative numbers of mothers giving birth to children with congenital anomalies, as calculated by us from data of the different authors. The risk, approximated from the literature, seems to be about 1 : 11. TABLE XII
Number of mothers with live -born children with congenital anomalies compared to all mothers with epilepsy receiving anticonvulsant medication during pregnancy author and year of publication
number of mothers with epilepsy, taking anticonvulsants during pregnancy
number of mothers with live-born children with congenital anomalies
Watson and Spellacy 1971 Elshove and Van Eck 1970, 1971 Speidel and Meadow 1972 South 1972 Lowe 1973 Koppe et al. 1973 Millar and Nevin 1973
42 62 168 22 134 125 57
3 7 16 2 (9)* (I 1)* (7)*
total
610
55 (9,070)
* Brackets indicate that the number of live-born infants is not specifically stated.
90 TABLE Xlll
Relative occurrence of cleft lip with or without cleft pamte and congenital heart lesions in children with congenital lesions, born to mothers with epilepsy, in literature author and year of publication
total number of cases with congenital anomalies
Janz and Fuchs German et al. Watson and Spellacy Van Duyne (publ. bij Elshove) 1970, Elshove (et al.) 1970, Ritter and Weidekamm Speidel and Meadow South Lowe Koppe et al. Millar and Nevin This study
1964 1970 1971
5 14 3
3 I
1971 1971 1972 1972 1972 1973 1973 1973
18 10 3 17 2 9 13 7 22
10 5 I 3 2 I I 2 9
123
38
Total
CL + CP
congenital heart defects
other defects
1
I
2
I1
1
2
4 2
4 3
1
I
6
8
1
7
4
8
-
5
7
6
29
56
Relative frequency of types of anomalies In Table XIII the relative occurrence of malformations as found in the literature is reviewed. MEADOW (1968) raised the possibility of an association between anticonvulsant medication during pregnancy and syndrome of the first arch anomalies. FRASER and MACGILLIVRAY(1969) suggested this syndrome being identical with the Wildervanck syndrome (WILDERVANCK, 1960), which they postulate is being caused by chromosomal damage. The w h o Report (STEVENSON et al., 1966) found cleft lip with or without cleft palate to occur in 7,7 9/0 of all cases of congenital anomalies. In our patients a ratio of 9 in 22 cases is found (.approximated percentage 40), the ratio in the reviewed literature we found to be 29 in 101 cases (percentage approximately 29). Cases of cleft lip with or without cleft palate seem to have a definite preponderance over the other congenital anomalies in the offspring of mothers with epilepsy, requiring treatment during pregnancy. Congenital malformations of the heart seem to take the second place. KUENSSBERG and KNOX (1973) found no cases of cleft lip with or without cleft palate in the offspring of 48 mothers with epilepsy, taking anticonvulsant drugs during pregnancy. They reported a prospective study in Scotland between 1965 and 1967, when 272 general practitioners reported on over 15.000 pregnancies. They did find 5 cases of other anomalies (1 hydrocephalus, 1 hypospadias, 1 supra-anal sinus, 1 meconiumileus and one systolic heart murmur). They believe that the evidence for an association between anticonvulsant therapy and congenital abnormality is insufficient. BiRD (1969) denied observing any congenital anomalies during 20 years
91 of treating patients with epilepsy (about 3200 pregnancies included). KOPPE et al. (1973) found within the category of children with congenital anomalies born to mothers with epilepsy no preponderance of cleft lip with or without cleft palate. They did find an unusually high incidence of cheiloschisis and (or) palatoschisis among 4540 deliveries (none of epileptic women) in the Temporary Hospital Zeeburg of Amsterdam over the period 1963 to 1967 inclusive. This incidence was 0,427o and four times as high as the world average. The authors warn that unexplained clusters like these may influence the outcome in studies of a causal relationship between for instance epilepsy of the mother and cleft lip anomaly in the offspring.
