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Obstetric risks for women with epilepsy during pregnancy
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Epilepsy & Behavior 11 (2007) 283–291 www.elsevier.com/locate/yebeh
Obstetric risks for women with epilepsy during pregnancy Peter W. Kaplan a,*, Errol R. Norwitz b, Elinor Ben-Menachem c, Page B. Pennell d, Maurice Druzin e, Julian N. Robinson f, Jacki C. Gordon g a
e
Johns Hopkins University School of Medicine, Baltimore, MD, USA b Yale University School of Medicine, New Haven, CT, USA c Institute for Clinical Neuroscience and Rehabilitation, Sahlgrenska Academy, Sahlgrenska University Hospital, Goteborg, Sweden d Emory Epilepsy Program, Emory University School of Medicine, Atlanta, GA, USA Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, CA, USA f Harvard Medical School, Cambridge, MA, USA g Epilepsy Therapy Development Project, Reston, VA, USA Received 9 August 2007; accepted 14 August 2007
Abstract Women with epilepsy (WWE) face particular challenges during their pregnancy. Among the several obstetric issues for which there is some concern and the need for further investigation are: the effects of seizures, epilepsy, and antiepileptic drugs on pregnancy outcome and, conversely, the effects of pregnancy and hormonal neurotransmitters on seizure control and antiepileptic drug metabolism. Obstetric concerns include preclampsia/eclampsia, preterm delivery, placental abruption, spontaneous abortion, stillbirth, and small-for-date babies in WWE whether or not they are taking antiepileptic drugs. The role of nutritional health elements, including body mass index, caloric and protein intake, vitamins and iron, and phytoestrogens, warrants further study. During the course of obstetric management, there is a need for a fuller understanding by neurologists of the risk–benefit calculations for various types and frequencies of fetal imaging, including CT, MRI, and ultrasound, as well as for the screening standards of care. As part of the Health Outcomes in Pregnancy and Epilepsy (HOPE) project, this expert panel provides a brief overview of these concerns, offers some approaches to management, and outlines potential areas for further investigation. More detailed information and guidelines are available elsewhere. 2007 Elsevier Inc. All rights reserved. Keywords: Women; Epilepsy; Pregnancy; Outcome; Nutrition; Neurosteroids; Seizures; Antiepileptic drugs; Stillbirth; Small for dates; Abruptio; Eclampsia; Imaging; Ultrasound
1. Introduction Women with epilepsy face a number of challenges to their health and well-being in the course of planning pregnancy. The management of maternal epilepsy and the health of the developing fetus must be considered together. Of particular concern are problems of diminished fertility, altered seizure control, and the many risk factors for fetal maldevelopment or loss. Such risks may come in the form * Corresponding author. Address: B-123, Department of Neurology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA. Fax: +1 410 550 0539. E-mail address: [email protected] (P.W. Kaplan).
1525-5050/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.08.012
of maternal alimentary and vitamin needs, appropriate radiologic and ultrasonic screening during fetal development, teratogenic potential of medications including antiepileptic drugs (AEDs) taken during pregnancy, and alteration in sex hormone–epilepsy interactions. Further considerations are AED levels, the changes in seizure control, and the effects of seizures on mother and child. Finally, women with epilepsy face overall increases in maternal–fetal morbidity, small-for-dates babies, and pregnancy-specific disorders such as eclampsia. Many of these areas remain understudied, with practitioners lacking important information useful for optimal clinical practice and necessary to be able to address patient questions and concerns more adequately. The obstetric risk factor section
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of the Health Outcomes in Pregnancy with Epilepsy (HOPE) project has investigated unmet research needs on many of these topics through a multidisciplinary meeting and relevant literature review so as to formulate a list of questions pertinent to these issues. The group’s goal was not so much to be comprehensive (given the limitations of the scope of the endeavor), but rather to initiate a dialogue and act as a springboard to the investigation into problems faced by women with epilepsy. What follows is a brief overview of issues, followed by questions in the form of bullets generated by the members of the expert, multidisciplinary panel. 2. The effect of seizures, epilepsy, and AEDs on pregnancy outcome 2.1. Overview Seizure disorders are the most frequent major neurological complication in pregnancy, affecting 0.3–0.6% of all gestations [1–4]. Most pregnant women with idiopathic epilepsy have a good outcome [5], but the incidence of obstetric complications is higher (hyperemesis gravidarum, 1.6fold; preterm delivery, 3-fold; pregnancy-induced hypertension/preeclampsia, 1.7-fold; cesarean delivery; placental abruption, 2- to 3-fold; and perinatal mortality [1–8]). Here we outline the data regarding a number of these adverse pregnancy outcomes and identify potential areas for future study. Preeclampsia (gestational proteinuric hypertension) occurs in 5–6% of all pregnancies, and is a major cause of maternal/perinatal morbidity and mortality. Preeclampsia is reportedly more common in women with epilepsy, with an odds ratio (OR) of approximately 1.7–2.0 [9–15]. Unfortunately, many of these are small, retrospective studies that included women on anticonvulsant drugs, making it difficult to determine whether it was the epilepsy itself or the anticonvulsant drug that increased the risk of preeclampsia. Also, eclampsia (defined as seizures or coma in the setting of preeclampsia and in the absence of an alternative neurological explanation) is a known complication of preeclampsia, and a seizure in a woman with epilepsy may lead to the erroneous diagnosis of preeclampsia. Lastly, several studies—many of which are more recent and larger—have not been able to confirm an increase in preeclampsia in women with epilepsy [16– 18]. Spontaneous abortion (defined as pregnancy loss prior to 20 weeks of gestation) is a very common event, and may complicate up to 20% of all pregnancies. The data regarding the risk of abortion in women with epilepsy are extremely limited and conflicting [1–8,19–21]. Interestingly, one study suggested that spontaneous abortion was also more common in pregnancies fathered by men with epilepsy and those with a positive family history of epilepsy [19]. Stillbirth (defined as intrauterine fetal death after 20 weeks of gestation and before delivery) is a vastly underap-
preciated problem, and accounts for more perinatal death than either complications of prematurity or sudden infant death syndrome (SIDS) [22]. The data regarding the risk of stillbirth in women with epilepsy are extremely limited [1–8,23]. Preterm birth currently complicates approximately 12.5% of all deliveries in the United States [24], and the incidence is rising steadily. Although the data are conflicting, the weight of evidence suggests that women with epilepsy are at significantly increased risk of preterm birth and small-for-gestational-age infants, with an OR of approximately 2.5–2.8 [6,9–15,25]. One study suggested that epileptic women who smoked were at significantly higher risk (OR = 3.4) of preterm delivery and low birth weight than healthy nonepileptic women who smoked [25], suggesting a gene/disease–environment interaction. Placental abruption (decidual hemorrhage) is associated with significant perinatal morbidity and mortality. The data again are conflicting, but there is a suggestion that women with epilepsy have an increased risk of placental abruption [1,7–9,18,23]. This is certainly true in women who have seizures (especially if the seizure lasts longer than 5 minutes), but may also be true in epileptic women who are seizure-free throughout pregnancy. 2.2. Questions for further research
• Is epilepsy associated with increases in preeclampsia, spontaneous abortion, preterm birth, placental abruption, and small-for-date (SFD) babies? • Where demonstrated, are these increases due to the epilepsy or the AEDs? • Is magnesium sulfate given to all women with preeclampsia to prevent eclampsia (seizures) equally effective in women with epilepsy? • In women with epilepsy with eclampsia, would magnesium sulfate or other AEDs be the best treatment? • Do AEDs in women with epilepsy prevent or increase the occurrence of preeclampsia/eclampsia, spontaneous abortion, preterm birth, placental abruption, stillbirth, or SFD babies? • Are spontaneous abortion, placental abruption, stillbirth, and SFD babies more common in women with epilepsy whose seizures are poorly controlled in the early part of pregnancy? • Is epilepsy, seizures in early pregnancy, or epilepsy treatment associated with an increase in stillbirth? • Traditional obstetric teaching is that, when managing a seizure in a pregnant patient, every attempt should be made to stabilize the mother and resuscitate the fetus in utero before making a decision about delivery. How long can delivery be delayed in the setting of maternal seizure and nonreassuring fetal testing before proceeding with emergent cesarean? Does this time interval change with gestational age? • Can effective anticonvulsant therapy abrogate the risk of stillbirth?
