Maternal complications in pregnancy and childbirth for women with epilepsy: Time trends in a nationwide cohort.

OBJECTIVE: Obstetric trends show changes in complication rates and maternal characteristics such as caesarean section, induced labour, and maternal age. To what degree such general time trends and changing patterns of antiepileptic drug use influence pregnancies of women with epilepsy (WWE) is unknown. Our aim was to describe changes in maternal characteristics and obstetric complications in WWE over time, and to assess changes in complication risks in WWE relative to women without epilepsy. METHODS: This was a nationwide cohort study of all first births in the Medical Birth Registry of Norway, 1999-2016. We estimated maternal characteristics, complication rates, and risks for WWE compared to women without epilepsy. Main maternal outcome measures were hypertensive disorders, bleeding in pregnancy, induction of labour, caesarean section, postpartum hemorrhage, preterm birth, small for gestational age, and epidural analgesia. Time trends were analyzed by logistic regression and comparisons made with interaction analyses. RESULTS: 426 347 first births were analyzed, and 3077 (0.7%) women had epilepsy. In WWE there was an increase in proportions of induced labour (p<0.005) and use of epidural analgesia (p<0.005), and a reduction in mild preeclampsia (p = 0.006). However, the risk of these outcomes did not change over time. Only the risk of severe preeclampsia increased significantly over time relative to women without epilepsy (p = 0.006). In WWE, folic acid supplementation increased significantly over time (p<0.005), and there was a decrease in smoking during pregnancy (p<0.005), but these changes were less pronounced than for women without epilepsy (p<0.005). CONCLUSIONS: During 1999-2016 there were important changes in maternal characteristics and complication rates among WWE. However, outcome risks for WWE relative to women without epilepsy did not change despite changes in antiepileptic drug use patterns. The relative risk of severe preeclampsia increased in women with epilepsy.

A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption.

Background: Although both genetic and environmental factors have been reported to influence the risk of isolated cleft lip with or without cleft palate (CL/P), the exact mechanisms behind CL/P are still largely unaccounted for. We recently developed new methods to identify parent-of-origin (PoO) interactions with environmental exposures (PoOxE) and applied them to families with children born with isolated cleft palate only. Here, we used the same genome-wide association study (GWAS) dataset and methodology to screen for PoOxE effects in the larger sample of CL/P triads. Methods: Genotypes from 1594 complete triads and 314 dyads (1908 nuclear families in total) with CL/P were available for the current analyses. Of these families, 1024 were Asian, 825 were European and 59 had other ancestries. After quality control, 341,191 SNPs remained from the original 569,244. The exposures were maternal cigarette smoking, use of alcohol, and use of vitamin supplements in the periconceptional period. The methodology applied in the analyses is implemented in the R-package Haplin. Results: Among Europeans, there was evidence of a PoOxSmoke effect for ANK3 with three SNPs (rs3793861, q=0.20, p=2.6e-6; rs7087489, q=0.20, p=3.1e-6; rs4310561, q=0.67, p=4.0e-5) and a PoOxAlcohol effect for ARHGEF10 with two SNPs (rs2294035, q=0.32, p=2.9e-6; rs4876274, q=0.76, p=1.3e-5). Conclusion: Our results indicate that the detected PoOxE effects have a plausible biological basis, and thus warrant replication in other independent cleft samples. Our demonstration of the feasibility of identifying complex interactions between relevant environmental exposures and PoO effects offers new avenues for future research aimed at unravelling  the complex etiology of cleft lip defects.

Factors associated with prenatal folic acid and iron supplementation among 21,889 pregnant women in Northern Tanzania: a cross-sectional hospital-based study.

BACKGROUND: Folate and iron deficiency during pregnancy are risk factors for anaemia, preterm delivery, and low birth weight, and may contribute to poor neonatal health and increased maternal mortality. The World Health Organization recommends supplementation of folic acid (FA) and iron for all pregnant women at risk of malnutrition to prevent anaemia. We assessed the use of prenatal folic acid and iron supplementation among women in a geographical area with a high prevalence of anaemia, in relation to socio-demographic, morbidity and health services utilization factors. METHODS: We analysed a cohort of 21,889 women who delivered at Kilimanjaro Christian Medical Centre (KCMC), Moshi, Tanzania, between 1999 and 2008. Logistic regression models were used to describe patterns of reported intake of prenatal FA and iron supplements. RESULTS: Prenatal intake of FA and iron supplements was reported by 17.2% and 22.3% of pregnant women, respectively. Sixteen percent of women reported intake of both FA and iron. Factors positively associated with FA supplementation were advanced maternal age (OR = 1.17, 1.02-1.34), unknown HIV status (OR = 1.54, 1.42-1.67), a diagnosis of anaemia during pregnancy (OR = 12.03, 9.66-14.98) and indicators of lower socioeconomic status. Women were less likely to take these supplements if they reported having had a malaria episode before (OR = 0.57, 0.53-0.62) or during pregnancy (OR = 0.45, 0.41-0.51), reported having contracted other infectious diseases (OR = 0.45, 0.42-0.49), were multiparous (OR = 0.73, 0.66-0.80), had preeclampsia/eclampsia (OR = 0.48, 0.38-0.61), or other diseases (OR = 0.55, 0.44-0.69) during pregnancy. Similar patterns of association emerged when iron supplementation alone and supplementation with both iron and FA were evaluated. CONCLUSIONS: FA and iron supplementation are low among pregnant women in Northern Tanzania, in particular among women with co-morbidities before or during pregnancy. Attempts should be made to increase supplementation both in general and among women with pregnancy complications.

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts.

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.

Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.

Folic acid supplements and risk of facial clefts: national population based case-control study.

OBJECTIVE: To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. DESIGN: National population based case-control study. SETTING: Infants born 1996-2001 in Norway. PARTICIPANTS: 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. MAIN OUTCOME MEASURES: Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. RESULTS: Folic acid supplementation during early pregnancy (> or =400 microg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). CONCLUSIONS: Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

[Sense and sensibility in delivery care]. / Fornuft og følelser i fødselsomsorgen.

The organisation of delivery care engages both professional and laypersons. When the Norwegian princess Märtha Louise in 2005 chose to give birth at home instead of in hospital, the intensity of the debate in media increased. Some professionals claim with great persuasion that among selected low-risk women, birth at home or in small midwifery units is as safe as in larger delivery units in hospitals. The scientific evidence for this statement is, however, weak. The Norwegian National Advisory Committee for Maternal Care is an important contributor to this debate. The Committee should, however, pay more respect to the scientific disagreement within the field.