Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to ...high-dose folic acid is associated with increases in the risk of childhood cancer is unknown.
To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer.
Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates.
Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth.
First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk.
The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% 95% CI, 0.3%-0.5%). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%).
Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.
Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.
To examine ...the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy.
This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023.
Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth.
The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported.
Among the 38 661 children of mothers with epilepsy (16 458 42.6% exposed to ASM; 19 582 51.3% male; mean SD age at the end of study, 7.5 4.6 years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 95% CI, 1.60-2.03; cumulative risk at 18 years in ASM-exposed children, 42.1% 95% CI, 38.2%-45.8%; cumulative risk at 18 years in unexposed children, 31.3% 95% CI, 28.9%-33.6%), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07).
Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.
Objective
Research points to disparities in disease burden and access to medical care in epilepsy. We studied the association between socioeconomic status (SES) and antiseizure medication (ASM) use ...in pregnancies with maternal epilepsy.
Methods
We conducted a cross‐sectional study consisting of 21 130 pregnancies with maternal epilepsy identified from Nordic registers during 2006–2017. SES indicators included cohabitation status, migrant background, educational attainment, and household income. Main outcomes were the proportion and patterns of ASM use from 90 days before pregnancy to birth. We applied multiple imputation to handle SES variables with 2%–4% missingness. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) using modified Poisson regression with the highest SES category as reference.
Results
Mothers with the highest education and the highest income quintile used ASMs least frequently (56% and 53%, respectively). We observed increased risks of ASM discontinuation prior to or during the first trimester for low SES. The risk estimates varied depending on the SES indicator from aRR = 1.27 for low income (95% CI: 1.03–1.57) to aRR = 1.66 for low education (95% CI: 1.30–2.13). Migrant background was associated with ASM initiation after the first trimester (aRR 2.17; 95% CI 1.88–2.52). Low education was associated with the use of valproate during pregnancy in monotherapy (aRR 1.70; 95% CI 1.29–2.24) and in polytherapy (aRR 2.65; 95% CI 1.66–4.21). Low education was also associated with a 37% to 39% increased risk of switching from one ASM to another depending on the ASM used. For the other SES indicators, aRRs of switching varied from 1.16 (foreign origin; 95% CI 1.08–1.26) to 1.26 (not married or cohabiting; 95% CI 1.17–1.36).
Significance
Low SES was associated with riskier patterns of ASM use: discontinuation, late initiation, and switching during pregnancy. These findings may reflect unplanned pregnancies, disparities in access to preconception counseling, and suboptimal care.
Objective
This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with ...antiseizure medication (ASM).
Methods
In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country‐specific time trends.
Results
Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM‐treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid.
Significance
Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM‐treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real‐world applicability.
Women using antiseizure medication in pregnancy is often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report ...showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that has emerged.
Please cite this paper as: Bouvier‐Colle M, Mohangoo A, Gissler M, Novak‐Antolic Z, Vutuc C, Szamotulska K, Zeitlin J for The Euro‐Peristat Scientific Committee. What about the mothers? An analysis ...of maternal mortality and morbidity in perinatal health surveillance systems in Europe. BJOG 2012;119:880–890.
Objective To assess capacity to develop routine monitoring of maternal health in the European Union using indicators of maternal mortality and severe morbidity.
Design Analysis of aggregate data from routine statistical systems compiled by the EURO‐PERISTAT project and comparison with data from national enquiries.
Setting Twenty‐five countries in the European Union and Norway.
Population Women giving birth in participating countries in 2003 and 2004.
Methods Application of a common collection of data by selecting specific International Classification of Disease codes from the ‘Pregnancy, childbirth and the puerperium’ chapter. External validity was assessed by reviewing the results of national confidential enquiries and linkage studies.
Main outcome measures Maternal mortality ratio, with distribution of specific obstetric causes, and severe acute maternal morbidity, which included: eclampsia, surgery and blood transfusion for obstetric haemorrhage, and intensive‐care unit admission.
Results In 22 countries that provided data, the maternal mortality ratio was 6.3 per 100 000 live births overall and ranged from 0 to 29.6. Under‐ascertainment was evident from comparisons with studies that use enhanced identification of deaths. Furthermore, routine cause of death registration systems in countries with specific systems for audit reported higher maternal mortality ratio than those in countries without audits. For severe acute maternal morbidity, 16 countries provided data about at least one category of morbidity, and only three provided data for all categories. Reported values ranged widely (from 0.2 to 1.6 women with eclampsia per 1000 women giving birth and from 0.2 to 1.0 hysterectomies per 1000 women).
Conclusions Currently available data on maternal mortality and morbidity are insufficient for monitoring trends over time in Europe and for comparison between countries. Confidential enquiries into maternal deaths are recommended.
Abstract
Background
Increasing evidence suggests that adverse birth outcomes, including preterm birth, small for gestational age (SGA) and large for gestational age (LGA), are associated with ...increased risks of hypertension, ischemic heart disease, stroke and heart failure. However, knowledge regarding their associations with atrial fibrillation (AF) is limited and inconsistent.
Objective
To investigate whether preterm birth, SGA and LGA are associated with increased risks of AF later in life.