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• Can folic acid supplementation abrogate the risk of spontaneous abortion, stillbirth, SFD babies, or preterm births, or placental abruption? What dosage is optimal? • Women with epilepsy who are at high risk of preterm birth may receive corticosteroid, tocolytic, or progesterone therapy. Are these therapies effective? Do they affect AED therapy? Do they alter seizure threshold?
3. The interrelationships among seizures/status epilepticus, pregnancy, and AEDs, on the mother and fetus 3.1. Overview Current therapeutic strategies typically employ monotherapy and lowest AED dose to control tonic–clonic seizures. The literature consists of case reports, reviews, and opinions, with few controlled studies [26]. Outcome data are confounded by: concurrent use of multiple AEDs, lack of controls for comorbid risk factors (age of mother, other drugs, smoking, diet), and ascertainment bias. Seizure control during pregnancy is compared with a pregestational baseline, mixing prospective with retrospective study design [7,27–39]. Regarding the effects of partial seizures on the fetus, isolated case studies have reported changes in fetal heart rate, without lasting effect. With complex partial seizures, there are two case reports of seizures during pregnancy/labor that were followed by ‘‘strong, prolonged’’ uterine contraction and/or fetal heart deceleration [40,41]. One review of epilepsy in pregnancy notes that, ‘‘There is no evidence that a nonconvulsive seizure adversely affects a pregnancy or developing fetus apart from the result of trauma’’ [42]. In the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) study, 406 women with epilepsy had nonconvulsive seizures (23.4%), and there was no maternal morbidity, stillbirth, or miscarriage attributable to a single seizure [26]. In isolated case reports, tonic–clonic seizures have been reported to be associated with fetal intracranial hemorrhage [43] and to cause transient fetal bradycardia, reduced beat-to-beat variability, and cardiac slowing [8], but reputedly only when the mother is acidotic [44]. The EURAP study noted that no maternal deaths, miscarriages, or stillbirths occurred with isolated tonic–clonic seizures in the 317 affected women [26]. For status epilepticus, a review of 29 cases from the literature reported 9 maternal and 14 fetal deaths [39]. As noted [1], older case reports probably reflect publication bias favoring adverse outcomes. A review of cases in 1980 [30] revealed that less than 1% of pregnant women with epilepsy had status epilepticus, comparable to rates seen between 1982 and 1994 [37]. EURAP [26] is not a population-based study. It is, however, heterogeneous, multinational, multiethnic, and purely observational. In EURAP, status epilepticus is reported in almost 2% (36/ 1956) of pregnancies, with convulsive seizures in one-third of these [26]. Status epilepticus was distributed over the
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three trimesters. In 53% of these women, there were no prior seizures during the pregnancy when status epilepticus occurred. Of the 12 women with epilepsy with convulsive status epilepticus, only one instance was associated with stillbirth and none with maternal mortality. No status epilepticus risk factors were identified. Nineteen of the 36 patients had seizure control during pregnancy until the onset of status epilepticus; 30 were on AED monotherapy. Regarding spontaneous abortions and stillbirths, EURAP noted that, ‘‘among pregnancies ending in spontaneous abortion, 100 (74.1%) were completely seizure-free during pregnancy. Multivariate analysis revealed that increase (OR: 2.5; 1.7 to 3.7) or decrease (OR: 3.3; 2.5 to 4.3) in AED dosage occurred more frequently . . . with incomplete seizure control’’ [26]. 3.2. The impact of pregnancy on seizure control For seizure control in pregnancy, some studies note worsening of control in the first trimester [31,34,35]; other investigators have reported an increase in seizures in the last trimester [28,29,36]. In a case review of more than 2000 pregnancies in publications before 1980, seizure frequency increased in 24% of women with epilepsy, decreased in 23%, and was unchanged in 53% [30]. Older studies suggest that about 5% of women with epilepsy have seizures in the perinatal period [7,28,29,32,33,37,38]. Problems with these studies include their retrospective nature and ascertainment bias. Studies have shown that 15–32% worsened; 54–67% were unchanged [28–36]. In EURAP, when comparing seizure control in second and third trimesters with that in the first trimester, there was no change in 1093 of the 1718 cases (63.6%) across trimesters; 92.7% remained seizure-free. Of the other 625 pregnancies, 273 (15.9%) improved in the second and third trimesters compared with the first, and 298 (17.3%) had worse seizure control [risk of deterioration of seizures higher in localization-related epilepsies (OR = 1.9, 1.1–3.5) and in polytherapy (OR = 3.9, 2.2–7.1); with the proportion higher in localization-related epilepsies (OR = 2.2, 1.2–4.1) and pregnancies with polytherapy (OR = 6.3, 3.4–11.8)] [26]. 3.3. Conclusions Older data largely include case reports and small case series, subject to publication bias toward adverse outcomes. There are few case reports on the effect (deleterious or not) of partial seizures on the fetus or the pregnancy, with the large prospective EURAP study of 1956 pregnancies failing to show any fetal loss attributable to nonconvulsive seizures or nonconvulsive status epilepticus. Early retrospective case series reveal maternal and fetal death with convulsive status epilepticus, whereas the prospective recent EURAP experience with convulsive status epilepticus revealed one stillbirth and no maternal mortality. Such studies suggest that the morbidity of status epilepticus (as a whole) appears to be less than previously reported.
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For seizure control during pregnancy, older studies reveal it to be largely unchanged in 53% of women with epilepsy. In the remainder, it was almost equally divided between those with more and those with fewer seizures. EURAP reported similar findings, with 64% unchanged. 3.4. Questions for further research 3.4.1. Needs for future studies To provide more useful data, study designs for future research need to include the following parameters: • Control population • Prospective data collection on seizure control before pregnancy • Categorization into seizure type, epilepsy syndrome, monitoring of AED levels, and changes during pregnancy • Comparison for each trimester
3.4.2. Research questions • What are the effects on (1) mother and (2) fetus of (i) partial seizures, (ii) generalized convulsive seizures, and (iii) status epilepticus? • What are the effects of being pregnant on seizure control?
4. Nutritional considerations: Other factors to be considered when evaluating teratogenic effects in offspring of women with epilepsy taking AEDs 4.1. Overview Maternal nutrition is an important and underinvestigated factor in fetal malformations and prematurity, with or without concurrent AEDs. Several studies have indicated that women with low BMI or who had lost weight between pregnancies have a greater risk of preterm infants [45–47]. In a large prospective study, 51 of 7928 male offspring had hypospadias, with positive correlation to vegetarian diets and iron supplementation in the first half of pregnancy (OR = 4.99), possibly exposing women to phytoestrogens, which may have a deleterious effect on the developing male reproductive system [48]. In a Norwegian study, obese mothers (BMI >30) had a fivefold increased risk of giving birth to very large babies as well as an increased risk of neural tube deficits [47]. This increased risk cannot be explained by folic acid deficiency or diabetes [49]. Substance abuse is another area to consider when evaluating the cause of teratogenicity of the offspring. Fetal alcohol spectrum disorders (FASDs) are very similar to the fetal AED syndrome in utero. Exposure to alcohol can result in teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioral problems,
which are the same as those seen in AED exposure [50,51]. Narcotic use is more common than probably recognized, and even here the spectrum of neonatal disorders can be similar to that found with AED use. For example, behavioral and cognitive effects are commonly seen after prenatal cocaine exposure [52]. The most common form of substance abuse during pregnancy is smoking, which is generally associated with increased risks of spontaneous abortions, ectopic pregnancies, and placenta previa and may increase risks of behavioral disorders in childhood [53]. Thus, when considering teratogenic effects of AEDs, even maternal nutrition during pregnancy needs to be carefully accounted for, as well as alcohol, drugs, and smoking habits. 4.2. Questions for further research
• What is the role of BMI or other weight measures in terms of spontaneous abortion, stillbirth, preterm birth, or SFD babies? • What effect is there of weight change during or between pregnancies on the above? • What are the effects of nutrition, caloric intake, vitamin supplementation, and phytoestrogens in women with epilepsy on AEDs? • What part do weight and BMI play in fetal malformations (neural tube defects), macrosomia, and shoulder dystocia? • What are the paternal genetic contributions to malformations and cognitive functioning? • How does substance abuse influence outcome in offspring to mothers being treated with AEDs?
