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Does maternal epilepsy increase the risk of congenital malformations, or are the antiepileptic drugs to blame? Either way, the primary goal of therapy during pregnancy is to control a woman's seizures while minimizing fetal exposure to anticonvulsive drugs.
|Jump to:||Choose article section... How pregnancy impacts epilepsy Impact of maternal seizures on the fetus Epilepsy/AEDs contribute to miscarriages and malformations Key study ties abnormalities to anticonvulsive drugs Pregnancy registries monitor safety of drugs Should women with epilepsy breastfeed? Management begins with pre-pregnancy counseling Good seizure control protects mother and fetus Conclusions Key points Coding for epilepsy in pregnancy|
Does maternal epilepsy increase the risk of congenital malformations, or are the antiepileptic drugs to blame? Either way, the primary goal of therapy during pregnancy is to control a woman's seizures while minimizing fetal exposure to anticonvulsive drugs.
Roughly one out of every 100 pregnancies occurs in a woman with epilepsy.1 These pregnancies present a unique challenge to patient and clinician alike: the threat of maternal complications and malformations in fetuses exposed to antiepileptic drugs (AEDs) in utero. The good news, however, is that most women with epilepsy will have uncomplicated pregnancies and labors, and deliver a normal baby. But for others, the physiologic changes of pregnancy itself can complicate disease management.
Conversely, epilepsy and AEDs can affect pregnancy and its outcome. My goal here is to discuss the impact of pregnancy on epilepsy and the impact of epilepsy and AEDs on fetal and maternal outcomes, and to offer practical advice on managing patients.
For some women with epilepsy, changes in the frequency of seizures will occur throughout pregnancy, but the time of greatest risk for seizures is during labor and delivery.
Seizures during pregnancy. Studies show that the frequency of seizures during pregnancy remains stable in some women (roughly half, 48% to 57%), increases in one quarter to one third, and actually decreases in 9% to 22%.2-6 Many studies on seizure frequency during pregnancy have been criticized for their inconsistent methodology, lack of rigorous reporting, and inexact approach to assessing seizure frequency. The latter is often evaluated retrospectively to obtain pre-pregnancy data and prospectively to obtain pregnancy data.7 However, prospective, well-conducted studies attest to more frequent seizures in a portion of women.8,9 The probability that seizures will occur more often during pregnancy appears to be unrelated to type or duration of epilepsy or to seizure frequency during previous pregnancies.10
There may be several mechanisms by which seizures become more or less frequent during pregnancy; one hypothesis centers on hormonal fluctuations.11 During pregnancy, there's a marked rise in circulating estrogens (primarily estriol) and progesterone, which can modulate seizure frequency via their direct effects on neuronal hormone receptors. In animal studies, estrogen increases the likelihood of seizures, while progesterone decreases it.12 These findings are consistent with the premise that changes in circulating hormones alter seizure frequency during pregnancy. Also consistent with that possibility is the phenomenon of catamenial seizures (exacerbations at certain phases of the menstrual cycle), which are thought to occur because of fluctuations in progesterone and/or estrogen or changes in the estrogen/progesterone ratio.12,13 However, the contrary findings by other researchers that seizures do not increase in some women over the course of pregnancy suggest that not all women with epilepsy are sensitive to changes in circulating hormone levels.4
Hormones can influence seizure frequency not only via a direct effect on neurons, but also by altering the pharmacokinetics of AEDs, many of which are metabolized by the same liver enzymes that metabolize estrogen and progesterone.14-16 Other pregnancy-related changes that can influence the pharmacokinetics of AEDs are: (1) increased cardiac output resulting in increased renal blood flow and glomerular filtration; (2) increased adipose tissue, plasma volume, and extravascular fluid, resulting in increased volume of distribution; (3) decreased serum albumin, resulting in reduced protein binding and increased clearance of drugs; and (4) decreased gastrointestinal transit time, which can decrease drug absorption.11 Any of these pregnancy-associated changes can significantly alter the blood levels of AEDs with a resultant change in seizure control.
