Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

BACKGROUND: Prenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. OBJECTIVES: To examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. METHODS: We included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. RESULTS: We included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5-8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). CONCLUSIONS: In this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

Folic Acid and Risk of Preterm Birth, Preeclampsia, and Fetal Growth Restriction Among Women With Epilepsy: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Women with epilepsy treated with antiseizure medication (ASM) have increased risk of pregnancy complications including preterm birth, fetal growth restriction, and preeclampsia. We aimed to investigate whether folic acid supplementation is associated with these pregnancy complications in women with epilepsy using ASM. METHODS: Singleton pregnancies in the prospective Norwegian Mother and Child Cohort Study (MoBa) (1999-2008) were included. Information on maternal epilepsy, ASM, folic acid supplementation, and pregnancy outcomes was obtained from the MoBa questionnaires and the Norwegian Medical Birth Registry. The main exposure, periconceptional folic acid supplementation, was defined as intake between 4 weeks before pregnancy and 12 weeks into pregnancy, retrospectively collected by recall of the mothers in weeks 17-19. The primary outcomes were preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia. RESULTS: The study included 100,105 pregnancies: 99,431 without maternal epilepsy, 316 with maternal epilepsy and ASM exposure in pregnancy, and 358 with untreated maternal epilepsy. Among ASM-treated women with epilepsy, the risk of preterm birth was higher in those who did not use periconceptional folic acid (n = 64) compared with those who did (n = 245, the reference) (adjusted odds ratio [aOR] 3.3, 95% CI 1.2-9.2), while the risk of preterm birth among the reference was similar to the risk among women without epilepsy using folic acid periconceptionally (aOR 0.9, 95% CI 0.5-1.6). ASM-treated women with epilepsy starting folic acid after the first trimester had a higher risk compared with women without epilepsy with similar timing of folic acid (aOR 2.6, 95% CI 1.1-6.5), and even higher if not using folic acid (aOR 9.4, 95% CI 2.6-34.8). Folic acid was not associated with risk of preterm birth among women with epilepsy without ASM or among women without epilepsy. Folic acid was not associated with risk of preeclampsia or SGA among women with epilepsy. DISCUSSION: In women with epilepsy using ASM, periconceptional folic acid was associated with a lower risk of preterm birth. This finding supports the recommendation that ASM-treated women with epilepsy of childbearing potential should use folic acid supplementation on a regular basis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with epilepsy using ASM, periconceptional folic acid supplementation decreases the risk of preterm birth.

Prevalence of self-reported emotional, physical, and sexual abuse and association with fear of childbirth in pregnant women with epilepsy: The Norwegian Mother, Father, and Child Cohort Study.

OBJECTIVE: This study was undertaken to examine the prevalence of self-reported experiences with abuse in pregnant women with epilepsy and the association between having experienced abuse and childbirth expectations, particularly the fear of childbirth. METHODS: We performed a cross-sectional study of women with and without epilepsy enrolled in the Norwegian Mother, Father, and Child Cohort Study 1999-2008. Data on epilepsy diagnosis; antiseizure medication (ASM) use; emotional, physical, and sexual abuse; and childbirth expectations were collected from questionnaires completed during gestational Weeks 17-19 and 30. RESULTS: Our study population included 295 women with ASM-treated epilepsy, 318 women with ASM-untreated epilepsy, and 93 949 women without epilepsy. A total of 115 women (47%) with ASM-treated and 132 women (57%) with ASM-untreated epilepsy reported any emotional, physical, or sexual abuse, compared to 25 100 women (32%) without epilepsy. The adjusted odds ratios (aORs) for having experienced any abuse were 1.8 (95% confidence interval [CI] = 1.4-2.3) and 1.8 (95% CI = 1.4-2.2) for ASM-treated and ASM-untreated epilepsy, respectively. A total of 29 women (11%) with ASM-treated and 34 women (11%) with ASM-untreated epilepsy reported having been raped, compared to 3088 women (4%) without epilepsy (aORs = 2.8 [95% CI = 1.8-4.1] and 2.9 [95% CI = 2.0-4.2], respectively). In nulliparous women with ASM-untreated epilepsy, having experienced abuse was associated with fear of childbirth; 22 women (31%) with abuse experiences reported fear of childbirth compared to five women (7%) with no experience of abuse (aOR = 5.4 [95% CI = 1.7-17.2]). This association was not seen in multiparous women or in women with ASM-treated epilepsy. SIGNIFICANCE: More women with epilepsy reported emotional, physical, and sexual abuse than women without epilepsy. Such experiences may be associated with childbirth expectations.

Plasma unmetabolized folic acid in pregnancy and risk of autistic traits and language impairment in antiseizure medication-exposed children of women with epilepsy.