5. Risk–benefit ratio of fetal imaging including ultrasound, magnetic resonance imaging, and other imaging modalities during pregnancy 5.1. Overview Fetal imaging of the pregnant uterus and its contents is often required for optimal obstetric management. The safety of radiation exposure during pregnancy is a common concern; however, a missed or delayed diagnosis can pose a greater risk to the patient and her pregnancy than any hazard associated with the particular imaging modality. In many cases, the perception of teratogenic risk from exposure to imaging modalities is higher than the actual risk [54]. It has been recommended that pregnant women have occupational exposure not exceeding 5 mGy (500 mrad) during the entire pregnancy [55]. There are no significant fetal effects from exposure to ultrasound or magnetic fields related to magnetic resonance imaging. Deleterious effects of radiation include [56] intrauterine fetal death, malformation, disturbances of growth and development, and mutagenic and carcinogenic effects. These depend on dose and gestational age, with the preimplantation embryo being
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most sensitive to the lethal effects of radiation. The effects of radiation can be considered either deterministic (exposure affects severity of outcome) or stochastic (exposure affects probability of outcome). The deterministic effects are dose-related and occur when many cells are affected by radiation; a large number of affected cells result in more significant clinical problems. If injury to these cells occurs during a critical stage of organogenesis (usually the first 12 weeks of fetal development), impairment, agenesis, or deformity of the developing organ can occur. As an example, microcephaly develops when a large number of differentiating central nervous system cells are injured. Stochastic effects are monoclonal, resulting in changes to the cell genome and altered differentiation and function of the affected cells. The probability, but not the severity, of the effect increases with the radiation dose. The increased risk of thyroid cancer as a result of in utero exposure to radiation after the Chernobyl accident is an example of a stochastic effect [57]. 5.2. Preimplantation The embryo is most sensitive to the effects of ionizing radiation during the preimplantation period (implantation begins 5.5 to 6 days after ovulation). During this period, the exposed embryo will survive undamaged or will be resorbed (termed the all or none phenomenon); no radiation-induced increase in teratogenesis or growth restriction has been observed during this interval [58]. The pluripotent nature of each cell of the very early embryo may enable complete repair of damage at this stage, thereby avoiding teratogenesis if the embryo survives the initial insult. For human exposure, the best estimate of the threshold for preimplantation death is more than 0.1 Gy (10 rad) [59]. 5.3. Physical and mental effects During the period of organogenesis (approximately from Weeks 3 to 10), embryonic damage may be caused by irradiation-induced cell death, disturbances in cell migration and proliferation, and mitotic delay [60]. Fetal growth restriction and congenital malformations, particularly of the central nervous system, are the major sequelae of radiation damage at this stage. Microcephaly is the most frequently cited manifestation of radiation exposure in utero [61]. Other types of radiation-induced malformations (e.g., skeletal, genital) have never been reported in humans in the absence of growth restriction or central nervous system effects (e.g., microcephaly, mental retardation, or gross eye abnormalities) [58]. 5.4. Structural anomalies Research on rodents suggests a small risk may exist for malformations, as well as for effects on the central nervous system, in the range 0.05–0.10 Gy (5–10 rad) for some stages of gestation. However, in the human embryo/fetus
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under 16 weeks of gestation, a practical threshold for congenital effects is most likely between 0.10 and 0.20 Gy (10 and 20 rad) [55]. Most researchers agree that after 16 weeks of gestation, the threshold for congenital effects in the human fetus is approximately 0.50–0.70 Gy (50–70 rad). 5.5. Growth restriction Atomic bomb survivor data also showed a permanent restriction of physical growth with increasing dose, particularly above 1 Gy (100 rad) [59]. This was most pronounced when exposure occurred in the first trimester, and a 3 to 4% reduction in height at age 18 occurred when the dose was greater than 1 Gy (100 rad). 5.6. Procedures using ionizing radiation 5.6.1. Computed tomography (CT) The fetal radiation dose from a CT scan is affected by several variables including the number, location, and thickness of slices. A narrow collimation and wide pitch enable shorter exposure times, although diminishing image quality slightly, and provide a marked reduction in radiation exposure. Iodinated contrast materials cross the placenta and can produce transient effects on the developing fetal thyroid gland, although clinical sequelae from brief exposure have not been reported. Iodinated contrast materials can be used in pregnancy when indicated. 5.6.2. Dental X rays The radiation dose to the fetus from maternal dental radiography is minute, 0.0001 mGy (0.01 mrad) for an average study, and has not been considered harmful. However, a population-based case–control study in which the investigators hypothesized that radiation to the maternal hypothalamic–pituitary–thyroid axis (as opposed to the fetus) might affect fetal growth found an association between antepartum dental radiography of >0.4 mGy (40 mrad) to the maternal thyroid and low birth weight (<2500 g) [63]. 5.6.3. Ventilation–perfusion and helical CT A ventilation–perfusion scan for suspected pulmonary embolus is among the most common nuclear medicine studies obtained in pregnant women. The procedure involves perfusion with 99mTc macroaggregates of albumin and ventilation with radiolabeled xenon gas or 99mTcDTPA aerosol. Fetal exposure has been estimated to be approximately 0.5 mGy (50 mrad) [64]. Helical CT is another test commonly used for diagnosis of suspected pulmonary embolus and is also associated with a low radiation dose to the fetus (mean of 60 mGy, range 3–131 mGy vs 100–370 mGy for ventilation–perfusion scanning) [65]. 5.6.4. Positron emission tomography (PET) There is minimal information regarding PET in pregnancy. This technique involves injection of a radioisotope,
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[18F]fludeoxyglucose. Animal reproduction studies have not been conducted with [18F]fludeoxyglucose injection and it is not known whether [18F]fludeoxyglucose injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The radiation dose to the uterus is 3.70–7.40 mGy, for the usual dose range of isotope injected [66]. As discussed above, this is a low fetal dose and not associated with adverse effects on development or growth. Because of the lack of safety data in human pregnancy, magnetic resonance imaging and CT are generally preferred to PET as they usually provide similar information, but the decision needs to be made on a patient-specific basis [67].
medically indicated diagnostic procedures using the best available modality. When ionizing radiation is required, various techniques will minimize radiation exposure. No biological effects have been documented from diagnostic ultrasound in the pregnant patient despite intensive use over several decades. There are potential risks from MRI through induction of fields and currents, and radiofrequency heating, and it is not recommended in the first trimester as safety information during organogenesis is limited. Guidelines for diagnostic imaging and ultrasonography/Doppler ultrasound may be found elsewhere [68,69].
5.6.5. Ultrasound No biological effects have been documented from diagnostic ultrasound in the pregnant patient despite intensive use over several decades. The potential for deleterious consequences from heat and cavitation exists, as ultrasound uses sound waves that interact with biological tissues. Bmode and M-mode imaging operate at acoustic outputs that do not produce harmful temperature rises. However, Doppler ultrasound does have this potential; therefore, guidelines for Doppler use in pregnancy have been formulated [68,69].
• What are the risks of CT scanning, dental X rays, contrast materials (iodine, gadolinium), ventilation–perfusion scanning, helical CT, and PET on fetal target structures, malformation, cognitive development, and later risk for mutagenesis? • Does three- or four-dimensional ultrasound or MRI offer greater benefits than routine two-dimensional ultrasound in detection of anomalies? • Are there deleterious effects of multiple ultrasounds throughout pregnancy, including in the latter two trimesters, to monitor fetal growth and position and amniotic fluid? • Are all patients on AEDs being screened for neural tube defects, oral clefts, and urogenital or cardiac defects? • Will functional MRI improve prediction of neurological status of children of women with epilepsy?