The antiepileptic drugs From Tables VI and X it becomes apparent that no single drug can very well be accused of eratogenicity. Combinations of anticonvulsants that include phenytoin and barbiturates are found to lead to the occurrence of congenital anomalies in 14 of the 124 cases (I 1,3 7O) in which they are prescribed. If phenytoin and barbiturates are given together without any other drug congenital lesions occur in 12,9 % of cases. Barbiturates given exclusively in 61 cases led to 2 cases with congenital anomalies, phenytoin given singly in 3 cases did not lead to congenital anomalies. Of course, these numbers are too small to reach definite conclusions and of course the combination of barbiturates with phenytoin is the one most often given, with or without other drugs. In the literature usually phenytoin is incriminated, but it is in fact difficult to find many cases where phenytoin was given as the single anticonvulsant in the case of a congenital anomaly. WATSON and SPELLAC¥ (1971) included in their drug group women who were receiving phenytoin in doses of 300 mg/day or more during pregnancy. In 46 of of these 51 cases, however, barbiturates had also been used, in 5 cases phenytoin alone. The 3 cases with anomalies were hydrocephalus (phenytoin with phenobarbital), congenital heart lesion (phenytoin and phenobarbital) and a cystic hygroma, measuring 1,5 cm in diameter (phenytoin alone). MILLAR and NEVIN (1973) reported phenytoin alone given in 5 cases in which two children proved not normal: one had a strabismus and one child was mentally retarded. LOWE (1973) mentions phenytoin as the only medication in 9 cases, leading to a minor malformation of the ear in one and in another case bilateral talipes equinovarus. Phenytoin has proven teratogenic in mice (MASSEV 1966, HARmSON and BECKER 1969 and 1970, GmSON and BECKER 1968, ELSHOVE 1969 and 1970). The teratogenic effect proved to be dose-dependent and influenced by factors enhancing or inhibiting phenytoin metabolism (HARmSOWand BECKER 1969, 1970). Phenobarbital was found by WHEA'rLEV (1963) to cause congenital anomalies in 4 children of 61 women who had used it because of threatening abortion. NELSON and FORFAR (1971) in a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without found the most significant association between any drug or group of drugs and the
92 occurrence of congenital abnormalities with barbiturates. Dosage tended to be higher in mothers giving birth to abnormal infants. The anomalies seen included anencephaly, congenital heart disease, severe limb deformities, cleft lip and palate and intersex. GERMAN et al. (1970) presented evidence strongly suggesting a teratogenic action in man of trimethadione. Carbamazepine is relatively new as an antiepileptic. After the 50 pregnancies in our patients during which it had been taken in various combinations with other antiepileptic drugs, not one congenital anomaly was observed. HAGEN (1969) reported three normal children after pregnancies in mothers with epilepsy, treated with carbamazepine throughout pregnancy. Recently (SONNEN, personal comm.) a case of atresia ani in a child of an epileptic mother, using carbamazepine, came to our attention.
Causal aspects In some forms of epilepsy as in some types of congenital abnormalities a genetic predisposition is present. ELSHOVE(1970, 1971) found in the ten women with epilepsy who gave birth to children with congenital abnormalities a familial occurrence of congenital anomalies in 4 cases. In our study 6 out of the 18 mothers of malformed children had relatives with congenital malformations (Table III); about the remaining 135 mothers congenital malformations in relatives were reported in 7 cases. This may indicate that a predisposition for epilepsy and congenital anomalies may occur combined. In fact Marchand, cited in LENNOX (1960), in his discussion of hereditary organic epilepsy observes that patients and their non-epileptic relatives frequently exhibit signs of a dysplasia of the neuroectodermal layer, and specifically includes 'bone defects such as harelip and spina bifida'. It is interesting to note in this context that DRONAMRAJU (1970) found epilepsy in a first or second degree relative in 34 out of 204 patients with cleft lip with and without cleft palate (16,77o). He suggests further investigation of the possibility of a genetic relationship between epilepsy and oral clefts, particularly not only from the clinical evidence of overt seizures but also by studying the occurrence of abnormal electroencephalogram patterns in relatives. In our study familial occurrence of epilepsy was reported in 52 out of 154 cases. These were distributed in fair proportions with respect to the groups of mothers with, respectively without malformed children (7 out of 18 respectively 45 out of 136 cases). The seven mothers having a child with cleft lip reported in 3 out of 7 cases a familial history of epilepsy.
