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

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.

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

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.

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

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.

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

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.

Relationships between umbilical cord arterial blood pH levels at delivery and Bayley Psychomotor Development Index scores in early childhood.

AIMS: To correlate data on umbilical cord arterial blood pH (pHa) levels obtained at delivery with subsequent Bayley Psychomotor Development (PDI) scores determined on the same cohort of children at age 18 months. METHODS: At delivery, we obtained umbilical cord bloods for pHa levels along with other biological parameters. Following the birth cohort prospectively, at age 18 months we did a comprehensive, blinded neurodevelopmental examination to determine a PDI score for each child. RESULTS: Over the broad range of umbilical cord arterial blood pH levels from 7.03 to 7.52, no statistically significant correlation (Pearson correlation coefficient, -0.016, P=0.88) was found between pHa at delivery and PDI scores at age 18 months. To study our finding in greater detail, we formed a subset of the data consisting only of lower pHa levels at delivery (defined as

Special relationships between fetal inflammatory response syndrome and bronchopulmonary dysplasia in neonates.

OBJECTIVE: To confirm previous known relationships between Fetal Inflammatory Response Syndrome (FIRS) and neonatal bronchopulmonary dysplasia (BPD) and to present information on previously unknown special relationships between inflammatory variables and BPD. STUDY DESIGN: At delivery, we obtained biological specimens including umbilical cord venous blood for plasma interleukin-6 levels, as well as placental histology and bacteriology. Among other neonatal outcomes, we collected prospective information on BPD. RESULTS: Of 141 newborns in the study, 16 had BPD; 79% of these had antecedent FIRS, 27% of those without FIRS had BPD. By multivariable regression, only very low birth weight (adjusted [adj] odds ratio [OR] 32.0, 95% Confidence Interval [CI] 5.0 to positive infinity) and FIRS (adj OR 5.7, 95% CI 1.1 to 42.3) remained significant risk factors. Escherichia coli, perhaps due to its pyogenic nature (strongly elicits inflammatory responses), may have had a special relationship with BPD. CONCLUSIONS: In our data, FIRS and neonatal BPD are highly associated. It is possible that certain pyogenic bacteria in the chorioamnion space may be implicated more often than others. CONDENSATION: Neonates having Fetal Inflammatory Response Syndrome at delivery may later develop BPD. Pyogenic bacteria, such as Escherichia coli, may be implicated more frequently.

A review of the role for magnesium sulphate in preterm labour.

During the last decade, the body of medical knowledge concerning the use of pharmacological doses of magnesium sulphate (MgSO(4)) for preterm labour has increased substantially. Several randomised controlled trials (RCTs) have provided compelling evidence that MgSO(4) is the drug of choice for maternal seizure prophylaxis in pre-eclampsia, whether preterm or term. In contrast, a recent Cochrane systematic review of the relevant contemporary literature has found no evidence basis to support the use of MgSO(4) for tocolysis in preterm labour. Furthermore, associated with high-dosage tocolytic MgSO(4), recent data indicate a possible increased risk for neonatal intraventricular haemorrhage (IVH), as well as increased total paediatric mortality. It is possible, on the other hand, that the prophylactic administration of much lower dosages of MgSO(4), in selected cases of preterm labour, may have a neuroprotective effect for a small number of infants.

Antenatal risk factors associated with the development of lenticulostriate vasculopathy (LSV) in neonates.

OBJECTIVE: To determine the antenatal risk factors associated with neonatal lenticulostriate vasculopathy (LSV). STUDY DESIGN: Women in preterm labor were randomized to magnesium sulfate (MgSO4), other tocolytic, or saline control. The surviving babies underwent head ultrasounds (HUS) (weeks of life 1, 2, and 4) and periodic developmental examinations (months 4, 8, 12, and 18). RESULTS: Of 140 infants, 17.1% (24) had neonatal intraventricular hemorrhage (IVH), and 10.0% (14) had LSV (half of the latter (7 of 14) had both IVH and LSV). In a regression model in which other risk factors were controlled for, the association between antenatal exposures to tocolytic MgSO4 >or=50 g and LSV were significant (adjusted odds ratio (OR), 8.3; 95% confidence interval (CI), 1.5 to 45.0; p=0.01). CONCLUSION: Based on our data and their analyses, we infer that antenatal exposure to high-dosage, tocolytic MgSO4 may be associated with LSV.