5.6.6. Magnetic resonance imaging (MRI) At the cellular level, possible direct biological effects of MRI consist of (1) induction of local electric fields and currents from the static and time-varying magnetic fields, and (2) radiofrequency radiation resulting in heating of tissue. Gadolinium is currently not recommended for use in the pregnant patient unless the potential benefit justifies the potential risk to the fetus [62]. In animal studies, the risks of gadolinium included spontaneous abortion and skeletal and visceral anomalies. Despite these concerns, there are no reported harmful effects from MRI of the pregnant woman or fetus without gadolinium contrast [62,67]. In some cases, MRI is the preferred diagnostic modality because it provides better images than ultrasonography while avoiding the ionizing radiation of CT. The National Radiological Protection Board advises that MRI be avoided in the first trimester because there is limited experience assessing safety during organogenesis. 5.7. Summary The available data show no evidence of increased risk for fetal anomalies, mental retardation, growth restriction, or pregnancy loss from ionizing radiation at doses less than 5 rad [59,63]. The margin of safety is augmented by the fact that most human exposures from diagnostic imaging will be fractionated over time, which is less harmful than an acute exposure [59]. During pregnancy, alternative imaging procedures (e.g., ultrasound, MRI) are preferred to those using ionizing radiation. However, this should not prevent
5.8. Questions for future research
6. Effects of neurosteroids on seizure control in women with epilepsy during pregnancy 6.1. Overview The substantial alterations in sex steroid hormone concentrations and their central nervous system-active metabolites (neurosteroids) may have a significant impact on seizure control during pregnancy. In nonpregnant women, a correlation has been observed between the cyclic monthly levels of estrogen and progesterone and seizure frequency [69]. In animal studies, estrogen is generally proconvulsant [70,71]. Estrogen can create new cortical seizure foci when applied topically, activate preexisting cortical foci, increase the severity of pentylenetetrazol-induced seizures, lower the electroshock seizure threshold, and increase the number of dendritic spines and excitatory synapses on hippocampal CA1 pyramidal cells. Progesterone, conversely, generally has an anticonvulsant effect [70,71]. Animal studies demonstrate that progesterone elevates the seizure threshold, suppresses kindling, and decreases interictal spikes caused by cortically applied penicillin. Allopregnanolone is an active metabolite of progesterone, and works as a neurosteroid by potentiating GABA-activated chloride currents.
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Pregnanolone is another 3a-reduced metabolite of progesterone and a potent modulator of c-aminobutyric acid type A receptors [70]. Bag et al. [73] evaluated seizure frequency during pregnancy in relation to sex steroid hormone concentrations. Pregnancies with increased seizure frequency were compared with those without increased seizures. The increased seizure group had significantly higher estrogen levels, lower levels of progesterone, and lower levels of AEDs [73]. Additionally, the authors noted that patients who had abortions and those who developed status epilepticus had high serum estrogen levels. In pregnancy, estradiol (E2) and estriol (E3) are the major circulating unconjugated estrogens, and estrone (E1) is present in lower concentrations. Mucci et al. [74] studied 230 healthy women during pregnancy; the mean E2 and E3 concentrations at the 16th gestational week were 14.2 ± 6.6 and 3.8 ± 1.7 nM, respectively. At the 27th gestational week, the values were 39.5 ± 17.4 and 14.0 ± 4.5 nM, respectively, reflecting a threefold increase in the estrogenic index over this period. Gilbert Evans et al. [72] examined levels of several 3a-reduced neuroactive pregnane and progesterone precursors at five time points during pregnancy and in the postpartum period in a group of 37 healthy women without epilepsy. Progesterone is first converted to 5a- and 5b-dihydroprogesterone (5a/b-DHP) followed by 3-ketoreduction to the neuroactive pregnanes allopregnanolone (ALLO) and pregnanolone (3ahydroxy-5b-pregnan-20-one). ALLO increases throughout pregnancy, with the highest level reached at 36–38 weeks of gestation. In contrast, 5b-DHP levels are relatively low compared with the levels of other pregnanes, but peak levels are reached at 18–20 weeks and gradually decline thereafter. At 6 weeks postpartum, all steroids are significantly reduced compared with late prenatal values, with 5aDHP being the most abundant postpartum steroid. 6.2. Susceptible pregnancy/delivery stages Labor and delivery is an especially susceptible time with respect to generalized tonic–clonic seizures, with occurrence in up to 4% of women with epilepsy. Women with primary generalized epilepsy may be especially vulnerable during this time, with seizures occurring in 12.5% of women [75]. Contributors to worsened seizure control during this time are numerous but poorly studied. The precipitous decline in progesterone levels just prior to parturition may contribute to seizures. The inevitable disruption of sleep in the peripartum period can contribute to seizure worsening. Although the benefits of breastfeeding need to be weighed against additional effects on maternal sleep disruption, lactation could theoretically contribute to improved seizure control because lactation generates a hypoestrogenic state [72]. No human clinical studies have comprehensively evaluated the effect of sex steroid hormone levels and neurosteroids during pregnancy, parturition, or the
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postpartum period on seizure control. These modulators of seizure frequency play an important role in obtaining and maintaining seizure control during pregnancy, especially if it can be translated into reduced fetal exposure to AEDs. 6.3. Questions for future research • What are the relationships of sex and neurosteroid hormones to seizure control? • How do seizures correlate with increasing levels of proconvulsant compounds, decreasing levels of anticonvulsant compounds, and increased ratios of proconvulsant/ anticonvulsant compounds? • Falling serum levels of progesterone and allopregnanolone may be associated with increased seizure frequency, and may be most prevalent around parturition. How might we quantify these relationships? • What are the effects of sex steroid hormone and neurosteroid properties on seizures in women with epilepsy and in pregnancy? What are the particular roles of estrogens and progesterones and the active neurosteroid metabolites (allopregnanolone and pregnanolone)? • What are the implications for therapy of progesterone administration to improve seizure control during pregnancy and, ultimately, enhance maternal and fetal outcomes? 7. Summary Risk factors for unfavorable obstetric outcomes in women with epilepsy remain inadequately studied and understood. There are complex interactions among the mother, the fetus, and epilepsy, as well as alterations in maternal homeostasis and sex steroid levels. There is information on the risks of maternal–fetal imaging, use of AEDs and other medications, diet, maternal weight, and teratogenesis in particular in this interplay. This overview provides some guidance on our present understanding and approach to the management of pregnant women with epilepsy, and points to what questions might appear most pertinent to further study of these issues. References [1] Bjerkedal T, Bahna SL. The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 1973;52:245–8. [2] Nelson KB, Ellenberg JH. Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children. Neurology 1982;32:1247–54. [3] Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:534–44. [4] Pschirrer ER, Monga M. Seizure disorders in pregnancy. Obstet Gynecol Clin North Am 2001;28:601–11. [5] Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992;42:149–60.
