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Ch. 13: Neurologic Complications of Pregnancy

Michelle Bell, MD

Pregnancy and Epilepsy
Morrow J et al. “Malformation risks of antiepileptic drugs in pregnancy: a prospective study from
the UK Epilepsy and Pregnancy Registrar.” J Neurology Neurosurgery Psychiatry 2006; 77: 193-
198.

What are the relative risks of major congential malformation from in utero exposure to antiepileptic drugs?
These are the results from the UK Epilepsy and Pregnancy Registrar. The study included 3607 births. At
the time of publication, it was the largest reported epilepsy AED registrar to-date. The MCM (major
congenital malformation) rate for women with epilepsy who had not taken AEDs during pregnancy
(n = 239) was 3.5%. The rate among patients receiving monotherapy (n=2598) was 3.7%, and the rate
among patients receiving polytherapy (n = 770) was 6.0%. Polytherapy combinations containing
valproate carried a higher risk than polytherapy containing combinations without valproate.
The rate of malformation was 0% for levetiracetam, 2.2% for carbamazepine, 3.2% for gabapentin and
lamotrigine, 3.7% for phenytoin, 6.2% for valproate, and 7.1% for topiramate. The most common
malformations for valproic acid were facial cleft (1.5%), hypospadias (1.3%), and neural tube defects
(1%). Though the rate of malformation was 7.1% for topiramate, this only constituted two cases of MCM
(one case of cleft palate and one case of hypospadias).
Take home message: Valproic acid and polytherapy confer higher risks for major congenital
malformation.

Hernández-Díaz S et al. “Comparative safety of antiepileptic drugs during pregnancy.” Neurology
2012; 78: 1692-1698.
What are the safety profiles of the newer antiepileptics during pregnancy?
This is prospective study of pregnant women enrolled in North American AED Pregnancy Registry
between 1997 and 2011. The study reviewed the fetal outcomes of 4,899 women taking AEDs and also
an internal comparison group of 442 women without epilepsy, not taking AEDs. The risk of major
malformations (in order of increasing frequency, RR as compared to unexposed reference) in patients
exposed to AEDs were as follows: gabapentin 0.7% (RR 0.6), lamotrigine 2% (RR 1.8), oxcarbazepine
2.2% (RR 2.0), levetiracetam 2.4% (RR 2.2), phenytoin 2.9% (RR 2.6), carbamazepine 3.0% (RR 2.7),
clonazepam 3.1% (RR 2.8), topiramate 4.2% (RR 3.8), phenobarbital 5.5% (RR 5.1), valproic acid 9.3%
(RR 9.0). The risk of malformations increased with VPA dose. The median average first trimester dose
was 1,000mg/day for patient with malformations and 750mg/day for patients without malformations.
AEDs with a higher risk of seizures tended to have a lower risk of malformations. Different AEDs were
associated with different malformations. VPA was associated with neural tube defects, hypospadias,
cardiovascular malformations and oral cleft lift. The most commonly reported AED monotherapies (in
order of decreasing frequency) were lamotrigine, carbamazepine, leveitracetam and topiramate.
Lamotrigine had a 0.45% rate of cleft palate, 0.19% risk of cardiovascular abnormalities, and 0.13% risk
for neural tube defects. Carbamazepine had a 0.48% rate of oral cleft palate, 0.29% rate of
cardiovascular abnormalities, 0.29% rate of neural tube defects and 0.19% rate of hypospadias.
Levetiracetam had a 0.2% rate of cardiovascular abnormalities and neural tube defects. Topiramate had
a 1.4% rate of oral cleft palate, 1.1% rate of hypospadias, and 0.28% rate of cardiovascular
abnormalities.
One limitation of this study is that the reference group consisted of women without epilepsy and since
some other studies have suggested that women with epilepsy may have a higher baseline risk of
malformations, these numbers may overestimate the risk added by the antiepileptic.
Take home message: This provides even more evidence that valproic acid increases the risk of major
malformations. Lamotrigine, oxcarbazepine, and levetiracetam may provide the best balance between
risk of malformation and seizure control.

EURAP Study Group “Seizure control and treatment in pregnancy: Observations from the EURAP
Epilepsy Pregnancy Registry.” Neurology 2006; 66: 354-359.

What is the impact of pregnancy on seizure control?

