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Maternal anticonvulsants and perinatal risk
EUROP. J. OBSTET. GYNEC. REPROD.
BIOL., 1975, S/S, 277-282.
EXCERPTA
MEDICA
Maternal anticonvulsants and perinatal risk L. H. J. Ramaekers and T. S. The Department
of Neonatology,
RAMAEKERS,
St. Annadal Hospital,
Maastricht,
The Netherlands
L. H. J. and THE, T. S. (1975): Maternal anticonvulsants
and perinatal
risk. Europ. J. Obsret.
Gynec.
reprod.
Biol., 515, 277-287.
According to data found in the literature, children born to epileptic mothers on anticonvulsant therapy have an increased perinatal mortality rate, namely 2-3 times the average. The congenital malformations attributed to anticonsulvant drugs cannot fully account for this high mortality rate. A case is described in which a severe bleeding disorder manifested itself in successive offspring. A discussion follows in which this defect in blood coagulation in the newborn and the role played by vitamin K is con- ; sidered as representing an important and preventable cause of neonatal death and morbidity. Other features of the postnatal syndrome (CNS depression, congenital heart disease, withdrawal symptoms, anemia) are mentioned in the case report. Suggested preventative measures employing vitamin K, folic acid and vitamin D are briefly discussed. coagulation defect; hemorrhage;
epilepsy; vitamin K
Introduction
The combined efforts of obstetricians and neonatologists can reduce perinatal mortality to its minimum, but increased emphasis should be placed upon efforts to reduce infant morbidity by preventative measures. Several reports of anticonvulsants as a cause of abnormalities of the fetus and newborn have appeared in the literature of the last decennium. Bjerkedal and Bahna (1973) found a tripling of the infant mortality rate (34.6 versus 11.4/1000) in a retrospective study of 371 pregnancies in epileptic women. The majority of the deaths were neonatal (29.3 versus S.O/lOOO). An exact analysis of the cause of perinatal mortality was not given, although complications such as vaginal hemorrhage and toxemia were reported almost twice as frequently as in the control group. The incidence of intervention during the delivery (forceps, vacuum extraction, cesarian section) and of hypoxia was more than double that reported in the control group. Similar
findings had previously been reported by SpeideI and Meadow (1972) in a retrospective survey of the follow-up of 427 pregnancies in 186 epileptic women. The perinatal mortality rate was 42.5/1000, which was twice the regional rate. This higher rate was reported to be mainly due to congenital malformations and spontaneous hemorrhage. Most reports, Meadow (1968), Elshove and Van Eck (1971), Hill, Verniaud, Horning, McCulley and Morgan (1974), Fedrick (1973), Lowe (1973), Monson, Rosenberg, Hartz, Shapiro, Heinonen and Slone (1973), Zellweger (1974) deal particularly with congenital malformations and the teratogenic The Oxford Record effects of anticonvulsants. Linkage Study, however, mentions also a higher incidence of stillbirths and a slight increase in asphyxia and intracranial hemorrhage. The authors are of the opinion that the nature and severity of most of the congenital malformations seen in the offspring of epileptic mothers, are not sufficient to account for the doubling or tripling of the perinatal mortality rate. Other possible
L. H. J. Ramaekers and T. S. The, Maternal anticonvulsants and perinatal risk
278
causes must therefore be seriously considered. We should therefore like to draw the attention to bleeding disorders associated with anticonvulsant therapy since this seems to be not only an important but also a preventable and curable cause of perinatal mortality and morbidity. The following case is reported because it illustrates such a bleeding disorder. Many other aspects of the syndrome are also briefly mentioned, more detailed descriptions having appeared in pediatric literature elsewhere.
hydantoin (150 mgjday), without interruption, since her 19th birthday. Two pregnancies had ended in spontaneous abortions at 4 weeks’ gestation. A third pregnancy (1962) had ended in a spontaneous normal delivery at 40 weeks. The newborn died in shock on the third day. Autopsy revealed extensive bleedings in lung, liver and peritoneal cavity. Familial hemorrhagic disease was excluded. The fourth pregnancy (1972) had ended spontaneously at 42 weeks’ gestation. The child was a breech presentation with prolapsed cord. Fetal hypoxia had resulted in a low Apgar score and the child died on the first day. At autopsy there was 150 ml blood in the peritoneal cavity, bilateral subdural hemorrhage, and subcapsular hemorrhage in the liver. Being unaware at the time of a possible causal relationship between anticonvulsant therapy and
Case report Obstetrical history (see Fig. 1): The patient, a 36-year-old woman, had been treated for epilepsy with a relatively low dosage of primidone (250 mg/ day), phenobarbital (150 mg/day) and diphenyl-
9
Cath.