Another finding supports the importance of AED levels as a determinant of seizure control during pregnancy. Researchers have found that subtherapeutic serum levels of AEDs were linked to more frequent seizures in 30 women with epilepsy over 50 pregnancies.17 Conversely, among 78 pregnancies in 66 epileptic women whose closely monitored drug dosages remained at therapeutic levels, seizures during pregnancy were no more frequent or severe, when compared with the 9-month period before pregnancy.9
Behavioral factors like poor medication adherence may also affect antiepileptic levels during pregnancy. Because of concerns about the drugs' effects on the fetus, women with epilepsy appear to frequently skip or reduce doses of prescribed antiepileptic medications or discontinue them altogether. In a study of 125 pregnant women with epilepsy, for example, 27% adhered poorly to their drug regimen.18 Oft-cited reasons given for poor compliance were their anxiety about side effects (including teratogenicity) and worries about exposing the newborn to drugs through breastfeeding.
Another way pregnancy may promote more frequent seizures in some women is by bringing about or exacerbating other conditions or factors that heighten the risk of seizures. Sleep deprivation, which is particularly common during the third trimester of pregnancy, is a case in point. In one study of 136 pregnancies in 122 women with epilepsy, sleep deprivation or nonadherence to the AED regimen was responsible for more frequent seizures in 34 of the 50 pregnancies that had more frequent convulsions.19 Physical or psychological stress, too, can raise the risk of seizures.20
Seizures during labor. Studies show that generalized tonic-clonic seizures occur during labor or delivery in 1% to 2% of women with epilepsy.21,22 A woman is nine times likelier to experience seizures during labor and delivery, when compared to the rest of her pregnancy. Stress, subtherapeutic AED levels, and sleep deprivationthe same factors that elevate the risk of seizures during pregnancy overallmay all be responsible for the increased susceptibility during labor and delivery.
In a recent retrospective assessment, researchers identified primary generalized epilepsy (epilepsy with seizures generalized from onset) and subtherapeutic AED levels as risk factors for seizure during labor.23 They found that seizures during labor and delivery occurred in four of 32 pregnancies with primary generalized epilepsy, compared with none of 57 pregnancies with partial epilepsy. The investigators identified subtherapeutic AED levels as possibly precipitating seizures in three of the four women with seizures, while sleep deprivation was the most likely culprit in the fourth.
We still have much to learn about how maternal seizures affect the fetus. A woman's seizures during pregnancy or labor are associated with transient fetal bradycardia, which is possibly caused by maternal acid-base disequilibrium.10,24,25 Furthermore, repeated generalized tonic-clonic seizures, complex partial seizures, and status epilepticus may deprive the fetus of adequate oxygen.26
However, possibly because repeated seizures during pregnancy are relatively rare, no substantive evidence exists that maternal seizures during pregnancy convey lasting harm to the fetus.10 Similarly, excluding isolated cases, maternal seizures during labor or delivery haven't been linked with lasting harmful effects, although, hypothetically, they could lead to fetal trauma or death.10,27
Although more than 90% of pregnancies in women with epilepsy are uneventful, pregnancy outcomes in women with epilepsy are still poorer than those for the general population. These pregnancies are more likely to result in fetal loss, and infants are at increased risk for major and minor malformations and psychomotor or cognitive impairment.
Fetal loss. Miscarriage and preterm delivery are three to five times more common in women with epilepsy, when compared with those without the disease.1 The likelihood of fetal loss in epilepsy appears to rise with the severity of maternal epilepsy.28,29
Vitamin K deficiency, a factor integral to coagulation, may contribute to this higher rate of fetal and neonatal loss in the offspring of mothers taking antiepileptic medications.30 A pregnant woman's use of AEDs is linked to vitamin K deficiency (liver enzyme-inducing AEDs increase vitamin K metabolism and AEDs may also interfere with vitamin K absorption) and can increase the risk of hemorrhage in the newbornalthough the incidence of that has not been established and appears to be low.31
Teratogenicity. Congenital malformationsmost commonly congenital heart disease, orofacial clefts, neural-tube defects, intestinal atresia, and urogenital defectsare seen in 4% to 8% of babies of women with epilepsy, compared with 2% to 4% of babies in the general population.32-35 Moreover, minor congenital abnormalities occur two to three times more often in infants of mothers with epilepsy (10% to 30% of infants) than in infants in the general population.20
Minor congenital abnormalities include hypertelorism; upslanted palpebral fissures; broad nasal bridge; posteriorly rotated, low-set ears; distal digit/nail hypoplasia; short, upturned nose;finger-like thumb; dermatoglyphic variations; genital anomalies; widely spaced, hypoplastic nipples; epicanthal folds; strabismus; ptosis; wide mouth with prominent lips; head size/shape variations; low hairline; long philtrum; pinnal deformities; short neck; sutural ridging; wide fontanelles; and sternal/rib abnormalities. Fortunately, many of these improve or are outgrown.20,36 The offspring of women with this disease, however, may also show impaired cognitive or psychomotor development. Across several prospective population- and clinic-based studies, the intelligence scores of these children were slightly lower than those of controls.37-41
Probably a host of variables contributes to the congenital malformations and mental impairment in offspring of women with epilepsy: teratogenicity of AEDs, the effects of maternal seizures on the fetus, and maternal genes (that is, a genetic association between epilepsy and birth defects).41 Although limited data make it difficult to rank the relative importance of each of these factors, the weight of the evidence points to AEDs as a primary contributor. And while we can't say categorically that seizures during pregnancy and labor cause birth defects or other complications, again there's insufficient data to rule them nonteratogenic.41-43 Some research suggests that maternal (or paternal) genes associated with epilepsy can contribute to congenital malformations. However, numerous weaknesses in study designs render the findings inconclusive.41,44 On the other hand, the teratogenicity of older AEDs (for example, benzodiazepines, phenytoin, carbamazepine, phenobarbital, and valproate) is well-established.