This is a prospective study of 1,956 pregnancies in women with epilepsy. At the time of its publication it
was the largest registrar to investigate this question. In this cohort, 58.3% of patients remained seizure
free. Seizures were more likely to occur in patients with localization-related epilepsy (OR 2.5) and
polytherapy (OR 9.0). Tonic clonic seizures were more likely to occur among patients on oxcarbazepine
monotherapy (OR 5.4). For most patients there was not a significant change in seizure frequency.
Seizures occurred during delivery in 3.5% of patients and most commonly occurred in women with
seizures during pregnancy.
Take home message: Seizure rate usually remains fairly stable during pregnancy. Those patients whose
seizures were poorly controlled were more likely to have seizures during pregnancy.

Thomas et al. “Predictors of seizures during pregnancy in women with epilepsy,” Epilepsia 2012;
53:85-88.

What is the likelihood of a patient with epilepsy having seizures during pregnancy?
This is a prospective study of women enrolled in the Kerala AED Pregnancy Registry. The study reviewed
1,297 pregnancies. 52.2% of patients had seizures during pregnancy. The main predictor for seizures
during pregnancy was seizures in the month prior to pregnancy (15 times higher risk). Patients with
localization-related epilepsy were more likely to have seizures during pregnancy (58.7%) as compared to
those with generalized epilepsy (47%). For all women in the study, seizure relapse was highest during the
peripartum days (1 day before delivery, day of delivery, one day after delivery). In patients with
localization-related epilepsy, there were two additional seizure peaks: one during the third and fourth
month of pregnancy and one during the sixth month. Patients with generalized epilepsy had a peak during
the first trimester.
Take home message: Main predictor for seizures during pregnancy is having a seizure in the month
before pregnancy.

Eclampsia
The Eclampsia Trial Collaborative Group “Which anticonvulsant for women with eclampsia?
Evidence from the Collaborative Eclampsia Trial.” Lancet 1995;345:1455-63.
Which anticonvulsant most effectively reduces recurrent seizures in an eclamptic patient? Eclampsia accounts for approximately 50,000 maternal deaths per year. Until this landmark study was published, there was significant geographic variation in the antiepileptic used to treat eclamptic seizures. Magnesium sulfate was commonly used in the United States whereas diazepam and phenytoin were popular in Europe and elsewhere. The Collaborative Eclampsia trial was a double blind controlled trial aimed to answer this important and widely-debated question. The trial enrolled 1687 women from twenty- three centers in eight countries. Each center chose two of the three anticonvulsants to compare. In other
words, a center either compared phenytoin versus magnesium sulfate or diazepam versus magnesium
sulfate. The magnesium was administered as a 4gram bolus followed by a 1gram/hour infusion over
24hours or a 5gram IM injection every 4 hours. The diazepam therapy was 10mg IV over 2 minutes
followed by 40mg in 500mL normal saline for 24 hours, then 20mg in 500mL normal saline “to be given
and slowly reduced.” For the phenytoin treatment, first diazepam 10mg IV was given for immediate
control of the seizures, followed by a phenytoin 1gram IV loading dose over 20 minutes followed by
100mg every 6hours for the next 24 hours. The primary outcome measures were recurrence of seizures
and maternal death. The secondary outcome measures were potentially life-threatening maternal events
and fetal morbidity and mortality. Women allocated magnesium sulfate had 52% and 67% lower risk of
recurrent convulsions than those allocated diazepam and phenytoin respectively. There was no
significant difference in maternal mortality in those allocated magnesium as compared to those using
phenytoin or diazepam but the mothers receiving phenytoin did have a higher rate of maternal morbidity
(more likely to be intubated, develop pneumonia, admitted to an intensive care unit) and fetal morbidity
(more likely to be intubated and more likely to be admitted to a special nursery) as compared to those
receiving magnesium.
Take home message: In women with eclampsia, magnesium sulfate reduces the rate of recurrent
seizures more effectively than diazepam or phenytoin.

Pregnancy and Multiple Sclerosis
Vukusic S et al. “Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of
postpartum relapse.” Brain 2004; 127:1353–136.
How does pregnancy affect the clinical course of multiple sclerosis?
This is a cohort study of 227 women with multiple sclerosis. The women were followed during their
pregnancy and 2 years post-partum. The pre-pregnancy annual relapse rate in this cohort was 0.7. The
annual relapse rate was 0.5, 0.6, and 0.2 in the first, second, and third trimester respectively. The annual
relapse rate was 1.2, 0.9, 0.9, 0.6, and 0.5 in the first, second, third, fourth, and fifth post-partum
trimesters. The main predictors of post-partum relapse were the number of relapses during the pre-
pregnancy year (1.7 fold increased risk with each relapse experienced during the pre-pregnancy year),
the number relapses during pregnancy (1.8 fold increased risk for each relapse during pregnancy), and a
higher Kurtzke’s Disability Status Score (odds ratio 1.3). There was no association between postpartum
relapse and breast-feeding, epidural analgesia, age of multiple sclerosis onset, age at pregnancy onset,
disease duration, total number of relapses during pregnancy, number of previous pregnancies or child
gender.
Take home message: Patients with multiple sclerosis are most likely to have a relapse immediately post-
partum and least likely to have a relapse in the third trimester of pregnancy.

