Pregnancy, antiseizure medications and unexplained intrauterine foetal death.

OBJECTIVE: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR). RESULTS: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders. CONCLUSIONS: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE.

Changes over 24 years in a pregnancy register - Teratogenicity and epileptic seizure control.

OBJECTIVES: To trace (i) changes in Australian Pregnancy Register (APR) records concerning antiseizure medications (ASMs) prescribed for women with epilepsy (WWE) over the course of 24 years and correlate the changes with (ii) rates of occurrence of pregnancies involving foetal malformations, (iii) the body organs involved in the malformations, and (iv) freedom from epileptic seizures. RESULTS: Use of valproate and carbamazepine decreased progressively, use of lamotrigine remained relatively static, and the use of levetiracetam increased progressively, whereas the use of topiramate first increased and then fell again, associated with a temporary increase in malformation-associated pregnancy rate. More serious malformations, such as spina bifida, became less frequent, whereas more trivial ones tended to increase, whereas epileptic seizure freedom rates improved. CONCLUSIONS: The increasing use of newer ASMs in pregnant women has been associated with overall advantages in relation to the frequency and severity of foetal malformation and with advantages in relation to freedom from epileptic seizures.

Specific fetal malformations following intrauterine exposure to antiseizure medication.

OBJECTIVE: To investigate in the Australian Pregnancy Register of Antiepileptic Drugs patterns of fetal malformation associated with intrauterine exposure to particular currently available antiseizure medications taken by women with epilepsy. RESULTS: There was statistically significant evidence (P < 0.05) of an increased hazard of fetal malformation associated with exposure to valproate, carbamazepine, topiramate, zonisamide, and with conception after assisted fertilization, but a reduced hazard in the offspring of women who continued to smoke during pregnancy. Valproate exposure was associated with malformations in a wide range of organs and organ systems, carbamazepine and topiramate with hydronephrosis, topiramate also with hypospadias, zonisamide with spina bifida and assisted fertilization with heart and great vessel maldevelopment. CONCLUSIONS: Prenatal valproate exposure appears to interfere with the development of many if not all, fetal tissues. It seems likely that prenatal exposure to carbamazepine and topiramate, and possibly exposure to zonisamide, but also some process related to in vitro fertilization, may more selectively affect the normal development of particular fetal tissues or organs.

Seizure control in successive pregnancies in Australian women with epilepsy.

OBJECTIVES: To investigate control of epileptic seizures during pairs of successive pregnancies in antiseizure medication (ASM)-treated women with epilepsy. MATERIALS AND METHODS: Analysis of seizure freedom rates during 436 pairs of successive pregnancies in Australian women with epilepsy, in nearly all instances long-standing epilepsy. RESULT: There was a higher rate of seizure-free second pregnancies compared with first paired pregnancies (63.1% vs. 51.4%; Relative Risk (R.R.) = 1.2277; 95% CI 1.0930, 1.3789) and of seizure-free pre-pregnancy years before second as compared with first paired pregnancies in the same women (63.6% vs. 52.4%; R.R. = 1.2616; 95% CI 1.1337, 1.4040). In 108 women whose ASM therapy was unaltered throughout both of their pregnancies, the seizure-freedom rate was higher in the second of the paired pregnancies (82.4% vs. 69.4%; R.R. = 1.1867, 95% CI 1.0189, 1.3821). CONCLUSIONS: Altered ASM therapy after the first of a pair of successive pregnancies did not fully account for the better overall seizure control in the corresponding second pregnancies. Some additional factor may have been in operation, possibly a greater preparedness to undertake a further pregnancy if seizures were already fully controlled.

Epileptic seizure control during and after pregnancy in Australian women.

