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.

The importance of adequate referrals for chronic kidney disease

DISCUSSION: Regional Australia remains a district of workforce shortage for nephrology. Thus, it is imperative that patients who have the greatest need for nephrologist services are effectively identified upon referral. The aim of this study was to assess referrals to a regional nephrology service against Australian guidelines by assessing the patient's renal function and the information contained in the referral document at the time of first consultation. We conducted a retrospective study of all referrals to a regional Australian nephrology service between 2013 and 2015. The 582 referrals that met the inclusion criteria were compared with Australian nephrology referral guidelines. Less than half of the referral documents (n = 253; 43.5%) described a clinical situation that met referral guidelines, typically due to insufficient pathology investigation. However, after consideration of renal functional test results performed at the initial consultation, an additional 82 cases met referral guidelines (n = 335; 57.6%). More than 40% of nephrology referrals to a regional Australian service did not meet Australian nephrology referral guidelines. This has implications for a regional nephrology service that is experiencing workforce pressures, in addition to the health system more broadly, and for patients. Many referrals contained insufficient information to allow differentiation of patients who would benefit most from nephrology care from patients who could be appropriately managed within primary care.