BACKGROUND: Fetal exposure to unmetabolized folic acid (UMFA) during pregnancy may be associated with adverse neurodevelopment. Antiseizure medication (ASM) may interact with folate metabolism. Women with epilepsy using ASM are often recommended high-dose folic acid supplement use during pregnancy. OBJECTIVES: The aim was to determine the association between UMFA concentrations in pregnant women with epilepsy using ASM and risk of autistic traits or language impairment in their children aged 1.5-8 y. METHODS: We included children of women with epilepsy using ASM and with plasma UMFA measurement enrolled in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Data on ASM use, folic acid supplement use, autistic traits, and language impairment were obtained from parent-reported questionnaires during pregnancy and when the child was 1.5, 3, 5, and 8 y old. Plasma UMFA concentrations were measured during gestational weeks 17-19. RESULTS: A total of 227 ASM-exposed children of 203 women with epilepsy were included. Response rates at ages 1.5, 3, 5, and 8 y were 67% (n = 151), 54% (n = 122), 36% (n = 82), and 37% (n = 85), respectively. For 208 (94%) children, the mother reported intake of folic acid supplement. There was no association between UMFA concentrations and autistic traits score in the adjusted multiple regression analyses at age 3 y (unstandardized B: -0.01; 95% CI: -0.03, 0.004) or 8 y (unstandardized B: 0.01; 95% CI: -0.02, 0.03). Children exposed to UMFA had no increased risk of autistic traits at age 3 y [adjusted OR (aOR): 0.98; 95% CI: 0.2, 4.2] or 8 y (aOR: 0.1; 95% CI: 0.01, 1.4) compared with unexposed children. We found no association between UMFA concentrations and language impairment in children aged 1.5-8 y. CONCLUSIONS: Our findings do not support any adverse neurodevelopmental effects of UMFA exposure in utero in children of women with epilepsy using ASM.

Vitamin B status and association with antiseizure medication in pregnant women with epilepsy.

OBJECTIVE: Antiseizure medication (ASM) use interacts with vitamin B status in nonpregnant epilepsy populations. We aimed to examine the association between ASM and vitamin B status in pregnant women with epilepsy. METHODS: We performed a cross-sectional study of pregnancies in women with epilepsy enrolled in the Norwegian Mother, Father and Child Cohort Study from 1999 to 2008. Data on ASM and vitamin supplement use were collected from questionnaires. We analyzed maternal plasma concentrations of ASM and metabolites of folate, including unmetabolized folic acid (UMFA), riboflavin (vitamin B2), pyridoxine (vitamin B6), and niacin (vitamin B3) during gestational weeks 17-19. RESULTS: We included 227 singleton pregnancies exposed to ASM with available plasma samples (median maternal age 29 years, range 18 to 41 years). From the preconception period to gestational week 20, any supplement of folic acid was reported in 208 of pregnancies (94%), riboflavin in 72 (33%), pyridoxine in 77 (35%), and niacin in 45 (20%). High ASM concentrations correlated with high concentrations of UMFA and inactive folate metabolites, and with low concentrations of riboflavin and metabolically active pyridoxine. There was no association between ASM and niacin status. SIGNIFICANCE: ASM concentrations during pregnancy were associated with vitamin B status in pregnant women with epilepsy. Additional studies are needed to determine the clinical impact of these findings, and to define the optimal vitamin doses that should be recommended to improve pregnancy outcomes.

Verbal abilities in children of mothers with epilepsy: Association to maternal folate status.

OBJECTIVE: To examine the effect of maternal folic acid supplementation and maternal plasma folate and antiepileptic drug (AED) concentrations on language delay in AED-exposed children of mothers with epilepsy. METHODS: Children of mothers with and without epilepsy enrolled from 1999 to 2008 in the Norwegian Mother and Child Cohort study were included. Information on medical history, AED use, and folic acid supplementation during pregnancy was collected from parent-completed questionnaires. Maternal plasma folate and maternal plasma and umbilical cord AED concentrations were measured in blood samples from gestational weeks 17 to 19 and immediately after birth, respectively. Language development at 18 and 36 months was evaluated by the Ages and Stages Questionnaires. RESULTS: A total of 335 AED-exposed children of mothers with epilepsy and 104,222 children of mothers without epilepsy were surveyed. For those with no maternal periconceptional folic acid supplementation, the fully adjusted odds ratio (OR) for language delay in AED-exposed children compared to the controls at 18 months was 3.9 (95% confidence interval [CI] 1.9-7.8, p < 0.001) and at 36 months was 4.7 (95% CI 2.0-10.6, p < 0.001). When folic supplementation was used, the corresponding ORs for language delay were 1.7 (95% CI 1.2-2.6, p = 0.01) and 1.7 (95% CI 0.9-3.2, p = 0.13), respectively. The positive effect of folic acid supplement use on language delay in AED-exposed children was significant only when supplement was used in the period from 4 weeks before the pregnancy and until the end of the first trimester. CONCLUSION: Folic acid use early in pregnancy may have a preventive effect on language delay associated with in utero AED exposure.

Targeted program for provision of mother's own milk to very low birth weight infants.

OBJECTIVE: Evaluate the effect of an evolving targeted program to encourage mothers to provide own milk (MM) to their very low birth weight (VLBW) infants in a traditional open-bay NICU. METHODS: Retrospective review of medical records on all VLBW infants (birth weight <1500 g) born in a geographical region of Norway in 1986/1987, 1996, and 2007/2008 (n = 203). Types of nutrition and data on maternal and infant health were prospectively and similarly recorded during all time periods. Between each period, targeted programs were initiated to encourage provision of MM. RESULTS: The rates of providing MM (exclusively MM in parenthesis) for the 3 periods were 55% (33%), 85% (60%), and 89% (62%) when achieving full enteral feeds; 48% (11%), 76% (39%), and 92% (60%) at discharge; 15%, 42%, and 62% at 2 to 4 months' corrected age; and 10%, 40%, and 53% at 6 to 8 months' corrected age (P < .001 at all end points). Neither maternal or pregnancy disorders nor neonatal morbidity had significant effects on provision of MM, but smoking was associated with a lower rate after discharge. CONCLUSIONS: Both early and long-term provision of MM for their VLBW infants were strongly associated with targeted programs to encourage provision. We suggest that almost all mothers are able to provide their own milk if given targeted encouragement and guidance, even in crowded open-bay NICUs.