Epileptic
W.E ., lX,24-1938
‘henobarbitol
m
150mg/doy
Iiphenylhydantoin
m
lSOmg/day
‘rimidone
m
250mgjdoy
1961
treatment
since
1967
1972
1970
1962
1974
OBSTETRICAL spont. abortion 8 weeks
HISTORY
Fig.
1
at
S~rr.xna~y of the most imyortent
full term pregnancy 0 $e~ay
rpont. abortion ot 8 weeks
data of the obstetrical
history.
full
term
p$:;;cy
full term pregnancy Elective Caes. sect.
219
L. H. J. Rumaekers and T. S. The, Maternal anticonvulsants and perinatal risk
WEEKS
El ANAEMIA
Haemoglobin
g v*
= Diphenylhydontoin . Primidone
C.N.S.
signs I-
Phcnc
t
2 mg VITAMIN
Therapy
Fig.
2
Schematic
representation
K i.v.
of the postnatal
morbidity
hemorrhagic disease in the newborn the cause of death was attributed to fetal anoxia with hemorrhage. On account of the above obstetric history an elective cesarian section at 39 weeks was planned for the fifth pregnancy. The neonate (Fig. 2) cried within one minute of birth, the Apgar score was 8 at one minute, and the child was transferred to the neonatal intensive care unit for further close observation. The newborn showed normal vital functions and normal reflexes (Moro, sucking, rooting, posture, muscle tonicity). On routine blood examination normal Astrup values were found shortly after birth. A persistent oozing from the heel puncture was the first alarming symptom. Coagulation time was 9’, thrombocytes 288,000/mm3, the normotest, measuring vitamin K dependent factors, was less than 5 % (normal 70-130 %). 2 mg vitamin K was given intravenously and within 12 hours the bleeding disturbance had been reversed
data.
and coagulation returned to normal. 24 hours after birth the infant blood showed a phenobarbital level of 38 mg/l, 8 mg diphenylhydantoin, and 7 mg/l primidone. In the postnatal period (Fig. 2) we were confronted with the following problems: 1. Increasing depression of the central nervous system in the days following birth as evidenced by poor sucking, inability to swallow, increasing muscle hypotonicity and sleepiness. 2. A holosystolic grade III/IV murmur which was heard shortly after birth, and was diagnosed as a small ventricular septal defect. 3. A classical withdrawal syndrome which developed after the period of CNS depression and which was treated successfully with phenobarbital. 4. A normochromic anemia, as described by Massimo, Pantarotto and Vianello (1972) which developed at 4 weeks (8 g%). At this time the serum folic acid level was shown to be normal in the child
280
L. H. J, Ramaekers
(21 nmol/l), but low in the mother (7.0 nmol/l, normal values 7-45 nmol/l). 5. Slightly subnormal psychomotor development and head growth which have persisted up to the present (age 6 months). Discussion
Cade, Hirsh and Martin (1969) assessed an almost complete placental barrier to coagulation factors. The fetal liver synthesizes all clotting factors except possibly factors VIII and XIII for which the site of biosynthesis is unknown (Bleyer, Hakami and Shepard, 1971). Synthesis of factors II, VII, IX and XXrequires vitamin K. Suttie (1967) produced experimental data indicating that the site of action of vitamin K in promoting the production of these clotting factors is at some step beyond the formation of a specific mRNA and prior to the release of the complete protein from the liver. Healthy full-term newborn infants normally show a whole-blood clotting time which is often shortened in comparison with the blood of adults, despite poorer platelet aggregation and moderately low activities of vitamin K dependent factors and of factors XI and XII. Bleeding in the newborn at term is rare, however, except in hypoxia and acidosis. The ‘physiologic dip’ in coagulation in the first few days of life is thought to be due to a combination of vitamin K deficiency and hepatic immaturity and is more pronounced in the premature infant. Though usually of little clinical importance the early dip can cause hemorrhagic problems if other factors are present which contribute to this tendency. Hemorrhagic disease in the newborn after maternal anticonvulsant drugs was suggested in 1957 by Van Creveld. In the British literature case reports of neonatal bleeding (intracranial and intraabdominal) after maternal phenobarbital and/or diphenylhydantion therapy were reported by Lawrence (1963), Douglas (1966), Kohler (1966), Evans (1970) and Stevenson and Gilbert (1970). Mountain, Hirsh and Gallus (1970) were the first to report a prospective study of coagulation factors in 16 neonates of 16 epileptic mothers and found particularly after phenobarbital a serious coagulation defect in 7 neonates which was similar to vitamin K deficiency and characterized by a long prothrombin time, a long activated thromboplastin
and T. S. The, Maternal
anticonvulsants
and perinatal
risk
time, and low levels of factor II, VII, IX and X. Two of the neonates had clinical evidence of bleeding (oozing from the cord). The effect of vitamin K was assessed in one neonate, the defect being no longer evident at 22 hours. The results of coagulation investigations performed on 2 mothers of neonates with a severe defect were normal. Experimental evidence of an association between diphenylhydantoin and coagulation abnormalities was shown in cats by Hilgartner, Solomon and Kutt (1971). Cats on 2.5-10 mg diphenylhydantoin showed a 50 % decrease in factors I-II-V-VII and X, preventable by administration of vitamin K. We found normal and no significant differences in coagulation factors before and after 3 days vitamin K in the mother described above (Table I). TABLE I
Coagulation
factors of the mother*
Factors
II
V
VII
x
Before vitamin K After vitamin K
98 92
104 117
87 94
97 92
* Determined by Dr. H. C. Hemker, Med. Fat., Maastricht, The Netherlands.