OBJECTIVES: To study factors that affected previous epileptic seizure control throughout pregnancy, during labour, and in the post-natal weeks. MATERIALS & METHODS: Analysis of data concerning seizure freedom that was available at various stages of 2337 pregnancies in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs, mainly employing multiple variable logistic regression techniques. RESULTS: Based on data available at the outset of pregnancy, the risk of seizure-affected that is, not seizure-free pregnancy was statistically significantly (p < .05) higher in pregnancies where there was previously uncontrolled epilepsy (78.1% vs. 20.8%) and focal epilepsy (51.3% vs. 39.7%), and decreased with later onset-age epilepsy (41.8% vs. 52.2% with onset before age 13 years), The risk did not differ between initially antiseizure medication (ASM)-treated or untreated pregnancies. For epilepsy receiving ASM therapy, 90.6% of 160 pregnancies of women with uncontrolled focal epilepsy that began before the age of 13 were seizure-affected. None of the above factors influenced the risk of seizures during labour, though having seizures during pregnancy increased the hazard (3.93 vs. 0.6%). Either ASM-treated pregnancy or labour being seizure-affected increased the risk of post-partum period seizures (33.0% vs. 6.67% for both stages being seizure-free). Use of particular ASMs had no statistically significant effect on the seizure control situation at any of the pregnancy stages studied. CONCLUSIONS: Obtaining full seizure control before pregnancy appeared to be the main factor in maintaining seizure freedom during pregnancy, labour and the post-natal weeks.

Fetal malformations in successive pregnancies in Australian women with epilepsy.

OBJECTIVES: To utilize data from the Australian Register of Antiepileptic Drugs in Pregnancy (APR) to determine the hazard of fetal malformation in the subsequent pregnancy or pregnancies in women with epilepsy following a pregnancy associated with a fetal malformation, and to identify factors relevant to the hazard. RESULTS: There was a 7.4% initial pregnancy fetal malformation rate. The subsequent pregnancy malformation rate was 4.2% if there was no initial pregnancy malformation, but 21.2% if there was an initial pregnancy malformation (O.R. = 6.1448, 95% C.I. 2.3396, 16.1386). For pregnancies where antiseizure medication (ASM) therapy was unchanged between pregnancies (N = 196), the initial pregnancy malformation rate was 10.2%, but 30.0% in the subsequent pregnancy if there was a malformation in the initial pregnancy, and 2.35% if there was none (O.R. = 17.7857, 95% C.I. 4.4847, 70.5361). A cohort comprising 24% of the women with fetal malformations in their initial pregnancies seemed to be intrinsically vulnerable to fetal malformation during successive pregnancies: when their seizure disorder type had been recorded all had genetic generalized epilepsies, compared with a 45.8% generalized epilepsy rate in women with initial but not subsequent pregnancy malformations (P = 0.0121). CONCLUSIONS: If fetal malformation had occurred in an initial ASM-treated pregnancy there was a significantly increased hazard of fetal malformation in the subsequent pregnancy, particularly if the woman involved had a genetic generalized epilepsy.

Achieving neurologically desirable outcomes to pregnancy in women with epilepsy.

OBJECTIVES: To investigate possible factors that influenced whether pregnancy in women with epilepsy resulted in the desirable outcome of a live-born non-malformed infant and a mother whose pregnancy had been seizure free. RESULTS: The desirable outcome, as defined, occurred in 46.3% of unselected pregnancies in the database of the Australian Register of Antiepileptic Drugs in Pregnancy (APR). The only factor investigated that had a statistically significant (P < 0.05) effect, increasing the chance of such a desirable outcome, was freedom from seizures in the pre-pregnancy year. However, anti-seizure medication (ASM) doses, particularly valproate doses, had been reduced prior to 15.6% of the pregnancies, and this may have concealed factors that otherwise may have adversely affected the desirable outcome rate. Analysis of data for monotherapy with the more commonly used ASMs appears to suggest that employing levetiracetam at the outset of antiseizure therapy may offer a better chance of a desirable outcome to future pregnancies than monotherapy with other ASMs, but this finding is not confirmed statistically. CONCLUSIONS: In pregnancies where valproate use has already been minimized, seizure control throughout the pre-pregnancy year was associated with the best chance of a desirable outcome, as defined above. In most Australian women starting therapy for epilepsy initiating treatment with levetiracetam monotherapy may offer the best chance of such a desirable outcome to a future pregnancy, yet to be confirmed.