Risk-benefit effects of tocolytic therapy.

Tocolytics are potent drugs that are used to interdict preterm labour. Although all of these agents have some side effects, if not frankly adverse effects under certain clinical situations, two of these drugs, the beta-mimetics and magnesium sulphate (MgSO(4)), have been found to have considerable potential for adverse maternal cardiovascular and respiratory effects. Furthermore, magnesium sulphate has been shown to have harmful, indeed, sometimes lethal, effects in some babies. Although less well established, NSAIDs, the most common example of which is indomethacin, also have some important adverse effects in fetuses. Within the limits of contemporary scientific knowledge, calcium channel blockers, such as nifedipine, appear to be among the more efficacious and safer drugs that are currently being used for tocolysis.

Association between lenticulostriate vasculopathy (LSV) and neonatal intraventricular hemorrhage (IVH).

OBJECTIVES: To determine whether there is an unconfounded association between neonatal intraventricular hemorrhage (IVH) and lenticulostriate vasculopathy (LSV (also known as thalamostriate or mineralizing vasculopathy)). STUDY DESIGN: During the conduct of the Magnesium and Neurologic Endpoints Trial (MagNET), a randomized controlled trial involving maternal, hence fetal, exposure to antenatal magnesium sulfate in the context of preterm labor, head ultrasounds were obtained for each of the surviving neonates. Because of our previous experience in the diagnosis of LSV, when ascertaining the presence of IVH, as called for by the research protocol of our study, the presence or absence of LSV was also determined. RESULTS: We found LSV to be relatively prevalent (10% (14 of 140) among surviving babies). More importantly, it was significantly associated with the occurrence of neonatal IVH, even when controlled for possible confounding (adjusted OR 9.8, 95% confidence interval 1.3 to 73.1; p=0.03). CONCLUSION: Given the known relationships between IVH and neonatal morbidity and mortality, the finding of a statistically significant association between neonatal IVH and LSV may suggest more substantial implications for the latter than previously believed.

Second overview of relationships between antenatal pharmacologic magnesium sulfate and neurologic outcomes in children.

In the last ten years, the body of scientific knowledge concerning the use of antenatal pharmacologic magnesium sulfate (MgSO4) has become substantially larger. Several randomized controlled trials have provided compelling evidence that MgSO4 is the drug of choice for maternal seizure prophylaxis in toxemia. In contrast, the recent Cochrane Systematic Review, as well as other studies, have shown there is no evidence basis for the use of MgSO4 for tocolysis. Furthermore, when tocolytic-strength doses of MgSO4 are employed, there is an excess risk for total pediatric mortality (Cochrane Systematic Review and our own previous work). It is conceivable, nonetheless, that low doses of MgSO4, when used as prophylaxis in some selected cases of preterm labor, may ultimately be shown to be neuroprotective for a relatively small number of children. Unfortunately, the indiscriminate use of high-dosage MgSO4 for attempted tocolysis in preterm labor is much more likely to cause harm than do good.

Components of the systemic fetal inflammatory response syndrome as predictors of impaired neurologic outcomes in children.

OBJECTIVE: The purpose of this study was to compare interleukin-6 and funisitis as predictors of impaired neurologic outcomes in children by performing a secondary analysis on data that were collected prospectively for another purpose. STUDY DESIGN: We examined umbilical cords for funisitis and obtained cord blood for interleukin-6 levels. A psychomotor developmental index score was determined for each child at age 18 months. RESULTS: The prevalence (46%) of elevated interleukin-6 levels (> or = 10 pg/mL) among children with low psychomotor developmental index scores (<100) was not significantly different from that of children with normal scores (47%). Among children with funisitis (n = 21), the median psychomotor developmental index score was 94; for children without funisitis (n = 92), it was 99 (P <.02). When the data were regressed for confounding, funisitis remained significant (adjusted odds ratio, 1.3; 95% CI, 1.1-1.9). Furthermore, funisitis was a more specific predictor of low psychomotor developmental index scores (P <.001), although elevated interleukin-6 levels were more sensitive. CONCLUSION: When used for the prediction of impaired neurologic outcomes in children, funisitis has better specificity and thus a better positive predictive value than does interleukin-6.