The clinical picture of hemorrhagic disease in the newborn after anticonvulsant therapy of the mother differs clearly from the classical hemorrhagic disease of the newborn. Bleeding occurs earlier, namely within 24 hours and in the pleural and abdominal cavities, the pericardium, the liver and intracranially. This is in contrast to classical bleeding disease where bleeding occurs from the gastrointestinal tract on the second or third day coinciding with the ‘physiologic dip’ in coagulation levels postnatally. Both previous full-term neonates in our case report showed the above-mentioned bleeding sites but a causal relationship with the anticonvulsants, although highly probable, cannot be proved. The clinical bleeding in our patient subsided promptly after administration of vitamin K, 2 mg i.v., as in most of the reports in the literature. How precisely anticonvulsants interfere with vitamin K metabolism needs to be further elucidated. Preventive
measures
The incidence of epilepsy is reported to be 0.5 % in the population as a whole. In the case of The
L. H. J. Ramaekers
and T. S. The, Maternal
anticonvulsants
and perinatal
Netherlands this means that 1000 children are born to epileptic mothers annually. Perinatal treatment of bleeding disorders seems to be an important contribution in efforts made to lower perinatal mortality and morbidity rates. We should therefore like to stress the need for a well-planned prospective study of the subject by obstetricians and neonatologists. Mountain et al. (1970) suggested the intravenous administration of vitamin K during labor, in addition to the oral administration. Margolin and Kantor (1972) attributed the comparatively low incidence of bleeding accidents in the U.S.A. to the practically routine administration of vitamin K in the nurseries. Seip (1973) advocates the prophylactic use of vitamin K 10 mg daily by mouth during the last two months of pregnancy. After birth 1 mg should be given intramuscularly to the baby. Although oral administration of vitamin K is probably a safe procedure, a controlled clinical trial still needs to be done, including coagulation studies in the infant. Possible negative effects of prophylactic use of vitamin K on the fetus and the newborn such as increased hemolysis with hyperbilirubinemia (Oski and Naiman, 1972) should be investigated at the same time so that an optimal nontoxic dosage can be arrived at. We do not agree with those advocating vitamin K exclusively to the newborn because harm to the fetus might occur during the birth process. This probably happened in the second and fourth pregnancies referred to in our case report. In an attempt to decrease the number of congenital malformations due to anticonvulsant therapy, attributed by many to folic acid deficiency, monitoring of maternal blood folic acid and anticonvulsant levels in the first trimester of pregnancy seems a logical procedure. Pregnancy in itself increases the normal daily requirement of folic acid. The administration of anticonvulsant drugs, in particular diphenylhydantoin is associated with a high incidence of subnormal levels of folic acid.This folatedepleting action of diphenylhydantoin appears to be dose related and to be enhanced by the addition of barbiturates. However, the role of folic acid decifiency has still to be established with certainty. A prospective study by Hall (1972) on the role of folic acid in congenital malformations even casts doubts as to whether such a causal relationship exists.
risk
281
In addition it should be borne in mind that the noncontrolled administration of folic acid might lower serum diphenylhydantoin levels, thus precipitating seizures in stabilized epileptics as shown by Strauss and Bernstein (1974). The observations by Schmid (1967) confirmed by Silver, Davies, Kupersmitt, Orme, Petrie and Vajda (1974) that rickets and osteomalacia occur in on long-term anticonvulsant epileptic patients therapy, bring to mind the unanswered question: does a 25-hydroxy-cholecalciferol deficiency state in the mother have an influence upon the extremely rapid growth of the skeleton of the fetus? Both clinical and experimental evidence indicate that the administration of phenobarbital enhances the conversion of cholecalciferol to 25-hydroxy-cholecalciferol by hepatic enzyme induction and increases the excretion of biliary metabolites. In view of these observations it is necessary to determine the dietary vitamin D requirements for the pregnant epileptic. According to Silver et al. (1974) growing children on anticonvulsive therapy should be given a vitamin D supplement of 75 mg (= 3000 IU) cholecalciferol weekly. This would probably be an acceptable nontoxic dosage for the pregnant epileptic and her child. Acknowledgements The determinations of phenobarbital, diphenylhydantion and primidone were carried out in the Department of Clinical Pharmacy of the St. Annadal Hospital, Maastricht, The Netherlands. Thanks are due to Mrs. Saat and Mrs. Geelen for preparing the manuscript. References Bjerkedal, T. and Bahna, S. L. (1973): The course. and outcome of pregnancy in women with epilepsy. Aeta obstet. gynec. stand., 52, 245. Bleyer, W. A., Hakami, N. and Shepard, T. H. (1971): The development of hemostasis in the human fetus and newborn infant. Fetal neonat. Med., 79, 838. Cade, J. F., Hirsh, J. and Martin, M. (1969): Placental barrier to coagulation factors: Its relevance to the coagulation defect at birth and to haemorrhage in the newborn. Brir. med. J., 2, 281.