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.

BACKGROUND: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. METHODS: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. RESULTS: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. CONCLUSION: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

BACKGROUND: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy. METHODS: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction. RESULTS: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (pinteraction = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012). CONCLUSIONS: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.

Prenatal valproate exposure and adverse neurodevelopmental outcomes: Does sex matter?

OBJECTIVE: Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes. METHODS: The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4-11 years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient-Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed-effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores. RESULTS: A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644 ± 310 mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p = .006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p = .01); however, this typical sex dynamic was not evident in VPA-exposed children. There was no evidence of any dose-response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure. SIGNIFICANCE: Prenatal VPA exposure seems to negate the usual male sex-related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.

Pregnancy outcomes in women with surgically treated epilepsy.

OBJECTIVE: To ascertain whether epileptic seizure control during pregnancy differed between Australian women with previously surgically treated epilepsy, and those with only medically treated epilepsy. MATERIALS/METHODS: Analysis of data for 74 pregnancies of women with surgically treated focal epilepsy, compared with that from 1013 pregnancies in women with medically treated focal epilepsy, both groups drawn from the Australian Register of Antiepileptic Drugs in Pregnancy between 1999 and 2020. RESULTS: Seizures of all types, and also convulsive seizures, were less well controlled during pregnancy in the previously surgically treated cases, the difference for seizures of all types (68.9% versus 50.1%) being statistically significant (p < .05). This result was contrary to the outcome of a previously published study of the same question carried out in India. CONCLUSIONS: At present, it may be premature to conclude that previous epilepsy surgery will be associated with a better chance of seizure-free, or seizure-controlled, pregnancy.

The control of treated generalized and focal epilepsies during pregnancy.

OBJECTIVES: To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy. RESULTS: Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy. CONCLUSIONS: The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy.

The contribution of non-drug factors to fetal malformation in anti-seizure-medication-treated pregnancy.

PURPOSE: To assess the possible contribution of factors in additional to intrauterine anti-seizure medication (ASM) exposure in the occurrence of fetal malformation in women with ASM-treated epilepsy. RESULTS: Logistic regression analysis showed that maternal age over 31 years, family histories of fetal malformation, and conception after assisted fertility treatment, and also dosage of valproate, carbamazepine, and topiramate, made statistically significant (P<0.05) contributions to the fetal malformation rate in 2223 pregnancies in Australian women with epilepsy. The malformation rates were lower in pregnancies where the non-ASM-associated contributory factors were not present: statistically significantly so for all ASM-exposed pregnancies, and those pregnancies exposed to the more potent teratogenic drugs. CONCLUSION: It is important to consider the possible roles of identified, and also possible non-identified, non-ASM factors in relation to the occurrence of fetal malformations in the pregnancies of women with ASM-treated epilepsy.

Folic acid dose, valproate, and fetal malformations.

OBJECTIVE: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. METHODS: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. RESULTS: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). CONCLUSIONS: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for hemodialysis vascular access since 1996. Since the last update in 2006, there has been a great accumulation of new evidence and sophistication in the guidelines process. The 2019 update to the KDOQI Clinical Practice Guideline for Vascular Access is a comprehensive document intended to assist multidisciplinary practitioners care for chronic kidney disease patients and their vascular access. New topics include the end-stage kidney disease "Life-Plan" and related concepts, guidance on vascular access choice, new targets for arteriovenous access (fistulas and grafts) and central venous catheters, management of specific complications, and renewed approaches to some older topics. Appraisal of the quality of the evidence was independently conducted by using a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and interpretation and application followed the GRADE Evidence to Decision frameworks. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research.

Systemic Inflammation and Outcome in 2295 Patients with Stage I-III Colorectal Cancer from Scotland and Norway: First Results from the ScotScan Colorectal Cancer Group.

