Comparative safety of antiepileptic drugs during pregnancy.

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.

Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor.

High-dosage, tocolytic magnesium sulfate (MgSO4) administered to pregnant women during preterm labor can be toxic, and sometimes lethal, for their newborns (Cochrane Database of Systematic Reviews (relative mortality risk 2.82, 95% confidence interval 1.2-6.6)). Based on the results of the Magnesium and Neurologic Endpoints Trial and the work of many others, a unifying triangular concept is proposed to account for the increased prevalence of brain lesions, with their likely resultant mortality, in neonates and infants exposed to high-dose MgSO4 in the context of preterm labor. We review the evidence that: (1) elevated circulating levels of serum ionized magnesium occurring in mothers, and therefore in their babies, at the time of delivery are associated with subsequent neonatal intraventricular hemorrhage (IVH); (2) neonatal IVH is strongly associated with lenticulostriate vasculopathy (LSV), an unusual mineralizing lesion involving the thalami and basal ganglia of the neonate; and, (3) exposure to 50 g or more of tocolytic MgSO4 during preterm labor is associated with the development of LSV.

Adverse and beneficial effects of tocolytic therapy.

In addition to questions raised about the efficacy of many tocolytics, appropriate concern has been voiced about the safety of these potent drugs. Although some degree of risk for adverse effects with drugs promising a strong therapeutic effect can be accepted, caution needs to be exercised when benefits are marginal or unproven. Unfortunately, some of the tocolytics, most notably the betamimetics and magnesium sulfate, have been found to have considerable potential for adverse maternal cardiovascular and respiratory effects. Although less clearly established, the use of indomethacin appears to be associated with increased fetal and neonatal risks. Concerning magnesium sulfate, in addition to the well-known maternal effects, the accumulating evidence showing an increased frequency of adverse outcomes in the fetus and neonate has led to the recommendations to abandon its use entirely as a tocolytic. Given the limitations of our current state of knowledge, nifedipine would appear to be among the more efficacious and safer tocolytics available to use when properly indicated.

Infant mortality from congenital malformations in the United States, 1970-1997.

OBJECTIVE: We examined a trend in infant mortality caused by congenital malformations in the United States, particularly for the racial disparity between whites and nonwhites. METHODS: We used US annual summary data on cause-specific infant mortality for 1970-97 and detailed birth and infant death linked data for 1985-87, 1989-91, and 1995-97. RESULTS: Congenital malformations became a more prominent cause of infant mortality in 1997 and accounted for 22.1% of all infant deaths compared with 15.1% in 1970. Congenital malformations of nervous, cardiovascular, and respiratory systems accounted for more than 60% of all malformation deaths. Malformations incompatible with life (anencephaly, encephalocele, hypoplastic lungs, renal agenesis, and trisomies 13 and 18) were the cause of one-third of all malformation deaths. In 1970-71, infant mortality caused by congenital malformations in nonwhites was lower, 2.6 (confidence interval [CI] 2.5, 2.7) per 1000, compared with whites, 3.1 (CI 3.0, 3.1) per 1000. However, in 1996-97, the rate of congenital malformation-specific infant mortality was higher in nonwhites, 1.7 (CI 1.7, 1.8) per 1000, compared with whites, 1.6 (CI 1.5, 1.6) per 1000. This trend was most pronounced with central nervous system malformations. Although whites had an almost two-fold higher infant mortality rate from central nervous system malformations compared with nonwhites in 1970-71, this disparity was no longer present by 1996-97. CONCLUSION: Congenital malformations have become a leading cause of infant mortality in the 1990s. Over the last several decades, this mortality declined more slowly in nonwhites than in whites.

Tocolytic magnesium sulfate toxicity and unexpected neonatal death.

A 31-year-old primigravida with twins had spontaneous rupture of the membranes at 32 weeks' gestation. On admission, because of contractions, the mother was started on tocolytic magnesium sulfate (MgSO4) along with betamethasone and prophylactic antibiotics. About a day later, she was found to have magnesium toxicity. Her serum total magnesium level was 9.0 mg/dl. Tocolysis was immediately discontinued. At cesarean delivery the following day, twin A, a female, died at 30 minutes of age despite a vigorous resuscitation. Although the preceding fetal heart rate patterns had been reassuring and the umbilical blood gases were normal, quite unexpectedly, the Apgar scores were 1/1/0. An autopsy revealed no anatomic abnormalities. Twin B, a female who survived, was also intubated at delivery. During her stay in the Neonatal Intensive Care Unit, she was found to have modestly elevated levels of serum cardiotroponin T. In our opinion, it is probable that the death of twin A can be directly attributed to magnesium sulfate toxicity. Neonatologists who attend deliveries should be aware that unexpected death may occur in babies who were exposed to high doses of tocolytic MgSO4.

