Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303
Mark S. Yerby M.D., M.P.H.
Clinical Associate Professor of Neurology, Public Health and Ob-Gyn
Oregon Health Sciences University
CONCLUSION
A coordinated approach by obstetricians, gynecologists and neurologists is important in promoting optimal treatment and adequate patient education. Despite the risks (TABLE 2), with proper management, over 90% of WWE can have a successful pregnancy and healthy child.
Antiepileptic drugs may interfere with the hypothalamic pituitary axis. Amenorrhea, oligomenorrhea, prolonged or irregular cycles were seen in 20% of 238 WWE (44). Though only 12% of the 238 women were treated with valproate, 45% of those on valproate monotherapy and 25% on valproate polytherapy had menstrual disturbances. Polycystic ovaries were found in 43% of valproate treated women. Furthermore 80% of women treated with valproate before the age of 29 had polycystic ovarian disease.
Women with epilepsy have more variation in lutienizing hormone (LH) pulse frequency and lower LH concentrations than controls (45). In addition women with left sided ictal epileptiform foci had polycystic ovarian disease, and those with right sided foci hypogonadotropic hypogonadism.
The problem of infertility in WWE is clearly complicated. There are probably multiple factors: both seizure type, frequency and lateralization; as well as AEDs which may effect an individual patient. Infertility in a couple deserves a careful evaluation of both partners. For WWE ultrasonography to rule out polycystic ovarian disease, serum LH and FSH concentrations, and an evaluation of AED use will help one narrow the focus of treatment. While there is evidence that valproate may adversely impact the fertility of some women, unless polycystic ovarian disease or hypogondaotropic hypogonadism is found, discontinuation of valproate in a well controlled person is not warrented.
PREGNANCY
The ultimate goal for many women is a successful pregnancy and healthy child. Fortunately the majority of WWE can conceive and bear normal healthy children. The pregnancies of WWE do present a greater risk for complications, they are more likely to have difficulties during labor, and there is a higher risk of adverse pregnancy outcomes (TABLE 2).
Increased Seizure Frequency
During pregnancy, one-quarter to one-third of WWE will have an increase in seizure frequency (46), (TABLE 3), (47). This increase is unrelated to seizure type, duration of epilepsy, or seizure frequency in a previous pregnancy.
A variety of hypotheses have been proposed to explain the increase in seizure frequency seen during pregnancy (TABLE 4). Plasma concentrations of anticonvulsant drugs decline as pregnancy progresses, even in the face of constant and in some instances increasing doses (48). Plasma concentrations tend to rise postpartum (49). Although reduction of plasma drug concentration is not always accompanied by an increase in seizure frequency, virtually all women with increased seizures in pregnancy have subtherapeutic drug levels (50, 51, 52, 53, 54). Several mechanisms have been proposed to explain the decline of anticonvulsant levels during pregnancy (52). Intestinal malabsorption (55), decreased plasma protein binding (56, 39), reduced concentration of albumin, and increased drug clearance (48, 51, 57, 58) may all play some role. The rate of clearance appears to be greatest during the third trimester. Maternal weight gain alone without an increase in drug dose should result in a modest decrease in free an total drug level. TABLE 5 summarizes some of the pharmacokinetics of anticonvulsant drugs during pregnancy.
Though it is appealing to equate falling levels of anticonvulsant drugs with increasing seizure frequency, some clinical observations are at variance with this explanation. The increase in seizure frequency has been described both in the first trimester (59, 47, 60, 53) and evenly distributed throughout pregnancy (61), and not exclusively in the third trimester when the levels have fallen their lowest.
Other factors particularly compliance, may contribute to the decline in levels. In a prospective study, Schmidt and coworkers (53) discovered that 50 of 136 (37%) of pregnant WWE had an increase in seizure frequency. Upon careful questioning, 68% of these women were not compliant or were suffering from sleep deprivation. A prospective Japanese study, Otani (54), described an increase in seizure frequency in 27% of women. One half of these women were deliberately non compliant because of concerns about the effect of anticonvulsants on their children. With all of these factors contributing to the fall of drug levels during pregnancy, monthly monitoring of anticonvulsant drugs using free levels is advised (62).
Convulsions are undesirable during pregnancy. First trimester seizures have been found to increase the risk of congenital malformations in the offspring 12.3% vs. 4% for children exposed to maternal seizure at other times (63). Generalized, tonic-clonic seizures place both mother and fetus at risk for hypoxia and acidosis (64) as well as injury from blunt trauma. Canadian researchers have found that maternal seizures during gestation increase the risk of developmental delay (Leonard et al 1997). Although rare, stillbirths have occurred following a single generalized convulsion (65, 66), or series of seizures (67). Status epilepticus carries a high mortality rate for mother and fetus. In Teramo and Hiilesmaa's review, status epilepticus was an uncommon complication of epileptic pregnancies. Yet of the 29 reported cases, 9 of the mothers and 14 of the infants died during or shortly after an episode of status (68). The child of a woman who had three generalized tonic clonic seizures during her preg ancy, (at 19, 28, and 32 weeks gestation), developed an intracerebral hemorrhage (69).