BACKGROUND: Systemic inflammatory response (SIR) is an adverse prognostic marker in colorectal cancer (CRC) patients. The ScotScan Colorectal Cancer Group was established to examine how markers of the SIR differ between populations and may be utilised to guide prognosis. PATIENTS AND METHODS: Patients undergoing resection of stage I-III CRC from two prospective datasets in Scotland and Norway were included. The relationship between the modified Glasgow Prognostic Score (mGPS; combination of C-reactive protein and albumin) and overall survival (OS) was examined. The relationship between OS, adjuvant chemotherapy regime and mGPS was examined in patients with stage III colon cancer. RESULTS: A total of 2295 patients were included. Patients from Scotland were more inflamed despite controlling for associated characteristics using multivariate logistic regression or propensity score matching (OR 2.82, 95% CI 1.98-4.01, p < 0.001). mGPS had similar independent prognostic value in both cohorts (Scotland: HR 1.27, 95% CI 1.12-1.45; Norway: HR 1.23, 95% CI 1.01-1.49) and stratified survival independent of TNM group in the whole cohort. In patients with stage III colon cancer receiving adjuvant therapy, there appeared to be a survival benefit in systemically inflamed patients receiving oxaliplatin but not single-agent 5-fluorouracil or capecitabine. CONCLUSIONS: The SIR differs between populations from different countries; however prognostic value remains similar. The present study strongly supports the routine reporting of the mGPS in patients with CRC.

Twin pregnancy in women with epilepsy.

OBJECTIVE: We report data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) to see if there are significant differences in relation to the courses and outcomes of the twin pregnancies contained in the register, as compared with the singleton ones. METHODS: The APR has been under the oversight of Melbourne institutional Human Ethics Research Committees; all women enrolled in the APR have provided written informed consent. Data from the APR were transferred to a spreadsheet and then analyzed using simple statistical techniques including logistic regression. RESULTS: The population studied comprised 44 twin and 2261 singleton pregnancies; thus, twin pregnancies accounted for 1.91% of all pregnancies studied. The women carrying twins tended to be older than the women with singleton pregnancies to a statistically significant extent, their pregnancies more often originated from assisted fertilization techniques, and their babies were more often delivered by cesarean section. There were no statistically significant differences in relation to antiepileptic drug (AED) therapy. Individual twins had statistically significantly lower mean birthweights than singleton babies and they were statistically significantly more often involved structurally malformed foetuses. In the first year of life, the twin pregnancies statistically significantly more often produced offspring that were affected by seizures in infancy. SIGNIFICANCE: The data suggest that there may be an increased hazard of fetal malformation in the offspring of twin pregnancy in women with epilepsy, but that with contemporary standards of management of epilepsy and pregnancy, there is unlikely to be an increased hazard of seizure-affected pregnancy.

Pregnancy after valproate withdrawal-Fetal malformations and seizure control.

OBJECTIVE: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. METHODS: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. RESULTS: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR 0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. SIGNIFICANCE: Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Seizures in infancy in the offspring of women with epilepsy.

OBJECTIVES: To assess (a) the incidence of seizures in the first year of life in infants born to mothers with epilepsy and (b) factors that might contribute to the seizure incidence. MATERIALS & METHODS: Analysis of data collected in the Australian Register of Antiepileptic Drugs in Pregnancy during and at the end of the year after pregnancy. RESULTS: By the end of a year following pregnancy, seizures had occurred in the progeny of 47 pregnancies (2.40%), including febrile seizures in 18 (0.92%), the latter rate being higher than the 0.40% and 0.59% rates for the same situation in the general population reported in the recent literature. Seizures in infancy were more likely in the offspring of mothers with generalized as compared with focal epilepsies (3.65% vs 1.56%; RR = 2.332; P < .05) and within the generalized epilepsy mothers in those who were not seizure free during pregnancy (4.83% vs 2.89%). Seizures were also more likely in infants with foetal malformations, especially ones not discovered until after the first post-natal month. CONCLUSIONS: These findings may help in advising mothers with epilepsy regarding the chance of their offspring experiencing seizures in the first year of life; they also suggest the desirability of achieving maternal seizure control throughout pregnancy.