Umbilical cord serum ionized magnesium level and total pediatric mortality.

OBJECTIVE: To estimate whether higher magnesium levels in umbilical cord blood at delivery are associated with increased total pediatric (fetal + neonatal + postneonatal) mortality. METHODS: During the Magnesium and Neurologic Endpoints Trial, in addition to randomizing mothers having preterm labor into arms containing magnesium sulfate, other tocolytic agents, or saline controls, we obtained biologic specimens at delivery, including umbilical cord venous blood on which was determined the serum ionized magnesium level using the AVL 988-4 analyzer (Graz, Austria). Laboratory results were then matched with the pediatric mortalities. The study power was based on the anticipated reductions in neonatal intraventricular hemorrhage related to magnesium usage from 18.9% to 4.4%. For alpha =.05, 1-beta (power)=80%, two tailed, the total number of infants needed would be 140. RESULTS: Of 149 mothers who gave permission for randomization, ionized magnesium levels were available for 82 children. Seven deaths occurred (one immediately before delivery, three as neonates, and three in the postneonatal period). The median level of ionized magnesium among the seven dead children was 0.76 mmol/L; among the 75 survivors, the median level of ionized magnesium was 0.55 mmol/L (Mann-Whitney U test, P =.03). Using multivariable logistic regression analysis, the association remained statistically significant when controlling for possible confounding factors (adjusted odds ratio 7.7, 95% confidence interval 1.2, 47.6, P =.03). CONCLUSION: These findings of a dose response between serum ionized magnesium and deaths in children increase our concern about the improper use of tocolytic magnesium.

Presurgical plasma exchange for severe factor V deficiency.

We report two patients with severe congenital factor V deficiency, one of whom also had a factor V inhibitor, who required correction of their coagulopathy prior to surgical procedures. They underwent plasma exchange (PE) with fresh frozen plasma or solvent/detergent treated plasma (S/DP), with achievement of factor V levels satisfactory for hemostasis for their procedures. PE makes it possible to raise factor levels quickly and sufficiently without volume overload. In addition, transient reduction of inhibitor titers by PE may improve the level of correction achievable during the perioperative period. The advent of S/DP promises to provide an added increment of safety in patients exposed to significant volumes of plasma during PE.

The association of coagulase-negative staphylococci isolated from the chorioamnion at delivery and subsequent development of cerebral palsy.

OBJECTIVE: To find out whether there is an association between cultures positive for coagulase negative staphylococci (CONS) taken from babies in the Neonatal Intensive Care Unit (NICU) and a subsequent outcome of cerebral palsy. STUDY DESIGN: At delivery, we obtained cultures from the chorioamnion space and, when medically indicated, we obtained bacterial cultures from children in the NICU. Surviving neonates underwent final examination for cerebral palsy at age 18 months. RESULTS: Of six children in the Magnesium and Neurologic Endpoints Trial who had cerebral palsy, chorioamnion cultures had been obtained for five of six. Four of these five children (80%) had CONS-positive cultures, whereas 26 of 102 (25%) children without cerebral palsy were CONS positive (p = 0.02). In the NICU, of children with cerebral palsy, the prevalence of culture-proven CONS was 80% (4/5); for those without cerebral palsy, the prevalence was 17% (15/86) (p = 0.01). Using multivariable logistic regression to control for confounding, CONS in the chorioamnion remained significant (adjusted odds ratio [OR] 37.7, 95% confidence interval [CI] 3.0 to +infinity; p = 0.003). However, when controlled for extremely low birth weight, nonvertex presentation, and being on a ventilator > or = 20 days, the association between culture-proven CONS in the NICU and cerebral palsy became insignificant (adjusted OR 3.0, 95% CI 0.2 to +infinity; p = 0.42). CONCLUSION: CONS in the chorioamnion space are associated with cerebral palsy, but in these data, CONS in the NICU are not found to be associated with cerebral palsy.

Association between funisitis and elevated interleukin-6 in cord blood.