The risk of congenital malformations increases with antiepileptic polytherapy (vs. monotherapy) and with increasing daily doses of AEDs, findings that support a causal relationship between AEDs and malformations.45 The association of specific AEDs or generations of drugs with particular patterns of birth defects also points to a causal association between exposure to AEDs and birth defects.
Years ago, researchers identified two syndromes characterized by a unique pattern of abnormalitiesfetal phenytoin syndrome and fetal valproate syndrome. Also known as fetal hydantoin syndrome, fetal phenytoin syndrome is manifested by small head circumference, dysmorphic facies, orofacial clefts, cardiac defects, and distal digital hypoplasia with small nails.
Fetal valproate syndrome, on the other hand, is characterized by ridged metopic suture leading to trigonocephaly; short, anteverted nose; broad nasal ridge; and small mouth with thin upper lip and everted lower lip.41 Similar anomalies are also seen in children exposed in utero to carbamazepine and phenobarbital. Therefore, these anomalies are usually referred to as fetal anticonvulsant syndrome. The syndrome is nearly indistinguishable physically from fetal phenytoin syndrome. Figures 1 and 2 illustrate fetal anticonvulsant syndrome.
In a 7-year study conducted at five maternity hospitals from 1986 to 1993, researchers assessed whether maternal epilepsy itself or anticonvulsant drugs were to blame for anticonvulsant embryopathy.42 More than 100,000 pregnant women were screened at delivery to identify three groups of infants: those exposed to AEDs, infants unexposed to AEDs but with a maternal history of seizures, and infants unexposed to AEDs and having no maternal history of seizures. This study corrected many of the methodologic flaws of previous studies by (1) employing examiners who assessed for birth defects while being almost always unaware of the infants' drug exposure, (2) by systematically and prospectively assessing infants for all features of embryopathy known to be associated with AEDs, and (3) by including a control group of infants born to mothers with a history of seizures and no AED use during pregnancy.
The results show that the 98 infants born to women with a history of seizures but no AED use during pregnancy were no more likely to have birth defects (major malformations, hypoplasia of midface and fingers, microcephaly, growth retardation as reflected in small body size) than the 508 infants born to control women with no seizures and no AED use. On the other hand, birth defects were 2.8 times more likely to occur in infants exposed to one AED (20.6% of 223 infants) than infants not exposed to AEDs and whose mothers had no seizure history (8.5% of 508 infants). Infants prenatally exposed to two or more AEDs had the highest prevalence of birth defects (28.0% of 93 infants), which were 4.2 times more likely to occur in these infants than in the group not exposed to AEDs and whose mothers had no seizure history.42
Whereas the teratogenicity of older AEDs is well-documented, that of antiepileptics introduced after 1990 is not. The Food and Drug Administration assigns the newer AEDs a Pregnancy Rating Category of C (Table 1), indicating that the fetal risk of prenatal exposure to these drugs is unknown. In contrast, the agency assigns the older AEDs including carbamazepine, phenobarbital, phenytoin, primidone, and valproate a Pregnancy Rating Category of D, indicating that they pose risks to the human fetus but that therapeutic benefits may outweigh these risks.46
Pregnancy registries created by physician groups and pharmaceutical companies monitor pregnancy outcomes associated with the newer AEDs.47 Established in 1992, the International Lamotrigine Pregnancy Registry provides the most comprehensive data to date on one of the newer AEDs.48,49 As of March 2003, the registry included data on 337 outcomes of pregnancies exposed during the first trimester to lamotrigine monotherapy and 238 outcomes of pregnancies exposed to lamotrigine polytherapy. After exposure to lamotrigine monotherapy during the first trimester, 3% (9 of 302) of outcomes (95% CI, 1.5%5.8%) were associated with major birth defects. These data support, with 95% confidence, the conclusion that the prevalence of major birth defects after first-trimester exposure to lamotrigine monotherapy does not increase more than twofold over the baseline risk of 3%.