Douglas, H. (1966): Haemorrhage in the newborn. Lancer, 1, 816. Elshove, J. and Van Eck, 3. H. M. (1971): Aangeboren misvormingen, met name gespleten lip met of zonder gespteten verhemelte, bij kinderen van moeders met epilepsie. Ned. T. Geneesk.,
115133.
L. H. J. Ramaekers
282
Evans, A. R. (1970): Neonatal haemorrhage following maternal anticonvulsant therapy. Lancet, I, 517. Fedrick, J. (1973): Epilepsy and pregnancy: A report from the Oxford Record Linkage Study. &it. med. J., 2, 442.
Hall, M. H. (1972): Folic acid deficiency and congenital malformation. J. Obstet. Gynaec. &it. Cwlth, 79, 159. Hilgartner, M., Solomon, G. E. and Kutt, H. (1971): Diabnormalities. coagulation phenylhydantoin induced Pediat.
Res., 5, 408.
Hill, R. M., Verniaud, W. M., Horning, M. G., McCulley, L. B. and Morgan, N. F. (1974): Infants exposed in utero to antiepileptic drugs. Amer. J. Dis. Child., 127, 645. Kohler, H. G. (1966): Haemorrhage in the newborn of epileptic mothers. Lancet, I, 267. Lawrence, A. (1963): Anti-epileptic drugs and the foetus. Brit. med. J., 2, 1267.
Lowe, C. R. (1973): Congenital malformations among infants born to epileptic women. Lancet, I, 9. Margolin, F. and Kantor, N. M. (1972): Hemorrhagic disease of the newborn. Clin. Pediat., II, 59. Massimo, L., Pantarotto, M. F. and Vianello, M. G. (1972): Haematological and cytogenetic effects induecd in the newborn by anticonvulsant treatment of the mother during pregnancy. In: Summaries of Communications, 3rd Scientific Meeting of the European Society for Paediatric logy and Immunology, Hamburg 1972, p.24.
Haemato-
Meadow, S. R. (1968): Anticonvulsant drugs and congenital abnormalities. Lancet, 2, 1296. Monson, R. R., Rosenberg, L., Hartz, S. C., Shapiro, S., Heinonen, 0. P. and Slone, D. (1973): Diphenylhydantoin and selected congenital malformations. N. Engl. J. Med., 289, 1049.
and T. S. The, Maternal
anticonvulsants
and perinatal
risk
Mountain, K. R., Hirsh, J. and Gallus, A. S. (1970): Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet, I, 265. Oski, F. A. and Naiman, J. L. (1972): Haematologic Problems in the Newborn, 2nd ed., p. 252. W. B. Saunders, Philadelphia - London. Schmid, F. (1967): Osteopathien bei antiepileptischer Dauerbehandlung. Fortschr. Med., 9, 381. Seip, M. (1973): Effects of antiepileptic drugs in pregnancy on the fetus and newborn infant. Ann. clin. Res., 5, 205. Silver, J., Davies, T. J., Kupersmitt, E., Orme, M., Petrie A. and Vajda, F. (1974): Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs. Arch. Dis. Childh., 49, 344.
Speidel, B. D. and Meadow, S. R. (1972): Maternal epilepsy and abnormalities of the fetus and newborn. Lancer, 2, 839. Stevenson, M. M. and Gilbert, E. F. (1970): Anticonvulsants and hemorrhagic diseases of the newborn infant. J. Pediat., 77, 516.
Strauss, R. G. and Bernstein, R. (1974): Folic acid and dilantin antagonism in pregnancy. Obstet. and Gynec., 44, 345.
Suttie, J. W. (1967): Control of prothrombin and factor VII biosynthesis by vitamin K’. Arch. Biochem. Eiophys., 118, 166.
Van Creveld, S. (1957): Morbus haemorrhagicus neonatorum. Ned. T. Geneesk., 101, 2109. Zellweger, H. (1974): Anticonvulsants during pregnancy: A danger to the developing fetus? Clin. Pediat., 13, 338. Address for reprints:
Dr L. H. J. Ramaekers, The Netherlands.
