Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate. A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy. A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 micrograms/20 micrograms versus triphasic norethindrone/ethinylestradiol 500-750-1000 micrograms/35 micrograms: a multicenter, randomized, open-label study. Normal intelligence in children with prenatal exposure to carbamazepine. Effect of oral prostaglandin E2 on uterine contractility and outcome of treatment in women receiving RU 486 (mifepristone) for termination of early pregnancy.
Antiepileptic drugs (AEDs) are potential teratogenic agents. The purpose of this study was to examine the long-term effects of intrauterine AED exposure on neurologic and psychological functioning.
                Of a prospective study, "Epilepsy, pregnancy, and child development," children could be retraced at school age and adolescence. Sixty-seven were born to mothers with epilepsy [no drugs during pregnancy (n = 13), monotherapy (n = 31), polytherapy (n = 23)]; 49 were nonafflicted control children. Assessments included an intelligence test (Wechsler), a neurologic examination (Touwen), and an EEG. Data analyses were performed, controlling for parental social status, type of maternal drug therapy and drug dosage, type of epilepsy, frequency of seizures during pregnancy, the original subgroups, and specific drug effects.
                Type of maternal epilepsy and type and kind of AED therapy, but not maternal seizures during pregnancy correlated with an increase in abnormal EEG patterns. Minor neurologic dysfunction was diagnosed, with increased frequency from the control to the risk/no drug or monotherapy to the polytherapy group. The compromised intelligence score of the polytherapy group was primarily due to those children who had been exposed to primidone (PRM). Level of IQ was negatively associated with PRM dosage.
                Maternal epilepsy and AED therapy during pregnancy appear to have long-term effects on the offspring well into adolescence, as evinced in EEG patterns, minor neurologic dysfunction, and intellectual performance. Severity of effects increased from control group to epilepsy/no-drug group to monotherapy group and was most marked in the polytherapy group. These group differences are assumed to reflect differential neural vulnerability to social and family factors. The risk of an adverse outcome to pregnancy is increased in women with epilepsy. This is partly attributable to antiepileptic drugs. Guidelines for the management of pregnancy in women with epilepsy generally advise against polytherapy but make no distinction between the risks of different drugs. Several recent studies have however shown greater risk of adverse outcome in offspring exposed to sodium valproate in utero, particularly at higher doses. The outcome of pregnancy was monitored to identify antiepileptic drug treatment associated with a poor outcome in a mainly prospective study of women attending an outpatient clinic. From January 1990 to December 1999 all 69 pregnancies in women referred to the clinic were monitored. Drug treatments and other risk factors were recorded. In each child dysmorphic features, developmental delay and structural anomalies were assessed and graded. Data were analysed for drug- and dosage-dependent differences in outcome. In each assessment area a positive association between adverse outcome and dose was found for sodium valproate but not for carbamazepine. Severe adverse outcomes were found only in children exposed to sodium valproate at maternal doses above 1000 mg per day. A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective. To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45).
                A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG.
                During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason.
                LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated. The aim of this study was to assess psychomotor development, using Griffiths' test, and the incidence of minor anomalies at birth in children who had been exposed to antiepileptic drugs (AEDs) in utero. The study sample comprised 100 children of mothers who were treated with AEDs during pregnancy and 100 matched control children. Women with epilepsy were recruited from a pregnant urban population (450 000 inhabitants). The lowest possible dose of the fewest AEDs to maintain seizure control was used. Drug levels were controlled on a monthly basis. The children were assessed at 9 months of age. The study children had a significant increase in the number of minor anomalies (31 compared with 18 control children; odds ratio 2.4, CI 1.15 to 5.02, P=0.02 McNemars test), and an increased number of facial anomalies after carbamazepine exposure (11 compared with six control children). Drug exposure did not influence the Griffiths' score at 9 months of age. Even a meticulous AED treatment strategy during pregnancy increases the number of minor anomalies. However, treatment with AEDs does not necessarily influence short-term psychomotor development. This study compares pyridoxine-metoclopramide combination therapy to prochlorperazine and promethazine monotherapies in the outpatient treatment of nausea and vomiting in pregnancy.
                In total, 174 first trimester, singleton pregnancies were evaluated for nausea and vomiting. Patients were prospectively randomized into three treatment groups: pyridoxine-metoclopramide, prochlorperazine, or promethazine. Prior to, and on the third day, patients recorded their subjective responses to the given treatment and their number of emesis episodes. The three treatment groups were compared for therapy response.
                There were no differences in the number of emesis episodes prior to treatment. Both subjective and objective responses to treatment differed among the three groups when comparing the combination therapy to the monotherapies (p<0.05).