After exposure to lamotrigine polytherapy without valproate and with valproate, respectively, five of 148 or 3.4% (95% CI, 1.3%8.1%) and seven of 67 or 10.4% (95% CI, 4.7%20.9%) of pregnancy outcomes were associated with major birth defects. These rates are comparable to those observed in other studies of antiepileptic polytherapy and similar to findings in a pregnancy registry maintained in the United Kingdom.50 The UK registry tallied major birth defects in 2.7% (seven of 260) of pregnancy outcomes after first-trimester exposure to lamotrigine monotherapy and 5.2% (11 of 212) of pregnancy outcomes after first-trimester exposure to polytherapy, including lamotrigine. The sample sizes are insufficient to draw definitive conclusions, but the available data with lamotrigine monotherapy are encouraging. Based on data like these and the demonstrated efficacy and tolerability of lamotrigine, some experts recommend it as first-line therapy for pregnant or breastfeeding women.46
Less data are available for the other newer AEDs, except for oxcarbazepine, which is possibly teratogenic. A prospective single-center study monitoring outcomes of 970 pregnancies of women with epilepsy from 1980 through 1998 established prenatal exposure to oxcarbazepine as an independent risk factor for major fetal malformations.43 The elevated risk of major malformations with oxcarbazepine in this study is not surprising, given the structural and pharmacologic similarities of oxcarbazepine and carbamazepine, an established teratogen.
Prenatal exposure to the older AEDs carbamazepine and valproate also significantly heightened the risk of major malformations. The North American Antiepileptic Drug Pregnancy Registry was established in 1997 to ascertain the fetal effects of AEDs taken during the first trimester of pregnancy. This registry is purely prospective with women identified in the first trimester before pregnancy outcome is known. While most pregnancies represent women with epilepsy, the registry is open to pregnant women using AEDs for any indication.
To date, the registry has released data on only two AEDs: phenobarbital and valproate. According to the registry, malformations were present in only 1.62% of pregnancies with no AED exposure as assessed up to day 2 of neonatal life. There was evidence of increased risk of birth defects in offspring of women exposed to phenobarbital. Major birth defects were seen in 7.8% of 65 pregnancies exposed to phenobarbital in monotherapy and enrolled in the first trimester.51 Major malformations included heart defects in four, and cleft lip and palate in one. As for valproate, of 123 completed pregnancies in which the fetus was exposed to that drug in monotherapy during the first trimester, nearly 9% resulted in major birth defects.52 Anomalies included heart defects in four, neural tube defects in two, and hypospadias, polydactyly, bilateral inguinal hernia, dysplastic kidneys, and clubfoot in one each.
The mechanisms by which older AEDs cause teratogenicity are not known, but there are several proposed explanations (Table 2).
Most health organizations strongly recommend breastfeeding to promote mother-child bonding and reduce the risk of infection and immunological disorders in later life.53,54 Antiepileptic drugs cross into breast milk in varying degrees, usually through simple diffusion, and the ratio is determined by the drug's molecular weight, pKa, lipophilicity, and, most importantly, the degree of protein binding.55,56 Concentrations in breast milk of phenytoin, carbamazepine, valproate, and tiagabine are negligible because they bind tightly to proteins. On the other hand, ethosuximide, phenobarbital, and primidone result in measurable concentrations, while lamotrigine reaches approximately 30% of the maternal serum concentration.57 Concentrations of topiramate, oxcarbazepine, and oxcarbazepine are similar in maternal serum, cord blood, and placental tissue, indicating extensive transplacental passage.58,59 However, this does not necessarily indicate ultimate exposure for breastfed infants. For topiramate, the milk-to-maternal-plasma ratio is 0.69 at 3 months, and breastfed infants have concentrations below detectable limits (2.8 microM).58
The best advice for most women is to seriously consider breastfeeding, keeping in mind that once started, the infant can be observed for proper weight gain and sleep cycles. Also advise a patient that AED metabolism and clearance will remain elevated as long as she continues to breast-feed. When she stops breastfeeding, the mother may experience an increase in serum AED concentrations requiring a dosage adjustment.