St. Annadal
Hospital,
Maastricht,
BIOL., 1975, S/S, 277-282.
EXCERPTA
MEDICA
Maternal anticonvulsants and perinatal risk L. H. J. Ramaekers and T. S. The Department
of Neonatology,
RAMAEKERS,
St. Annadal Hospital,
Maastricht,
The Netherlands
L. H. J. and THE, T. S. (1975): Maternal anticonvulsants
and perinatal
risk. Europ. J. Obsret.
Gynec.
reprod.
Biol., 515, 277-287.
According to data found in the literature, children born to epileptic mothers on anticonvulsant therapy have an increased perinatal mortality rate, namely 2-3 times the average. The congenital malformations attributed to anticonsulvant drugs cannot fully account for this high mortality rate. A case is described in which a severe bleeding disorder manifested itself in successive offspring. A discussion follows in which this defect in blood coagulation in the newborn and the role played by vitamin K is con- ; sidered as representing an important and preventable cause of neonatal death and morbidity. Other features of the postnatal syndrome (CNS depression, congenital heart disease, withdrawal symptoms, anemia) are mentioned in the case report. Suggested preventative measures employing vitamin K, folic acid and vitamin D are briefly discussed. coagulation defect; hemorrhage;
epilepsy; vitamin K
Introduction
The combined efforts of obstetricians and neonatologists can reduce perinatal mortality to its minimum, but increased emphasis should be placed upon efforts to reduce infant morbidity by preventative measures. Several reports of anticonvulsants as a cause of abnormalities of the fetus and newborn have appeared in the literature of the last decennium. Bjerkedal and Bahna (1973) found a tripling of the infant mortality rate (34.6 versus 11.4/1000) in a retrospective study of 371 pregnancies in epileptic women. The majority of the deaths were neonatal (29.3 versus S.O/lOOO). An exact analysis of the cause of perinatal mortality was not given, although complications such as vaginal hemorrhage and toxemia were reported almost twice as frequently as in the control group. The incidence of intervention during the delivery (forceps, vacuum extraction, cesarian section) and of hypoxia was more than double that reported in the control group. Similar
findings had previously been reported by SpeideI and Meadow (1972) in a retrospective survey of the follow-up of 427 pregnancies in 186 epileptic women. The perinatal mortality rate was 42.5/1000, which was twice the regional rate. This higher rate was reported to be mainly due to congenital malformations and spontaneous hemorrhage. Most reports, Meadow (1968), Elshove and Van Eck (1971), Hill, Verniaud, Horning, McCulley and Morgan (1974), Fedrick (1973), Lowe (1973), Monson, Rosenberg, Hartz, Shapiro, Heinonen and Slone (1973), Zellweger (1974) deal particularly with congenital malformations and the teratogenic The Oxford Record effects of anticonvulsants. Linkage Study, however, mentions also a higher incidence of stillbirths and a slight increase in asphyxia and intracranial hemorrhage. The authors are of the opinion that the nature and severity of most of the congenital malformations seen in the offspring of epileptic mothers, are not sufficient to account for the doubling or tripling of the perinatal mortality rate. Other possible
L. H. J. Ramaekers and T. S. The, Maternal anticonvulsants and perinatal risk
278
causes must therefore be seriously considered. We should therefore like to draw the attention to bleeding disorders associated with anticonvulsant therapy since this seems to be not only an important but also a preventable and curable cause of perinatal mortality and morbidity. The following case is reported because it illustrates such a bleeding disorder. Many other aspects of the syndrome are also briefly mentioned, more detailed descriptions having appeared in pediatric literature elsewhere.
hydantoin (150 mgjday), without interruption, since her 19th birthday. Two pregnancies had ended in spontaneous abortions at 4 weeks’ gestation. A third pregnancy (1962) had ended in a spontaneous normal delivery at 40 weeks. The newborn died in shock on the third day. Autopsy revealed extensive bleedings in lung, liver and peritoneal cavity. Familial hemorrhagic disease was excluded. The fourth pregnancy (1972) had ended spontaneously at 42 weeks’ gestation. The child was a breech presentation with prolapsed cord. Fetal hypoxia had resulted in a low Apgar score and the child died on the first day. At autopsy there was 150 ml blood in the peritoneal cavity, bilateral subdural hemorrhage, and subcapsular hemorrhage in the liver. Being unaware at the time of a possible causal relationship between anticonvulsant therapy and
Case report Obstetrical history (see Fig. 1): The patient, a 36-year-old woman, had been treated for epilepsy with a relatively low dosage of primidone (250 mg/ day), phenobarbital (150 mg/day) and diphenyl-
9
Cath.
Epileptic
W.E ., lX,24-1938
‘henobarbitol
m
150mg/doy
Iiphenylhydantoin
m
lSOmg/day
‘rimidone
m
250mgjdoy
1961
treatment
since
1967
1972
1970
1962
1974
OBSTETRICAL spont. abortion 8 weeks
HISTORY
Fig.