OBJECTIVE: [corrected] To determine whether elevated plasma interleukin-6 (IL-6) in umbilical venous cord blood at delivery is associated with funisitis and whether IL-6 can be used to screen for funisitis in preterm neonates. METHODS: At the time of delivery, umbilical venous cord blood samples were collected from 92 infants for whom placental pathology results were also available. Interleukin-6 concentrations in the umbilical venous cord blood plasma were measured by immunoassay. Histologic examinations of the placenta and umbilical cord were done to determine the presence or absence of funisitis and chorioamnionitis. For a power of 90% with an alpha of.05, 12 subjects were required in each group. RESULTS: We found a significant association between the presence of histologic funisitis and elevated umbilical venous cord blood plasma IL-6 concentrations (defined as 10 pg/mL or greater). Of 15 infants whose umbilical cords showed funisitis, 93% (14 of 15) had elevated umbilical venous cord blood plasma IL-6 concentrations. Of 77 infants without funisitis, 32% (25 of 77) had elevated IL-6 concentrations in their cords (P <.001, two-sided Fisher exact test). The negative predictive value of IL-6 as a screening test for funisitis was 98%. CONCLUSION: In preterm neonates, screening for funisitis by using the immunoassay for IL-6 appears to be valid. In the near future, elevated umbilical venous cord blood IL-6 concentrations at delivery could be clinically useful to identify children who might benefit from early treatment for systemic fetal inflammatory syndrome.

Is intrapartum vibroacoustic stimulation an effective predictor of fetal acidosis?

OBJECTIVE: The hypothesis of this prospective study is that intrapartum vibroacoustic stimulation (VAS) is an effective predictor of fetal acidosis during labor. Various clinical conditions, such as term versus preterm gestation, first stage versus second stage of labor, and fetal heart rate (FHR) variable decelerations versus late decelerations will be tested. METHODS: During the study period, 113 patients were studied prospectively in either active phase of first stage (n = 53) or during the second stage of labor (n = 60). They were selected from cases exhibiting moderate to severe FHR variable decelerations or late decelerations. The fetuses of study subjects received a VAS for three seconds and FHR changes were recorded. Fetal scalp blood pH or umbilical arterial blood pH was obtained within 15 minutes of VAS. The relationship between FHR responses to VAS and fetal blood pH in term and preterm gestations, the relationship of two tests (VAS and fetal blood pH) to type of FHR decelerations, and the predictability of neonatal morbidity by two tests were analyzed. Where appropriate, Fisher's exact test (p < 0.05 was considered statistically different) and the odd ratio with 95% confidence intervals were used for statistical analyses. RESULTS: Excellent association between acceleration response to VAS and pH > or = 7.20, and between a negative response to VAS (no acceleration or decelerations) and pH < 7.20 were found in the first stage of labor, the second stage of labor, and the combination of both stages together (p = 0.0001, OR = 10.6 [3.3-34.0]). It was observed that negative VAS responses for predicting fetal acidosis (pH < 7.20) were comparable between term (> or = 37 weeks) and preterm (< 37 weeks, > or = 34 weeks) fetuses. Since the preterm fetuses enrolled in the study were limited in number, it is difficult to draw adequate conclusions. The positive predictive value (PPV) of fetal acidosis was 67% in both groups of FHR variable decelerations and late decelerations, but the false negative rate of acceleration VAS response for predicting no acidosis was significantly higher in the group of late decelerations (29% vs 8%, p = 0.034). Finally, both a negative VAS response and fetal acidosis (pH < 7.20) have equal predictability for neonatal morbidity. The PPV of NICU admission by a negative VAS response was two times higher than that of fetal acidosis (PPV = 61% vs 29%, p = 0.038). CONCLUSION: We found that intrapartum VAS was an effective predictor of fetal acidosis in cases of FHR variable decelerations, but its predictability for fetal acidosis in cases of FHR late decelerations was limited. Both VAS and fetal blood pH are good predictors of neonatal morbidity.

Ethnic differences in the impact of advanced maternal age on birth prevalence of Down syndrome.

OBJECTIVES: This study explored whether ethnic differences in the impact of advanced maternal age on the risk of Down syndrome might reflect differences in use of prenatal diagnostic technologies. METHODS: Maternal age-specific odds of Down syndrome and amniocentesis use were compared among African Americans, Mexican Americans, and non-Hispanic Whites via birth data for the years 1989 to 1991. RESULTS: The odds ratio and population attributable risk of Down syndrome due to maternal age of 35 years or older were highest for Mexican Americans, intermediate for African Americans, and lowest for non-Hispanic Whites. CONCLUSIONS: Advanced maternal age has a greater impact on the risk of Down syndrome for African American and, particularly, Mexican American women than for non-Hispanic White women. This difference in impact might reflect lower availability or use of prenatal diagnostic technologies.