                Combination therapy with pyridoxine and metoclopramide appears to be superior to either monotherapy in the treatment of nausea and vomiting in pregnancy. This multicenter, randomized, open-label study was undertaken to compare the effects on menstrual cycle control of two oral contraceptive regimens: monophasic levonorgestrel (LNG) 100 micrograms/ethinylestradiol (EE) 20 micrograms (Alesse or Loette) and triphasic norethindrone (NET) 500-750-1000 micrograms/EE 35 micrograms (OrthoNovum 7/7/7).
                Healthy women with normal menstrual cycles were enrolled and completed up to four cycles of study medication. A total of 384 cycles in the LNG/EE group and 400 cycles in the NET/EE group were evaluable for analysis of cycle control.
                For all treatment cycles, the percentage of cycles classified as normal was consistently higher in the LNG/EE group than in the NET/EE group. By cycle 4, 69.9% of cycles with LNG/EE and 54.4% with NET/EE (p < 0.05) were normal. In individual cycles, consistently lower occurrences of intermenstrual bleeding (total bleeding and/or spotting) were seen for the LNG/EE group, although these differences were not statistically significant. Withdrawal bleeding characteristics were comparable between the two groups, except for the length of the latent period, which was significantly longer in the LNG/EE group. The incidence of treatment-emergent adverse events was similar in the two groups.
                This study indicates that the monophasic LNG/EE 100 micrograms/20 micrograms provides better cycle control than the multiphasic NET/EE product, despite its lower EE dose. To investigate the effect of antiepileptic drugs, especially carbamazepine and valproate, on intelligence in prenatally exposed children of mothers with epilepsy.
                Intelligence of 182 children of mothers with epilepsy (study group) and 141 control children was tested in a blinded setting at preschool or school age using Wechsler Preschool and Primary Scale of Intelligence-Revised or Wechsler Intelligence Scale for Children-Revised. Data on maternal antiepileptic treatment and seizures during pregnancy were gathered prospectively. The study group represented approximately 50% of the children born to mothers with epilepsy in Uusimaa province during 1989 through 1994. One hundred seven children were exposed to antiepileptic monotherapy: 86 to carbamazepine and 13 to valproate. Thirty children were exposed to polytherapy: 23 combinations included carbamazepine, and 17 included valproate. The median maternal doses and blood levels during the second half of pregnancy were 600 mg and 26 micro mol/L for carbamazepine and 950 mg and 300 micro mol/L for valproate.
                The mean verbal and nonverbal IQ scores in the children exposed in utero to carbamazepine monotherapy were 96 (95% CI, 93-100) and 103 (95% CI, 100-106). They did not differ from control subjects, whose mean verbal and nonverbal IQ scores were 95 (95% CI, 92-97) and 102 (95% CI, CI, 100-105). Significantly reduced verbal IQ scores were found in children exposed to valproate (mean, 82; 95% CI, 78-87) and to polytherapy (mean, 85; 95% CI, 80-90) compared with the other study group children and control subjects.
                Carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in prenatally exposed offspring. Exposures to polytherapy and to valproate during pregnancy were associated with significantly reduced verbal intelligence. The independent effects of valproate remain unconfirmed because the results were confounded by low maternal education and polytherapy. It has been shown that the antiprogestin RU 486 (mifepristone) increases the sensitivity of the early pregnant human uterus to the stimulatory action of synthetic prostaglandin E (PGE) analogues. To examine if RU 486 also increases uterine sensitivity to the naturally occurring PGE2 given orally, two investigative approaches were used in the present studies: (i) direct registration of uterine contractions before and after PGE2 administration in untreated and RU 486-treated early pregnant women; and (ii) a double-blind, randomized, controlled efficacy trial involving treatment of pregnant women (amenorrhoea of less than or equal to 49 days) with RU 486 (25 mg twice daily for 4 days) and PGE2 (1 mg once or twice) or placebo on the last day of RU 486 treatment. The results indicate that oral PGE2 at the doses employed had little or no stimulatory effect on uterine contractility and that it did not improve the rate of complete abortion achieved with RU 486 alone. Overall, 25 of 42 women (59%) had a complete abortion, 15 women (36%) did not abort and the remaining two had incomplete abortions. Women with complete abortions had significantly lower pretreatment levels of progesterone and a longer duration of induced bleeding than those who did not abort. Thus oral PGE2, when given in clinically acceptable doses, is not a suitable alternative to synthetic PGE analogues for use in combination with RU 486 for termination of early pregnancy.
PART A 1b - Developmental outcomes

Based on the best current available evidence it would seem advisable for women to continue medication during pregnancy using monotherapy at the lowest dose required to achieve seizure control. Polytherapy would seem best avoided where possible. More population based studies adequately powered to examine the effects of in utero exposure to specific monotherapies which are used in everyday practice are required.