1
at
S~rr.xna~y of the most imyortent
full term pregnancy 0 $e~ay
rpont. abortion ot 8 weeks
data of the obstetrical
history.
full
term
p$:;;cy
full term pregnancy Elective Caes. sect.
219
L. H. J. Rumaekers and T. S. The, Maternal anticonvulsants and perinatal risk
WEEKS
El ANAEMIA
Haemoglobin
g v*
= Diphenylhydontoin . Primidone
C.N.S.
signs I-
Phcnc
t
2 mg VITAMIN
Therapy
Fig.
2
Schematic
representation
K i.v.
of the postnatal
morbidity
hemorrhagic disease in the newborn the cause of death was attributed to fetal anoxia with hemorrhage. On account of the above obstetric history an elective cesarian section at 39 weeks was planned for the fifth pregnancy. The neonate (Fig. 2) cried within one minute of birth, the Apgar score was 8 at one minute, and the child was transferred to the neonatal intensive care unit for further close observation. The newborn showed normal vital functions and normal reflexes (Moro, sucking, rooting, posture, muscle tonicity). On routine blood examination normal Astrup values were found shortly after birth. A persistent oozing from the heel puncture was the first alarming symptom. Coagulation time was 9’, thrombocytes 288,000/mm3, the normotest, measuring vitamin K dependent factors, was less than 5 % (normal 70-130 %). 2 mg vitamin K was given intravenously and within 12 hours the bleeding disturbance had been reversed
data.
and coagulation returned to normal. 24 hours after birth the infant blood showed a phenobarbital level of 38 mg/l, 8 mg diphenylhydantoin, and 7 mg/l primidone. In the postnatal period (Fig. 2) we were confronted with the following problems: 1. Increasing depression of the central nervous system in the days following birth as evidenced by poor sucking, inability to swallow, increasing muscle hypotonicity and sleepiness. 2. A holosystolic grade III/IV murmur which was heard shortly after birth, and was diagnosed as a small ventricular septal defect. 3. A classical withdrawal syndrome which developed after the period of CNS depression and which was treated successfully with phenobarbital. 4. A normochromic anemia, as described by Massimo, Pantarotto and Vianello (1972) which developed at 4 weeks (8 g%). At this time the serum folic acid level was shown to be normal in the child
280
L. H. J, Ramaekers
(21 nmol/l), but low in the mother (7.0 nmol/l, normal values 7-45 nmol/l). 5. Slightly subnormal psychomotor development and head growth which have persisted up to the present (age 6 months). Discussion
Cade, Hirsh and Martin (1969) assessed an almost complete placental barrier to coagulation factors. The fetal liver synthesizes all clotting factors except possibly factors VIII and XIII for which the site of biosynthesis is unknown (Bleyer, Hakami and Shepard, 1971). Synthesis of factors II, VII, IX and XXrequires vitamin K. Suttie (1967) produced experimental data indicating that the site of action of vitamin K in promoting the production of these clotting factors is at some step beyond the formation of a specific mRNA and prior to the release of the complete protein from the liver. Healthy full-term newborn infants normally show a whole-blood clotting time which is often shortened in comparison with the blood of adults, despite poorer platelet aggregation and moderately low activities of vitamin K dependent factors and of factors XI and XII. Bleeding in the newborn at term is rare, however, except in hypoxia and acidosis. The ‘physiologic dip’ in coagulation in the first few days of life is thought to be due to a combination of vitamin K deficiency and hepatic immaturity and is more pronounced in the premature infant. Though usually of little clinical importance the early dip can cause hemorrhagic problems if other factors are present which contribute to this tendency. Hemorrhagic disease in the newborn after maternal anticonvulsant drugs was suggested in 1957 by Van Creveld. In the British literature case reports of neonatal bleeding (intracranial and intraabdominal) after maternal phenobarbital and/or diphenylhydantion therapy were reported by Lawrence (1963), Douglas (1966), Kohler (1966), Evans (1970) and Stevenson and Gilbert (1970). Mountain, Hirsh and Gallus (1970) were the first to report a prospective study of coagulation factors in 16 neonates of 16 epileptic mothers and found particularly after phenobarbital a serious coagulation defect in 7 neonates which was similar to vitamin K deficiency and characterized by a long prothrombin time, a long activated thromboplastin
and T. S. The, Maternal
anticonvulsants
and perinatal
risk
time, and low levels of factor II, VII, IX and X. Two of the neonates had clinical evidence of bleeding (oozing from the cord). The effect of vitamin K was assessed in one neonate, the defect being no longer evident at 22 hours. The results of coagulation investigations performed on 2 mothers of neonates with a severe defect were normal. Experimental evidence of an association between diphenylhydantoin and coagulation abnormalities was shown in cats by Hilgartner, Solomon and Kutt (1971). Cats on 2.5-10 mg diphenylhydantoin showed a 50 % decrease in factors I-II-V-VII and X, preventable by administration of vitamin K. We found normal and no significant differences in coagulation factors before and after 3 days vitamin K in the mother described above (Table I). TABLE I
Coagulation
factors of the mother*
Factors
II
V
VII
x
Before vitamin K After vitamin K
98 92
104 117
87 94
97 92
* Determined by Dr. H. C. Hemker, Med. Fat., Maastricht, The Netherlands.