Generalized (though not partial) convulsions occurring during labor can have a profound effect on fetal heart rate (70). The increased rate of neonatal hypoxia and low Apgar scores may be related to such events (71). Though generalized convulsions may have an adverse effect on fetal heart rate, partial seizures do not appear to do so.
Complications of Pregnancy
WWE are at greater risk for obstetrical complications during pregnancy. Vaginal bleeding has been described significantly more often in WWE than in controls. Not surprisingly, anemia has been described twice as often in WWE. Hyperemesis gravidarum occurs more frequently in these patients, and may complicate compliance with oral medication. Pre-eclampsia has also been described more frequently in these women, (72, 73, 74, 75,76).
Labor and delivery may offer more difficulties for WWE. Abruptio placentae and premature labor have been described more often in these patients. Weak uterine contractions have also been described in women taking anticonvulsant drugs, which may explain why interventions; induced labor, mechanical rupture of membranes, forceps, vacuum assistance, and cesarean sections are utilized twice as often in these pregnancies (71, 72, 77, 78, 79, 80).
Meperidine is frequently used for pain control post partum. It should used with caution due to its propensity for lowering seizure threshold. Serum AED levels tend to rise in the post partum period, plateauing around 8 to 10 weeks. Women whose dosage has been increased during pregnancy may therefore develop clinical toxicity, and need to be carefully monitored in the post partum period (81).
Complications in the Offspring
The infants of epileptic mothers are at greater risk for a variety of adverse pregnancy outcomes. These include fetal death, congenital malformations, neo natal hemorrhage, low birth weight, microcephaly, developmental delay, feeding difficulties, and childhood epilepsy (
).
Infant Mortality
Fetal death (defined as fetal loss after 20 weeks gestation) appears to be as common and perhaps as great a problem as congenital malformations and anomalies. Studies comparing stillbirth rates found higher rates in infants of mothers with epilepsy (1.3 - 14.0%) compared to infants of mothers without epilepsy (1.2 - 7.8%) (TABLE 6).
Spontaneous abortions, defined as fetal loss prior to 20 weeks of gestation, do not appear to occur more commonly in infants of mothers with epilepsy (71). Other studies have, however, demonstrated increased rates of neonatal and perinatal death. Perinatal death rates range from 1.3% to 7.8% compared to 1.0% to 3.9% for controls (64, 72, 77, 82, 83, 84, 85) (TABLE 6).
Malformations
Fetal malformations have been associated with in utero exposure to AED. Congenital malformations are defined as a physical defect requiring medical or surgical intervention and resulting in a major functional disturbance. In distinction congenital anomalies are defined as deviations from normal morphology that do not require intervention. It is uncertain whether these aberrations represent distinct entities or a spectrum of physiological responses to insult to the developing fetus: malformations at one extreme and anomalies at the other. For the purposes of this review, congenital malformations and anomalies will be discussed separately.
Congenital malformations are the most widely reported and dramatic adverse outcome of pregnancy. The first report of a malformation associated with anticonvulsant drugs described a child exposed to mephenytoin in utero who developed microcephaly, cleft palate, a speech defect, and an IQ of 60 (86). Speidel and Meadow (82), initiated a retrospective survey of 427 pregnancies in 186 WWE, and found increased rates of malformations. They concluded that: 1) congenital malformations were twice as common in infants exposed to anticonvulsant drugs in utero; 2) no single abnormality was specific for anticonvulsant exposure; 3) a group of these children had a characteristic pattern of anomalies which at its fullest expression consisted of trigonocephaly, microcephaly, hypertelorism, low set ears, short neck, transverse palmar creases, and minor skeletal abnormalities.
Congenital malformations remain the most commonly reported adverse pregnancy outcome. Infants of mothers with epilepsy, exposed to anticonvulsant drugs in utero, are twice as likely to develop birth defects as infants not exposed to these drugs (82, 87). Malformation rates in the general population range from 2 to 3% (79, 88). Reports of malformation rates in various populations of exposed infants range from 1.25 to 11.5% (88, 89, 90). These combined estimates yield a risk of malformations in an individual epileptic pregnancy of 4 to 6%. Cleft lip, cleft palate, or both, and congenital heart disease account for many of the reported cases. Orofacial clefts are responsible for 30% of the increased risk of malformations in these infants (88,91).
Virtually every type of congenital malformation has been reported, and every anticonvulsant drug has been implicated as a cause. No anticonvulsant drug can be considered absolutely safe in pregnancy, yet most of these drugs do not produce any specific pattern of major malformations.