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[30] Schmidt D. The effect of pregnancy on the natural history of epilepsy: a review of the literature. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982. p. 3–14. [31] Schmidt D, Canger R, Avanzini G, et al. Change of seizure frequency in pregnant epileptic women. J Neurol Neurosurg Psychiatry 1983;46:751–5. [32] Otani K. Risk factors for the increased seizure frequency during pregnancy and puerperium. Folia Psychiatr Neurol Jpn 1985;39:33–41. [33] Tanganelli P, Regesta G. Epilepsy, pregnancy, and major birth anomalies: an Italian prospective, controlled study. Neurology 1992;42:89–93. [34] Knight AH, Rhind EG. Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia 1975;16:99–110. [35] Canger R, Avanzini G, Battino D, Bossi L, Franceschetti S, Spina S. Modifications of seizure frequency in pregnant patients with epilepsy: a prospective study. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982. p. 33–8. [36] Remillard G, Dansky L, Andermann E, Andermann F. Seizure frequency during pregnancy and puerperium. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982. p. 15–25. [37] Tomson T. Seizure control during pregnancy and delivery. In: Tomson T, Gram L, Sillanpaa M, Johannessen S, editors. Epilepsy and pregnancy. Petersfield: Wrightson Biomedical; 1997. p. 113–23. [38] Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an obstetric perspective. Am J Obstet Gynecol 2004;190:371–9. [39] Teramo K, Hiilesmaa VK. Pregnancy and fetal complications in epileptic pregnancies. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982. p. 53–9. [40] Sahoo S, Klein P. Maternal complex partial seizure associated with fetal distress. Arch Neurol 2005;62:1304–5. [41] Nei M, Daly S, Liporace J. A maternal complex partial seizure in labor can affect fetal heart rate. Neurology 1998;51:904–6. [42] Crawford P. Management of epilepsy in pregnancy. Rev Future Neurol 2006;1:303–10. [43] Minkoff H, Schaffer RM, Delke I, Grunebaum AN. Diagnosis of intracranial henmorrhage in utero after a maternal seizure. Obstet Gynecol 1985;65:22S–4S. [44] Goetting MG, Davidson BN. Status epilepticus during labour: a case report. J Reprod Med 1987;32:313–4. [45] Hendler I, Goldenberg R, Mercer B, Iams J, Meis P, Moawad A. The preterm Prediction Study: association between maternal body mass index and spontaneous and indicated preterm birth. Am J Obstet Gynecol 2005;192:882–6. [46] Melino A, Laffineuse L, Collin M, Mercer B. Impact of weight loss between pregnancies on recurrent preterm birth. Am J Obstet Gynecol 2006;195:818–21. [47] Henriksen T. Nutrition and pregnancy outcome. Nutr Rev 2006;64:S19–23. [48] North L, Golding J, the Alspac Study Team. A maternal vegetarian diet in pregnancy is associated with hypospadias. Br J Urol Int 2000;85:107–13. [49] Scialli AR for the Public Affairs Committee of the Teratology Society. Maternal obesity and pregnancy [position paper]. Birth Defects Res A Clin Mol Teratol 2006;76:73–7. [50] Green JH. Fetal alcohol sprectrum disorder: understanding the effects of prenatal alcohol exposure and supporting students. J Sch Health 2007;77:103–8. [51] Kini U, Adab N, Vinten J, Fryer A, Clayton-Smith J for the Liverpool and Manchester Neurodevelopmental Study Group. Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed 2006;91:F90–5.
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Obstetric risks for women with epilepsy during pregnancy Peter W. Kaplan a,*, Errol R. Norwitz b, Elinor Ben-Menachem c, Page B. Pennell d, Maurice Druzin e, Julian N. Robinson f, Jacki C. Gordon g a
e
Johns Hopkins University School of Medicine, Baltimore, MD, USA b Yale University School of Medicine, New Haven, CT, USA c Institute for Clinical Neuroscience and Rehabilitation, Sahlgrenska Academy, Sahlgrenska University Hospital, Goteborg, Sweden d Emory Epilepsy Program, Emory University School of Medicine, Atlanta, GA, USA Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, CA, USA f Harvard Medical School, Cambridge, MA, USA g Epilepsy Therapy Development Project, Reston, VA, USA Received 9 August 2007; accepted 14 August 2007
Abstract Women with epilepsy (WWE) face particular challenges during their pregnancy. Among the several obstetric issues for which there is some concern and the need for further investigation are: the effects of seizures, epilepsy, and antiepileptic drugs on pregnancy outcome and, conversely, the effects of pregnancy and hormonal neurotransmitters on seizure control and antiepileptic drug metabolism. Obstetric concerns include preclampsia/eclampsia, preterm delivery, placental abruption, spontaneous abortion, stillbirth, and small-for-date babies in WWE whether or not they are taking antiepileptic drugs. The role of nutritional health elements, including body mass index, caloric and protein intake, vitamins and iron, and phytoestrogens, warrants further study. During the course of obstetric management, there is a need for a fuller understanding by neurologists of the risk–benefit calculations for various types and frequencies of fetal imaging, including CT, MRI, and ultrasound, as well as for the screening standards of care. As part of the Health Outcomes in Pregnancy and Epilepsy (HOPE) project, this expert panel provides a brief overview of these concerns, offers some approaches to management, and outlines potential areas for further investigation. More detailed information and guidelines are available elsewhere. 2007 Elsevier Inc. All rights reserved. Keywords: Women; Epilepsy; Pregnancy; Outcome; Nutrition; Neurosteroids; Seizures; Antiepileptic drugs; Stillbirth; Small for dates; Abruptio; Eclampsia; Imaging; Ultrasound
1. Introduction Women with epilepsy face a number of challenges to their health and well-being in the course of planning pregnancy. The management of maternal epilepsy and the health of the developing fetus must be considered together. Of particular concern are problems of diminished fertility, altered seizure control, and the many risk factors for fetal maldevelopment or loss. Such risks may come in the form * Corresponding author. Address: B-123, Department of Neurology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA. Fax: +1 410 550 0539. E-mail address: [email protected] (P.W. Kaplan).
1525-5050/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.08.012
of maternal alimentary and vitamin needs, appropriate radiologic and ultrasonic screening during fetal development, teratogenic potential of medications including antiepileptic drugs (AEDs) taken during pregnancy, and alteration in sex hormone–epilepsy interactions. Further considerations are AED levels, the changes in seizure control, and the effects of seizures on mother and child. Finally, women with epilepsy face overall increases in maternal–fetal morbidity, small-for-dates babies, and pregnancy-specific disorders such as eclampsia. Many of these areas remain understudied, with practitioners lacking important information useful for optimal clinical practice and necessary to be able to address patient questions and concerns more adequately. The obstetric risk factor section
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of the Health Outcomes in Pregnancy with Epilepsy (HOPE) project has investigated unmet research needs on many of these topics through a multidisciplinary meeting and relevant literature review so as to formulate a list of questions pertinent to these issues. The group’s goal was not so much to be comprehensive (given the limitations of the scope of the endeavor), but rather to initiate a dialogue and act as a springboard to the investigation into problems faced by women with epilepsy. What follows is a brief overview of issues, followed by questions in the form of bullets generated by the members of the expert, multidisciplinary panel. 2. The effect of seizures, epilepsy, and AEDs on pregnancy outcome 2.1. Overview Seizure disorders are the most frequent major neurological complication in pregnancy, affecting 0.3–0.6% of all gestations [1–4]. Most pregnant women with idiopathic epilepsy have a good outcome [5], but the incidence of obstetric complications is higher (hyperemesis gravidarum, 1.6fold; preterm delivery, 3-fold; pregnancy-induced hypertension/preeclampsia, 1.7-fold; cesarean delivery; placental abruption, 2- to 3-fold; and perinatal mortality [1–8]). Here we outline the data regarding a number of these adverse pregnancy outcomes and identify potential areas for future study. Preeclampsia (gestational proteinuric hypertension) occurs in 5–6% of all pregnancies, and is a major cause of maternal/perinatal morbidity and mortality. Preeclampsia is reportedly more common in women with epilepsy, with an odds ratio (OR) of approximately 1.7–2.0 [9–15]. Unfortunately, many of these are small, retrospective studies that included women on anticonvulsant drugs, making it difficult to determine whether it was the epilepsy itself or the anticonvulsant drug that increased the risk of preeclampsia. Also, eclampsia (defined as seizures or coma in the setting of preeclampsia and in the absence of an alternative neurological explanation) is a known complication of preeclampsia, and a seizure in a woman with epilepsy may lead to the erroneous diagnosis of preeclampsia. Lastly, several studies—many of which are more recent and larger—have not been able to confirm an increase in preeclampsia in women with epilepsy [16– 18]. Spontaneous abortion (defined as pregnancy loss prior to 20 weeks of gestation) is a very common event, and may complicate up to 20% of all pregnancies. The data regarding the risk of abortion in women with epilepsy are extremely limited and conflicting [1–8,19–21]. Interestingly, one study suggested that spontaneous abortion was also more common in pregnancies fathered by men with epilepsy and those with a positive family history of epilepsy [19]. Stillbirth (defined as intrauterine fetal death after 20 weeks of gestation and before delivery) is a vastly underap-
preciated problem, and accounts for more perinatal death than either complications of prematurity or sudden infant death syndrome (SIDS) [22]. The data regarding the risk of stillbirth in women with epilepsy are extremely limited [1–8,23]. Preterm birth currently complicates approximately 12.5% of all deliveries in the United States [24], and the incidence is rising steadily. Although the data are conflicting, the weight of evidence suggests that women with epilepsy are at significantly increased risk of preterm birth and small-for-gestational-age infants, with an OR of approximately 2.5–2.8 [6,9–15,25]. One study suggested that epileptic women who smoked were at significantly higher risk (OR = 3.4) of preterm delivery and low birth weight than healthy nonepileptic women who smoked [25], suggesting a gene/disease–environment interaction. Placental abruption (decidual hemorrhage) is associated with significant perinatal morbidity and mortality. The data again are conflicting, but there is a suggestion that women with epilepsy have an increased risk of placental abruption [1,7–9,18,23]. This is certainly true in women who have seizures (especially if the seizure lasts longer than 5 minutes), but may also be true in epileptic women who are seizure-free throughout pregnancy. 2.2. Questions for further research
• Is epilepsy associated with increases in preeclampsia, spontaneous abortion, preterm birth, placental abruption, and small-for-date (SFD) babies? • Where demonstrated, are these increases due to the epilepsy or the AEDs? • Is magnesium sulfate given to all women with preeclampsia to prevent eclampsia (seizures) equally effective in women with epilepsy? • In women with epilepsy with eclampsia, would magnesium sulfate or other AEDs be the best treatment? • Do AEDs in women with epilepsy prevent or increase the occurrence of preeclampsia/eclampsia, spontaneous abortion, preterm birth, placental abruption, stillbirth, or SFD babies? • Are spontaneous abortion, placental abruption, stillbirth, and SFD babies more common in women with epilepsy whose seizures are poorly controlled in the early part of pregnancy? • Is epilepsy, seizures in early pregnancy, or epilepsy treatment associated with an increase in stillbirth? • Traditional obstetric teaching is that, when managing a seizure in a pregnant patient, every attempt should be made to stabilize the mother and resuscitate the fetus in utero before making a decision about delivery. How long can delivery be delayed in the setting of maternal seizure and nonreassuring fetal testing before proceeding with emergent cesarean? Does this time interval change with gestational age? • Can effective anticonvulsant therapy abrogate the risk of stillbirth?