An overview of the possible relationship between antenatal pharmacologic magnesium and cerebral palsy.

Magnesium sulfate is currently being used in obstetric practice for either eclamptic seizure prophylaxis or for tocolysis, in some countries. Evidence for its use in preeclampsia is credible, whereas the evidence for its use as a tocolytic is limited, if not absent. Of interest, the findings of two epidemiologic studies have suggested a third possible use for antenatal pharmacologic magnesium sulfate, namely, as a neuroprotectant against the later development of cerebral palsy in the newborn. In support of this hypothesis are laboratory data, much of which have to do with the modulation of cellular membrane receptors. Unfortunately, during the Magnesium and Neurologic Endpoints Trial (MagNET), while attempting to confirm the neuroprotective effect of magnesium sulfate, the occurrence of excess total pediatric mortality in those children exposed to magnesium led to early termination of the trial. Nonetheless, despite the alarming findings in MagNET, it is conceivable that exposures to doses of magnesium sulfate less than those often used for aggressive tocolysis may be neuroprotective without being lethal. Other randomized controlled trials now underway may answer this important question.

Perinatal death and tocolytic magnesium sulfate.

OBJECTIVE: To determine whether there is a significant association between perinatal mortality and exposure to total doses of tocolytic magnesium sulfate larger than 48 g. METHODS: We did a case-control study in which cases were defined as neonates or fetuses who died after being exposed to tocolytic magnesium sulfate and controls were those who survived exposure. The study included fetuses and neonates who weighed between 700 and 1249 g and whose mothers had received tocolytic magnesium sulfate at Chicago Lying-in Hospital between January 1, 1986, and March 31, 1999. We excluded women who received prophylactic magnesium sulfate for preeclampsia or preeclampsia superimposed on chronic hypertension, and fetuses or neonates with major congenital anomalies. Data were analyzed by Fisher exact test, chi(2) test, Student t test, Mann-Whitney U test, multivariable logistic regression, and Cochrane-Armitage trend test. RESULTS: Controlling for birth weight or gestational age, year of delivery, receipt of betamethasone, acute maternal disease, and maternal race in a multivariable model, we found that exposure to total doses of tocolytic magnesium sulfate exceeding 48 g was significantly associated with increased perinatal mortality (adjusted odds ratio 4. 7; 95% confidence interval 1.1, 20.0; P =.035). Using the Cochrane-Armitage trend test, we found that a significant dose response was present (P =.03), but one that was most consistent with a threshold effect. CONCLUSION: Our findings support the hypothesis that high doses of tocolytic magnesium sulfate are associated with increased perinatal mortality among fetuses and neonates weighing 700-1249 g.

Early-life physical activity and postmenopausal breast cancer: effect of body size and weight change.

It is not yet known whether early-life physical activity reduces the risk of developing breast cancer. Subgroup analyses according to menopausal status and body mass may help clarify this association. Data from a population-based case-control study of female residents of Wisconsin, Massachusetts, Maine, and New Hampshire were used to examine associations between body mass and breast cancer risk. Cases (n = 4614) were identified by each state's tumor registry; controls (n = 5817) were randomly selected from population lists. Frequency of participation in strenuous physical activity when 14-22 years of age, weight at age 18 and 5 years before interview, height, and other factors were ascertained through structured telephone interviews. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression. Reductions in postmenopausal breast cancer risk associated with strenuous physical activity were greatest for women in the fourth quartile of body mass index at age 18; the OR for women with the highest activity frequency on average (> or =once/day) was 0.45 (95% CI = 0.26-0.79). Associations with frequency of activity also varied by weight change. Compared to women with no activity and little adult weight gain, frequent physical activity was associated with reduced postmenopausal breast cancer risk in women who had lost weight since age 18 (OR = 0.19, 95% CI = 0.05-0.70) or had gained little or modest amounts of weight (weight gain: first tertile, OR = 0.36, 95% CI = 0.05-0.85; second tertile, OR = 0.31, 95% CI = 0.14-0.66). Weighted MET score analyses yielded similar but less inverse results. These findings suggest that the reduced risk of postmenopausal breast cancer associated with frequent, early-life physical activity may be greatest in women who, over the adult years, either lost weight or gained only modest amounts.

Age at any full-term pregnancy and breast cancer risk.