Methods
We conducted a population-based cohort study involving 8,012,433 live singleton births based on the nation-wide Danish (1978–2016), Swedish (1973–2014) and Finnish (1987–2014) Medical Birth Registers. Information on birth outcomes, atrial fibrillation and covariates was obtained from nationwide health and socioeconomic registers. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for AF according to preterm birth (<37 weeks), SGA and LGA (<10th and >90th birth weight for gestational age percentiles, respectively) with multivariable Cox proportional hazard models and flexible parametric survival models. We conducted sibling analyses to control for unmeasured familial risk factors.
Results
Preterm birth and LGA were associated with increased AF risks in both the full population cohort and in the sibling analyses; the multivariate HRs (95% CI) from the cohort analyses were 1.53 (1.37–1.71) and 1.55 (1.44–1.65), respectively. The associations were stronger with AF in childhood than in adulthood. Children born SGA had an increased risk of AF in the first 18 years of life, but not later.
Conclusions
Individuals born preterm or LGA had an increased AF risk independently of familial confounding factors. Individuals born SGA had an increased AF risk only during childhood. Persons born prematurely or with abnormal foetal growth may benefit from early screening and prevention to reduce the risk of AF later in life.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Council for Working Life and Social Research; China Scholarship Council
Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish ...Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval CI 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.
Abstract
Background
At the onset of the COVID-19 pandemic, there were concerns about maternal and newborn health because of increased stress, economic difficulties and restrictions to healthcare. ...However, preterm birth (PTB) rates declined in some countries in 2020, while stillbirth (SB) rates remained stable or were slightly elevated. Hypotheses for the PTB result include positive consequences of lockdowns (more rest, less pollution, less exposure to infection) or restricted healthcare, leading to fewer indicated preterm births. These effects have not been examined on a population-level by socioeconomic (SES) group.
Methods
The Euro-Peristat network developed a Common Data Model and R scripts to produce aggregated data tables from vital statistics and birth registers. This analysis uses data from 2015 to 2020 on singleton PTB rates and SB rates as well as on mother's educational level (preferred) or area level deprivation/occupation of mother (if education unavailable). SES measures were harmonised into 3 groups (low, medium, high). We computed observed versus expected risks of the outcomes for the year 2020, given linear trends from 2015 to 2019, overall and by SES group; these estimates were pooled using random effects meta-analysis.
Results
19 countries provided data on perinatal outcomes by SES group. The overall pooled mixed effect measure for PTB was -0.04 (95%CI of -0.06 to -0.02), corresponding to a 4% decline in 2020 over expected levels. This estimate was the same in low and high SES groups (-0.04 (-0.07 to 0.02) versus -0.04 (-0.06 to -0.02)). For stillbirth, the overall pooled measure was 0.02 (-0.03 to 0.07), corresponding to an increase of 2%, with higher estimates in the low SES group 0.05 (-0.02 to 0.11) versus 0.2 (-0.3 to 0.7) in the high group, although confidence limits overlapped.
Conclusions
A small decrease in PTB was observed in all SES groups, while results are suggestive of increases in SB rates among women in lower SES groups.
Key messages
• Previous results in some countries of decreased preterm birth rates in the general population in 2020 were confirmed in this European study, with similar associations in all socioeconomic groups.
• Stillbirth rates were not increased in the overall population, but a 5% increase was observed in lower SES groups.
Postpartum psychiatric disorders (PPD) are common complications of childbirth. A common explanation for their development is that the psychological, hormonal, and immune changes associated with ...pregnancy and parturition may trigger psychiatric symptoms postpartum. Rheumatoid arthritis (RA) is characterized by abnormalities in the activity of the hypothalamic-pituitary-adrenal axis and of the immune system, but its association with PPD is unknown. We analyzed whether women with RA before childbirth have an increased risk of PPD.
We conducted a large population-based cohort study including mothers of singleton births in the Danish (1995-2015), Finnish (1997-2013), and Swedish Medical Birth Registers (2001-2013) (N = 3,516,849). We linked data from the Medical Birth Registers with data from several national socioeconomic and health registers. Exposure was defined as having a diagnosis of RA before childbirth, while the main outcome was a clinical diagnosis of psychiatric disorders 90 days postpartum. We analyzed the association between RA and PPD using Cox proportional hazard models, stratified by a personal history of psychiatric disorders.
Among women without a history of psychiatric disorders, the PPD incidence rate was 32.2 in the exposed and 19.5 per 1000 person-years in the unexposed group; women with RA had a higher risk of overall PPD than their unexposed counterparts adjusted hazard ratio (HR) = 1.52, 95% confidence intervals (CI) 1.17 to 1.98. Similar associations were also observed for postpartum depression (HR = 1.65, 95% CI 1.09 to 2.48) and other PPD (HR = 1.59, 95% CI 1.13 to 2.24). Among women with a history of psychiatric disorders, the incidence rate of overall PPD was 339.6 in the exposed and 346.6 per 1000 person-years in the unexposed group; RA was not associated with PPD. We observed similar associations between preclinical RA (RA diagnosed after childbirth) and PPD to those corresponding to clinical RA.
Rheumatoid arthritis was associated with an increased PPD risk in women without, but not in those with a psychiatric history. If our findings are confirmed in future studies, new mothers with RA may benefit from increased surveillance for new-onset psychiatric disorders postpartum.
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