The clinical picture of hemorrhagic disease in the newborn after anticonvulsant therapy of the mother differs clearly from the classical hemorrhagic disease of the newborn. Bleeding occurs earlier, namely within 24 hours and in the pleural and abdominal cavities, the pericardium, the liver and intracranially. This is in contrast to classical bleeding disease where bleeding occurs from the gastrointestinal tract on the second or third day coinciding with the ‘physiologic dip’ in coagulation levels postnatally. Both previous full-term neonates in our case report showed the above-mentioned bleeding sites but a causal relationship with the anticonvulsants, although highly probable, cannot be proved. The clinical bleeding in our patient subsided promptly after administration of vitamin K, 2 mg i.v., as in most of the reports in the literature. How precisely anticonvulsants interfere with vitamin K metabolism needs to be further elucidated. Preventive
measures
The incidence of epilepsy is reported to be 0.5 % in the population as a whole. In the case of The
L. H. J. Ramaekers
and T. S. The, Maternal
anticonvulsants
and perinatal
Netherlands this means that 1000 children are born to epileptic mothers annually. Perinatal treatment of bleeding disorders seems to be an important contribution in efforts made to lower perinatal mortality and morbidity rates. We should therefore like to stress the need for a well-planned prospective study of the subject by obstetricians and neonatologists. Mountain et al. (1970) suggested the intravenous administration of vitamin K during labor, in addition to the oral administration. Margolin and Kantor (1972) attributed the comparatively low incidence of bleeding accidents in the U.S.A. to the practically routine administration of vitamin K in the nurseries. Seip (1973) advocates the prophylactic use of vitamin K 10 mg daily by mouth during the last two months of pregnancy. After birth 1 mg should be given intramuscularly to the baby. Although oral administration of vitamin K is probably a safe procedure, a controlled clinical trial still needs to be done, including coagulation studies in the infant. Possible negative effects of prophylactic use of vitamin K on the fetus and the newborn such as increased hemolysis with hyperbilirubinemia (Oski and Naiman, 1972) should be investigated at the same time so that an optimal nontoxic dosage can be arrived at. We do not agree with those advocating vitamin K exclusively to the newborn because harm to the fetus might occur during the birth process. This probably happened in the second and fourth pregnancies referred to in our case report. In an attempt to decrease the number of congenital malformations due to anticonvulsant therapy, attributed by many to folic acid deficiency, monitoring of maternal blood folic acid and anticonvulsant levels in the first trimester of pregnancy seems a logical procedure. Pregnancy in itself increases the normal daily requirement of folic acid. The administration of anticonvulsant drugs, in particular diphenylhydantoin is associated with a high incidence of subnormal levels of folic acid.This folatedepleting action of diphenylhydantoin appears to be dose related and to be enhanced by the addition of barbiturates. However, the role of folic acid decifiency has still to be established with certainty. A prospective study by Hall (1972) on the role of folic acid in congenital malformations even casts doubts as to whether such a causal relationship exists.
risk
281
In addition it should be borne in mind that the noncontrolled administration of folic acid might lower serum diphenylhydantoin levels, thus precipitating seizures in stabilized epileptics as shown by Strauss and Bernstein (1974). The observations by Schmid (1967) confirmed by Silver, Davies, Kupersmitt, Orme, Petrie and Vajda (1974) that rickets and osteomalacia occur in on long-term anticonvulsant epileptic patients therapy, bring to mind the unanswered question: does a 25-hydroxy-cholecalciferol deficiency state in the mother have an influence upon the extremely rapid growth of the skeleton of the fetus? Both clinical and experimental evidence indicate that the administration of phenobarbital enhances the conversion of cholecalciferol to 25-hydroxy-cholecalciferol by hepatic enzyme induction and increases the excretion of biliary metabolites. In view of these observations it is necessary to determine the dietary vitamin D requirements for the pregnant epileptic. According to Silver et al. (1974) growing children on anticonvulsive therapy should be given a vitamin D supplement of 75 mg (= 3000 IU) cholecalciferol weekly. This would probably be an acceptable nontoxic dosage for the pregnant epileptic and her child. Acknowledgements The determinations of phenobarbital, diphenylhydantion and primidone were carried out in the Department of Clinical Pharmacy of the St. Annadal Hospital, Maastricht, The Netherlands. Thanks are due to Mrs. Saat and Mrs. Geelen for preparing the manuscript. References Bjerkedal, T. and Bahna, S. L. (1973): The course. and outcome of pregnancy in women with epilepsy. Aeta obstet. gynec. stand., 52, 245. Bleyer, W. A., Hakami, N. and Shepard, T. H. (1971): The development of hemostasis in the human fetus and newborn infant. Fetal neonat. Med., 79, 838. Cade, J. F., Hirsh, J. and Martin, M. (1969): Placental barrier to coagulation factors: Its relevance to the coagulation defect at birth and to haemorrhage in the newborn. Brir. med. J., 2, 281.
