Publications by authors named "R Mittendorf"

109 Publications

Association between topiramate and zonisamide use during pregnancy and low birth weight.

Obstet Gynecol 2014 Jan;123(1):21-28

Department of Epidemiology, Harvard School of Public Health, and North American Antiepileptic Drug Pregnancy Registry, Massachusetts General Hospital for Children, Boston, Massachusetts; Loyola University Health System, Chicago, Illinois; the College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, New York, New York; and Oregon Health and Science University, Portland, Oregon.

Objective: To assess the possible effects of topiramate and zonisamide use during pregnancy on fetal growth.

Methods: The study population was the singleton liveborns born to women who enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2012. Data were collected through telephone interviews at enrollment, 7 months of gestation, and postpartum. The prevalence of small for gestational age at birth among neonates exposed to topiramate and to zonisamide when either was used as monotherapy during pregnancy was compared with that among neonates exposed to lamotrigine monotherapy, a weight-neutral therapy, and the most common antiepileptic drug in the Registry. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated with multivariable log-binomial regression to control for potential confounders.

Results: Data were available for 347 topiramate, 98 zonisamide, and 1,581 lamotrigine-exposed neonates. The mean gestational length was 39 weeks for all comparison groups. Prenatal exposure to topiramate or zonisamide was associated with a mean lower birth weight of 221 and 202 g, respectively, and a mean lesser neonatal length of 1 cm as compared with lamotrigine exposure (p<.01). The prevalence of small for gestational age was 6.8% for lamotrigine, 17.9% for topiramate (RR 2.4, 95% CI 1.8-3.3) and 12.2% for zonisamide (RR 1.6, 0.9-2.8). Similar results were found when a group of 457 unexposed neonates was used as the reference.

Conclusions: Topiramate and zonisamide have been shown to reduce weight in adults. Our finding of a decrease in mean birth weight and length among neonates exposed in utero raises concern.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0000000000000018DOI Listing
January 2014

Comparative safety of antiepileptic drugs during pregnancy.

Neurology 2012 May 2;78(21):1692-9. Epub 2012 May 2.

Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.

Objective: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy.

Methods: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months' gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression.

Results: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0-8.5) for valproate, 2.9 (1.4-5.8) for phenobarbital, and 2.2 (1.2-4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip.

Conclusions: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.
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http://dx.doi.org/10.1212/WNL.0b013e3182574f39DOI Listing
May 2012

Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations.

Arch Neurol 2011 Oct 13;68(10):1275-81. Epub 2011 Jun 13.

North American AED Pregnancy Registry, Genetics Unit, MassGeneral Hospital for Children, Boston, MA 02114, USA.

Objective: To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy.

Design: A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews.

Setting: United States and Canada.

Patients: A total of 6857 pregnant women taking an AED for any reason.

Main Outcome Measures: Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs).

Results: The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results.

Conclusions: The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included.
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http://dx.doi.org/10.1001/archneurol.2011.133DOI Listing
October 2011

Using prophylactic, but not tocolytic, magnesium sulfate to reduce cerebral palsy related to prematurity: what dose, and what about infant mortality?

J Perinat Med 2011 07 14;39(4):375-8. Epub 2011 Apr 14.

University of Wisconsin Medical School, Madison, WI, USA.

Strategies for the prevention of cerebral palsy (CP) remain incompletely characterized. Recognizing that half of all cases are associated with preterm delivery (Australian CP Register Report, 2009), research protocols aimed at reducing its prevalence have focused on interventions in pregnancies at risk for preterm birth. Compelling data from recent clinical trials have led to an emerging consensus favoring the use of antenatal magnesium sulfate for preterm neuroprophylaxis. Unresolved, however, is the critical question regarding the "best dose". Acknowledging that any substance in high enough doses becomes toxic, the "best dose" is really the least dose that achieves efficacy, while minimizing potential toxicity among susceptible fetuses. Importantly, credible evidence from these CP prevention trials indicates that antenatal magnesium sulfate, if dosed appropriately, may also decrease infant mortality--a worthy goal in its own right. Accordingly, whether we achieve (a) reduction in CP only, (b) simultaneous reduction in CP and infant mortality, or (c) CP reduction offset by possibly increased pediatric mortality, may depend on selection of dose. In this Opinion paper, we review the findings of all major randomized trials that tested the magnesium hypothesis for prevention of CP. In addition, we discuss future research, in progress, that is hoped to refine estimates of best dose.
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http://dx.doi.org/10.1515/jpm.2011.036DOI Listing
July 2011

Contemporary usage of obstetric magnesium sulfate: indication, contraindication, and relevance of dose.

Obstet Gynecol 2009 Sep;114(3):669-673

From The University of Wisconsin Medical School, Madison, Wisconsin; and the Departments of Obstetrics and Gynecology and of Pediatrics, Loyola University Medical Center, Maywood, Illinois.

Magnesium sulfate, a biologically potent compound, given sometimes in extraordinarily high doses, is among the most commonly used pharmaceuticals in American obstetric practice. Although most clinicians are in accord regarding its value for seizure prophylaxis in the setting of preeclampsia, such unanimity is not the case regarding its role in preterm labor. Credible scientific data indicate not only a lack of efficacy, but also toxicity to susceptible fetuses when magnesium sulfate is used in the high dosages found in tocolysis. In apparent contrast, three recent clinical trials, although individually inconclusive, provide data from which a very recent meta-analysis affirms a potential role for magnesium sulfate in prophylaxis against fetal neurologic injury. Comparing outcomes from these trials, with attention to dosage, relationships are revealed that unify observations previously regarded as conflicting: Magnesium sulfate indeed may have both neuroprotective and fetal toxic effects. The better, and safer, neuroprotection seems to occur at comparatively low antenatal doses (perhaps in a range between 4 g and 10.5 g), whereas increasing dosages exceed a "therapeutic window" whereby, as with most drugs, toxic sequelae begin to accrue.
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http://dx.doi.org/10.1097/AOG.0b013e3181b43b0eDOI Listing
September 2009
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