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• Can folic acid supplementation abrogate the risk of spontaneous abortion, stillbirth, SFD babies, or preterm births, or placental abruption? What dosage is optimal? • Women with epilepsy who are at high risk of preterm birth may receive corticosteroid, tocolytic, or progesterone therapy. Are these therapies effective? Do they affect AED therapy? Do they alter seizure threshold?
3. The interrelationships among seizures/status epilepticus, pregnancy, and AEDs, on the mother and fetus 3.1. Overview Current therapeutic strategies typically employ monotherapy and lowest AED dose to control tonic–clonic seizures. The literature consists of case reports, reviews, and opinions, with few controlled studies [26]. Outcome data are confounded by: concurrent use of multiple AEDs, lack of controls for comorbid risk factors (age of mother, other drugs, smoking, diet), and ascertainment bias. Seizure control during pregnancy is compared with a pregestational baseline, mixing prospective with retrospective study design [7,27–39]. Regarding the effects of partial seizures on the fetus, isolated case studies have reported changes in fetal heart rate, without lasting effect. With complex partial seizures, there are two case reports of seizures during pregnancy/labor that were followed by ‘‘strong, prolonged’’ uterine contraction and/or fetal heart deceleration [40,41]. One review of epilepsy in pregnancy notes that, ‘‘There is no evidence that a nonconvulsive seizure adversely affects a pregnancy or developing fetus apart from the result of trauma’’ [42]. In the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) study, 406 women with epilepsy had nonconvulsive seizures (23.4%), and there was no maternal morbidity, stillbirth, or miscarriage attributable to a single seizure [26]. In isolated case reports, tonic–clonic seizures have been reported to be associated with fetal intracranial hemorrhage [43] and to cause transient fetal bradycardia, reduced beat-to-beat variability, and cardiac slowing [8], but reputedly only when the mother is acidotic [44]. The EURAP study noted that no maternal deaths, miscarriages, or stillbirths occurred with isolated tonic–clonic seizures in the 317 affected women [26]. For status epilepticus, a review of 29 cases from the literature reported 9 maternal and 14 fetal deaths [39]. As noted [1], older case reports probably reflect publication bias favoring adverse outcomes. A review of cases in 1980 [30] revealed that less than 1% of pregnant women with epilepsy had status epilepticus, comparable to rates seen between 1982 and 1994 [37]. EURAP [26] is not a population-based study. It is, however, heterogeneous, multinational, multiethnic, and purely observational. In EURAP, status epilepticus is reported in almost 2% (36/ 1956) of pregnancies, with convulsive seizures in one-third of these [26]. Status epilepticus was distributed over the
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three trimesters. In 53% of these women, there were no prior seizures during the pregnancy when status epilepticus occurred. Of the 12 women with epilepsy with convulsive status epilepticus, only one instance was associated with stillbirth and none with maternal mortality. No status epilepticus risk factors were identified. Nineteen of the 36 patients had seizure control during pregnancy until the onset of status epilepticus; 30 were on AED monotherapy. Regarding spontaneous abortions and stillbirths, EURAP noted that, ‘‘among pregnancies ending in spontaneous abortion, 100 (74.1%) were completely seizure-free during pregnancy. Multivariate analysis revealed that increase (OR: 2.5; 1.7 to 3.7) or decrease (OR: 3.3; 2.5 to 4.3) in AED dosage occurred more frequently . . . with incomplete seizure control’’ [26]. 3.2. The impact of pregnancy on seizure control For seizure control in pregnancy, some studies note worsening of control in the first trimester [31,34,35]; other investigators have reported an increase in seizures in the last trimester [28,29,36]. In a case review of more than 2000 pregnancies in publications before 1980, seizure frequency increased in 24% of women with epilepsy, decreased in 23%, and was unchanged in 53% [30]. Older studies suggest that about 5% of women with epilepsy have seizures in the perinatal period [7,28,29,32,33,37,38]. Problems with these studies include their retrospective nature and ascertainment bias. Studies have shown that 15–32% worsened; 54–67% were unchanged [28–36]. In EURAP, when comparing seizure control in second and third trimesters with that in the first trimester, there was no change in 1093 of the 1718 cases (63.6%) across trimesters; 92.7% remained seizure-free. Of the other 625 pregnancies, 273 (15.9%) improved in the second and third trimesters compared with the first, and 298 (17.3%) had worse seizure control [risk of deterioration of seizures higher in localization-related epilepsies (OR = 1.9, 1.1–3.5) and in polytherapy (OR = 3.9, 2.2–7.1); with the proportion higher in localization-related epilepsies (OR = 2.2, 1.2–4.1) and pregnancies with polytherapy (OR = 6.3, 3.4–11.8)] [26]. 3.3. Conclusions Older data largely include case reports and small case series, subject to publication bias toward adverse outcomes. There are few case reports on the effect (deleterious or not) of partial seizures on the fetus or the pregnancy, with the large prospective EURAP study of 1956 pregnancies failing to show any fetal loss attributable to nonconvulsive seizures or nonconvulsive status epilepticus. Early retrospective case series reveal maternal and fetal death with convulsive status epilepticus, whereas the prospective recent EURAP experience with convulsive status epilepticus revealed one stillbirth and no maternal mortality. Such studies suggest that the morbidity of status epilepticus (as a whole) appears to be less than previously reported.
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For seizure control during pregnancy, older studies reveal it to be largely unchanged in 53% of women with epilepsy. In the remainder, it was almost equally divided between those with more and those with fewer seizures. EURAP reported similar findings, with 64% unchanged. 3.4. Questions for further research 3.4.1. Needs for future studies To provide more useful data, study designs for future research need to include the following parameters: • Control population • Prospective data collection on seizure control before pregnancy • Categorization into seizure type, epilepsy syndrome, monitoring of AED levels, and changes during pregnancy • Comparison for each trimester
3.4.2. Research questions • What are the effects on (1) mother and (2) fetus of (i) partial seizures, (ii) generalized convulsive seizures, and (iii) status epilepticus? • What are the effects of being pregnant on seizure control?
