Sex differences in placenta-derived markers and later autistic traits in children.

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean= 13.5 [SD = 2.0] weeks gestation) and 2nd trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, compared to female pregnancies. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2nd: n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd: n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2nd trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.

Maternal steroid levels and the autistic traits of the mother and infant.

BACKGROUND: Prenatal sex steroids have been associated with autism in several clinical and epidemiological studies. It is unclear how this relates to the autistic traits of the mother and how early this can be detected during pregnancy and postnatal development. METHODS: Maternal serum was collected from pregnant women (n = 122) before or during their first ultrasound appointment [mean = 12.7 (SD = 0.7) weeks]. Concentrations of the following were measured via immunoassays: testosterone, estradiol, dehydroepiandrosterone sulphate, progesterone; and sex hormone-binding globulin which was used to compute the free fractions of estradiol (FEI) and testosterone (FTI). Standardised human choriogonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) values were obtained from clinical records corresponding to the same serum samples. Mothers completed the Autism Spectrum Quotient (AQ) and for their infants, the Quantitative Checklist for Autism in Toddlers (Q-CHAT) when the infants were between 18 and 20 months old. RESULTS: FEI was positively associated with maternal autistic traits in univariate (n = 108, Pearson's r = 0.22, p = 0.019) and multiple regression models (semipartial r = 0.19, p = 0.048) controlling for maternal age and a diagnosis of PCOS. Maternal estradiol levels significantly interacted with fetal sex in predicting infant Q-CHAT scores, with a positive relationship in males but not females (n = 100, interaction term: semipartial r = 0.23, p = 0.036) after controlling for maternal AQ and other covariates. The opposite was found for standardised hCG values and Q-CHAT scores, with a positive association in females but not in males (n = 151, interaction term: r = -0.25, p = 0.005). LIMITATIONS: Sample size of this cohort was small, with potential ascertainment bias given elective recruitment. Clinical covariates were controlled in multiple regression models, but additional research is needed to confirm the statistically significant findings in larger cohorts. CONCLUSION: Maternal steroid factors during pregnancy are associated with autistic traits in mothers and their infants.