A possible exception to this is the association of sodium valproate and carbamazepine with neural tube defects (NTD). Robert and Guibaud (92) were the first to make this association. Working in a birth defects registry in the Rhone Alps region of France they reported NTD in infants of mothers with epilepsy (IME), exposured to valproic acid in utero. More recent studies have revealed an association between carbamazepine exposure in utero and NTD, (93). Subsequent evaluations of these exposures identify spina bifida apperta (SB) as the specific NTD associated with the valproic acid or carbamazepine exposure (94). Methodologic problems make frequency estimates imprecise since most published data are case reports, case series, or very small cohorts from registries that were not designed to evaluate pregnancy outcomes. The prevalence of SB with valproate exposure is approximately 1% to 2% (95), and with carbamazepine 0.5% (93, 96). However, a recent prospective study in Holland found IME exposed to valproate had a 5.4% prevalence rate of SB. Average daily valproate doses were higher in the IME with SB (1,640 + 136 mg/d) than in the unaffected IME (941 + 48 mg/d). The authors recommend that valproate dose be reduced whenever valproate must be used in pregnancy (100).
Neonatal Hemorrhage
A hemorrhagic phenomenon has been described in the infants of mothers with epilepsy. It differs from other hemorrhagic disorders in infancy in that the bleeding tends to occur internally during the first 24 hours of life. First described by Van Creveld (97) and delineated as a syndrome by Mountain (98), it was initially associated with exposure to phenobarbital or primidone but has subsequently also been described in children exposed to phenytoin, carbamazepine, diazepam, mephobarbital, amobarbital, and ethosuximide. Prevalence figures are as high as 30% but appear to average 10%. Mortality is high, over 30%, because bleeding occurs within internal cavities and is often not noticed until the child is in shock.
The hemorrhage appears to be a result of a deficiency of vitamin K-dependent clotting Factors II, VII, IX, and X. Anticonvulsants can act like warfarin, and can inhibit vitamin K transport across the placenta. These effects can be overcome by large concentrations of the vitamin. Maternal coagulation parameters are invariably normal. The fetus, however, will demonstrate diminished clotting factors and prolonged prothrombin and partial thromboplastin times.
This phenomenon can be prevented by maternal ingestion of oral vitamin K1 in the last month of gestation (99). Despite lower coagulation factor levels, the fetus is generally able to obtain enough maternal vitamin K in utero. After birth it must rely on exogenous sources of vitamin K because the newborn gut is sterile. Routine intramuscular administration of vitamin K at birth is not adequate to prevent hemorrhage within the first 24 hours of life.
Low Birth Weight
Low birth weight (less than 2500 gm) and prematurity have been described in infants of epileptic mothers. The average rates range from 7-10% for low birth weight and 4-11% for prematurity (38, 70, 72, 75, 89, 101). These studies do not analyze the effect of specific seizure types, frequency or AED on this aspect of fetal development.
Developmental Delay
Infants of mothers with epilepsy have been reported to have higher rates of mental retardation than controls. This risk is increased by a factor of 2 to 7 fold according to various authors (78, 82, 102). None of these studies controlled for parental intelligence, although differences in IQ scores at age 7 between groups of children exposed (FSIQ = 91.7) or not exposed (FSIQ = 96.8) to phenytoin reached statistical significance, the clinical significance of such difference is unknown (78).
We have found that IME display lower scores in measures of verbal acquisition at both two and three years of age. Though there was no difference in physical growth parameters between IME and controls, IME scored significantly lower in the Bailey Scale of Infant Development's mental developmental index (MDI) at two and three years. They also performed significantly less well on the Bates Bretherton early language inventory (p<0.02) and in the peabody picture vocabulary's scales of verbal reasoning (p<0.001) and composite iq (p<0.01), and they displayed significantly shorter mean lengths of utterance (p<0.001), (103).<>
The question of whether maternal seizures or in utero exposure to AEDs are responsible for the developmental delay seen has in part been addressed by Leonard et al (1997). A group of children of mothers with epilepsy followed to school age were found to have a rate of intellectual deficiency of 8.6%. The Weschler Intelligence Scale for Children revealed significantly lower scores for children exposed to seizures during gestation (100.3), than for children whose mothers seizures were controlled (104.1) or controls (112.9).
Epilepsy in the Children of Parents with Epilepsy
The risk of epilepsy in children of parents with epilepsy is higher than that in the general population. Interestingly enough, this risk is higher (relative risk of 3.2) for children of mothers with epilepsy (104). Paternal epilepsy appears to have less impact on the development of seizures in children. The presence of maternal seizures during pregnancy, but not AED use, is associated with an increased risk of seizures in the offspring (relative risk 2.4) (105). Evidence to support a genetic component for seizure development in these infants comes from kindling studies in experimental animals. If rats with experimental epilepsy are made to have generalized seizures during pregnancy, their offspring are not more susceptible to kindling than rats with no seizures during parturition (106).
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Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303
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