Drug metabolism during pregnancy Both phenobarbital (MELCHIOR 1967) and phenytoin (MIRKIN 1971) seem to pass the human placenta readily. Neonatal elimination of both drugs seems slower than
93 in the adult. WESTMORELANDand BASS (1971) showed that blood and tissue levels of phenytoin in the pregnant rat were two to three times greater than those of nonpregnant controls. Westmoreland offers the hypothesis that inhibition of hydroxylation in maternal liver by high concentrations of female sex hormones as a probable mechanism for the accumulation of toxic concentrations of the drug in the tissues of the pregnant rat and fetus. LOUGHNANet al. (1973) found toxic bloodlevels of phenytoin (32.4 and 21.5 micrograms/ml) in two out of seven mothers with epilepsy, on phenytoin treatment in combination with phenobarbital), who gave birth to children with skeletal anomalies. In the review article by CONNEY (1967) covering 379 publications on the pharmacological implications of microsomal induction the fact is mentioned that inducers of liver microsomal enzymes like phenobarbital stimulate the catabolism or synthesis of several normal body substrates such as steroid hormones, pyridine, nucleotides, cytochrome and bilirubin. This is paralleled in vivo by a decreased action of steroids such as estradiol, estrone and progesterone. Enzyme induction may raise the need for vitamins especially pyridoxine and folate. This may very well explain the higher than normal abortion-rate in our patients with epilepsy. The high abortion rate merits more attention than it has received so far. DAVIS and WOODLIFF (1971) found that 87 out of 149 patients treated with anticonvuisants had serum folate concentrations below the lower limit of the normal range. The incidence of low folate concentrations was highest in females between the ages of l0 and 49 years. Patients receiving carbamazepine only did appear to have normal folate levels (KEUTER, pers.comm.). The suggested relation between folate metabolism and the teratogenic action of certain antiepileptic drugs seems to warrant further investigation in animal experiments and patient studies during early pregnancy. As STAPLES(1972) points out, consideration should be given to testing combinations of certain drugs to ascertain their interactions in the fields of teratology, since this is the usual nature of drug therapy used in the human epileptic. For the time being close surveillance of the pregnant woman who is being treated with anticonvulsant drugs is indicated with respect to folate levels, antiepileptic blood levels and hormonal levels. As pointed out by DAVlS (1973) there is little point in giving folate for the purpose of preventing embryopathy once conception has occurred, since the damage may already have been done. The regular administration of folic acid in a dosage of 1 mg/day to epileptic women of childbearing age seems to be indicated. However, REYNOLDS(1968) has pointed out that in certain cases an increase in seizure rate is observed (a daily dose of 15 mg folic acid was given). Neither SPAANS (1970) nor HOUBEN et al. (1971) have been able to confirm these data in hospitalized epileptics and recently the results of a controlled study over a six-month period by MATTSON et al. (1973) agreed to their view. Certain experimental data support the concept of an epileptogenic action of folate especially if the bloodbrain barrier is damaged (HOMMES and OBBENS, 1972). If the human female is less able to metabolize phenobarbital and phenytoin during pregnancy even closer observation of drug levels is indicated. Furthermore there is
94 suggestive evidence that - where possible - particularly in the women with epilepsy in the childbearing years, a shift in the antiepileptic medication towards carbamazepine may be considered.