Nearly half of all pregnancies in the United States are unplanned.60 Most women with unplanned pregnanciesand many with planned pregnancies for that matterdon't consult their health-care providers for pre-pregnancy counseling.7 Such counseling has to be an essential first step for all reproductive-aged women with epilepsy considering pregnancy.
Topics to address are listed in Table 3 and described below.20,26 A recent survey mailed to 795 reproductive-aged women with epilepsy in the UK revealed that fewer than half recalled receiving information from their health-care provider about issues like pre-pregnancy planning, folic acid, and teratogenicity.61 Clearly, we can do better in disseminating health-related information to women with epilepsy.
Good seizure control during pregnancy is important in ensuring the well-being of the woman with epilepsy and that of the fetus. Maintaining seizure control while minimizing fetal exposure to AEDs is the primary goal of therapy. If at all possible, maintain a pregnant patient with epilepsy on monotherapy at the lowest effective dose, which ideally should be established before conception.11 If a woman has only one type of seizure, has been seizure-free for 2 to 5 years, and has a normal neurologic and electroencephalographic (EEG) evaluation, you might consider withdrawing AEDs before she tries to conceive.20 But as a rule, don't attempt post-conception reductions in AED dosages or changes in medications, because doing so doesn't seem to reduce the risk of major malformations and you may risk losing seizure control.26
Typically, there are several appropriate AEDs for any seizure type. Selection of the most efficacious and well tolerated AED for an individual patient will be facilitated by a neurological consultation.
Monitoring antiepileptic drug levels. To ensure that therapeutic drug levels remain steady, vigilantly monitor them during pregnancy. I recommend measuring nonprotein-bound AED levels in plasma because it most accurately reflects CNS drug levels.7 The nonprotein-bound fraction often increases during pregnancy because of a reduction in albumin, while total plasma concentrations fall.1,7 Total plasma concentrations, therefore, may not be useful during pregnancyparticularly for highly protein-bound AEDs like carbamazepine, phenytoin, and valproate.62 Lamotrigine may require a twofold increase by the third trimester in order to maintain stable serum concentrations, but metabolism returns to the prepregnancy baseline within 48 hours after delivery, necessitating a rapid postpartum reduction in dosage.
Monitoring and controlling risk factors. Also assess patients for risk factors like sleep deprivation or nonadherence that may provoke more frequent seizures during pregnancy. If a woman is adhering to the therapeutic regimen and her risk factors are well-controlled, but seizures increase anyway, consider increasing the dosage of her AED.
Folic acid supplementation. Because most women in the US are not aware that they're pregnant until during or after the gestational time of neural tube development, the American Academy of Neurology and the American College of Obstetricians and Gynecologists recommend that all women of childbearing age who are taking AEDs receive daily folic acid supplementation (0.45.0 mg/day).33,63,64 This is also recommended for women who are not taking antiepileptic medications.65
Vitamin K supplementation. As mentioned earlier, vitamin K deficiencywith a resultant higher risk of hemorrhageis possible in the newborns of women taking AEDs. I therefore recommend 10 mg/day of vitamin K1 over the last month of gestation for women taking AEDs.11,31
Prenatal diagnostic testing. Clinicians can identify major congenital abnormalities in utero in three ways: (1) by measuring maternal serum a-fetoprotein, which is elevated between gestational weeks 16 and 18 in many fetuses with open neural-tube defects; (2) via level II fetal ultrasonography, which can detect many major malformations between gestational weeks 14 and 22; and (3) through amniocentesis, if warranted.1,11
Epilepsy poses unique challenges for both a pregnant woman and her clinician. Physiologic changes during pregnancy can influence epilepsy, and, conversely, epilepsy and AEDs can affect pregnancy and its outcome. Fortunately, we can control many pregnancy-associated risk factors in the mother and the fetus. Medical advances continue to help minimize fetal and maternal risk and have reduced the number of major birth defects and miscarriages among women with epilepsy.5,66 You can reassure patients that most women with epilepsy have uncomplicated pregnancies, labors, and deliveries and have normal babies with no loss of seizure control during pregnancy. With continued vigilance among pregnant women with epilepsy and their health-care providers, fetal and maternal outcomes will continue to improve.