4. Nutritional considerations: Other factors to be considered when evaluating teratogenic effects in offspring of women with epilepsy taking AEDs 4.1. Overview Maternal nutrition is an important and underinvestigated factor in fetal malformations and prematurity, with or without concurrent AEDs. Several studies have indicated that women with low BMI or who had lost weight between pregnancies have a greater risk of preterm infants [45–47]. In a large prospective study, 51 of 7928 male offspring had hypospadias, with positive correlation to vegetarian diets and iron supplementation in the first half of pregnancy (OR = 4.99), possibly exposing women to phytoestrogens, which may have a deleterious effect on the developing male reproductive system [48]. In a Norwegian study, obese mothers (BMI >30) had a fivefold increased risk of giving birth to very large babies as well as an increased risk of neural tube deficits [47]. This increased risk cannot be explained by folic acid deficiency or diabetes [49]. Substance abuse is another area to consider when evaluating the cause of teratogenicity of the offspring. Fetal alcohol spectrum disorders (FASDs) are very similar to the fetal AED syndrome in utero. Exposure to alcohol can result in teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioral problems,
which are the same as those seen in AED exposure [50,51]. Narcotic use is more common than probably recognized, and even here the spectrum of neonatal disorders can be similar to that found with AED use. For example, behavioral and cognitive effects are commonly seen after prenatal cocaine exposure [52]. The most common form of substance abuse during pregnancy is smoking, which is generally associated with increased risks of spontaneous abortions, ectopic pregnancies, and placenta previa and may increase risks of behavioral disorders in childhood [53]. Thus, when considering teratogenic effects of AEDs, even maternal nutrition during pregnancy needs to be carefully accounted for, as well as alcohol, drugs, and smoking habits. 4.2. Questions for further research
• What is the role of BMI or other weight measures in terms of spontaneous abortion, stillbirth, preterm birth, or SFD babies? • What effect is there of weight change during or between pregnancies on the above? • What are the effects of nutrition, caloric intake, vitamin supplementation, and phytoestrogens in women with epilepsy on AEDs? • What part do weight and BMI play in fetal malformations (neural tube defects), macrosomia, and shoulder dystocia? • What are the paternal genetic contributions to malformations and cognitive functioning? • How does substance abuse influence outcome in offspring to mothers being treated with AEDs?
5. Risk–benefit ratio of fetal imaging including ultrasound, magnetic resonance imaging, and other imaging modalities during pregnancy 5.1. Overview Fetal imaging of the pregnant uterus and its contents is often required for optimal obstetric management. The safety of radiation exposure during pregnancy is a common concern; however, a missed or delayed diagnosis can pose a greater risk to the patient and her pregnancy than any hazard associated with the particular imaging modality. In many cases, the perception of teratogenic risk from exposure to imaging modalities is higher than the actual risk [54]. It has been recommended that pregnant women have occupational exposure not exceeding 5 mGy (500 mrad) during the entire pregnancy [55]. There are no significant fetal effects from exposure to ultrasound or magnetic fields related to magnetic resonance imaging. Deleterious effects of radiation include [56] intrauterine fetal death, malformation, disturbances of growth and development, and mutagenic and carcinogenic effects. These depend on dose and gestational age, with the preimplantation embryo being
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most sensitive to the lethal effects of radiation. The effects of radiation can be considered either deterministic (exposure affects severity of outcome) or stochastic (exposure affects probability of outcome). The deterministic effects are dose-related and occur when many cells are affected by radiation; a large number of affected cells result in more significant clinical problems. If injury to these cells occurs during a critical stage of organogenesis (usually the first 12 weeks of fetal development), impairment, agenesis, or deformity of the developing organ can occur. As an example, microcephaly develops when a large number of differentiating central nervous system cells are injured. Stochastic effects are monoclonal, resulting in changes to the cell genome and altered differentiation and function of the affected cells. The probability, but not the severity, of the effect increases with the radiation dose. The increased risk of thyroid cancer as a result of in utero exposure to radiation after the Chernobyl accident is an example of a stochastic effect [57]. 5.2. Preimplantation The embryo is most sensitive to the effects of ionizing radiation during the preimplantation period (implantation begins 5.5 to 6 days after ovulation). During this period, the exposed embryo will survive undamaged or will be resorbed (termed the all or none phenomenon); no radiation-induced increase in teratogenesis or growth restriction has been observed during this interval [58]. The pluripotent nature of each cell of the very early embryo may enable complete repair of damage at this stage, thereby avoiding teratogenesis if the embryo survives the initial insult. For human exposure, the best estimate of the threshold for preimplantation death is more than 0.1 Gy (10 rad) [59]. 5.3. Physical and mental effects During the period of organogenesis (approximately from Weeks 3 to 10), embryonic damage may be caused by irradiation-induced cell death, disturbances in cell migration and proliferation, and mitotic delay [60]. Fetal growth restriction and congenital malformations, particularly of the central nervous system, are the major sequelae of radiation damage at this stage. Microcephaly is the most frequently cited manifestation of radiation exposure in utero [61]. Other types of radiation-induced malformations (e.g., skeletal, genital) have never been reported in humans in the absence of growth restriction or central nervous system effects (e.g., microcephaly, mental retardation, or gross eye abnormalities) [58]. 5.4. Structural anomalies Research on rodents suggests a small risk may exist for malformations, as well as for effects on the central nervous system, in the range 0.05–0.10 Gy (5–10 rad) for some stages of gestation. However, in the human embryo/fetus
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under 16 weeks of gestation, a practical threshold for congenital effects is most likely between 0.10 and 0.20 Gy (10 and 20 rad) [55]. Most researchers agree that after 16 weeks of gestation, the threshold for congenital effects in the human fetus is approximately 0.50–0.70 Gy (50–70 rad). 5.5. Growth restriction Atomic bomb survivor data also showed a permanent restriction of physical growth with increasing dose, particularly above 1 Gy (100 rad) [59]. This was most pronounced when exposure occurred in the first trimester, and a 3 to 4% reduction in height at age 18 occurred when the dose was greater than 1 Gy (100 rad). 5.6. Procedures using ionizing radiation 5.6.1. Computed tomography (CT) The fetal radiation dose from a CT scan is affected by several variables including the number, location, and thickness of slices. A narrow collimation and wide pitch enable shorter exposure times, although diminishing image quality slightly, and provide a marked reduction in radiation exposure. Iodinated contrast materials cross the placenta and can produce transient effects on the developing fetal thyroid gland, although clinical sequelae from brief exposure have not been reported. Iodinated contrast materials can be used in pregnancy when indicated. 5.6.2. Dental X rays The radiation dose to the fetus from maternal dental radiography is minute, 0.0001 mGy (0.01 mrad) for an average study, and has not been considered harmful. However, a population-based case–control study in which the investigators hypothesized that radiation to the maternal hypothalamic–pituitary–thyroid axis (as opposed to the fetus) might affect fetal growth found an association between antepartum dental radiography of >0.4 mGy (40 mrad) to the maternal thyroid and low birth weight (<2500 g) [63]. 5.6.3. Ventilation–perfusion and helical CT A ventilation–perfusion scan for suspected pulmonary embolus is among the most common nuclear medicine studies obtained in pregnant women. The procedure involves perfusion with 99mTc macroaggregates of albumin and ventilation with radiolabeled xenon gas or 99mTcDTPA aerosol. Fetal exposure has been estimated to be approximately 0.5 mGy (50 mrad) [64]. Helical CT is another test commonly used for diagnosis of suspected pulmonary embolus and is also associated with a low radiation dose to the fetus (mean of 60 mGy, range 3–131 mGy vs 100–370 mGy for ventilation–perfusion scanning) [65]. 5.6.4. Positron emission tomography (PET) There is minimal information regarding PET in pregnancy. This technique involves injection of a radioisotope,
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[18F]fludeoxyglucose. Animal reproduction studies have not been conducted with [18F]fludeoxyglucose injection and it is not known whether [18F]fludeoxyglucose injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The radiation dose to the uterus is 3.70–7.40 mGy, for the usual dose range of isotope injected [66]. As discussed above, this is a low fetal dose and not associated with adverse effects on development or growth. Because of the lack of safety data in human pregnancy, magnetic resonance imaging and CT are generally preferred to PET as they usually provide similar information, but the decision needs to be made on a patient-specific basis [67].
medically indicated diagnostic procedures using the best available modality. When ionizing radiation is required, various techniques will minimize radiation exposure. No biological effects have been documented from diagnostic ultrasound in the pregnant patient despite intensive use over several decades. There are potential risks from MRI through induction of fields and currents, and radiofrequency heating, and it is not recommended in the first trimester as safety information during organogenesis is limited. Guidelines for diagnostic imaging and ultrasonography/Doppler ultrasound may be found elsewhere [68,69].