The authors analyzed data from two multistate, population-based case-control studies to investigate the association between age at any full-term pregnancy (FP) and breast cancer risk. Study subjects included breast cancer cases aged 20-79 years identified from four statewide cancer registries and randomly selected controls interviewed from 1988 to 1996. Complete information on a comprehensive set of risk factors for breast cancer was available for 9,891 cases and 12,271 controls. The large number of subjects enabled simultaneous adjustment of the covariates and efficient application of various modeling approaches. Overall, each 5-year increase in age at first FP was associated with an odds ratio of 1.07 (95% confidence interval (CI): 1.01, 1.13) for breast cancer. The corresponding estimates were odds ratio = 1.02 (95% CI: 1.00, 1.05) for age at second through ninth FPs. For age at last FP, the effect estimate (odds ratio = 1.01, 95% CI: 0.97, 1.06) was indistinguishable from that for other FPs after the first. In this analysis, a modest and transient increase in breast cancer risk after childbirth was also observed. The relatively greater effect of age at first FP is consistent with the existence of a long-term effect of early first FP on the differentiation of mammary cells, causing them to become less susceptible to carcinogenesis.

Association between cerebral palsy and coagulase-negative staphylococci.

Coagulase-negative staphylococci were cultured from the space between the placental membranes at delivery in four of five neonates who were later diagnosed with cerebral palsy, and in 26 of 102 neonates who were not found to have the disorder (p=0.02).

Length of pregnancy in African Americans: validation of a new predictive rule.

This study evaluated whether a new predictive rule is more accurate for estimating the length of pregnancy in African Americans than Nägele's rule, the accepted standard. After identifying women in early pregnancy, telephone interviews were conducted to obtain information about 16 previously established determinants of gestational length. Based on these data, a linear multivariate regression model was used to predict an estimated delivery date (EDD) for each mother. In addition, the EDD was determined using Nägele's rule. Later, the actual delivery date was compared with the EDD predicted by the new rule and with the EDD predicted by Nägele's rule. Each pregnancy was assigned to its better prediction group, either the new rule's group or the Nägele's rule group. Fifty-seven pregnancies were identified prospectively and monitored. The new rule predicted the actual delivery date more accurately in 66% (37/56) of pregnancies, Nägele's rule was a better predictor in 34% (19/56) of pregnancies, and both rules were equally accurate in predicting the delivery date for one pregnancy. The new rule was more precise than Nägele's rule (P = .022) when the binomial distribution was used. When using the linear regression model rule, a more accurate EDD can be determined for African-American women. Moreover, it is possible to predict the risk of preterm delivery (those occurring > 3 weeks earlier than the EDD).

Maternal second trimester serum tumor necrosis factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of preeclampsia.

Preeclampsia is characterized by diffuse vascular endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha), which plays a key role in the cytokine network responsible for immunoregulation, is also known to contribute to endothelial dysfunction and other metabolic disturbances noted in preeclampsia. Results from cross-sectional studies and one longitudinal study indicate that TNF-alpha (or its soluble receptor, sTNFp55) is increased in the peripheral circulation and amniotic fluid of women with preeclampsia as compared with normotensive women. Between December 1993 and August 1994, prediagnostic sTNFp55 concentrations (a marker of excessive TNF-alpha release) were measured in 35 women with preeclampsia and 222 normotensive women to determine whether elevations precede the clinical manifestation of the disorder. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Mean second trimester (15-22 weeks' gestation) serum sTNFp55 concentrations, measured by enzyme-linked immunosorbent assay, were 14.4% higher in preeclamptic women than in normotensive controls (716.6 pg/ml (standard deviation 193.6) vs. 626.4 pg/ml (standard deviation 158.0); p = 0.003). The relative risk of preeclampsia increased across successively higher quintiles of sTNFp55 (odds ratios were 1.0, 1.3, 2.1, and 3.7, with the lowest quintile used as the referent; p for trend = 0.007). After adjustment for maternal age, adiposity, and parity, the relative risk between extreme quintiles was 3.3 (95% confidence interval 0.8-13.4). These findings indicate that the level of TNF-alpha in maternal circulation is increased prior to the clinical manifestation of the disorder, and they are consistent with the hypothesized role of cytokines in mediating endothelial dysfunction and the pathogenesis of preeclampsia. Further work is needed to identify modifiable risk factors for the excessive synthesis and release of TNF-alpha in pregnancy, and to assess whether lowering of TNF-alpha concentrations in pregnancy alters the incidence and severity of preeclampsia.