Boskovic R, Wide R, Wolpin J, et al. “The reproductive effects of beta interferon therapy in
pregnancy: a longitudinal cohort.” Neurology 2005; 65:807.
What is the evidence that Interferon may be harmful in pregnancy?
This is a longitudinal cohort study of three groups of women: a group of 16 women with 23 gestations
exposed to interferon beta 1a (Avonex, Rebif), a disease control group (MS but not on interferon)
consisting of 12 women with 21 gestations, and a healthy control group of 18 women with 20 gestations.
There were two malformations in the interferon group (abnormality in the X chromosome, Down’s
syndrome). There was an increase in miscarriages and stillbirths among the interferon-exposed group
and the disease control group as compared to the healthy control. The miscarriages/stillbirths constituted
5%, 19%, and 39% of births among the healthy controls, MS patients without interferon exposure, MS
patients with interferon exposure, respectively. There was not a statistically significant difference between
non live births among MS patient without interferon exposure and MS patients with interferon exposure.
The numbers suggest that having multiple sclerosis is a risk factor for non-live birth, and this is
confounded further by interferon use.
Of note, there is a decrease in the mean birth weight in the exposed group as compared to the healthy
control (3.189kg vs 3.793kg),
The main limitation of this study is its small size.
Take home message: Interferon is associated with increased risk of fetal death, and as such should be
avoided in pregnancy.

Stroke

Turrentine MA, Braems G, Ramirez MM. “Use of thrombolytics for the treatment of
thromboembolic disease during pregnancy.” Obstet Gynecol Surv 1995; 50:534.
What is the complication rate of administering thromboembolics during pregnancy?
This is a review of the 172 published cases of pregnant women receiving thrombolytic therapy.
Hemorrhagic complications occurred in 8.1% of patients, pregnancy losses in 5.8% of patients and
maternal morbidity in 1.2% of patients. As this is just a summary of the reported cases, it is difficult to
know how the complication rate compares to that of patients who did not receive antithrombotic therapy.
Take home message: Thrombolytics can be administered to pregnant women. They can be counseled
about their risk of complication, with the above data.

Jaigobin et al. “Stroke and Pregnancy.” Stroke 2000 (31): 2948-2951.
How frequently does stroke complicate pregnancy or the postpartum period? What types of strokes tend to occur during this time? This was a retrospective review of 50, 700 admissions for delivery to Toronto Hospital between 1980 and 1997. 34 patients were diagnosed with stroke. This number was about double that of non-pregnant strokes for women in the same age range. The incidence of strokes in nonpregnant women aged 15 to 44 years was 10.7/100,000. In this study the incidence was 69/ 100,000 pregnancies and 26/ 100,000 after exclusion of patients who were referred from an outside hospital for stroke management. 21 of the 34 strokes were ischemic, 12 of them being arterial and 8 venous. Most arterial strokes presented in the third trimester and puerperium (at the time of delivery and six weeks postpartum). All but one venous strokes presented in the puerperium period. 13 of the strokes were hemorrhages: 7 were subarachnoid and 6 were intracerebral. Of the 7 subarachnoid hemorrhages, 3 were due to aneurysmal rupture and all 3 were due to strokes in the posterior communicating artery. Patients presented with subarachnoid hemorrhage and aneurysm rupture during each trimester and the postpartum period. Patients presented with bleeding AVM after the first trimester. Bleeding as a consequence of DIC occurred postpartum. All patients with ischemic strokes survived and 3 patients with hemorrhage survived. Take home message: Pregnancy appeared to double the risk of stroke in this population. Various types
of stroke occurred during pregnancy. Ischemic strokes are more likely to occur in the third trimester or
postpartum period and venous strokes, in particular, are more likely to occur postpartum. Hemorrhagic
strokes occur at any time in the pregnancy or post-partum time period, but occur most frequently in the
second trimester and postpartum.

Source: http://niresidents.org/wp-content/uploads/2012/09/Pregnancy-and-Neurology1.pdf