Douglas, H. (1966): Haemorrhage in the newborn. Lancer, 1, 816. Elshove, J. and Van Eck, 3. H. M. (1971): Aangeboren misvormingen, met name gespleten lip met of zonder gespteten verhemelte, bij kinderen van moeders met epilepsie. Ned. T. Geneesk.,
115133.
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Evans, A. R. (1970): Neonatal haemorrhage following maternal anticonvulsant therapy. Lancet, I, 517. Fedrick, J. (1973): Epilepsy and pregnancy: A report from the Oxford Record Linkage Study. &it. med. J., 2, 442.
Hall, M. H. (1972): Folic acid deficiency and congenital malformation. J. Obstet. Gynaec. &it. Cwlth, 79, 159. Hilgartner, M., Solomon, G. E. and Kutt, H. (1971): Diabnormalities. coagulation phenylhydantoin induced Pediat.
Res., 5, 408.
Hill, R. M., Verniaud, W. M., Horning, M. G., McCulley, L. B. and Morgan, N. F. (1974): Infants exposed in utero to antiepileptic drugs. Amer. J. Dis. Child., 127, 645. Kohler, H. G. (1966): Haemorrhage in the newborn of epileptic mothers. Lancet, I, 267. Lawrence, A. (1963): Anti-epileptic drugs and the foetus. Brit. med. J., 2, 1267.
Lowe, C. R. (1973): Congenital malformations among infants born to epileptic women. Lancet, I, 9. Margolin, F. and Kantor, N. M. (1972): Hemorrhagic disease of the newborn. Clin. Pediat., II, 59. Massimo, L., Pantarotto, M. F. and Vianello, M. G. (1972): Haematological and cytogenetic effects induecd in the newborn by anticonvulsant treatment of the mother during pregnancy. In: Summaries of Communications, 3rd Scientific Meeting of the European Society for Paediatric logy and Immunology, Hamburg 1972, p.24.
Haemato-
Meadow, S. R. (1968): Anticonvulsant drugs and congenital abnormalities. Lancet, 2, 1296. Monson, R. R., Rosenberg, L., Hartz, S. C., Shapiro, S., Heinonen, 0. P. and Slone, D. (1973): Diphenylhydantoin and selected congenital malformations. N. Engl. J. Med., 289, 1049.
and T. S. The, Maternal
anticonvulsants
and perinatal
risk
Mountain, K. R., Hirsh, J. and Gallus, A. S. (1970): Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet, I, 265. Oski, F. A. and Naiman, J. L. (1972): Haematologic Problems in the Newborn, 2nd ed., p. 252. W. B. Saunders, Philadelphia - London. Schmid, F. (1967): Osteopathien bei antiepileptischer Dauerbehandlung. Fortschr. Med., 9, 381. Seip, M. (1973): Effects of antiepileptic drugs in pregnancy on the fetus and newborn infant. Ann. clin. Res., 5, 205. Silver, J., Davies, T. J., Kupersmitt, E., Orme, M., Petrie A. and Vajda, F. (1974): Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs. Arch. Dis. Childh., 49, 344.
Speidel, B. D. and Meadow, S. R. (1972): Maternal epilepsy and abnormalities of the fetus and newborn. Lancer, 2, 839. Stevenson, M. M. and Gilbert, E. F. (1970): Anticonvulsants and hemorrhagic diseases of the newborn infant. J. Pediat., 77, 516.
Strauss, R. G. and Bernstein, R. (1974): Folic acid and dilantin antagonism in pregnancy. Obstet. and Gynec., 44, 345.
Suttie, J. W. (1967): Control of prothrombin and factor VII biosynthesis by vitamin K’. Arch. Biochem. Eiophys., 118, 166.
Van Creveld, S. (1957): Morbus haemorrhagicus neonatorum. Ned. T. Geneesk., 101, 2109. Zellweger, H. (1974): Anticonvulsants during pregnancy: A danger to the developing fetus? Clin. Pediat., 13, 338. Address for reprints:
Dr L. H. J. Ramaekers, The Netherlands.
St. Annadal
Hospital,
Maastricht,