This was an observational study. The investigators played no part in clinical management. WWE were recruited from antenatal clinics at 11 National Health Service (NHS) hospitals within Merseyside and Greater Manchester between 2000 and 2006. Midwives in the antenatal clinics approached each woman, who gave a history of epilepsy, whatever her stage of gestation. An information sheet was provided with a verbal explanation of the project. The research nurse then made contact by phone, gave more detail, posted the consent form and arranged to meet the WWE as soon as possible. All consenting WWE were followed up but those with chronic medical conditions predisposing to abnormality in the child and those with an earlier pregnancy in the study are not included in this report.
The longer-term objective of this 6-year study is to monitor a cohort of children born to WWE and a corresponding cohort of children born to mothers without epilepsy. By comparing the physical and cognitive development of the two groups it is hoped to assess the impact of in utero exposure to different AED. Using the Differential Ability Scale as the primary outcome measure and seeking 80% power at a 95% confidence level to detect a difference of 1.5 SD, it was estimated that 45 children were required in each monotherapy group. To allow for fetal deaths and withdrawals the recruitment target became a minimum of 50 pregnancies in each monotherapy group.
WWE receiving monotherapy with carbamazepine (CBZ), lamotrigine (LTG) or valproate (VPA) were also invited to join an NIH funded, multi-centre study (Neurodevelopmental Effects of Antiepileptic Drugs; NEAD) which compares outcomes with different AED. Some results from children of these women have been published previously.6, 20, 21
The NEAD study excludes women on polytherapy and does not incorporate a control group of women without epilepsy.
Women without epilepsy were recruited from the same NHS hospital antenatal clinics. The research nurse after interviewing each WWE searched through the records of healthy women, who attended the clinic on the same day or a few days later. The aim was to find a woman control, who matched each WWE for age (within a five-year band), for parity, for residential district (postal code) and employment. Since the WWE and the healthy woman controls were attending the same clinic at about the same time it was assumed that there would be no systematic difference in gestational age. This assumption proved to be incorrect.
Antenatal and obstetric care outside the NHS is rare in the UK particularly for WWE but even within the NHS, WWE and healthy women follow different patterns of antenatal care. Both groups usually present themselves to their General Medical Practitioner for health care during the pregnancy but thereafter the management is different. A pregnant WWE is typically referred directly for hospital-led antenatal care, whereas a potential ‘control’ woman with no medical history is typically referred to the community mid-wife service often based in the local medical practice. Thus hospital midwives often meet WWE during the first trimester or early in the second, whereas they commonly meet women without epilepsy first at the 19-21 week scan. This phenomenon has created within this study a systematic difference between WWE and women controls with respect to gestational age at recruitment.
There was no payment to women for study visits to hospital beyond expenses for travel and refreshments. Nevertheless, it was expected that a high proportion of WWE would take part. Acceptance amongst control women was expected to be about 50%. Research nurses therefore approached two potential control subjects for each WWE.
At her first meeting with each newly recruited subject the research nurse took a personal and medical history in accordance with the prospectively designed Patient Basic and Control Basic Record Forms. Questions covered education, occupation, welfare benefits and lifestyle issues such as use of tobacco and alcohol. Previous miscarriages and terminations were recorded but the reasons for termination were not ascertained. The Patient Basic Forms also covered seizure history and details of the clinical units and physicians involved in the investigation and treatment of the epilepsy. An epilepsy specialist (G.M.) confirmed seizure type, syndrome diagnosis, current seizure frequency and antiepileptic medication. Information from the patient was supplemented from clinical records.
The epilepsy syndrome was classified as symptomatic/cryptogenic focal (localisation-related) or idiopathic generalised (IGE). When uncertain whether tonic clonic seizures were primary or secondarily generalised, the epilepsy was unclassified. Seizures were recorded as tonic clonic or non-convulsive (simple/complex partial, myoclonic, absence). Frequency was ascertained from the patient and an observer, if available, since not all WWE kept seizure diaries. Seizure-related injuries and hospital admissions were noted. Seizures after delivery were not recorded.
Details of each pregnancy were recorded in prospectively designed Patient and Control Pregnancy & Delivery Record Forms. These were filled in partly at a meeting with the research nurse during later pregnancy, often on the day of an ultrasound scan. The remainder was filled in after delivery, if possible before discharge from the maternity unit. Failing this the information was obtained by phone. The forms covered AED medication, the timing of dosage changes, nutritional supplements, presence of specific complications of pregnancy, investigations, attendance for ultrasound scans, the delivery and the immediate outcome. The occurrence of seizures, injuries and emergency admissions were recorded on the Patient Forms. Obstetric records were studied for details of complications, reports of ultrasound scans, fetal presentation and mode of delivery.
Condition at birth (Apgar score, neonatal problems, need for special care, birth weight) was recorded on the First Paediatric Assessment Form. Congenital abnormalities were identified from reports of fetal scans and paediatric medical examination of the baby before discharge. Length, occipito-frontal circumference and details of physical examination were recorded. Some congenital abnormalities were not identified until later during follow up, which is continuing up to 6 years. These have also been included. Major malformations (MCM) were distinguished from minor anomalies using Eurocat instructions for the Surveillance of Congenital Abnormalities.22
MCM in babies with chromosome abnormalities were not included in the analysis of possible adverse effects of AED.
The study was conceived and designed as a prospective study. The content of the Basic Form however related mainly to the previous medical history and was clearly retrospective. The content of the Pregnancy & Delivery Form was mixed. The data on pre-conceptual dosage of AED and folate related to the time before recruitment and was retrospective. Data on mode of delivery was prospective. The point of transition between the recording of past history and of events as they happened depended on the date of recruitment. Since a substantial proportion of WWE and most women controls were recruited in the second and third trimester, the term prospective has not been applied to the early results of this 6 year long study.
Physical examination and cognitive function assessments of each child were repeated at 1-2 years, 3 and 6 years. Details of the examinations, test batteries and Record Forms are beyond the scope of the present report.
The WWE were divided into two groups 1) those with ‘treated epilepsy’ (WWTE), who were taking AED to prevent seizures and 2) those with ‘untreated epilepsy’ (WWUTE), who were taking no AED. The treated group was expected to have a poorer outcome in terms of complications and MCM. Its results have been presented separately to avoid bias towards a good outcome arising from inclusion of the untreated group that was expected to resemble the control group. A similar approach was adopted by Viinikainen et al7
Differences between groups were expressed as Odds Ratios (OR) with 95% Confidence Intervals (CI). Explicit p values were derived from Chi2 test, or Fisher’s exact test for small samples. Unpaired t-test was used to compare continuous variables. Mann Whitney U test was used to compare variables not normally distributed. When repeated tests were applied to related features (obstetric complications) the effect of a multiple test correction (Bonferroni) was noted. Discriminant analysis (Wilks lambda) was used to identify and rank variables that were significant discriminators for MCM. Subject variables were converted to binary form for this analysis to ensure the samples were from multivariate normal populations and had equal variance-covariance matrices (Box’s M). Thus, for example, maternal age was recorded as below or above the study population mean, and gestational age at recruitment was recorded as early (up to 20 weeks, before anomaly scan) or late (more than 20 weeks, after anomaly scan). Because WWE and women controls were not matched for gestational age, particular attention has been given to the influence of this variable. Tests were accessed through Confidence Interval Analysis for Windows and SPSS version 16 for Windows. Missing data below 10% was ignored.