1. Morrell MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia. 2003;44(suppl 4):S11-S20.
2. Schmidt D, Beck-Mannagetta G, Janz D, et al. The effect of pregnancy on the course of epilepsy: a prospective study. In: Janz D, Dam M, Richens A, eds. Epilepsy, Pregnancy, and the Child. New York, NY: Raven Press; 1982:39-49.
3. Knight AH, Rhind EG. Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia. 1975;16:99-110.
4. Morrell MJ. Hormones and epilepsy through the lifetime. Epilepsia. 1992;33(suppl 4):S49-S61.
5. Herzog AG. Reproductive endocrine considerations and hormonal therapy for women with epilepsy. Epilepsia. 1991;32(suppl 6):S27-S33.
6. Sabers A, aRogvi-Hansen B, Dam M, et al. Pregnancy and epilepsy: a retrospective study of 151 pregnancies. Acta Neurol Scand. 1998;97:164-170.
7. Zahn CA, Morrell MJ, Collins SD, et al. Management issues for women with epilepsy: a review of the literature. Neurology. 1998;51:949-956.
8. Tomson T, Lindbom U, Ekqvist B, et al. Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia. 1994;35:122-130.
9. Gjerde IO, Strandjord RE, Ulstein M. The course of epilepsy during pregnancy: a study of 78 cases. Acta Neurol Scand. 1988;78:198-205.
10. Crawford P. CPD Education and self-assessment: Epilepsy and pregnancy. Seizure. 2001;10:212-219.
11. Pack AM, Morrell MJ. Treatment of women with epilepsy. Semin Neurol. 2002;22:289-2987.
12. Morrell MJ. Epilepsy in women: the science of why it is special. Neurology. 1999;53(4 suppl 1):S42-S48.
13. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia. 1997;38:1082-1088.
14. Bäckström T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand. 1976;54:321-347.
15. Shavit G, Lerman P, Korczyn AD, et al. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology. 1984;34:959-961.
16. Rosciszewska D, Buntner B, Guz I, et al. Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry. 1986;49:47-51.
17. Al-Bunyan MA. Random total antiepileptic drug levels and seizure control during pregnancy. Saudi Med J. 2001;22:355-359.
18. Otani K. Risk factors for the increased seizure frequency during pregnancy and puerperium. Folia Psychiatr Neurol Jpn. 1985;39:33-41.
19. Schmidt D, Canger R, Avanzini G, et al. Change of seizure frequency in pregnant epileptic women. J Neurol Neurosurg Psychiatry. 1983;46:751-755.
20. Foldvary N. Treatment issues for women with epilepsy. Neurol Clin. 2001;19:409-425.
21. Bardy AH. Incidence of seizures during pregnancy, labor and puerperium in epileptic women: a prospective study. Acta Neurol Scand. 1987;75:356-360.
22. Bardy AH. Seizure frequency in epileptic women during pregnancy and puerperium: results of the prospective Helsinki study. In: Janz D, Dam M, Richens A, et al, eds. Epilepsy, Pregnancy, and the Child. New York, NY: Raven Press; 1982:27-37.
23. Katz JM, Devinsky O. Primary generalized epilepsy: a risk factor for seizures in labor and delivery? Seizure. 2003;12:217-219.
24. Yerby M, Koepseall T, Daling J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia. 1985;26:631-635.
25. Nei M, Daly S, Liporace J. A maternal complex partial seizure in labor can affect fetal heart rate. Neurology. 1998;51:904-906.
26. Tettenborn B, Genton P, Polson D. Epilepsy and women's issues: an update. Epileptic Disord. 2002;4(suppl 2):S23-S32.
27. Higgins TA, Comerford JB. Epilepsy in pregnancy. J Ir Med Assoc. 1974;67:317-320.
28. Schupf N, Ottman R. Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for spontaneous abortion. Epilepsia. 1997;38:824-829.
29. Devinsky O, Yerby MS. Women with epilepsy. Reproduction and effects of pregnancy on epilepsy. Neurol Clin. 1994;12:479-495.
30. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol. 1993;168:923-928.
31. Thorp JA, Gaston L, Caspers DR, et al. Current concepts and controversies in the use of vitamin K. Drugs. 1995;49:376-387.
