乌鸦传媒

Paternal use of the anti-seizure medication valproate during spermatogenesis was not associated with a risk of congenital malformations or neurodevelopmental disorders in offspring, an observational cohort study from Denmark suggested.

The adjusted relative risk of major congenital malformations in children with valproate exposure versus without exposure was 0.89 (95% CI 0.67-1.18), and the adjusted hazard ratio (aHR) was 1.10 (95% CI 0.88-1.37) for neurodevelopmental disorders, and 0.92 for autism spectrum disorder (95% CI 0.65-1.30), reported Jakob Christensen, DrMedSci, of Aarhus University Hospital in Denmark, and colleagues in .

These findings contradict from the Pharmacovigilance Risk Assessment Committee (PRAC), the safety committee of the European Medicines Agency (EMA), which found that paternal valproate exposure was associated with an increased risk of neurodevelopmental disorders (aHR 1.50, 95% CI 1.09-2.07), but not congenital malformations (crude OR 0.81, 95% CI 0.48-1.36), among offspring.

"Danish health registers have previously been able to identify adverse outcomes associated with maternal exposure to ASMs [anti-seizure medications] (including valproate), and we should therefore expect that we would be able to identify similar adverse outcomes associated with paternal exposure, should they exist," Christensen and colleagues wrote. "It is therefore puzzling that we were unable to identify the risk of neurodevelopmental disorders reported by PRAC, especially because our analyses are based partly on the same register data."

The FDA strongly cautions against the in pregnant women, stating that "children born to mothers who take the anti-seizure medication valproate sodium or related products (valproic acid and divalproex sodium) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy."

The EMA warning further cautioned against valproate use in men during the 3 months prior to conception, based on an unpublished that used multiple registry databases in Scandinavia.

"There was concern in this warning because all observational studies are susceptible to bias due to unmeasured confounding variables, and thus require replication," Kimford Meador, MD, of Stanford University School of Medicine in Palo Alto, California, told 乌鸦传媒.

"Given the conflicting results in these two observational studies, the EMA warning is not supported at this time. Additional research is needed to further clarify this concern for men taking valproate," continued Meador, who was not involved in the study.

Christensen and colleagues included 1,235,353 singleton children (51.4% boys) in Denmark's Medical Birth Register born from January 1997 through December 2017. Children with unknown or unlikely values of gestational age, no link to the father in registries, and whose mothers had filled prescriptions for valproate from 30 days before the first day of the last menstrual period and birth were excluded.

The median follow-up was 10.1 years for valproate-exposed children and 10.3 years for unexposed children. A total of 43,903 children (3.6%) were diagnosed with major congenital malformations in the first year of life, and 51,633 (4.2%) were diagnosed with neurodevelopmental disorders during follow-up.

Paternal valproate exposure was defined as fathers who filled one or more prescriptions for valproate from 120 days before the beginning of the mother's pregnancy to conception. Valproate used with other anti-seizure medications during spermatogenesis was included.

The researchers used the Danish National Patient Registry, Danish Psychiatric Central Research Register, Danish Register of Causes of Death, and the European Network of Population-Based Registries for Epidemiological Surveillance of Congenital Anomalies to identify parents diagnosed with epilepsy, parents with psychiatric disorders, congenital malformations in children, and neurodevelopmental disorders in children. Neurodevelopmental disorders included intellectual disability, autism spectrum disorder, psychological development disorders, and attention deficit-hyperactivity disorder.

In subgroup analyses, Christensen and team evaluated dose response, siblings of the same fathers, children of fathers with epilepsy and no valproate exposure, children of fathers who took lamotrigine, and children of fathers who took valproate only before spermatogenesis. They still found no increased risk of congenital malformations and neurodevelopmental disorders.

The authors acknowledged a number of limitations. The study excluded terminations of pregnancy for fetal anomaly, which could have led to under-capture of congenital malformations. The use of lamotrigine increased over the study period, which meant a shorter follow-up time for children with lamotrigine exposure. Meanwhile, diagnoses for neurodevelopmental disorders have increased and are "highly age specific," which made comparing lamotrigine- and valproate-exposure groups difficult.

The study did not capture parental epilepsy diagnoses from private practitioners or private neurologists, only from hospitals, outpatient care, and emergency departments.

Data on paternal smoking status were not available, nor were data on medically untreated psychiatric disorders and undiagnosed parental substance use. Misclassification of parental neurodevelopmental disorders may have also been substantial, especially earlier in the study period when valproate use was more common.

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