REFERENCES BIRD, A. V. (1969)Anticonvulsant drugs and congenital abnormalities, Lancet, 1." 311. CONNEY, A. H. (1967) Pharmacological implications of microsomal enzyme induction, Pharmacol. Rev. 19: 317. DAVIS, R. E. and WOODLI~E, H. J. (1971) Folic acid deficiency in patients receiving anticonvulsant drugs, Med. J. Aust., 2: 1070. DAVIS, R. E. (1973) Congenital malformations and anticonvulsant drugs, Lancet 1: 492. DRONAMRAJU,K. R. (1970) Epilepsy and cleft lip and palate, Lancet, 2: 876. DUYNE, W. M. J. VAN (1963) Enqu6te aangeboren afwijkingen, Bull. Geneesk. Hoofdinsp., juni 1965. ELSHOVE,J. (1969) Cleft palate in the offspring of female mice treated with phenytoin, Lancet 2: 1074. ELSHOVE, J. (1970) Teratogene werking van fenytoine, Groningen, dissertatie, 142. ELSHOVE, J. and VAN ECK, J. H. M. (1971) Aangeboren misvormingen, met name gespleten lip met of zonder gespleten verhemelte, bij kinderen van moeders met epilepsie, Ned. T. Geneesk. 115: 1371. FRASER, W. I. and MACGILLIVRAY,R. C. (1969) Anticonvulsant drugs and congenital abnormalities, Lancet 1: 56. GERMAN,J., KOWAL, A. and EHLERS, K. H. (1970) Trimethadione and human teratogenesis, TeratoIogy 3: 349. GlaSON, J. E. and BECKER, B. A. (1968) Teratogenic effects of diphenylhydantoin in Swiss-Webster and A/J mice, Proc. Soc. exp. Biol. Med., 128: 905. HAGEN, K. (1969) Zur Frage der Verordnung yon Tegretal bei graviden Anfallskranken, Nervenarzt, 40: 590. HARBISON,R. D. and BECKER,B. A. (1969) Phenobarbital and SKF 525-A effect on placental transfer, distribution andexcretion of diphenylhydantoin in pregnant mice, Pharmacologist, Fall, 11: 248. HARBISON, R. D. and BECKER,B. A. (1970) Effect of phenobarbital and SKF 525-A pretreatment on diphenylhydantoin teratogenicity in mice, J. Pharmacol. exp. Ther., 175: 283. HOMMES, O. R. and OSBENS, E. A. M. T. (1972) The epileptogenic action of Na-folate in the rat, J. Neurol. Sci., 16: 271. HOUBEN, P. F. M., HOMMES,O. R. and KNAVEN,P. J. H. (1971) Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients, Epilepsia, 12: 235. JANZ, D. und FUCHS, U. (1964) Sind antiepileptische Medikamente w~ihrend der Schwangerschaft schadlich?, Dtsch. reed. Wschr., 89: 241. KENNEDY, W. P. (1967) Epidemiologic aspects of the problem of congenital malformations, Birth defects original article series, 3: I . KOPPE, J. G., BOSMAN,W., OPPERS,Y. M., SPAANS,F. and KLOOSTERMAN,G. J. (1973) Epilepsie en aangeboren afwijkingen, Ned. T. Geneesk., 117: 220. KUENSSBERG,E. V. and KNox, J. D. E. (1973) Teratogenic effect of anticonvulsants, Lancet, 1: 198. LENNOX, W. G. (1960) Epilepsy and related disorders, vol. 2, Little, Brown & Co., Boston, Mass., 579. LOOGHNAN, P. M., GOLD, H. and VANCE,J. C. (1973) Phenytoin teratogenicity in man, Lancet, 1: 70. LOWE, C. R. (1973) Congenital malformations among infants born to epileptic women, Lancet, 1: 9. MASSEY, K. M. (1966) Teratogenic effects of diphenylhydantoin sodium, J. Oral. Ther., 2: 380. MATTSON, R. H., GALLAGHER,B. B., REYNOLDS, E. H. and GLASS, D. (1973) Folate therapy in epilepsy, a controlled study, Arch. NeuroL, 29: 78. MEADOW, S. R. (1968) Anticonvulsant drugs and congenital abnormalities, Lancet, 2: 1296. MELCHIOR, J. C., SVENSMARK,O., and TROLLE, D. (1967) Placental transfer of phenobarbitone in epileptic women, and elimination in newborns, Lancet, 2: 860. MILLAR, J. H. D. and NEVIN, N. C. (1973) Congenital malformations and anticonvulsant drugs, Lancet, 1: 328.
95 MIRKIN, B. L. (1971) Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects, J. Pediat., 78: 329. MONSON, R. R., ROSENBERG,L., HARTZ, S. C., SrtAPmO, S., HEINONEN,O. P. and SLONE, D. (1973) Diphenylhydantoin and selected congenital malformations, New Engl. J. Med., 289: 1049. NELSON, M. M. and FORFAR,J. O. (1971) Associations between drugs administered during pregnancy and congenital abnormalities of the fetus, Brit. reed. J., 1: 523. REYNOLDS,E. H. (1968) Mental effects of anticonvulsants, and folic acid metabolism, Brahl, 91: 197. RITTER, G. and WEIDEKAMM,B. (1972) Epilepsie und Graviditiit, Dtsch. Aerztebl. no. 20: 1275. SOUTH, J. (1972) Teratogenic effect of anticonvulsants, Lancet, 2:1154. SPAANS, F. (1970) Epilepsie en foliumzuur, Amsterdam, dissertatie, 128. SPEIDEL, B. D. and MEADOW, S. R. (1972) Maternal epilepsy and abnormalities of the fetus and newborn, Lancet, 2: 839. STAPLES, R. E., TERATOLOGY,(1972) In: D. M. Woodbury, J. Kiffin Penry and R. P. Schmidt (Eds.), Antiepileptic drugs, Raven Press Publ., New York, 55. STEVENSON, A. C., JOHNSTON, H. A., STEWART, M. I. P. and GOLDING, D. R. (1966) Congenital malformations, A report of a study of series of consecutive births in 24 centres, Bull. WId. Hlth. Org., 34: suppl. 9, 127. WATSON, J. D. and SPELLACY,W. N. (1971) Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin, Obstet. and Gynec., 37: 881. WESTMORELAND, B. and BASS, N. H. (1971) Diphenylhydantoin intoxication during pregnancy, Arch. Neurol., 24: 158. WHEATLV, D. (1963) Drugs in pregnancy survey, Practitioner, 191: 775. WlLOERVANCK L. S. (1960) Een cervico-oculo-acusticussyndroom, Ned. T. Geneesk., 104: 2600.