32. Dravet C, Julian C, Legras C, et al. Epilepsy, antiepileptic drugs, and malformations in children of women with epilepsy: a French prospective cohort study. Neurology. 1992;42(4 suppl 5):S75-S82.
33. Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.
34. Samrén EB, van Duijn CM, Christiaens GC, et al. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol. 1999;46:739-746.
35. Steegers-Theunissen RP, Renier WO, Borm GF, et al. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multicentre prospective study. Epilepsy Res. 1994;18:261-269.
36. Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malformations and antiepileptic drugs. Neurology. 1992;42(4 suppl 5):S83-S88.
37. Shapiro S, Hartz SC, Siskind V, et al. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet. 1976;1:272-275.
38. Hanson JW, Myrianthopoulos NC, Harvey MA, et al. Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr. 1976;89:662-668.
39. Gaily E, Kantola-Sorsa E, Granstrom ML. Intelligence of children of epileptic mothers. J Pediatr. 1988;113:677-684.
40. Wide K, Winbladh B, Tomson T, et al. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Dev Med Child Neurol. 2000;42:87-92.
41. Barrett C, Richens A. Epilepsy and pregnancy: Report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 2003;42:147-187.
42. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344:1132-1138.
43. Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology. 2003;60:575-579.
44. Friis ML, Holm NV, Sindrup EH, et al. Facial clefts in sibs and children of epileptic patients. Neurology. 1986;36:346-350.
45. Mawer G, Clayton-Smith J, Coyle H, et al. Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate. Seizure. 2002;11:512-518.
46. Karceski S, Morrell M, Carpenter D. The expert consensus guidelines series: treatment of epilepsy. Epilepsy Behav. 2001;2:A1-A50.
47. Beghi E, Annegers JF. Collaborative Group for the Pregnancy Registries in Epilepsy. Pregnancy registries in epilepsy. Epilepsia. 2001;42:1422-1425.
48. Tennis P, Eldridge RR. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia. 2002;43:1161-1167.
49. Lamotrigine Pregnancy Registry. Interim Report:. September 1992 through March 2003. PharmaResearch Corporation, Research Park, Wilmington, NC.
50. Morrow JI, Russell A, Craig JJ, et al. Major malformations in the offspring of women with epilepsy: a comprehensive prospective study. Epilepsia. 2001:42(suppl 2):S125.
51. Holmes LB, et al. Evidence of increased risk of birth defects in offspring of women exposed to phenobarbital as a monotherapy. Teratology. 2001;63:250.
52. Holmes LB, et al. Evidence of increased risk of birth defects in offspring of women exposed to valproate (Depakote, Depakene, Epival). Am J Obstet Gynecol. 2002;187(suppl):S137.
53. American Academy of Pediatrics Committee on Drugs:. The transfer of drugs and other chemicals into human milk. Pediatrics. 1994;93:137-150.
54. Guidelines for the care of women of childbearing age with epilepsy. Commission on Genetics, Pregnancy, and the Child, International League Against Epilepsy. Epilepsia. 1993;34(4):588-589.
55. Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Saf. 2000;22:425-440.
56. Bar-Oz B, Nulman I, Koren G, et al. Anticonvulsants and breast-feeding: a critical review. Paediatr Drugs. 2000;2:113-26.
57. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia. 2000;41:709-713.
58. Ohman I, Vitols S, Luef G, et al. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia. 2002;43:1157-1160.
59. Myllynen P, Pienimaki P, Jouppila P, et al. Transplacental passage of oxcarbazepine and its metabolites in vivo. Epilepsia. 2001;42:1482-1485.
60. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. 1998;30:24-29, 46.
61. Bell GS, Nashef L, Kendall S, et al. Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study. Epilepsy Res. 2002;52:139-146.
62. Tran TA, Leppik IE, Blesi K, et al. Lamotrigine clearance in pregnancy. Neurology. 2002;59:251-255..
63. Seizure disorders in pregnancy. American College of Obstetric and Gynecologic Physicians Educational Bulletin. 1996;231:1-13.
64. Van Allen MI, Fraser FC, Dallaire L, et al. Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Clinical Teratology Committee, Canadian College of Medical Geneticists. CMAJ. 1993;149:1239-1243.
65. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41:1-7.