5.6.5. Ultrasound No biological effects have been documented from diagnostic ultrasound in the pregnant patient despite intensive use over several decades. The potential for deleterious consequences from heat and cavitation exists, as ultrasound uses sound waves that interact with biological tissues. Bmode and M-mode imaging operate at acoustic outputs that do not produce harmful temperature rises. However, Doppler ultrasound does have this potential; therefore, guidelines for Doppler use in pregnancy have been formulated [68,69].
• What are the risks of CT scanning, dental X rays, contrast materials (iodine, gadolinium), ventilation–perfusion scanning, helical CT, and PET on fetal target structures, malformation, cognitive development, and later risk for mutagenesis? • Does three- or four-dimensional ultrasound or MRI offer greater benefits than routine two-dimensional ultrasound in detection of anomalies? • Are there deleterious effects of multiple ultrasounds throughout pregnancy, including in the latter two trimesters, to monitor fetal growth and position and amniotic fluid? • Are all patients on AEDs being screened for neural tube defects, oral clefts, and urogenital or cardiac defects? • Will functional MRI improve prediction of neurological status of children of women with epilepsy?
5.6.6. Magnetic resonance imaging (MRI) At the cellular level, possible direct biological effects of MRI consist of (1) induction of local electric fields and currents from the static and time-varying magnetic fields, and (2) radiofrequency radiation resulting in heating of tissue. Gadolinium is currently not recommended for use in the pregnant patient unless the potential benefit justifies the potential risk to the fetus [62]. In animal studies, the risks of gadolinium included spontaneous abortion and skeletal and visceral anomalies. Despite these concerns, there are no reported harmful effects from MRI of the pregnant woman or fetus without gadolinium contrast [62,67]. In some cases, MRI is the preferred diagnostic modality because it provides better images than ultrasonography while avoiding the ionizing radiation of CT. The National Radiological Protection Board advises that MRI be avoided in the first trimester because there is limited experience assessing safety during organogenesis. 5.7. Summary The available data show no evidence of increased risk for fetal anomalies, mental retardation, growth restriction, or pregnancy loss from ionizing radiation at doses less than 5 rad [59,63]. The margin of safety is augmented by the fact that most human exposures from diagnostic imaging will be fractionated over time, which is less harmful than an acute exposure [59]. During pregnancy, alternative imaging procedures (e.g., ultrasound, MRI) are preferred to those using ionizing radiation. However, this should not prevent
5.8. Questions for future research
6. Effects of neurosteroids on seizure control in women with epilepsy during pregnancy 6.1. Overview The substantial alterations in sex steroid hormone concentrations and their central nervous system-active metabolites (neurosteroids) may have a significant impact on seizure control during pregnancy. In nonpregnant women, a correlation has been observed between the cyclic monthly levels of estrogen and progesterone and seizure frequency [69]. In animal studies, estrogen is generally proconvulsant [70,71]. Estrogen can create new cortical seizure foci when applied topically, activate preexisting cortical foci, increase the severity of pentylenetetrazol-induced seizures, lower the electroshock seizure threshold, and increase the number of dendritic spines and excitatory synapses on hippocampal CA1 pyramidal cells. Progesterone, conversely, generally has an anticonvulsant effect [70,71]. Animal studies demonstrate that progesterone elevates the seizure threshold, suppresses kindling, and decreases interictal spikes caused by cortically applied penicillin. Allopregnanolone is an active metabolite of progesterone, and works as a neurosteroid by potentiating GABA-activated chloride currents.
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Pregnanolone is another 3a-reduced metabolite of progesterone and a potent modulator of c-aminobutyric acid type A receptors [70]. Bag et al. [73] evaluated seizure frequency during pregnancy in relation to sex steroid hormone concentrations. Pregnancies with increased seizure frequency were compared with those without increased seizures. The increased seizure group had significantly higher estrogen levels, lower levels of progesterone, and lower levels of AEDs [73]. Additionally, the authors noted that patients who had abortions and those who developed status epilepticus had high serum estrogen levels. In pregnancy, estradiol (E2) and estriol (E3) are the major circulating unconjugated estrogens, and estrone (E1) is present in lower concentrations. Mucci et al. [74] studied 230 healthy women during pregnancy; the mean E2 and E3 concentrations at the 16th gestational week were 14.2 ± 6.6 and 3.8 ± 1.7 nM, respectively. At the 27th gestational week, the values were 39.5 ± 17.4 and 14.0 ± 4.5 nM, respectively, reflecting a threefold increase in the estrogenic index over this period. Gilbert Evans et al. [72] examined levels of several 3a-reduced neuroactive pregnane and progesterone precursors at five time points during pregnancy and in the postpartum period in a group of 37 healthy women without epilepsy. Progesterone is first converted to 5a- and 5b-dihydroprogesterone (5a/b-DHP) followed by 3-ketoreduction to the neuroactive pregnanes allopregnanolone (ALLO) and pregnanolone (3ahydroxy-5b-pregnan-20-one). ALLO increases throughout pregnancy, with the highest level reached at 36–38 weeks of gestation. In contrast, 5b-DHP levels are relatively low compared with the levels of other pregnanes, but peak levels are reached at 18–20 weeks and gradually decline thereafter. At 6 weeks postpartum, all steroids are significantly reduced compared with late prenatal values, with 5aDHP being the most abundant postpartum steroid. 6.2. Susceptible pregnancy/delivery stages Labor and delivery is an especially susceptible time with respect to generalized tonic–clonic seizures, with occurrence in up to 4% of women with epilepsy. Women with primary generalized epilepsy may be especially vulnerable during this time, with seizures occurring in 12.5% of women [75]. Contributors to worsened seizure control during this time are numerous but poorly studied. The precipitous decline in progesterone levels just prior to parturition may contribute to seizures. The inevitable disruption of sleep in the peripartum period can contribute to seizure worsening. Although the benefits of breastfeeding need to be weighed against additional effects on maternal sleep disruption, lactation could theoretically contribute to improved seizure control because lactation generates a hypoestrogenic state [72]. No human clinical studies have comprehensively evaluated the effect of sex steroid hormone levels and neurosteroids during pregnancy, parturition, or the
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postpartum period on seizure control. These modulators of seizure frequency play an important role in obtaining and maintaining seizure control during pregnancy, especially if it can be translated into reduced fetal exposure to AEDs. 6.3. Questions for future research • What are the relationships of sex and neurosteroid hormones to seizure control? • How do seizures correlate with increasing levels of proconvulsant compounds, decreasing levels of anticonvulsant compounds, and increased ratios of proconvulsant/ anticonvulsant compounds? • Falling serum levels of progesterone and allopregnanolone may be associated with increased seizure frequency, and may be most prevalent around parturition. How might we quantify these relationships? • What are the effects of sex steroid hormone and neurosteroid properties on seizures in women with epilepsy and in pregnancy? What are the particular roles of estrogens and progesterones and the active neurosteroid metabolites (allopregnanolone and pregnanolone)? • What are the implications for therapy of progesterone administration to improve seizure control during pregnancy and, ultimately, enhance maternal and fetal outcomes? 7. Summary Risk factors for unfavorable obstetric outcomes in women with epilepsy remain inadequately studied and understood. There are complex interactions among the mother, the fetus, and epilepsy, as well as alterations in maternal homeostasis and sex steroid levels. There is information on the risks of maternal–fetal imaging, use of AEDs and other medications, diet, maternal weight, and teratogenesis in particular in this interplay. This overview provides some guidance on our present understanding and approach to the management of pregnant women with epilepsy, and points to what questions might appear most pertinent to further study of these issues. References [1] Bjerkedal T, Bahna SL. The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 1973;52:245–8. [2] Nelson KB, Ellenberg JH. Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children. Neurology 1982;32:1247–54. [3] Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:534–44. [4] Pschirrer ER, Monga M. Seizure disorders in pregnancy. Obstet Gynecol Clin North Am 2001;28:601–11. [5] Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992;42:149–60.
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