66. Oguni M, Dansky L, Andermann E, et al. Improved pregnancy outcome in epileptic women in the last decade: relationship to maternal anticonvulsant therapy. Brain Dev. 1992;14:371-380.
Although managing epilepsy in pregnancy begins with preconceptual counseling, there are no CPT codes specifically designed for this particular counseling service. Counseling codes in the Preventive Medicine section (99401-99429) are not used for services provided to patients with symptoms or established illnesses. Therefore, you should report counseling you provide to patients with epilepsy using Evaluation and Management (E/M) codes from the office, inpatient, or consultation sections of CPT.
Since the service involves a discussion with the patient, the time spent face-to-face with her will be the determining factor for selecting the level of care. You must document in the medical record the general content of the discussion and the total time you spent with the patient. You don't need to meet the requirements for performing a history and physical exam when counseling is the predominate service.
|Codes Times||99201 10 min||99202 20 min||99203 30 min||99204 45 min||99205 60 min|
|Codes Times||99211 5 min||99212 10 min||99213 15 min||99214 25 min||99215 40 min|
|Codes Times||99241 15 min||99242 30 min||99243 40 min||99244 60 min||99245 80 min|
Consultation codes are used when another health-care provider has requested an opinion or advice regarding the evaluation and/or management of a specific problem. The consultant must provide a written report outlining the findings and recommendations that go back to the requesting provider. There are codes for outpatient (99241-99245) and inpatient (99251-99255) consultations. You report office or other outpatient codes (99201-99215) when the patient initiates the counseling. Select confirmatory consultation codes (99271-99275) when the patient is seeking a second opinion on the appropriateness of previous medical advice. The confirmatory consultation codes cannot be selected based on time, therefore it's usually better to use new or established outpatient E/M codes. Average times are noted in the CPT descriptors. The above table notes the times associated with key outpatient codes.
Use ICD-9 code V25.09 (Family planning advice) to indicate the nature of the encounter. You should also report the appropriate epilepsy code from the 345 series. Some of these codes require a fifth digit to designate conditions with and without mention of intractable epilepsy. Report an additional code identifying a personal history of obstetric disorders if the patient had a problem during a previous pregnancy. V13.21 is used to report a personal history of preterm labor, while V13.29 describes a personal history of "other genital system and obstetric disorders."
Pregnant patients with epilepsy may require more intensive monitoring, additional studies, or both. If the number of antepartum visits exceeds 13 and the added visits are related to a current complication, you can report these extra visitsin addition to the global packageusing E/M codes. Also report medically necessary inpatient hospital admissions, subsequent hospital visits, and observation services. Hospital visits that lead to delivery within 24 hours, however, are considered part of the global service. Anytime you perform ultrasounds, stress tests, amniocentesis, and laboratory studies, you should also report them separately. Additional visits simply to monitor a condition are considered part of the routine obstetric care and are not reported separately. High risk is not the same as having a current complication requiring additional care and evaluation.
CPT 2003 introduced new obstetrical ultrasound codes (76811-76812) to describe what previously had been referred to as a level II ultrasound. The codes include all the elements of a typical maternal/fetal evaluation plus detailed anatomic evaluation of the fetal brain/ventricles, face, heart/outflow tracts and chest anatomy, abdominal organ-specific anatomy, number/length/architecture of limbs, and detailed evaluation of the umbilical cord and placenta and other fetal anatomy as clinically indicated.
It is important to report a diagnosis code specific to the complication or reason for the service. This establishes the medical necessity for any services reported outside the global package. ICD-9 provides codes for complications of pregnancy in the code range 630 to 677. This section contains codes that describe problems relating to the placenta, fetal growth, amniotic fluid volume, and maternal conditions.
There are no codes that specifically relate to pregnancy complicated by epilepsy. The best choice might be 648.9 (other current conditions in the mother complicating pregnancy, childbirth, or the puerperium). ICD-9 instructions state that an additional code should be reported to describe the condition. Therefore you should also report the appropriate epilepsy code.
Use codes in the 655-656 section to report known or suspected fetal abnormalities that affect the mother. There are also ICD-9 codes that describe a high-risk condition (V23.9 other high-risk pregnancy) and reasons for antenatal screening tests (V28 series) that are useful for justifying additional services to third-party payors. Take care to select the ICD-9 code most specific to the patient's condition and that most specifically describes the reason for the additional service(s).
Martha Morrell. Epilepsy and pregnancy: minimizing the risks.
Jan. 1, 2004;49:51-70.